Metabolic risk profile in kidney transplant candidates and recipients

Metabolic risk profile in kidney transplant candidates and recipients Abstract Metabolic risk factors of cardiovascular disease such as abnormal glucose regulation, obesity and metabolic syndrome, dyslipidaemia, metabolic bone disease, hyperuricaemia and other less traditional abnormalities are common in both kidney transplant candidates and recipients. In kidney transplant candidates, the presence of these risk factors may impede patient access to transplantation by increasing the risk of developing comorbidities while on the waiting list, prolonging the time to wait-listing and, in some patients, eventually jeopardizing their suitability for kidney transplantation or increasing the risk of severe perioperative complications. In transplant recipients, metabolic risk factors may be associated with increased mortality with a functioning graft and with reduced long-term renal graft survival. Although most transplant recipients have no contraindication to the use of drugs that undergo renal excretion, they may be at risk of drug-to-drug pharmacokinetic interactions with anti-rejection medicines. In this review, we have highlighted the main objectives of evaluating the metabolic abnormalities in transplant candidates and recipients, how this evaluation should be carried out in practice and what currently the most valuable treatment strategies are for modifying the associated risks. We conclude that, for every potential transplant candidate, every effort should be made to control metabolic abnormalities causing arterial calcification, which may impede access to transplantation and impair transplant outcome. In transplant recipients, metabolic abnormalities that result from adverse effects of anti-rejection therapy may be effectively controlled by lifestyle changes and judicious use of drugs for the treatment of abnormal glucose metabolism and dyslipidaemia. diabetes, dyslipidaemia, kidney transplantation, metabolic syndrome, vascular calcification INTRODUCTION Metabolic risk factors of cardiovascular disease (CVD) are common in kidney transplant candidates and recipients. In kidney transplant candidates, their presence is associated with advanced chronic kidney disease (CKD). Some of these metabolic abnormalities are not fully reversed despite successful kidney transplantation and contribute to exacerbating cardiovascular risk in kidney transplant recipients, together with the toxicity of anti-rejection therapy. However, metabolic risk factors pose different challenges in transplant candidates and transplant recipients. In kidney transplant candidates, prolonged exposure to metabolic risk factors may jeopardize their suitability for kidney transplantation or increase the risk of severe perioperative complications. In kidney transplant recipients, metabolic risk factors may increase mortality with a functioning graft and reduce long-term renal graft survival. Finally, treatments to correct metabolic risk factors may differ between the two categories of patients. Unlike transplant candidates, most transplant recipients have no contraindication to the use of drugs that undergo renal excretion, but they may be at risk of drug-to-drug pharmacokinetic interactions with anti-rejection treatments. In this review, we have highlighted: (i) the main objectives of evaluating metabolic abnormalities in transplant candidates and recipients, (ii) how this evaluation should be carried out in practice and (iii) what the most valuable treatment strategies are for modifying the associated risks. DIABETES MELLITUS, OBESITY AND METABOLIC SYNDROME Diabetes adversely affects transplant candidate survival and access to the waiting list [1]. Nevertheless, diabetic candidates are the category of dialysis patients who benefit the most from deceased donor kidney transplantation in terms of proportional increase in life expectancy [2, 3], even when the graft is procured from extended criteria donors [4]. The beneficial effect of kidney transplantation on life expectancy is maximized when diabetic patients undergo pre-emptive living donor kidney transplantation [5]. Therefore, the survival benefit of transplantation over haemodialysis and peritoneal dialysis is considerable, despite the use of anti-rejection diabetogenic drugs post-transplantation. On the other hand, transplant candidates without known diabetes who develop diabetes post-transplantation have their renal graft survival reduced because of diabetes [6]. The reasons are unclear, although they may be related to physicians’ efforts to decrease diabetogenic immunosuppressive treatment, which, in turn, increases the risk of rejection contributing to the increase T-cell alloreactivity observed in diabetic patients [7], an increased incidence of infections and major cardiovascular events [8] and the development of diabetic complications, including diabetic allograft nephropathy. Therefore, it is important to identify transplant candidates at risk of developing diabetes post-transplantation, to correct their modifiable risk factors before and after transplantation and to adopt strategies aimed at diagnosing and correcting hyperglycaemia after transplantation. Diabetes mellitus is a condition that is often unrecognized in transplant candidates. In a Norwegian study, systematic screening using the oral glucose tolerance test (OGTT) revealed unknown diabetes in 8% of candidates [9]. Indeed, despite the fact that renal function decline in CKD causes impaired insulin sensitivity [10], end-stage kidney disease (ESKD) leads to improvement in glucose tolerance because of the drop in renal insulin clearance and an improved uraemic milieu upon dialysis initiation. In fact, up to one-third of diabetic dialysis patients may experience spontaneous resolution of hyperglycaemia, with haemoglobin A1c (HbA1c) levels of <6% [11]. Since several cases of post-transplant diabetes are represented by patients with unknown pre-transplant diabetes, a recent position paper suggested that the old definition of new-onset diabetes after transplantation (NODAT) should be replaced by post-transplant diabetes mellitus (PTDM) [12]. The diagnosis of PTDM may be even more challenging in transplant recipients, compared with transplant candidates, due to the use of steroids. In the presence of moderate-dose steroids, peak plasma glucose occurs 7–8 h after administration; therefore, the sensitivity of fasting blood glucose (FBG) for diabetes diagnosis is poor [13]. Although FBG sensitivity can be increased by measuring plasma glucose at 4 p.m. [14], this procedure is currently not recommended for routine clinical practice because normal values are not sufficiently standardized. Therefore, the diagnosis of PTDM is usually based on the OGTT or HbA1c [with a cut-off point of 6.2% (44 mmol/mol) in place of the traditional 6.5% (48 mmol/mol)] [15], starting from 3 months following transplantation. In the first 3 months after transplantation, hyperglycaemia may be transient, and HbA1c may be unreliable [15]. Post-surgery, hyperglycaemia occurs in 80% of transplant recipients, regardless of their diabetic status, and often improves over the first 3 months post-transplantation [13]. However, albeit transient, perioperative hyperglycaemia is associated with a subsequent risk of PTDM [16]. A relatively limited number of characteristics define the risk profile of transplant candidates for developing PTDM after transplantation. A recently developed predictive score, which was subsequently validated in a predominantly white population in the United States (US) and therefore would require further validation before it can be universally used in routine clinical practice, provides some useful evidence of how each of the traditional determinants of PTDM may affect the risk, individually as well as in combination with each other. The score was based on the following items: older age (≥50 years), FBG ≥100 mg/dL, body mass index (BMI) ≥30 kg/m2, triglycerides ≥200 mg/dL, prescription for gout medicine, being assigned to maintenance steroids post-transplantation and family history of type 2 diabetes [17]. According to this prediction model, the risk of PTDM would be ∼10, 30 and ≥50% in transplant candidates with 0–1, 2–3 and ≥4 risk factors, respectively [17]. Therefore, apart from the rather obvious baseline risk factors such as older age and pre-diabetes, three factors, namely obesity, metabolic syndrome and genetic background, accounted for most of the risk of PTDM. Obesity in transplant candidates is a major risk factor for both early (≤3 months) and late PTDM [18]. Since transplant candidates on dialysis must limit their intake of fresh fruits and vegetables to prevent hyperkalaemia, and their protein intake to prevent hyperphosphataemia, it is hard for obese candidates to lose weight with dietary measures alone. Freeman et al. [19] showed that in morbidly obese transplant candidates, laparoscopic sleeve gastrectomy achieved in 6 months 38% of excess weight loss, as opposed to 4% of excess weight loss obtained using specialized medical treatment in the 6 months before surgery. Moreover, compared with conservative treatment, pre-transplant sleeve gastrectomy has been associated with 15% lower rates of delayed graft function and renal dysfunction-related readmissions post-transplantation [20]. In non-morbidly obese patients, there may be medical alternatives to sleeve gastrectomy, based on drugs such as liraglutide, a glucagon-like peptide-1 receptor agonist with an anti-hyperglycaemic effect that carries a low risk of hypoglycaemia (Table 1). Despite its gastrointestinal side effects, liraglutide represents a promising agent, since it has been proven to be efficacious in the treatment of obesity and might be used at reduced dosage in patients with ESKD [30]. That said, strategies aimed at achieving drastic weight loss in transplant candidates might be associated with an increased risk of malnutrition. In a US cohort of 15 000 transplant candidates on haemodialysis who were active on the waiting list, a weight loss of 5 kg over >6 months was associated with a 20% increase in mortality after adjusting for all comorbidities and malnutrition inflammation indexes [31]. Though this study could not differentiate between intentional and unintentional weight loss, we recommend that interventions aimed at losing weight in obese transplant candidates should be carried out under close surveillance to prevent malnutrition and loss of muscle mass. Moreover, weight loss achieved in transplant candidates may be transient, as most transplant recipients, especially those with large pre-transplant weight decline, often experience significant weight gain following surgery with a functional allograft [32]. Finally, despite an increased rate of post-transplant surgical complications, all obese patients improve their life expectancy with kidney transplantation, as opposed to remaining on dialysis, irrespective of their BMI [33]. Table 1. Drugs for the treatment of diabetes, obesity and dyslipidaemia in transplant candidates and recipients Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  The table reports on cyclosporine, as opposed to tacrolimus, because tacrolimus is more of a victim, and less of a perpetrator, in terms of drug-to-drug pharmacokinetic interactions, compared with cyclosporine, due the low molar quantity of tacrolimus, compared with cyclosporine, competing with the other compound (i.e. an anti-diabetic drug or statin) for binding with CYP3A/transporter. For instance, as for statins, whereas tacrolimus has no pharmacokinetic interaction with atorvastatin, cyclosporine causes several-fold increase in exposure to atorvastatin by decreasing the intestinal and hepatic efflux by P-gp [27] and by decreasing hepatic uptake by OATP1B1 [23]. a SGLT2 inhibitors may not be able to reduce HbA1c in patients with reduced GFR (e.g. <60 mL/min). b Although no specific adverse reaction, such as rhabdomyolysis or hepatitis, has emerged for transplant candidates and recipients treated with statins, the risk of toxicity is deemed to be augmented due to drug interactions or accumulation. Atorvastatin, lovastatin and simvastatin undergo metabolic degradation by cytochrome-P4503A4 (CYP3A4); this group of CYP3A4-dependent statins interact with grapefruit [28] and medications such as non-dihydropyridine calcium channel blockers, protease inhibitors, macrolides and azole antifungals [29]. c Doses of statins with cyclosporine are those reported by the summary of product characteristics. AUC, area under the curve; CYP, cytochrome P; DPP-IV, dipeptidyl peptidase-4; OATP1B1, organic anion transport polypeptide 1B1; P-gp, P-glycoprotein; GLP-1, GLP glucagon-like-peptide-1; MRP2, multidrug-associated protein 2; OAT3, organic anion transporter; BRCP, breast cancer resistance protein. Table 1. Drugs for the treatment of diabetes, obesity and dyslipidaemia in transplant candidates and recipients Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  The table reports on cyclosporine, as opposed to tacrolimus, because tacrolimus is more of a victim, and less of a perpetrator, in terms of drug-to-drug pharmacokinetic interactions, compared with cyclosporine, due the low molar quantity of tacrolimus, compared with cyclosporine, competing with the other compound (i.e. an anti-diabetic drug or statin) for binding with CYP3A/transporter. For instance, as for statins, whereas tacrolimus has no pharmacokinetic interaction with atorvastatin, cyclosporine causes several-fold increase in exposure to atorvastatin by decreasing the intestinal and hepatic efflux by P-gp [27] and by decreasing hepatic uptake by OATP1B1 [23]. a SGLT2 inhibitors may not be able to reduce HbA1c in patients with reduced GFR (e.g. <60 mL/min). b Although no specific adverse reaction, such as rhabdomyolysis or hepatitis, has emerged for transplant candidates and recipients treated with statins, the risk of toxicity is deemed to be augmented due to drug interactions or accumulation. Atorvastatin, lovastatin and simvastatin undergo metabolic degradation by cytochrome-P4503A4 (CYP3A4); this group of CYP3A4-dependent statins interact with grapefruit [28] and medications such as non-dihydropyridine calcium channel blockers, protease inhibitors, macrolides and azole antifungals [29]. c Doses of statins with cyclosporine are those reported by the summary of product characteristics. AUC, area under the curve; CYP, cytochrome P; DPP-IV, dipeptidyl peptidase-4; OATP1B1, organic anion transport polypeptide 1B1; P-gp, P-glycoprotein; GLP-1, GLP glucagon-like-peptide-1; MRP2, multidrug-associated protein 2; OAT3, organic anion transporter; BRCP, breast cancer resistance protein. Besides obesity, the other major risk factor for PTDM is metabolic syndrome, which carries an increased risk of graft loss and death from CVD per se [34]. Among the constellation of abnormalities that can be detected, based on the clinical criteria for metabolic syndrome, the two simplest are the simultaneous presence of an increased waist girth (i.e. waist-to-hip ratio, an indirect measure of visceral fat) and fasting triglyceride levels, a condition that has been described as ‘hypertriglyceridaemic waist’ [35]. Using standard dual-energy X-ray absorptiometry scans, an easy and inexpensive way to assess visceral fat in transplant candidates, von During et al. showed that visceral fat is better related to PTDM than BMI [36]. The other identifying characteristic of metabolic syndrome is high triglyceride levels; in a study on >300 transplant candidates, pre-transplant triglyceride levels of ≥200 mg/dL were associated with an increased risk of PTDM, with the risk varying according to the type of calcineurin inhibitor (CNI), being 7% and 26% with cyclosporine and tacrolimus immunosuppression, respectively [37]. Various studies have suggested that uraemic adipose tissue may be dysfunctional and be a contributing factor to the development of CVD in CKD patients. In fact, it has been postulated that visceral fat could cause metabolic abnormalities by secreting inflammatory adipokines, which increase the risk of CVD [38] (see Table 2, which describes the use of adipokines as biomarkers, along with the use of biomarkers associated with other metabolic abnormalities). It is important to stress that metabolic syndrome and visceral adiposity are sensitive to lifestyle changes [35]. Table 2. Biomarkers related to the metabolic risk profile of kidney transplant candidates and recipients Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  a In dialysis patients and transplant recipients, homocysteine levels are around 25–35 µmol/L (normal value <15), far below than the extreme hyperhomocysteinaemia (>80 µmol/L) that directly causes thrombotic microangiopathy in cases of methylmalonic acidosis with homocystinuria. AA, amino acid; ACE-I, angiotensin-converting enzyme inhibitor; ADMA, asymmetric dimethylarginine; apo(a), apolipoprotein (a); ARB, angiotensin receptor blocker; HD, hemodialysis; PD, peritoneal dialysis; Vit, vitamin; RCT, randomized clinical trial. Table 2. Biomarkers related to the metabolic risk profile of kidney transplant candidates and recipients Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  a In dialysis patients and transplant recipients, homocysteine levels are around 25–35 µmol/L (normal value <15), far below than the extreme hyperhomocysteinaemia (>80 µmol/L) that directly causes thrombotic microangiopathy in cases of methylmalonic acidosis with homocystinuria. AA, amino acid; ACE-I, angiotensin-converting enzyme inhibitor; ADMA, asymmetric dimethylarginine; apo(a), apolipoprotein (a); ARB, angiotensin receptor blocker; HD, hemodialysis; PD, peritoneal dialysis; Vit, vitamin; RCT, randomized clinical trial. Family history of diabetes or gestational diabetes may help to identify transplant candidates with genetic background as a risk factor. It has been recently recognized that beta-cell dysfunction (i.e. impaired insulin secretion) plays a greater role in the pathogenesis of PTDM than in type 2 diabetes [66]. Predisposition to beta-cell dysfunction post-transplantation is strongly affected by several genetic risk variants. For instance, the homozygous risk allele of the transcription factor 7-like 2 (TCF7L2) gene, which, in an Italian study, showed a 14% prevalence in transplant candidates, is associated with 100% long-term PTDM risk [67]. On the other hand, autosomal dominant polycystic kidney disease has been associated with increased insulin resistance, causing an 8% increased risk of PTDM [68]. The main anti-diabetic drug for the treatment of hyperglycaemia early after transplantation is insulin. Because the safety and efficacy of more, compared with less, intensive insulin therapy are currently uncertain [69], the optimal target of glucose levels and HbA1c may be based on the European Renal Best Practice Clinical Practice Guideline on the management of patients with diabetes and CKD stage 3b or higher [estimated glomerular filtration rate (eGFR) <45 mL/min] [69]. Based on a flow chart diagram, they recommend targeting HbA1c values of ≤8.5% (69 mmol/mol) in patients at risk of hypoglycaemia, ≤7.0% (≤53 mmol/mol) in patients at low risk of hypoglycaemia whose diabetes is controlled by drugs, ≤8.0% (≤64 mmol/mol) in patients with long-standing diabetes (>10 years) and ≤7.5% (≤58 mmol/L) in other cases [22]. Oral agents are usually introduced at later stages (e.g. beyond the first post-operative month) by replacing insulin or by being given in addition to insulin (e.g. added to insulin glargine at night in patients with impaired morning FBG). Because of the lack of strong evidence supporting one drug over another [69], selection of the oral agent should be based on efficacy, non-renal drug elimination (especially in patients with reduced GFR and/or non-stable renal function), side effects and costs (Table 1). The most preferred options include the sulfonylureas glipizide and glimepiride, repaglinide (despite its short duration of action and low efficacy) and the newest dipeptidyl peptidase-4 inhibitor linagliptin (which does not require dose adjustment for renal function). Rosiglitazone is rarely used because it may necessitate the use of diuretics and predisposes to CNI toxicity. Only a few clinical studies have explored the efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with CKD. These studies have predominantly included patients with CKD stage 3 and have demonstrated that the glucose-lowering efficacy of SGLT2 inhibitors in these patients is diminished, most likely as a result of reduced GFR [70]. Metformin may be used only in closely monitored stable transplant recipients, who have been instructed to temporarily withdraw the drug in conditions of pending dehydration or when they undergo contrast media investigations or any other situation that predisposes to an increased risk of acute graft dysfunction. Metformin may cause some weight loss in obese patients. Liraglutide might help to induce and maintain weight loss in obese transplant recipients though studies in this setting are lacking. Hypomagnesaemia, vitamin D deficiency and hepatitis C virus (HCV) infection are additional conditions that might be potentially amenable to treatment by drug therapy. Hypomagnesaemia [71, 72], a frequent post-transplant complication that may be precipitated by the use of CNIs and proton pump inhibitors, is often persistent, thus requiring magnesium supplementation (Table 3). Vitamin D deficiency, the correction of which might reduce CVD risk (Table 3), may also increase the risk of PTDM [73]. Chronic HCV infection is associated with insulin resistance that normalizes after viral eradication [74]. However, current recommendations suggest that, in most cases, anti-HCV direct-acting antiviral agents should be started after transplantation [75] because HCV RNA-positive transplant candidates can take advantage of access to the HCV-positive donor pool to increase their chance of deceased donor transplantation. Table 3. Supplementations in transplant candidates and recipients   Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –    Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –  HCO3, bicarbonate; KCl, potassium chloride; Mg, magnesium; MgSO4, magnesium sulfate; NaHCO3, sodium bicarbonate; PPI, proton pump inhibitor; pts, patients. Table 3. Supplementations in transplant candidates and recipients   Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –    Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –  HCO3, bicarbonate; KCl, potassium chloride; Mg, magnesium; MgSO4, magnesium sulfate; NaHCO3, sodium bicarbonate; PPI, proton pump inhibitor; pts, patients. HYPERLIPIDAEMIA AND DYSLIPIDAEMIA Ischaemic heart disease (IHD) and other vascular diseases, such as cerebrovascular and peripheral artery disease, are the leading causes of death at any stage of CKD [76] and also after kidney transplantation [77]. Moreover, IHD is one of the most common causes for delayed or denied access to kidney transplantation for otherwise suitable transplant candidates [78]. Therefore, a critical goal in the evaluation of transplant candidates and recipients is the identification and correction of modifiable risk factors that contribute to IHD and other vascular diseases. Hypercholesterolaemia, a traditional risk factor for IHD, is common, but not universal, in dialysis patients, with its prevalence ranging between 25% and 50% [79]. As CKD progresses, hypercholesterolaemia becomes less frequent and contributes less to IHD because of the underlying U-shaped relationship between hypercholesterolaemia and mortality [80]. Following successful kidney transplantation, hypercholesterolaemia not only becomes an almost universal finding, but also restores the standard relationship with the incidence of IHD. In fact, in transplant recipients, hypercholesterolaemia is a strong independent risk factor for post-transplant IHD [42]. However, besides hypercholesterolaemia, transplant candidates and recipients have increased levels of triglycerides and atherogenic low-density lipoprotein-cholesterol (LDL-C), and reduced levels of protective high-density lipoprotein-cholesterol (HDL-C) [81], a picture to which we refer by the term dyslipidaemia. Dyslipidaemia has multiple aetiologies (Figure 1), which can be grouped into traditional factors (such as genetic predisposition, nutritional status and inactivity, presence of diabetes mellitus and tobacco smoking), CKD-specific factors (such as loss of renal function, nephrotic proteinuria, maintenance dialysis) [81] and anti-rejection drugs, particularly corticosteroids, cyclosporine (more so than tacrolimus) and mTOR inhibitors (sirolimus and everolimus), the latter bearing the strongest effect among the anti-rejection drugs in causing hypercholesterolaemia [82]. FIGURE 1 View largeDownload slide Lipid metabolism and mechanisms of dyslipidaemia in renal transplant candidates and recipients. Dietary lipids represent 30–40% of the daily caloric intake and mainly consist of triglycerides and, to a lesser extent, cholesterol (exogenous pathway). Triglycerides and cholesterol are also synthesized in the liver (endogenous pathway). Dietary triglycerides are carried by intestinal chylomicrons and by hepatic very low-density lipoproteins (VLDLs) to tissues where they are metabolized by the endothelial enzyme lipoprotein lipase (LPL), with the help of HDL, and eventually become chylomicron remnants and intermediate-density lipoproteins (IDLs). IDLs are partially metabolized by hepatic lipase to LDL. LDL is picked up by specific LDL-receptors (LDL-Rs) expressed by hepatocytes and other cell types. HDL induces the esterification of plasmatic cholesterol released by the cells, a reaction catalysed by lecithin-cholesterol acyltransferase (LCAT). As a result of this reaction, excess cholesterol is transported back to the liver (reverse cholesterol transport). In the liver, accumulation of intracellular cholesterol causes a negative feedback on the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A reductase (HMG-CoA Red), which causes the inhibition of cholesterol and LDL-R synthesis and promotes the esterification of free cholesterol. When these homeostatic mechanisms are saturated, macrophages of arterial walls start accumulating plasmatic cholesterol as oxidated LDL and eventually become ‘foam cells’, which contribute to the formation of atherosclerotic plaques. Patients with ESKD develop hypertriglyceridaemia as a consequence of reduced LPL activity, caused by insulin resistance and the accumulation of LPL inhibitors such as APO-CII [81, 143]. Moreover, low HDL levels and dysfunctional LCAT cause impairment of reverse cholesterol transport, which results in accumulation of oxidated LDL [81, 143]. These modifications, which are further enhanced by dialysis, contribute to the inflammatory milieu of ESKD that is known to promote atherosclerosis. In patients with nephrotic syndrome, triglyceride levels increase due to inhibition of LPL and hepatic lipase [144]. Cholesterol levels increase because LDL-Rs are downregulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) and hepatic acyl-coenzyme A cholesterol acyltransferase-2 (ACAT-2) activity is augmented. These modifications result in a significant reduction in intracellular free cholesterol, which, in turn, halts the negative feedback on cholesterol synthesis, further promoting hypercholesterolaemia [144, 145]. Among anti-rejection drugs, corticosteroids are known to induce dyslipidaemia by determining insulin resistance, but also by directly inhibiting LPL, inducing HMG-CoA-Red and downregulating LDL-Rs [82]. CNIs, particularly cyclosporine, inhibit LPL and reduce LDL-Rs, thus increasing LDL levels and inducing their oxidation [82]. The mTOR inhibitors sirolimus and everolimus are associated with significant dyslipidaemia [47]. Given that mTOR signalling plays a central role in lipid homeostasis [146], identifying single mechanisms of dyslipidaemia under mTOR inhibition is complex; a recent experimental paper suggested that elevation in LDL levels under mTOR inhibition is caused by an increase in PCSK9 which, in turn, downregulates LDL-Rs [147]. FIGURE 1 View largeDownload slide Lipid metabolism and mechanisms of dyslipidaemia in renal transplant candidates and recipients. Dietary lipids represent 30–40% of the daily caloric intake and mainly consist of triglycerides and, to a lesser extent, cholesterol (exogenous pathway). Triglycerides and cholesterol are also synthesized in the liver (endogenous pathway). Dietary triglycerides are carried by intestinal chylomicrons and by hepatic very low-density lipoproteins (VLDLs) to tissues where they are metabolized by the endothelial enzyme lipoprotein lipase (LPL), with the help of HDL, and eventually become chylomicron remnants and intermediate-density lipoproteins (IDLs). IDLs are partially metabolized by hepatic lipase to LDL. LDL is picked up by specific LDL-receptors (LDL-Rs) expressed by hepatocytes and other cell types. HDL induces the esterification of plasmatic cholesterol released by the cells, a reaction catalysed by lecithin-cholesterol acyltransferase (LCAT). As a result of this reaction, excess cholesterol is transported back to the liver (reverse cholesterol transport). In the liver, accumulation of intracellular cholesterol causes a negative feedback on the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A reductase (HMG-CoA Red), which causes the inhibition of cholesterol and LDL-R synthesis and promotes the esterification of free cholesterol. When these homeostatic mechanisms are saturated, macrophages of arterial walls start accumulating plasmatic cholesterol as oxidated LDL and eventually become ‘foam cells’, which contribute to the formation of atherosclerotic plaques. Patients with ESKD develop hypertriglyceridaemia as a consequence of reduced LPL activity, caused by insulin resistance and the accumulation of LPL inhibitors such as APO-CII [81, 143]. Moreover, low HDL levels and dysfunctional LCAT cause impairment of reverse cholesterol transport, which results in accumulation of oxidated LDL [81, 143]. These modifications, which are further enhanced by dialysis, contribute to the inflammatory milieu of ESKD that is known to promote atherosclerosis. In patients with nephrotic syndrome, triglyceride levels increase due to inhibition of LPL and hepatic lipase [144]. Cholesterol levels increase because LDL-Rs are downregulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) and hepatic acyl-coenzyme A cholesterol acyltransferase-2 (ACAT-2) activity is augmented. These modifications result in a significant reduction in intracellular free cholesterol, which, in turn, halts the negative feedback on cholesterol synthesis, further promoting hypercholesterolaemia [144, 145]. Among anti-rejection drugs, corticosteroids are known to induce dyslipidaemia by determining insulin resistance, but also by directly inhibiting LPL, inducing HMG-CoA-Red and downregulating LDL-Rs [82]. CNIs, particularly cyclosporine, inhibit LPL and reduce LDL-Rs, thus increasing LDL levels and inducing their oxidation [82]. The mTOR inhibitors sirolimus and everolimus are associated with significant dyslipidaemia [47]. Given that mTOR signalling plays a central role in lipid homeostasis [146], identifying single mechanisms of dyslipidaemia under mTOR inhibition is complex; a recent experimental paper suggested that elevation in LDL levels under mTOR inhibition is caused by an increase in PCSK9 which, in turn, downregulates LDL-Rs [147]. The KDIGO guidelines recommend that levels of total cholesterol, LDL-C, HDL-C and triglycerides should be measured in dialysis patients and transplant recipients [83], but that treatment decision in dialysis patients should be based on overall cardiovascular risk, rather than lipid levels alone [83]. These recommendations reflect the results of randomized clinical trials in dialysis patients (4D and AURORA) [26, 84] that showed a lack of benefit of statins in lowering mortality and major adverse cardiovascular events (MACE), despite effective cholesterol reduction [83]. However, in the SHARP trial on 9270 CKD patients, 3023 of whom were on dialysis, addition of ezetimibe to simvastatin resulted in a significant reduction in MACE (17% relative risk reduction) [85]. Therefore, other guidelines propose targeting LDL-C levels of <100 mg/dL in patients without CVD or <70 mg/dL for patients with CVD and advanced CKD [86]. A lipid-lowering treatment should be started for LDL-C levels of  >100 mg/dL or non-HDL-C levels of >130 mg/dL with triglyceride levels of >200 mg/dL, with these thresholds being those that identify transplant candidates who may also benefit from undergoing non-invasive cardiac stress testing [78]. The American Heart Association and the American College of Cardiology Foundation suggest that the use of statins should be considered in any transplant candidate with dyslipidaemia for the purpose of CVD risk reduction [78], especially for risk prevention in the perioperative period when the hazard of CVD reaches its maximum [87]. On the other hand, HDL-C levels of <40 mg/dL are not an indication for any treatment other than lifestyle changes [78]. In this respect, as further detailed below, all transplant candidates and recipients should optimize their lifestyle habits, quit smoking, engage in regular physical activity and avoid being overweight [83, 86]. Concerning transplant recipients, based on the results of a key randomized controlled trial [88, 89], current guidelines and systematic reviews agree on starting statins to treat dyslipidaemia, with the aim to reduce MACE and cardiovascular mortality [83, 86, 90]. In the ALERT study, fluvastatin (40 mg) did not significantly reduce the risk of MACE, compared with placebo, in 2102 transplant recipients with total cholesterol levels of between 4 and 9 mmol/L (155–358 mg/dL) and followed up for 5.1 years, but reduced the risk of cardiac deaths or non-fatal IHD (35% relative risk reduction) [88]. In the ALERT extension study, in 1652 transplant recipients followed up for 6.7 years, 80 mg fluvastatin was associated with a reduced risk of MACE (21% relative risk reduction) and cardiac death or non-fatal IHD (29% relative risk reduction), but not of overall mortality and graft loss [89]. Table 1 shows the characteristics of lipid-lowering drugs and specific implications of their use in transplant candidates and recipients. ANTI-REJECTION DRUGS AND METABOLIC RISK Immunosuppressive medications significantly affect glucose metabolism in kidney transplant recipients, with steroids and tacrolimus among the strongest determinants of PTDM. Both cyclosporine and tacrolimus are associated with PTDM. However, tacrolimus exerts a stronger inhibitory action on pancreatic beta-cells, compared with cyclosporine [91]. A recent randomized study showed that, in transplant recipients developing PTDM, replacement of tacrolimus with cyclosporine significantly improves glucose metabolism and has the potential to reverse diabetes in one in four of these patients [92]. By contrast, use of mTOR inhibitors, instead of tacrolimus, does not reduce the risk of PTDM. On the contrary, a recent meta-analysis showed that, in low-risk patients, conversion from CNIs to mTOR inhibitors was associated with a non-significant trend towards an increased risk of PTDM [93]. Steroids, by additionally causing insulin resistance, strongly contribute to the incidence of PTDM. However, steroid avoidance and withdrawal protocols may also increase the incidence of acute rejection, especially in patients at increased immunological risk, and of post-transplant recurrence of IgA nephropathy [94] and other glomerulonephritides [95]. Conditions at increased risk of rejection include previous sensitization to human leucocyte antigens (HLAs), complete class II HLA mismatch with the donor, history of acute rejection or chronic graft dysfunction due to ongoing rejection and non-adherence to immunosuppressive treatment. Increased exposure to steroids in patients developing acute rejection and glomerulonephritis recurrence may provide an explanation for the lack of benefit in terms of PTDM incidence and transplant failure between steroid avoidance and withdrawal protocols, compared with steroid maintenance protocols, up to 5 years after transplantation [96]. Recent findings from the ADVANCE study, a large randomized controlled trial performed on >1000 kidney transplant recipients treated with basiliximab, tacrolimus and mycophenolate, showed that the safety of steroid avoidance protocols may be improved by giving a short course of steroids post-operatively. The study showed that a strategy based on tapering steroids over 10 days after an intraoperative corticosteroid bolus, as opposed to a strategy based on administering an intraoperative bolus only, reduces the risk of acute rejection by ∼5% (8.7% versus 13.6%), without increasing the risk of PTDM up to 2 years post-transplantation [97]. By inducing insulin resistance, steroids are also associated with worsening dyslipidaemia (Figure 1). Indeed, it has been shown that limiting steroid use improves dyslipidaemia in kidney transplant recipients [82]. Although CNIs also cause hyperlipidaemia, by far, the drugs with the strongest hyperlipidaemic effects are mTOR inhibitors (Figure 1). In fact, >60% of transplant recipients using mTOR inhibitors require a cholesterol-lowering treatment, a figure that is twice as high as in kidney transplant recipients not exposed to those drugs [98]. On the other hand, mTOR inhibitors also exert a number of anti-atherogenic effects such as inhibition of smooth muscle cell proliferation, inhibition of monocyte chemotaxis and inhibition of intra-plaque neoangiogenesis, so much so that the introduction of drug-eluting stents coated with mTOR inhibitors has proven successful in interventional cardiology [99]. Therefore, the strong hyperlipidaemic effect of mTOR inhibitors may not be associated with an increased risk of CVD. LIFESTYLE MODIFICATIONS There is ample evidence that physical exercise improves insulin sensitivity, prevents unhealthy weight gain, decreases central fat distribution and corrects other features of metabolic syndrome. In patients with CKD, regular exercise exerts a beneficial effect on blood pressure, heart rate and some nutritional parameters [100]. Few studies, however, have specifically investigated the effects of regular exercise on metabolic risk factors in CKD patients. A recent multi-centric randomized controlled trial showed that even a low-intensity, individualized, home-based 6-months’ walking exercise programme managed by dialysis staff (10-minute walking twice daily on non-dialysis days) improves the physical performance of patients on haemodialysis [101]. Moreover, a recent cross-sectional study showed that a proactive attitude of dialysis staff greatly affects the propensity of dialysis patients to engage in physical activity [102]. It has been shown that in transplant candidates, higher exercise capacity is a strong predictor of patient survival post-transplantation [103] and that both aerobic and resistance training is feasible and clinically beneficial post-transplantation [104, 105]. Lifestyle prevention of PTDM has only been tested in one small intervention study, with modest improvement in postprandial glycaemia in the intervention group [106]. On the other hand, a small randomized controlled trial in transplant recipients showed a non-statistically significant trend towards an improvement in HDL-C in patients undergoing exercise training [107]. On this basis, a recent position paper suggested to start regular exercise 45 days post-transplantation to reduce the risk of PTDM [12]. With regard to other healthy lifestyle measures, we recommend that transplant recipients follow current dietary guidelines for the prevention and management of dyslipidaemia in the general population [108]. Accordingly, transplant recipients should avoid being overweight. Rather, they should constantly adjust their total caloric intake to maintain the desirable body weight. Physical activity should be such to expend at least 200 kcal/day. They should limit the intake of LDL-C-raising nutrients (saturated fats should be <7% of total calories, and dietary cholesterol <200 mg/day), choose foods rich in fibre and complex carbohydrates and possibly increase the intake of LDL-C-lowering substances such as plant stanols/sterols (5–10 g/day) and viscous (soluble) fibres (2 g/day). Both transplant candidates and recipients should quit smoking and limit alcohol consumption. HYPERPHOSPHATAEMIA AND ABNORMAL CALCIUM METABOLISM CKD-mineral bone disorder (CKD-MBD), a term that describes related abnormalities of mineral metabolism, bone and the cardiovascular system, affects both transplant candidates and recipients. However, unlike other metabolic abnormalities such as diabetes, obesity and dyslipidaemia, which may develop de novo or worsen after transplantation as a consequence of the use of immunosuppressive drugs, in recipients of a well-functioning renal graft, CKD-MBD abnormalities are merely a consequence of the abnormalities that had progressed before transplantation. In transplant candidates, CKD-MBD develops as a consequence of reduced renal function causing hyperphosphataemia, hypocalcaemia and hormonal abnormalities such as decreased levels of 1,25-(OH)2-vitamin D and increased levels of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Hormonal abnormalities cause impaired bone turnover and exert direct adverse cardiovascular effects such as left ventricular hypertrophy; hyperphosphataemia eventually produces arterial calcification [109]. Arterial calcification is highly prevalent in dialysis patients [110], with abdominal and coronary artery calcification detected in more than two-thirds of these patients [111]. It has been shown that the extent of arterial calcification is predictive of subsequent cardiovascular mortality beyond the established conventional risk factors [112]. Moreover, severe vascular calcification of the iliac arteries may preclude successful vascular anastomosis with the renal graft, jeopardizing the transplantability of dialysis patients. Finally, in rare instances, severe coronary artery wall calcification causing occlusive coronary artery disease may expose the transplant candidate to an unacceptable risk with kidney transplant surgical operation [78]. Kidney transplantation slows down the progression of arterial calcification but, unfortunately, does not reverse the process [113]. In fact, the annual rate of progression of coronary artery calcification after transplantation is ∼12% despite restored kidney function [114]. Because reducing serum phosphate levels can prevent vascular calcification, every potential transplant candidate should be treated according to current recommendations for CKD-MBD from the early stages of CKD [115], with special regard to targeting normal serum phosphate levels (e.g. 4.5 mg/dL). On the other hand, phosphate binders or calcimimetics are of limited efficacy and do not reduce the rate of clinical adverse events in subjects with established vascular calcification [116]. Moreover, phosphate binders such as sevelamer cannot be used in transplant recipients with CKD-MBD because they result in intestinal chelation of CNIs and decreased drug absorption [117]. After successful kidney transplantation, some of the laboratory parameters of CKD-MBD reverse spontaneously. The most remarkable change is the restored renal tubular capacity of phosphate excretion, in response to high concentrations of FGF-23 and PTH [118], which, along with the phosphaturic response to anti-rejection drugs such as steroids, CNIs or mTOR inhibitors, causes hypophosphataemia in 50–85% of transplant recipients [119]. Hypophosphataemia, which develops early after transplantation and usually reverses before the 12th month post-transplantation [119], is usually mild and transient, requiring phosphate supplementation in only a minority of transplant recipients (Table 3). After successful transplantation, PTH and FGF-23 levels spontaneously return to near-normal values by the third post-transplant month [120], whereas 1,25-(OH)2-vitamin D levels may take up to 18 months. However, in 10–50% of transplant recipients, post-transplant hyperparathyroidism may persist after transplantation due to the acquired autonomy of parathyroid glands [121]. In fact, between 15% and 30% of transplant recipients develop various degrees of hypercalcaemia early after transplantation [121]. Symptomatic hypercalcaemia usually develops in transplant recipients with a history of elevated PTH levels, which has been controlled by the use of calcimimetics before transplantation [122]. Hypercalcaemia, by inducing renal vasoconstriction, causes graft dysfunction and acute kidney injury, requiring hospital readmission, and may eventually cause graft nephrocalcinosis [123]. Therefore, in transplant candidates who have severe hyperparathyroidism before transplant (e.g. an intact PTH level ≥800 pg/mL despite optimal medical therapy), parathyroidectomy should be preferred over controlling PTH with calcimimetics [124]. After transplantation, most subjects with persistent hyperparathyroidism will respond to either calcimimetics or parathyroidectomy, although a recent randomized controlled trial showed that parathyroidectomy is slightly superior to calcimimetics in terms of serum calcium and PTH control [125]. However, compared with parathyroidectomy, calcimimetics have the additional disadvantage of increasing urinary calcium excretion, which may result in nephrocalcinosis [126] and reduced bone mineral mass [127]. Therefore, in transplant recipients, calcimimetics should be used as a bridge therapy to post-transplant parathyroidectomy, rather than as a life-long treatment aimed at avoiding parathyroidectomty altogether [127]. OTHER ABNORMALITIES Hyperuricaemia Hyperuricaemia (uric acid levels >7 mg/dL) is common among kidney transplant candidates and even more so after transplantation, developing in up to 80% of patients taking CNIs, especially cyclosporine [128]. Hyperuricaemia occurs in many conditions associated with an increased cardiovascular risk such as metabolic syndrome, obesity, dyslipidaemia, older age and diuretic use. It is also associated with reduced renal function. However, evidence relating a causal effect of hyperuricaemia to CVD is conflicting. Moreover, available evidence suggests that uric acid should be considered more as an early marker of tubular dysfunction than a causative agent of kidney disease [129]. Finally, no uric acid-lowering drug is risk-free. It is therefore reasonable to recommend against the universal use of uric acid-lowering agents in asymptomatic kidney transplant candidates and transplant recipients with hyperuricaemia, unless they suffer from gout or have an increased risk of crystal nephropathy (e.g. for uric acid levels ≥12 mg/dL) or a history of uric acid stones [130]. In fact, the Canadian Society of Transplantation suggests not to measure uric acid levels as part of routine post-transplant care in asymptomatic kidney transplant recipients [131], whereas the KDIGO guidelines suggest to monitor uric acid levels to help diagnose atypical symptoms of gout [132], which has been associated with mortality and graft loss [133]. It is worth mentioning that losartan, which may be used in transplant recipients for the treatment of hypertension, proteinuria and rejection associated with circulating anti-angiotensin type 1 receptor (AT1R) antibodies, has a modest uricosuric effect; therefore, it might help in lowering uric acid levels [134]. Iron deficiency and overload Iron deficiency should be avoided in both transplant candidates and recipients. Iron is, in fact, crucial for T-cell, neutrophil and macrophage functions and for antibody response [135, 136]. On the other hand, it is important to avoid iron overload (ferritin levels >1000 mg/dL). In fact, in dialysis patients, iron overload has been associated with liver disease, infection and mortality, while in transplant recipients, it may aggravate graft ischaemia–reperfusion injury [137] and increase immunosuppression-induced susceptibility to post-transplant infections by causing macrophage dysfunction and increased bacterial growth [138], and it also may increase rejection rates by promoting the activation of alloreactive T and B cells [139–141]. In dialysis patients, increased levels of hepcidin (Table 2), which is produced in response to chronic inflammation and is an expression of functional iron deficiency (i.e. low plasma iron and intracellular sequestration), have been associated with anaemia and CVD [62]. Interestingly, hepcidin levels rapidly return to normal after successful transplantation [142]. CONCLUSIONS Interventions aimed at controlling the metabolic abnormalities underlying the development of arterial calcification, which may impede access to transplantation and impair transplant outcomes, need to be initiated early in the course of CKD, because by the time patients are offered a kidney graft, it may be too late to attenuate the arterial calcification-associated risks. Although there are no large randomized clinical trials on the treatment of obesity in transplant candidates, there is growing evidence that newer surgical and medical strategies may safely increase access to transplantation for obese patients. In transplant recipients, metabolic abnormalities that result from adverse effects of anti-rejection therapy, as opposed to those resulting from renal graft dysfunction and previous prolonged exposure to dialysis, may be effectively controlled by lifestyle changes and the judicious use of drugs for the treatment of abnormal glucose metabolism and dyslipidaemia. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Metabolic risk profile in kidney transplant candidates and recipients

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
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10.1093/ndt/gfy151
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Abstract

Abstract Metabolic risk factors of cardiovascular disease such as abnormal glucose regulation, obesity and metabolic syndrome, dyslipidaemia, metabolic bone disease, hyperuricaemia and other less traditional abnormalities are common in both kidney transplant candidates and recipients. In kidney transplant candidates, the presence of these risk factors may impede patient access to transplantation by increasing the risk of developing comorbidities while on the waiting list, prolonging the time to wait-listing and, in some patients, eventually jeopardizing their suitability for kidney transplantation or increasing the risk of severe perioperative complications. In transplant recipients, metabolic risk factors may be associated with increased mortality with a functioning graft and with reduced long-term renal graft survival. Although most transplant recipients have no contraindication to the use of drugs that undergo renal excretion, they may be at risk of drug-to-drug pharmacokinetic interactions with anti-rejection medicines. In this review, we have highlighted the main objectives of evaluating the metabolic abnormalities in transplant candidates and recipients, how this evaluation should be carried out in practice and what currently the most valuable treatment strategies are for modifying the associated risks. We conclude that, for every potential transplant candidate, every effort should be made to control metabolic abnormalities causing arterial calcification, which may impede access to transplantation and impair transplant outcome. In transplant recipients, metabolic abnormalities that result from adverse effects of anti-rejection therapy may be effectively controlled by lifestyle changes and judicious use of drugs for the treatment of abnormal glucose metabolism and dyslipidaemia. diabetes, dyslipidaemia, kidney transplantation, metabolic syndrome, vascular calcification INTRODUCTION Metabolic risk factors of cardiovascular disease (CVD) are common in kidney transplant candidates and recipients. In kidney transplant candidates, their presence is associated with advanced chronic kidney disease (CKD). Some of these metabolic abnormalities are not fully reversed despite successful kidney transplantation and contribute to exacerbating cardiovascular risk in kidney transplant recipients, together with the toxicity of anti-rejection therapy. However, metabolic risk factors pose different challenges in transplant candidates and transplant recipients. In kidney transplant candidates, prolonged exposure to metabolic risk factors may jeopardize their suitability for kidney transplantation or increase the risk of severe perioperative complications. In kidney transplant recipients, metabolic risk factors may increase mortality with a functioning graft and reduce long-term renal graft survival. Finally, treatments to correct metabolic risk factors may differ between the two categories of patients. Unlike transplant candidates, most transplant recipients have no contraindication to the use of drugs that undergo renal excretion, but they may be at risk of drug-to-drug pharmacokinetic interactions with anti-rejection treatments. In this review, we have highlighted: (i) the main objectives of evaluating metabolic abnormalities in transplant candidates and recipients, (ii) how this evaluation should be carried out in practice and (iii) what the most valuable treatment strategies are for modifying the associated risks. DIABETES MELLITUS, OBESITY AND METABOLIC SYNDROME Diabetes adversely affects transplant candidate survival and access to the waiting list [1]. Nevertheless, diabetic candidates are the category of dialysis patients who benefit the most from deceased donor kidney transplantation in terms of proportional increase in life expectancy [2, 3], even when the graft is procured from extended criteria donors [4]. The beneficial effect of kidney transplantation on life expectancy is maximized when diabetic patients undergo pre-emptive living donor kidney transplantation [5]. Therefore, the survival benefit of transplantation over haemodialysis and peritoneal dialysis is considerable, despite the use of anti-rejection diabetogenic drugs post-transplantation. On the other hand, transplant candidates without known diabetes who develop diabetes post-transplantation have their renal graft survival reduced because of diabetes [6]. The reasons are unclear, although they may be related to physicians’ efforts to decrease diabetogenic immunosuppressive treatment, which, in turn, increases the risk of rejection contributing to the increase T-cell alloreactivity observed in diabetic patients [7], an increased incidence of infections and major cardiovascular events [8] and the development of diabetic complications, including diabetic allograft nephropathy. Therefore, it is important to identify transplant candidates at risk of developing diabetes post-transplantation, to correct their modifiable risk factors before and after transplantation and to adopt strategies aimed at diagnosing and correcting hyperglycaemia after transplantation. Diabetes mellitus is a condition that is often unrecognized in transplant candidates. In a Norwegian study, systematic screening using the oral glucose tolerance test (OGTT) revealed unknown diabetes in 8% of candidates [9]. Indeed, despite the fact that renal function decline in CKD causes impaired insulin sensitivity [10], end-stage kidney disease (ESKD) leads to improvement in glucose tolerance because of the drop in renal insulin clearance and an improved uraemic milieu upon dialysis initiation. In fact, up to one-third of diabetic dialysis patients may experience spontaneous resolution of hyperglycaemia, with haemoglobin A1c (HbA1c) levels of <6% [11]. Since several cases of post-transplant diabetes are represented by patients with unknown pre-transplant diabetes, a recent position paper suggested that the old definition of new-onset diabetes after transplantation (NODAT) should be replaced by post-transplant diabetes mellitus (PTDM) [12]. The diagnosis of PTDM may be even more challenging in transplant recipients, compared with transplant candidates, due to the use of steroids. In the presence of moderate-dose steroids, peak plasma glucose occurs 7–8 h after administration; therefore, the sensitivity of fasting blood glucose (FBG) for diabetes diagnosis is poor [13]. Although FBG sensitivity can be increased by measuring plasma glucose at 4 p.m. [14], this procedure is currently not recommended for routine clinical practice because normal values are not sufficiently standardized. Therefore, the diagnosis of PTDM is usually based on the OGTT or HbA1c [with a cut-off point of 6.2% (44 mmol/mol) in place of the traditional 6.5% (48 mmol/mol)] [15], starting from 3 months following transplantation. In the first 3 months after transplantation, hyperglycaemia may be transient, and HbA1c may be unreliable [15]. Post-surgery, hyperglycaemia occurs in 80% of transplant recipients, regardless of their diabetic status, and often improves over the first 3 months post-transplantation [13]. However, albeit transient, perioperative hyperglycaemia is associated with a subsequent risk of PTDM [16]. A relatively limited number of characteristics define the risk profile of transplant candidates for developing PTDM after transplantation. A recently developed predictive score, which was subsequently validated in a predominantly white population in the United States (US) and therefore would require further validation before it can be universally used in routine clinical practice, provides some useful evidence of how each of the traditional determinants of PTDM may affect the risk, individually as well as in combination with each other. The score was based on the following items: older age (≥50 years), FBG ≥100 mg/dL, body mass index (BMI) ≥30 kg/m2, triglycerides ≥200 mg/dL, prescription for gout medicine, being assigned to maintenance steroids post-transplantation and family history of type 2 diabetes [17]. According to this prediction model, the risk of PTDM would be ∼10, 30 and ≥50% in transplant candidates with 0–1, 2–3 and ≥4 risk factors, respectively [17]. Therefore, apart from the rather obvious baseline risk factors such as older age and pre-diabetes, three factors, namely obesity, metabolic syndrome and genetic background, accounted for most of the risk of PTDM. Obesity in transplant candidates is a major risk factor for both early (≤3 months) and late PTDM [18]. Since transplant candidates on dialysis must limit their intake of fresh fruits and vegetables to prevent hyperkalaemia, and their protein intake to prevent hyperphosphataemia, it is hard for obese candidates to lose weight with dietary measures alone. Freeman et al. [19] showed that in morbidly obese transplant candidates, laparoscopic sleeve gastrectomy achieved in 6 months 38% of excess weight loss, as opposed to 4% of excess weight loss obtained using specialized medical treatment in the 6 months before surgery. Moreover, compared with conservative treatment, pre-transplant sleeve gastrectomy has been associated with 15% lower rates of delayed graft function and renal dysfunction-related readmissions post-transplantation [20]. In non-morbidly obese patients, there may be medical alternatives to sleeve gastrectomy, based on drugs such as liraglutide, a glucagon-like peptide-1 receptor agonist with an anti-hyperglycaemic effect that carries a low risk of hypoglycaemia (Table 1). Despite its gastrointestinal side effects, liraglutide represents a promising agent, since it has been proven to be efficacious in the treatment of obesity and might be used at reduced dosage in patients with ESKD [30]. That said, strategies aimed at achieving drastic weight loss in transplant candidates might be associated with an increased risk of malnutrition. In a US cohort of 15 000 transplant candidates on haemodialysis who were active on the waiting list, a weight loss of 5 kg over >6 months was associated with a 20% increase in mortality after adjusting for all comorbidities and malnutrition inflammation indexes [31]. Though this study could not differentiate between intentional and unintentional weight loss, we recommend that interventions aimed at losing weight in obese transplant candidates should be carried out under close surveillance to prevent malnutrition and loss of muscle mass. Moreover, weight loss achieved in transplant candidates may be transient, as most transplant recipients, especially those with large pre-transplant weight decline, often experience significant weight gain following surgery with a functional allograft [32]. Finally, despite an increased rate of post-transplant surgical complications, all obese patients improve their life expectancy with kidney transplantation, as opposed to remaining on dialysis, irrespective of their BMI [33]. Table 1. Drugs for the treatment of diabetes, obesity and dyslipidaemia in transplant candidates and recipients Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  The table reports on cyclosporine, as opposed to tacrolimus, because tacrolimus is more of a victim, and less of a perpetrator, in terms of drug-to-drug pharmacokinetic interactions, compared with cyclosporine, due the low molar quantity of tacrolimus, compared with cyclosporine, competing with the other compound (i.e. an anti-diabetic drug or statin) for binding with CYP3A/transporter. For instance, as for statins, whereas tacrolimus has no pharmacokinetic interaction with atorvastatin, cyclosporine causes several-fold increase in exposure to atorvastatin by decreasing the intestinal and hepatic efflux by P-gp [27] and by decreasing hepatic uptake by OATP1B1 [23]. a SGLT2 inhibitors may not be able to reduce HbA1c in patients with reduced GFR (e.g. <60 mL/min). b Although no specific adverse reaction, such as rhabdomyolysis or hepatitis, has emerged for transplant candidates and recipients treated with statins, the risk of toxicity is deemed to be augmented due to drug interactions or accumulation. Atorvastatin, lovastatin and simvastatin undergo metabolic degradation by cytochrome-P4503A4 (CYP3A4); this group of CYP3A4-dependent statins interact with grapefruit [28] and medications such as non-dihydropyridine calcium channel blockers, protease inhibitors, macrolides and azole antifungals [29]. c Doses of statins with cyclosporine are those reported by the summary of product characteristics. AUC, area under the curve; CYP, cytochrome P; DPP-IV, dipeptidyl peptidase-4; OATP1B1, organic anion transport polypeptide 1B1; P-gp, P-glycoprotein; GLP-1, GLP glucagon-like-peptide-1; MRP2, multidrug-associated protein 2; OAT3, organic anion transporter; BRCP, breast cancer resistance protein. Table 1. Drugs for the treatment of diabetes, obesity and dyslipidaemia in transplant candidates and recipients Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ substrate for transporters [25]  Maximum daily dose (mg)  Expected reduction in HbA1c (%)  Dose adjustment in advanced CKD [22]  Dose with cyclosporine [25]  Exposure increase with cyclosporine [25]  Anti-diabetic drugs [21]  Metformin (biguanide)  –  2000  1.0–2.0  eGFR <45: max 1000 mg/day eGFR <30: contraindicated  No dose adjustment  Unlikely  Glipizide (sulfonylurea)  CYP2C9, -2D1  20  1.0–1.5  In ESKD, the starting dose should not exceed 2.5 mg  No dose adjustment  Unlikely  Glimepiride (sulfonylurea)  CYP2C9  1    Avoid if eGFR <15  No dose adjustment  Unlikely  Repaglinide (meglitinide)  CYP3A4, -2C8/OATP1B1  6  0.5–1.0  None  Consider alternatives in patients taking cyclosporine  2.5-fold increase  Rosiglitazone (thiazolidinedione)  CYP2C9, -2C8  8    None  No dose adjustment  Unlikely  Linagliptin (DPP-IV inhibitor)  (CYP3A4)/P-gp  5  0.5–0.8  None  Monitor in patients taking cyclosporine  May be increased  Canaglifozin Dapagliflozin Empagliflozin (SGLT2 inhibitors)  (CYP3A4)/ P-gp and MRP2, OAT3, and BRCP, respectively  300 10 25  0.0–1.5a  eGFR <45: not recommended eGFR<30: contraindicated  Monitor in patients taking cyclosporine  May be increased  Injectable  Liraglutide (GLP-1 receptor agonist)  –  3 (obesity) 1.8 (diabetes)  0.5–1.5  Dosage reduction in patients with ESKD may be warranted  No dose adjustment  No  Insulin  –    1.0–2.5  –  No dose adjustment  No  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  Drug  Main metabolism/ effect of OATP1B1 variants on statin AUC [23]  Maximum daily dose (mg)  Average LDL-C reduction at maximum dose [24]  Dose adjustment in advanced CKD  Dose with cyclosporinec  Exposure increase with cyclosporine  Lipid-lowering drugsb  Atorvastatin  CYP3A4/++  80  57%  None  Maximum 10 mg  8.7-fold  Lovastatin  CYP3A4/  80  40%  Caution for dosage above 20 mg  Avoid  5- to 8-fold  Simvastatin  CYP3A4/+++  80  46%  Start with 5 mg, cautiously monitor  Maximum 10 mg  NA  Fluvastatin  CYP2C9/–  80  31%    Maximum 20 mg  90% increase  Rosuvastatin  CYP2C9/+  40  63%  Start with 5 mg Maximum 10 mg  Maximum 5 mg  7-fold  Pravastatin  Sulfation/+  80  34%  Start with 10 mg, cautiously monitor  Maximum 20 mg  282% increase  Ezetimibe  Glucuronide conjugation  10  –  None  Caution  Up to 12-fold  Ezetimibe/simvastatin  See above  10/80  77% [85]  See above  See above  See above  The table reports on cyclosporine, as opposed to tacrolimus, because tacrolimus is more of a victim, and less of a perpetrator, in terms of drug-to-drug pharmacokinetic interactions, compared with cyclosporine, due the low molar quantity of tacrolimus, compared with cyclosporine, competing with the other compound (i.e. an anti-diabetic drug or statin) for binding with CYP3A/transporter. For instance, as for statins, whereas tacrolimus has no pharmacokinetic interaction with atorvastatin, cyclosporine causes several-fold increase in exposure to atorvastatin by decreasing the intestinal and hepatic efflux by P-gp [27] and by decreasing hepatic uptake by OATP1B1 [23]. a SGLT2 inhibitors may not be able to reduce HbA1c in patients with reduced GFR (e.g. <60 mL/min). b Although no specific adverse reaction, such as rhabdomyolysis or hepatitis, has emerged for transplant candidates and recipients treated with statins, the risk of toxicity is deemed to be augmented due to drug interactions or accumulation. Atorvastatin, lovastatin and simvastatin undergo metabolic degradation by cytochrome-P4503A4 (CYP3A4); this group of CYP3A4-dependent statins interact with grapefruit [28] and medications such as non-dihydropyridine calcium channel blockers, protease inhibitors, macrolides and azole antifungals [29]. c Doses of statins with cyclosporine are those reported by the summary of product characteristics. AUC, area under the curve; CYP, cytochrome P; DPP-IV, dipeptidyl peptidase-4; OATP1B1, organic anion transport polypeptide 1B1; P-gp, P-glycoprotein; GLP-1, GLP glucagon-like-peptide-1; MRP2, multidrug-associated protein 2; OAT3, organic anion transporter; BRCP, breast cancer resistance protein. Besides obesity, the other major risk factor for PTDM is metabolic syndrome, which carries an increased risk of graft loss and death from CVD per se [34]. Among the constellation of abnormalities that can be detected, based on the clinical criteria for metabolic syndrome, the two simplest are the simultaneous presence of an increased waist girth (i.e. waist-to-hip ratio, an indirect measure of visceral fat) and fasting triglyceride levels, a condition that has been described as ‘hypertriglyceridaemic waist’ [35]. Using standard dual-energy X-ray absorptiometry scans, an easy and inexpensive way to assess visceral fat in transplant candidates, von During et al. showed that visceral fat is better related to PTDM than BMI [36]. The other identifying characteristic of metabolic syndrome is high triglyceride levels; in a study on >300 transplant candidates, pre-transplant triglyceride levels of ≥200 mg/dL were associated with an increased risk of PTDM, with the risk varying according to the type of calcineurin inhibitor (CNI), being 7% and 26% with cyclosporine and tacrolimus immunosuppression, respectively [37]. Various studies have suggested that uraemic adipose tissue may be dysfunctional and be a contributing factor to the development of CVD in CKD patients. In fact, it has been postulated that visceral fat could cause metabolic abnormalities by secreting inflammatory adipokines, which increase the risk of CVD [38] (see Table 2, which describes the use of adipokines as biomarkers, along with the use of biomarkers associated with other metabolic abnormalities). It is important to stress that metabolic syndrome and visceral adiposity are sensitive to lifestyle changes [35]. Table 2. Biomarkers related to the metabolic risk profile of kidney transplant candidates and recipients Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  a In dialysis patients and transplant recipients, homocysteine levels are around 25–35 µmol/L (normal value <15), far below than the extreme hyperhomocysteinaemia (>80 µmol/L) that directly causes thrombotic microangiopathy in cases of methylmalonic acidosis with homocystinuria. AA, amino acid; ACE-I, angiotensin-converting enzyme inhibitor; ADMA, asymmetric dimethylarginine; apo(a), apolipoprotein (a); ARB, angiotensin receptor blocker; HD, hemodialysis; PD, peritoneal dialysis; Vit, vitamin; RCT, randomized clinical trial. Table 2. Biomarkers related to the metabolic risk profile of kidney transplant candidates and recipients Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  Biomarker  Pathophysiology  Dialysis patients and interventions  Transplant recipients and interventions  Adiponectin (and visfatin) Peptide, adipocytokine  Insulin-sensitivity Anti-inflammation Energy expenditure up to malnutrition [8] and reduced bone density [39]  Inverse association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Healthy lifestyle Dialysis adequacy Fish oil, statins, pioglitazone, L-carnitine, ACE-I, and ARB Weak evidence  Inverse association with PTDM [40]  Pioglitazone Reduction in adiponectin and carotid intima-media thickness [41]  Leptin Peptide, adipocytokine  Insulin resistance Inflammation Fullness up to anorexia [8]  Association with cardiovascular and all-cause mortality (after adjustment for waist circumference) [38]  Same as above  Inverse association with all-cause mortality [31]  No RCT available  ResistinPeptide, adipocytokine  Same as for leptin [8]  Association with cardiovascular and all-cause mortality (after adjustment for adiponectin) [42]  Same as above  Association with all-cause mortality and graft loss [43]  No RCT available  Lipoprotein(a) A single LDL particle and a highly polymorphic apo(a) Levels inversely correlated with apo(a) isoform sizes (no. of kringle iv repeats) [44]  Association with IHD, dependent on small apo(a) isoforms [44]  Increased levels of large apo(a) isoforms in HD, any apo(a) isoform in PD [45] Association with IHD [44]  No RCT available  Decreased levels with functioning transplant [44]  No RCT available  Homocysteine AA from essential AA methionine  Endothelial dysfunction Inflammation and oxidation Thrombosis [45]  Increased levelsa Association with MACE and mortality [46] U-shaped epidemiology [45]  Folic acid ± Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (meta-analysis) [47]  Increased levelsa [48]  Folic acid, Vit B6 and B12 No reduction in cardiovascular and all-cause mortality (FAVORIT RCT) [49]  ADMA AA from metabolism of L-arginine  Association with endothelial dysfunction [50] and atherosclerosis [51]  Association with kidney dysfunction [52], intima-media thickness, [53], impaired erythropoietin response [54], cardiovascular events, and mortality [55]  Amlodipine, valsartan [56] Weak evidence  Decreased levels with functioning transplant [57]  No RCT available  Hepcidin Peptide (liver, urinary excreted), binds to ferroportin to reduce iron gut absorption and iron release from cells [22, 58]  It increases to reduce iron availability, thus preventing bacterial overgrowth [59]  Increased levels are associated with anaemia [60], impaired immune function [61], and fatal and non-fatal cardiovascular events [62]  No RCT available  Levels return to normal after successful kidney transplantation [9]  No RCT available  Klotho Membrane Klotho acts as kidney co-receptor for FGF-23. Soluble Klotho act as endocrine factor  Renal Klotho mediates phosphaturic effect of FGF-23  Markedly reduced in CKD. Reduced circulating levels are associated with the presence and severity of soft tissue calcification [63]  No RCT available  Decreased Klotho transcripts in renal grafts after rejection and ischaemia–reperfusion injury. Decreased levels in transplant recipients [64, 65]  No RCT available  a In dialysis patients and transplant recipients, homocysteine levels are around 25–35 µmol/L (normal value <15), far below than the extreme hyperhomocysteinaemia (>80 µmol/L) that directly causes thrombotic microangiopathy in cases of methylmalonic acidosis with homocystinuria. AA, amino acid; ACE-I, angiotensin-converting enzyme inhibitor; ADMA, asymmetric dimethylarginine; apo(a), apolipoprotein (a); ARB, angiotensin receptor blocker; HD, hemodialysis; PD, peritoneal dialysis; Vit, vitamin; RCT, randomized clinical trial. Family history of diabetes or gestational diabetes may help to identify transplant candidates with genetic background as a risk factor. It has been recently recognized that beta-cell dysfunction (i.e. impaired insulin secretion) plays a greater role in the pathogenesis of PTDM than in type 2 diabetes [66]. Predisposition to beta-cell dysfunction post-transplantation is strongly affected by several genetic risk variants. For instance, the homozygous risk allele of the transcription factor 7-like 2 (TCF7L2) gene, which, in an Italian study, showed a 14% prevalence in transplant candidates, is associated with 100% long-term PTDM risk [67]. On the other hand, autosomal dominant polycystic kidney disease has been associated with increased insulin resistance, causing an 8% increased risk of PTDM [68]. The main anti-diabetic drug for the treatment of hyperglycaemia early after transplantation is insulin. Because the safety and efficacy of more, compared with less, intensive insulin therapy are currently uncertain [69], the optimal target of glucose levels and HbA1c may be based on the European Renal Best Practice Clinical Practice Guideline on the management of patients with diabetes and CKD stage 3b or higher [estimated glomerular filtration rate (eGFR) <45 mL/min] [69]. Based on a flow chart diagram, they recommend targeting HbA1c values of ≤8.5% (69 mmol/mol) in patients at risk of hypoglycaemia, ≤7.0% (≤53 mmol/mol) in patients at low risk of hypoglycaemia whose diabetes is controlled by drugs, ≤8.0% (≤64 mmol/mol) in patients with long-standing diabetes (>10 years) and ≤7.5% (≤58 mmol/L) in other cases [22]. Oral agents are usually introduced at later stages (e.g. beyond the first post-operative month) by replacing insulin or by being given in addition to insulin (e.g. added to insulin glargine at night in patients with impaired morning FBG). Because of the lack of strong evidence supporting one drug over another [69], selection of the oral agent should be based on efficacy, non-renal drug elimination (especially in patients with reduced GFR and/or non-stable renal function), side effects and costs (Table 1). The most preferred options include the sulfonylureas glipizide and glimepiride, repaglinide (despite its short duration of action and low efficacy) and the newest dipeptidyl peptidase-4 inhibitor linagliptin (which does not require dose adjustment for renal function). Rosiglitazone is rarely used because it may necessitate the use of diuretics and predisposes to CNI toxicity. Only a few clinical studies have explored the efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with CKD. These studies have predominantly included patients with CKD stage 3 and have demonstrated that the glucose-lowering efficacy of SGLT2 inhibitors in these patients is diminished, most likely as a result of reduced GFR [70]. Metformin may be used only in closely monitored stable transplant recipients, who have been instructed to temporarily withdraw the drug in conditions of pending dehydration or when they undergo contrast media investigations or any other situation that predisposes to an increased risk of acute graft dysfunction. Metformin may cause some weight loss in obese patients. Liraglutide might help to induce and maintain weight loss in obese transplant recipients though studies in this setting are lacking. Hypomagnesaemia, vitamin D deficiency and hepatitis C virus (HCV) infection are additional conditions that might be potentially amenable to treatment by drug therapy. Hypomagnesaemia [71, 72], a frequent post-transplant complication that may be precipitated by the use of CNIs and proton pump inhibitors, is often persistent, thus requiring magnesium supplementation (Table 3). Vitamin D deficiency, the correction of which might reduce CVD risk (Table 3), may also increase the risk of PTDM [73]. Chronic HCV infection is associated with insulin resistance that normalizes after viral eradication [74]. However, current recommendations suggest that, in most cases, anti-HCV direct-acting antiviral agents should be started after transplantation [75] because HCV RNA-positive transplant candidates can take advantage of access to the HCV-positive donor pool to increase their chance of deceased donor transplantation. Table 3. Supplementations in transplant candidates and recipients   Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –    Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –  HCO3, bicarbonate; KCl, potassium chloride; Mg, magnesium; MgSO4, magnesium sulfate; NaHCO3, sodium bicarbonate; PPI, proton pump inhibitor; pts, patients. Table 3. Supplementations in transplant candidates and recipients   Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –    Transplant candidates  Transplant recipients  Additional comments  Vitamin D and analogues, and calcium  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  Vitamin D deficiency: 25-(OH)-cholecalciferol <20 ng/mL → Cholecalciferol, 5000–10 000 IU/day  There is evidence, albeit weak, to support treatment of vitamin D deficiency with native vitamin D (cholecalciferol) in all phases of CKD because of its pleiotropic effects on the cardiovascular system  Secondary hyperparathyroidism: → Calcitriol and activated vitamin D analogues, with the sole purpose of reducing PTH levels  Prevention of post-transplant osteoporosis: → Cholecalciferol, 800 IU/day (pts with normal graft function) → 1,25-(OH)2 cholecalciferol, 0.25–0.50 µg/day (pts with reduced graft function) with calcium, 1000 mg/day (including food intake)  Vitamin D deficiency in transplant recipients has been associated with the development of PTDM  Phosphate  –  Severe hypophosphataemia (serum P <1.5 mg/dL or muscle weakness) → Phosphate supplementation to target serum P levels of 2 mg/dL: – IV fructose-1,6-diphosphate, 2–5 doses of 5–10 g each (0.35–0.75 g of P); – Oral phosphate tablets or syrup, max 2 g/day in 2–3 divided doses In less severe cases, increasing milk intake between meals may suffice (e.g. up to half a litre/day)  Hyperphosphataemia may occur in transplant recipients in cases of delayed graft function and chronic graft dysfunction Sevelamer should not be used to correct hyperphosphataemia in transplant recipients because it decreases CNI absorption by intestinal chelation  Magnesium  Serum Mg is usually normal or elevated in transplant candidates  Hypomagnesaemia: → Oral Mg-pidolate, 4.5 g/day (15 Mg mEq) → IV MgSO4, 2.5–5.0 g/day (20–40 Mg mEq) for 1–2 days  Hypomagnesaemia, which is mainly caused by CNIs and PPIs, has been associated with an increased risk of PTDM, dyslipidaemia and graft failure  Potassium  Hyperkalaemia before transplant surgery: → Indication to perform an additional dialysis session in the 24 h preceding the transplant procedure  Hypokalaemia: → Oral KCl, 1.8–3.6 g (20–50 K mEq) for few days  Mild hypokalaemia occurs frequently shorty after successful transplantation  Hyperkalaemia: → Oral polystyrene sulfonates, 5–10 g/day in the early post-operative weeks  Mild hyperkalaemia due to treatment with CNIs and co-trimoxazole occurs in 5–40% of transplant recipients and may also require bicarbonate for concomitant acidosis  Bicarbonate  Metabolic acidosis: → Oral NaHCO3, 1–6 g/day (24–72 HCO3 mEq) Supplementation is usually required in a minority of dialysis patients, and in virtually all CKD patients receiving pre-emptive transplantation  Metabolic acidosis: → Oral NaHCO3, 1–3 g/day (24–36 HCO3 mEq)  Mild non-anion gap metabolic acidosis, due to renal tubular acidosis or graft dysfunction, occurs in >50% of transplant recipients on CNIs Chronic metabolic acidosis is associated with muscle wasting, insulin resistance, and increased PTH Oral HCO3 should not be given with mycophenolate or valganciclovir because reduced stomach acidity decreases the absorption of such drugs  Folic acid and cyanocobalamin  Benefit not proven in the absence of documented deficiency  Benefit not proven in the absence of documented deficiency  –  HCO3, bicarbonate; KCl, potassium chloride; Mg, magnesium; MgSO4, magnesium sulfate; NaHCO3, sodium bicarbonate; PPI, proton pump inhibitor; pts, patients. HYPERLIPIDAEMIA AND DYSLIPIDAEMIA Ischaemic heart disease (IHD) and other vascular diseases, such as cerebrovascular and peripheral artery disease, are the leading causes of death at any stage of CKD [76] and also after kidney transplantation [77]. Moreover, IHD is one of the most common causes for delayed or denied access to kidney transplantation for otherwise suitable transplant candidates [78]. Therefore, a critical goal in the evaluation of transplant candidates and recipients is the identification and correction of modifiable risk factors that contribute to IHD and other vascular diseases. Hypercholesterolaemia, a traditional risk factor for IHD, is common, but not universal, in dialysis patients, with its prevalence ranging between 25% and 50% [79]. As CKD progresses, hypercholesterolaemia becomes less frequent and contributes less to IHD because of the underlying U-shaped relationship between hypercholesterolaemia and mortality [80]. Following successful kidney transplantation, hypercholesterolaemia not only becomes an almost universal finding, but also restores the standard relationship with the incidence of IHD. In fact, in transplant recipients, hypercholesterolaemia is a strong independent risk factor for post-transplant IHD [42]. However, besides hypercholesterolaemia, transplant candidates and recipients have increased levels of triglycerides and atherogenic low-density lipoprotein-cholesterol (LDL-C), and reduced levels of protective high-density lipoprotein-cholesterol (HDL-C) [81], a picture to which we refer by the term dyslipidaemia. Dyslipidaemia has multiple aetiologies (Figure 1), which can be grouped into traditional factors (such as genetic predisposition, nutritional status and inactivity, presence of diabetes mellitus and tobacco smoking), CKD-specific factors (such as loss of renal function, nephrotic proteinuria, maintenance dialysis) [81] and anti-rejection drugs, particularly corticosteroids, cyclosporine (more so than tacrolimus) and mTOR inhibitors (sirolimus and everolimus), the latter bearing the strongest effect among the anti-rejection drugs in causing hypercholesterolaemia [82]. FIGURE 1 View largeDownload slide Lipid metabolism and mechanisms of dyslipidaemia in renal transplant candidates and recipients. Dietary lipids represent 30–40% of the daily caloric intake and mainly consist of triglycerides and, to a lesser extent, cholesterol (exogenous pathway). Triglycerides and cholesterol are also synthesized in the liver (endogenous pathway). Dietary triglycerides are carried by intestinal chylomicrons and by hepatic very low-density lipoproteins (VLDLs) to tissues where they are metabolized by the endothelial enzyme lipoprotein lipase (LPL), with the help of HDL, and eventually become chylomicron remnants and intermediate-density lipoproteins (IDLs). IDLs are partially metabolized by hepatic lipase to LDL. LDL is picked up by specific LDL-receptors (LDL-Rs) expressed by hepatocytes and other cell types. HDL induces the esterification of plasmatic cholesterol released by the cells, a reaction catalysed by lecithin-cholesterol acyltransferase (LCAT). As a result of this reaction, excess cholesterol is transported back to the liver (reverse cholesterol transport). In the liver, accumulation of intracellular cholesterol causes a negative feedback on the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A reductase (HMG-CoA Red), which causes the inhibition of cholesterol and LDL-R synthesis and promotes the esterification of free cholesterol. When these homeostatic mechanisms are saturated, macrophages of arterial walls start accumulating plasmatic cholesterol as oxidated LDL and eventually become ‘foam cells’, which contribute to the formation of atherosclerotic plaques. Patients with ESKD develop hypertriglyceridaemia as a consequence of reduced LPL activity, caused by insulin resistance and the accumulation of LPL inhibitors such as APO-CII [81, 143]. Moreover, low HDL levels and dysfunctional LCAT cause impairment of reverse cholesterol transport, which results in accumulation of oxidated LDL [81, 143]. These modifications, which are further enhanced by dialysis, contribute to the inflammatory milieu of ESKD that is known to promote atherosclerosis. In patients with nephrotic syndrome, triglyceride levels increase due to inhibition of LPL and hepatic lipase [144]. Cholesterol levels increase because LDL-Rs are downregulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) and hepatic acyl-coenzyme A cholesterol acyltransferase-2 (ACAT-2) activity is augmented. These modifications result in a significant reduction in intracellular free cholesterol, which, in turn, halts the negative feedback on cholesterol synthesis, further promoting hypercholesterolaemia [144, 145]. Among anti-rejection drugs, corticosteroids are known to induce dyslipidaemia by determining insulin resistance, but also by directly inhibiting LPL, inducing HMG-CoA-Red and downregulating LDL-Rs [82]. CNIs, particularly cyclosporine, inhibit LPL and reduce LDL-Rs, thus increasing LDL levels and inducing their oxidation [82]. The mTOR inhibitors sirolimus and everolimus are associated with significant dyslipidaemia [47]. Given that mTOR signalling plays a central role in lipid homeostasis [146], identifying single mechanisms of dyslipidaemia under mTOR inhibition is complex; a recent experimental paper suggested that elevation in LDL levels under mTOR inhibition is caused by an increase in PCSK9 which, in turn, downregulates LDL-Rs [147]. FIGURE 1 View largeDownload slide Lipid metabolism and mechanisms of dyslipidaemia in renal transplant candidates and recipients. Dietary lipids represent 30–40% of the daily caloric intake and mainly consist of triglycerides and, to a lesser extent, cholesterol (exogenous pathway). Triglycerides and cholesterol are also synthesized in the liver (endogenous pathway). Dietary triglycerides are carried by intestinal chylomicrons and by hepatic very low-density lipoproteins (VLDLs) to tissues where they are metabolized by the endothelial enzyme lipoprotein lipase (LPL), with the help of HDL, and eventually become chylomicron remnants and intermediate-density lipoproteins (IDLs). IDLs are partially metabolized by hepatic lipase to LDL. LDL is picked up by specific LDL-receptors (LDL-Rs) expressed by hepatocytes and other cell types. HDL induces the esterification of plasmatic cholesterol released by the cells, a reaction catalysed by lecithin-cholesterol acyltransferase (LCAT). As a result of this reaction, excess cholesterol is transported back to the liver (reverse cholesterol transport). In the liver, accumulation of intracellular cholesterol causes a negative feedback on the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A reductase (HMG-CoA Red), which causes the inhibition of cholesterol and LDL-R synthesis and promotes the esterification of free cholesterol. When these homeostatic mechanisms are saturated, macrophages of arterial walls start accumulating plasmatic cholesterol as oxidated LDL and eventually become ‘foam cells’, which contribute to the formation of atherosclerotic plaques. Patients with ESKD develop hypertriglyceridaemia as a consequence of reduced LPL activity, caused by insulin resistance and the accumulation of LPL inhibitors such as APO-CII [81, 143]. Moreover, low HDL levels and dysfunctional LCAT cause impairment of reverse cholesterol transport, which results in accumulation of oxidated LDL [81, 143]. These modifications, which are further enhanced by dialysis, contribute to the inflammatory milieu of ESKD that is known to promote atherosclerosis. In patients with nephrotic syndrome, triglyceride levels increase due to inhibition of LPL and hepatic lipase [144]. Cholesterol levels increase because LDL-Rs are downregulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) and hepatic acyl-coenzyme A cholesterol acyltransferase-2 (ACAT-2) activity is augmented. These modifications result in a significant reduction in intracellular free cholesterol, which, in turn, halts the negative feedback on cholesterol synthesis, further promoting hypercholesterolaemia [144, 145]. Among anti-rejection drugs, corticosteroids are known to induce dyslipidaemia by determining insulin resistance, but also by directly inhibiting LPL, inducing HMG-CoA-Red and downregulating LDL-Rs [82]. CNIs, particularly cyclosporine, inhibit LPL and reduce LDL-Rs, thus increasing LDL levels and inducing their oxidation [82]. The mTOR inhibitors sirolimus and everolimus are associated with significant dyslipidaemia [47]. Given that mTOR signalling plays a central role in lipid homeostasis [146], identifying single mechanisms of dyslipidaemia under mTOR inhibition is complex; a recent experimental paper suggested that elevation in LDL levels under mTOR inhibition is caused by an increase in PCSK9 which, in turn, downregulates LDL-Rs [147]. The KDIGO guidelines recommend that levels of total cholesterol, LDL-C, HDL-C and triglycerides should be measured in dialysis patients and transplant recipients [83], but that treatment decision in dialysis patients should be based on overall cardiovascular risk, rather than lipid levels alone [83]. These recommendations reflect the results of randomized clinical trials in dialysis patients (4D and AURORA) [26, 84] that showed a lack of benefit of statins in lowering mortality and major adverse cardiovascular events (MACE), despite effective cholesterol reduction [83]. However, in the SHARP trial on 9270 CKD patients, 3023 of whom were on dialysis, addition of ezetimibe to simvastatin resulted in a significant reduction in MACE (17% relative risk reduction) [85]. Therefore, other guidelines propose targeting LDL-C levels of <100 mg/dL in patients without CVD or <70 mg/dL for patients with CVD and advanced CKD [86]. A lipid-lowering treatment should be started for LDL-C levels of  >100 mg/dL or non-HDL-C levels of >130 mg/dL with triglyceride levels of >200 mg/dL, with these thresholds being those that identify transplant candidates who may also benefit from undergoing non-invasive cardiac stress testing [78]. The American Heart Association and the American College of Cardiology Foundation suggest that the use of statins should be considered in any transplant candidate with dyslipidaemia for the purpose of CVD risk reduction [78], especially for risk prevention in the perioperative period when the hazard of CVD reaches its maximum [87]. On the other hand, HDL-C levels of <40 mg/dL are not an indication for any treatment other than lifestyle changes [78]. In this respect, as further detailed below, all transplant candidates and recipients should optimize their lifestyle habits, quit smoking, engage in regular physical activity and avoid being overweight [83, 86]. Concerning transplant recipients, based on the results of a key randomized controlled trial [88, 89], current guidelines and systematic reviews agree on starting statins to treat dyslipidaemia, with the aim to reduce MACE and cardiovascular mortality [83, 86, 90]. In the ALERT study, fluvastatin (40 mg) did not significantly reduce the risk of MACE, compared with placebo, in 2102 transplant recipients with total cholesterol levels of between 4 and 9 mmol/L (155–358 mg/dL) and followed up for 5.1 years, but reduced the risk of cardiac deaths or non-fatal IHD (35% relative risk reduction) [88]. In the ALERT extension study, in 1652 transplant recipients followed up for 6.7 years, 80 mg fluvastatin was associated with a reduced risk of MACE (21% relative risk reduction) and cardiac death or non-fatal IHD (29% relative risk reduction), but not of overall mortality and graft loss [89]. Table 1 shows the characteristics of lipid-lowering drugs and specific implications of their use in transplant candidates and recipients. ANTI-REJECTION DRUGS AND METABOLIC RISK Immunosuppressive medications significantly affect glucose metabolism in kidney transplant recipients, with steroids and tacrolimus among the strongest determinants of PTDM. Both cyclosporine and tacrolimus are associated with PTDM. However, tacrolimus exerts a stronger inhibitory action on pancreatic beta-cells, compared with cyclosporine [91]. A recent randomized study showed that, in transplant recipients developing PTDM, replacement of tacrolimus with cyclosporine significantly improves glucose metabolism and has the potential to reverse diabetes in one in four of these patients [92]. By contrast, use of mTOR inhibitors, instead of tacrolimus, does not reduce the risk of PTDM. On the contrary, a recent meta-analysis showed that, in low-risk patients, conversion from CNIs to mTOR inhibitors was associated with a non-significant trend towards an increased risk of PTDM [93]. Steroids, by additionally causing insulin resistance, strongly contribute to the incidence of PTDM. However, steroid avoidance and withdrawal protocols may also increase the incidence of acute rejection, especially in patients at increased immunological risk, and of post-transplant recurrence of IgA nephropathy [94] and other glomerulonephritides [95]. Conditions at increased risk of rejection include previous sensitization to human leucocyte antigens (HLAs), complete class II HLA mismatch with the donor, history of acute rejection or chronic graft dysfunction due to ongoing rejection and non-adherence to immunosuppressive treatment. Increased exposure to steroids in patients developing acute rejection and glomerulonephritis recurrence may provide an explanation for the lack of benefit in terms of PTDM incidence and transplant failure between steroid avoidance and withdrawal protocols, compared with steroid maintenance protocols, up to 5 years after transplantation [96]. Recent findings from the ADVANCE study, a large randomized controlled trial performed on >1000 kidney transplant recipients treated with basiliximab, tacrolimus and mycophenolate, showed that the safety of steroid avoidance protocols may be improved by giving a short course of steroids post-operatively. The study showed that a strategy based on tapering steroids over 10 days after an intraoperative corticosteroid bolus, as opposed to a strategy based on administering an intraoperative bolus only, reduces the risk of acute rejection by ∼5% (8.7% versus 13.6%), without increasing the risk of PTDM up to 2 years post-transplantation [97]. By inducing insulin resistance, steroids are also associated with worsening dyslipidaemia (Figure 1). Indeed, it has been shown that limiting steroid use improves dyslipidaemia in kidney transplant recipients [82]. Although CNIs also cause hyperlipidaemia, by far, the drugs with the strongest hyperlipidaemic effects are mTOR inhibitors (Figure 1). In fact, >60% of transplant recipients using mTOR inhibitors require a cholesterol-lowering treatment, a figure that is twice as high as in kidney transplant recipients not exposed to those drugs [98]. On the other hand, mTOR inhibitors also exert a number of anti-atherogenic effects such as inhibition of smooth muscle cell proliferation, inhibition of monocyte chemotaxis and inhibition of intra-plaque neoangiogenesis, so much so that the introduction of drug-eluting stents coated with mTOR inhibitors has proven successful in interventional cardiology [99]. Therefore, the strong hyperlipidaemic effect of mTOR inhibitors may not be associated with an increased risk of CVD. LIFESTYLE MODIFICATIONS There is ample evidence that physical exercise improves insulin sensitivity, prevents unhealthy weight gain, decreases central fat distribution and corrects other features of metabolic syndrome. In patients with CKD, regular exercise exerts a beneficial effect on blood pressure, heart rate and some nutritional parameters [100]. Few studies, however, have specifically investigated the effects of regular exercise on metabolic risk factors in CKD patients. A recent multi-centric randomized controlled trial showed that even a low-intensity, individualized, home-based 6-months’ walking exercise programme managed by dialysis staff (10-minute walking twice daily on non-dialysis days) improves the physical performance of patients on haemodialysis [101]. Moreover, a recent cross-sectional study showed that a proactive attitude of dialysis staff greatly affects the propensity of dialysis patients to engage in physical activity [102]. It has been shown that in transplant candidates, higher exercise capacity is a strong predictor of patient survival post-transplantation [103] and that both aerobic and resistance training is feasible and clinically beneficial post-transplantation [104, 105]. Lifestyle prevention of PTDM has only been tested in one small intervention study, with modest improvement in postprandial glycaemia in the intervention group [106]. On the other hand, a small randomized controlled trial in transplant recipients showed a non-statistically significant trend towards an improvement in HDL-C in patients undergoing exercise training [107]. On this basis, a recent position paper suggested to start regular exercise 45 days post-transplantation to reduce the risk of PTDM [12]. With regard to other healthy lifestyle measures, we recommend that transplant recipients follow current dietary guidelines for the prevention and management of dyslipidaemia in the general population [108]. Accordingly, transplant recipients should avoid being overweight. Rather, they should constantly adjust their total caloric intake to maintain the desirable body weight. Physical activity should be such to expend at least 200 kcal/day. They should limit the intake of LDL-C-raising nutrients (saturated fats should be <7% of total calories, and dietary cholesterol <200 mg/day), choose foods rich in fibre and complex carbohydrates and possibly increase the intake of LDL-C-lowering substances such as plant stanols/sterols (5–10 g/day) and viscous (soluble) fibres (2 g/day). Both transplant candidates and recipients should quit smoking and limit alcohol consumption. HYPERPHOSPHATAEMIA AND ABNORMAL CALCIUM METABOLISM CKD-mineral bone disorder (CKD-MBD), a term that describes related abnormalities of mineral metabolism, bone and the cardiovascular system, affects both transplant candidates and recipients. However, unlike other metabolic abnormalities such as diabetes, obesity and dyslipidaemia, which may develop de novo or worsen after transplantation as a consequence of the use of immunosuppressive drugs, in recipients of a well-functioning renal graft, CKD-MBD abnormalities are merely a consequence of the abnormalities that had progressed before transplantation. In transplant candidates, CKD-MBD develops as a consequence of reduced renal function causing hyperphosphataemia, hypocalcaemia and hormonal abnormalities such as decreased levels of 1,25-(OH)2-vitamin D and increased levels of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Hormonal abnormalities cause impaired bone turnover and exert direct adverse cardiovascular effects such as left ventricular hypertrophy; hyperphosphataemia eventually produces arterial calcification [109]. Arterial calcification is highly prevalent in dialysis patients [110], with abdominal and coronary artery calcification detected in more than two-thirds of these patients [111]. It has been shown that the extent of arterial calcification is predictive of subsequent cardiovascular mortality beyond the established conventional risk factors [112]. Moreover, severe vascular calcification of the iliac arteries may preclude successful vascular anastomosis with the renal graft, jeopardizing the transplantability of dialysis patients. Finally, in rare instances, severe coronary artery wall calcification causing occlusive coronary artery disease may expose the transplant candidate to an unacceptable risk with kidney transplant surgical operation [78]. Kidney transplantation slows down the progression of arterial calcification but, unfortunately, does not reverse the process [113]. In fact, the annual rate of progression of coronary artery calcification after transplantation is ∼12% despite restored kidney function [114]. Because reducing serum phosphate levels can prevent vascular calcification, every potential transplant candidate should be treated according to current recommendations for CKD-MBD from the early stages of CKD [115], with special regard to targeting normal serum phosphate levels (e.g. 4.5 mg/dL). On the other hand, phosphate binders or calcimimetics are of limited efficacy and do not reduce the rate of clinical adverse events in subjects with established vascular calcification [116]. Moreover, phosphate binders such as sevelamer cannot be used in transplant recipients with CKD-MBD because they result in intestinal chelation of CNIs and decreased drug absorption [117]. After successful kidney transplantation, some of the laboratory parameters of CKD-MBD reverse spontaneously. The most remarkable change is the restored renal tubular capacity of phosphate excretion, in response to high concentrations of FGF-23 and PTH [118], which, along with the phosphaturic response to anti-rejection drugs such as steroids, CNIs or mTOR inhibitors, causes hypophosphataemia in 50–85% of transplant recipients [119]. Hypophosphataemia, which develops early after transplantation and usually reverses before the 12th month post-transplantation [119], is usually mild and transient, requiring phosphate supplementation in only a minority of transplant recipients (Table 3). After successful transplantation, PTH and FGF-23 levels spontaneously return to near-normal values by the third post-transplant month [120], whereas 1,25-(OH)2-vitamin D levels may take up to 18 months. However, in 10–50% of transplant recipients, post-transplant hyperparathyroidism may persist after transplantation due to the acquired autonomy of parathyroid glands [121]. In fact, between 15% and 30% of transplant recipients develop various degrees of hypercalcaemia early after transplantation [121]. Symptomatic hypercalcaemia usually develops in transplant recipients with a history of elevated PTH levels, which has been controlled by the use of calcimimetics before transplantation [122]. Hypercalcaemia, by inducing renal vasoconstriction, causes graft dysfunction and acute kidney injury, requiring hospital readmission, and may eventually cause graft nephrocalcinosis [123]. Therefore, in transplant candidates who have severe hyperparathyroidism before transplant (e.g. an intact PTH level ≥800 pg/mL despite optimal medical therapy), parathyroidectomy should be preferred over controlling PTH with calcimimetics [124]. After transplantation, most subjects with persistent hyperparathyroidism will respond to either calcimimetics or parathyroidectomy, although a recent randomized controlled trial showed that parathyroidectomy is slightly superior to calcimimetics in terms of serum calcium and PTH control [125]. However, compared with parathyroidectomy, calcimimetics have the additional disadvantage of increasing urinary calcium excretion, which may result in nephrocalcinosis [126] and reduced bone mineral mass [127]. Therefore, in transplant recipients, calcimimetics should be used as a bridge therapy to post-transplant parathyroidectomy, rather than as a life-long treatment aimed at avoiding parathyroidectomty altogether [127]. OTHER ABNORMALITIES Hyperuricaemia Hyperuricaemia (uric acid levels >7 mg/dL) is common among kidney transplant candidates and even more so after transplantation, developing in up to 80% of patients taking CNIs, especially cyclosporine [128]. Hyperuricaemia occurs in many conditions associated with an increased cardiovascular risk such as metabolic syndrome, obesity, dyslipidaemia, older age and diuretic use. It is also associated with reduced renal function. However, evidence relating a causal effect of hyperuricaemia to CVD is conflicting. Moreover, available evidence suggests that uric acid should be considered more as an early marker of tubular dysfunction than a causative agent of kidney disease [129]. Finally, no uric acid-lowering drug is risk-free. It is therefore reasonable to recommend against the universal use of uric acid-lowering agents in asymptomatic kidney transplant candidates and transplant recipients with hyperuricaemia, unless they suffer from gout or have an increased risk of crystal nephropathy (e.g. for uric acid levels ≥12 mg/dL) or a history of uric acid stones [130]. In fact, the Canadian Society of Transplantation suggests not to measure uric acid levels as part of routine post-transplant care in asymptomatic kidney transplant recipients [131], whereas the KDIGO guidelines suggest to monitor uric acid levels to help diagnose atypical symptoms of gout [132], which has been associated with mortality and graft loss [133]. It is worth mentioning that losartan, which may be used in transplant recipients for the treatment of hypertension, proteinuria and rejection associated with circulating anti-angiotensin type 1 receptor (AT1R) antibodies, has a modest uricosuric effect; therefore, it might help in lowering uric acid levels [134]. Iron deficiency and overload Iron deficiency should be avoided in both transplant candidates and recipients. Iron is, in fact, crucial for T-cell, neutrophil and macrophage functions and for antibody response [135, 136]. On the other hand, it is important to avoid iron overload (ferritin levels >1000 mg/dL). In fact, in dialysis patients, iron overload has been associated with liver disease, infection and mortality, while in transplant recipients, it may aggravate graft ischaemia–reperfusion injury [137] and increase immunosuppression-induced susceptibility to post-transplant infections by causing macrophage dysfunction and increased bacterial growth [138], and it also may increase rejection rates by promoting the activation of alloreactive T and B cells [139–141]. In dialysis patients, increased levels of hepcidin (Table 2), which is produced in response to chronic inflammation and is an expression of functional iron deficiency (i.e. low plasma iron and intracellular sequestration), have been associated with anaemia and CVD [62]. Interestingly, hepcidin levels rapidly return to normal after successful transplantation [142]. CONCLUSIONS Interventions aimed at controlling the metabolic abnormalities underlying the development of arterial calcification, which may impede access to transplantation and impair transplant outcomes, need to be initiated early in the course of CKD, because by the time patients are offered a kidney graft, it may be too late to attenuate the arterial calcification-associated risks. Although there are no large randomized clinical trials on the treatment of obesity in transplant candidates, there is growing evidence that newer surgical and medical strategies may safely increase access to transplantation for obese patients. In transplant recipients, metabolic abnormalities that result from adverse effects of anti-rejection therapy, as opposed to those resulting from renal graft dysfunction and previous prolonged exposure to dialysis, may be effectively controlled by lifestyle changes and the judicious use of drugs for the treatment of abnormal glucose metabolism and dyslipidaemia. 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Nephrology Dialysis TransplantationOxford University Press

Published: May 25, 2018

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