Patients with chronic kidney disease (CKD) are affected by mineral and bone disorder (MBD), resulting in abnormalities in serum calcium (Ca), phosphorous (P) and parathyroid hormone (PTH). Changes in mineral metabolism have also been associated with higher rates of both all-cause and cardiovascular-related mortality. The majority of haemodialysis patients are also deﬁcient in the endogenous hormone 1,25-dihydroxyvitamin D (calcitriol), often contributing to increased secondary hyperparathyroidism (SHPT) and consequently to abnormal levels of Ca, P and PTH. Thus P overload and SHPT are well-known targets of medical treatments, such as P binders, vitamin D and calcimimetics, although with still limited evidence-based advantages in terms of survival. The tough hedge that is still keeping nephrologists far from a conclusive and winning approach against CKD-MBD is reasonably related to the still partial comprehension of the molecular pathways involved in a complex, multifactorial and extreme process. Key words: CKD-MBD, KDIGO, secondary hyperparathyroidism Despite therapeutic advances, mortality rates remain high among addition to the introduction of newer treatment options in clini- patients with chronic kidney disease (CKD), particularly those cal practice. Furthermore, clinical guidelines are available for undergoing haemodialysis (HD) . The main cause of mortality in optimal levels of serum markers of CKD-MBD, but target param- these patients is attributed to cardiovascular-related diseases . eters are not achieved in many HD patients . However, patients with CKD are also affected by mineral and bone The 2009 Kidney Disease: Improving Global Outcomes disorder (MBD), resulting in abnormalities in serum calcium (Ca), (KDIGO) Clinical Practice Guideline on the Management of CKD- phosphorous (P) and parathyroid hormone (PTH) . Changes in MBD was intended to assist clinicians in treating patients with mineral metabolism have also been associated with higher rates CKD Stages 3–5 who are also on dialysis . Very recently (July of both all-cause and cardiovascular-related mortality [3–6]. 2017), updated KDIGO guidelines confirm those targets for CKD- In 2003, the US National Kidney Foundation implemented MBD biomarkers . the Kidney Disease Outcomes Quality Initiative (KDOQI) inter- Although several studies have examined the association national guidelines to establish target levels for serum PTH, Ca between mineral levels and the impact of achievement of CKD- and P in an effort to help lower secondary hyperparathyroidism MBD target ranges on mortality rates in HD patients [12, 13], only (SHPT)-related mortality . Unfortunately, evidence suggests a few studies have been conducted to date on incident HD that these restrictive guidelines are difficult to achieve, espe- patients [14–16]. Furthermore, evidence indicates that in incident cially over the long term . Since these guidelines were imple- HD patients, mortality rates are higher in the early stages (first mented, there has been an increased awareness of SHPT in 3–4 months) of dialysis, warranting studies in this setting . Received: August 30, 2017. Editorial decision: September 4, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/70/4469412 by Ed 'DeepDyve' Gillespie user on 16 March 2018 CKD-MBD KDIGO guidelines | 71 Table 1. Comparison of the Photo-Graphe3 study and the FARO-2 In the present issue of Clinical Kidney Journal, Fouque et al. study in incident HD patients present data from the Photo-Graphe3 study in France . This is a prospective, multicentre, observational study in 9010 inci- Photo-Graphe3 FARO-2 dent HD patients followed for 32 months. Interestingly, authors observed that the proportion achieving the three KDIGO targets Country France Italy increased from 11% to 16% (P< 0.0001) over 24 months, remain- Number of patients 9010 610 ing stable afterwards, with significant improvement in serum P Follow-up (months) 32 36 Percentage of achieving 16 25.8 and serum Ca levels, without any significant improvement in KDIGO tri-targets serum PTH levels . Other studies were performed to investigate similar issues. In Italy, we performed the FARO-2 study. The aim of the FARO-2 study was to assess SHPT management and alignment with One of the difficulties in achieving multiple CKD-MBD tar- CKD-MBD guideline target ranges [15, 16] on mortality rates in a gets consistently is that the majority of treatment approaches subgroup of incident HD patients from the FARO study [6, 12, reflect a compromise between controlling PTH and controlling 18]. In the FARO-2 study, we showed that mortality rates at Ca and P . Although newer therapies, such as combined cal- 24 months are associated with a reduction by as much as 25% in cimimetic and active vitamin D therapy, have been shown to patients who achieved target ranges for three of the bone and enhance the ability of patients to reach CKD-MBD target values mineral parameters (Ca, P and PTH) according to KDOQI guide- for biochemical parameters , their long-term safety and lines. Moreover, by attaining target ranges for the three parame- efficacy, and ultimately mortality rates, still need to be verified ters at least once over the survey, survival rates were still 20% in randomized controlled trials. Long-term randomized con- greater than those never achieving the KDOQI targets. The find- trolled trials are still needed to determine the extent that these ings from our survival analysis supported these previous stud- therapies, administered in combination or as monotherapy, ies and, more importantly, extend our knowledge by provide a survival benefit. demonstrating that the achievement of KDOQI targets over In conclusion, considering the limitations of this time were associated with a significant improvement in sur- observational design, the benefit of achieving KDOQI targets vival. Furthermore, we performed a retrospective analysis to and the more recent KDIGO targets on survival in incident HD determine how patients fared in terms of achievement of target patients remains to be confirmed in long-term prospective ranges according to the newer KDIGO guidelines [10, 11]. It is randomized clinical trials. important to underline that while the target ranges for Stage 5 CKD HD patients for intact PTH concentrations are 150–300 pg/ References mL according to KDOQI guidelines , the newer KDIGO guide- lines recommend maintaining PTH levels 2- to 9-fold the upper 1. Iseki K, Shinzato T, Nagura Y et al. Factors inﬂuencing long- normal limit [10, 11], corresponding to a range of 130–600 pg/mL term survival in patients on chronic dialysis. Clin Exp Nephrol . 2004; 8: 89–97 In the FARO-2 study, as we had expected, the number of 2. Block GA, Hulbert-Shearon TE, Levin NW et al. Association of patients on target was increased by following the KDIGO guide- serum phosphorus and calcium x phosphate product with lines. While only 35.9% of patients were on target for PTH levels mortality risk in chronic hemodialysis patients: a national according to the KDOQI guidelines, this proportion increased to study. Am J Kidney Dis 1998; 31: 607–617 63% when the KDIGO guidelines were adopted. Likewise, the 3. Block GA, Klassen PS, Lazarus JM et al. Mineral metabolism, proportion of patients with three biochemical parameters on mortality, and morbidity in maintenance hemodialysis. JAm target (tri-target) at least once was higher for the KDIGO (46%) Soc Nephrol 2004; 15: 2208–2218 compared with the KDOQI guidelines (30.1%) and in patients 4. Tentori F, Blayney MJ, Albert JM et al. Mortality risk for dialy- who attained tri-target for all six visits (25.8% for KDIGO versus sis patients with different levels of serum calcium, phospho- 13.3% for KDOQI). Since the KDIGO guidelines are less restric- rus, and PTH: the Dialysis Outcomes and Practice Patterns tive, a greater proportion of patients will likely have more Study (DOPPS). Am J Kidney Dis 2008; 52: 519–530 severe hyperparathyroidism. Therefore it was not surprising 5. Floege J, Kim J, Ireland E et al. Serum iPTH, calcium and phos- that our analysis also revealed a higher mortality rate in those phate, and the risk of mortality in a European haemodialysis patients who were never on target according to KDIGO ranges population. Nephrol Dial Transplant 2011; 26: 1948–1955 (46%) compared with KDOQI ranges (29.7%). 6. Cozzolino M, Brancaccio D, Cannella G et al. VDRA therapy is Going back to the French cohort, a prospective observational associated with improved survival in dialysis patients with study was performed on 8377 prevalent patients receiving inter- serum intact PTH 150 pg/ml: results of the Italian FARO mittent HD therapy that examined the association between survey. Nephrol Dial Transplant 2012; 27: 3588–3594 mortality and serum concentrations of phosphate, Ca and PTH 7. National Kidney Foundation. K/DOQI clinical practice guide- through KDIGO target ranges . The authors described a ‘grey lines for bone metabolism and disease in chronic kidney dis- zone’ where the precise biochemical targets are difficult to ease. Am J Kidney Dis 2003; 42(4 Suppl 3): S1–S202 define, with the exception of avoiding extreme values. The 8. Wei M, Taskapan H, Esbaei K et al. K/DOQI guideline require- KDIGO guidelines did not recommend precise threshold values, ments for calcium, phosphate, calcium phosphate product, but rather ‘normal’ laboratory values, which may differ from and parathyroid hormone control in dialysis patients: can one PTH kit to another. This study also confirmed the relative we achieve them? Int Urol Nephrol 2006; 38: 739–743 9. Toussaint ND, Pedagogos E, Beavis J et al. Improving CKD- risk of low intact PTH values, as proposed by the KDIGO recom- mendations . MBD management in haemodialysis patients: barrier analy- Table 1 presents a summary of the present study  and sis for implementing better practice. Nephrol Dial Transplant the FARO-2 study  in incident HD patients. 2011; 26: 1319–1326 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/70/4469412 by Ed 'DeepDyve' Gillespie user on 16 March 2018 72 | M. Cozzolino mineral metabolism in incident hemodialysis patients: 10. KDIGO clinical practice guideline for the diagnosis, evalua- tion, and treatment of chronic kidney disease-mineral and results of the FARO-2 cohort. Blood Purif 2014; 38: 37–45 bone disorder (CKD-MBD). Kidney Int 2009; 76(Suppl 113): 17. Fouque D, Roth H, Darne´B et al. Achievement of kidney S1–S130 disease: improving global outcomes mineral and bone 11. KDIGO clinical practice guideline for the diagnosis, evalua- targets between 2010 and 2014 in incident dialysis patients tion, and treatment of chronic kidney disease-mineral and in France: the Photo-Graphe3 study. Clin Kidney J 2018; 11: bone disorder (CKD-MBD). Kidney Int 2017; 7(Suppl 1): S1–S59 73–79 12. Brancaccio D, Cozzolino M, Cannella G et al. Secondary 18. Uhlig K, Berns JS, Kestenbaum B et al. KDOQI US commentary hyperparathyroidism in chronic dialysis patients: results of on the 2009 KDIGO clinical practice guideline for the diagno- the Italian FARO survey on treatment and mortality. Blood sis, evaluation, and treatment of CKD-mineral and bone dis- Purif 2011; 32: 124–132 order (CKD-MBD). Am J Kidney Dis 2010; 55: 773–799 13. Palmer SC, Hayen A, Macaskill P et al, Serum levels of phos- 19. Fouque D, Roth H, Pelletier S et al. Control of mineral phorus, parathyroid hormone, and calcium and risks of metabolism and bone disease in haemodialysis patients: death and cardiovascular disease in individuals with which optimal targets? NephrolDialTransplant 2013; 28: 360–367 chronic kidney disease: a systematic review and meta-anal- ysis. JAMA 2011; 16: 1119–1127 20. Arenas MD, Alvarez-Ude F, Torregrosa V et al. Consequences 14. Danese MD, Belozeroff V, Smirnakis K et al. Consistent con- of the implementation of ‘K/DOQI Clinical Practice trol of mineral and bone disorder in incident hemodialysis Guidelines for Bone Metabolism and Disease in Chronic patients. Clin J Am Soc Nephrol 2008; 3: 1423–1429 Kidney Disease’ in a population of patients on chronic 15. Messa P, Cozzolino M, Brancaccio D et al. Effect of VDRA on hemodialysis. J Nephrol 2007; 20: 453–461 survival in incident hemodialysis patients: results of the 21. Block GA, Zeig S, Sugihara J et al. Combined therapy with FARO-2 observational study. BMC Nephrol 2015; 16: 11 cinacalcet and low doses of vitamin D sterols in patients 16. Cozzolino M, Messa P, Brancaccio D et al. Achievement of with moderate to severe secondary hyperparathyroidism. NKF/K-DOQI recommended target values for bone and Nephrol Dial Transplant 2008; 23: 2311–2318 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/70/4469412 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Clinical Kidney Journal – Oxford University Press
Published: Feb 1, 2018
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