Background: Pigment nephropathy represents one of the most severe complications of rhabdomyolysis or hemolysis. Methods: We performed a retrospective observational study to analyze the etiology, clinical manifestation, laboratory proﬁle and outcome in patients with biopsy-proven pigment-induced nephropathy between January 2011 and December 2016. History, clinical examination ﬁndings, laboratory investigations and outcome were recorded. Results: A total of 46 patients were included with mean follow-up of 14 6 5.5 months. Mean age was 40.15 6 12.3 years, 65% were males (male:female, 1.8:1) and 37 (80.4%) had oliguria. Mean serum creatinine at presentation and peak creatinine were 7.5 6 2.2 and 12.1 6 4.3 mg/dL, respectively. Evidence of rhabdomyolysis was noted in 26 patients (64%) and hemolysis in 20 patients (36%). Etiology of rhabdomyolysis include snake envenomation (10 patients), seizures (7), strenuous exercise (5), wasp sting (2) and rifampicin induced (2). The causes of hemolysis include rifampicin induced (7 patients), sepsis (5), malaria (3), mismatched blood transfusion/transfusion reaction (3) and paroxysmal nocturnal hemoglobinuria (2). On renal biopsy, two patients had acute interstitial nephritis and two had immunoglobulin A deposits in addition to pigment nephropathy. All except one (97.8%) required hemodialysis (HD) during hospital stay and mean number of HD sessions was 9 6 2. A total of three patients with sepsis/disseminated intravascular coagulation died, all had associated hemolysis. On statistical analysis, there was no difference between AKI due to rhabdomyolysis and hemolysis except for high creatine phosphokinase in patients with rhabdomyolysis and Lactate dehydrogenase level in patients with hemolysis. At mean follow-up, ﬁve patients (12%) progressed to chronic kidney disease (CKD). Conclusions: Pigment nephropathy due to rhabdomyolysis and hemolysis is an important cause of renal failure requiring HD. The prognosis was relatively good and depends on the etiology; however, long-term studies and follow-up are needed to assess the true incidence of CKD due to pigment nephropathy. Key words: AKI, hemolysis, pigment, renal biopsy, rhabdomyolysis Received: June 19, 2017. Editorial decision: September 7, 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/11/3/348/4596641 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Pigment nephropathy | 349 Table 1. Demographic and clinical data in patients Introduction Rhabdomyolysis-induced pigment nephropathy is common, Variables N ¼ 46 accounting for about 7–10% of all cases of acute kidney injury Males 30 (65%) (AKI) . Etiology of rhabdomyolysis and pigment nephropathy Mean age (years) 40.156 12.3 differ in Western and tropical countries. There is a paucity of data Oliguria at presentation 37 (80.4%) in the Indian literature; hence, we intend to study the etiology, Mean creatinine at presentation (mg/dL) 7.56 2.2 clinical manifestation, laboratory profile and outcome in patients Mean peak serum creatinine (mg/dL) 12.16 4.3 with biopsy-proven pigment-induced nephropathy. Mean serum CPK (IU/L) 23196 690 Mean serum LDH (IU/L) 21286 890 Mean serum potassium (mEq/L) 4.96 2.3 Mean serum calcium (mg/dL) 8.046 4.5 Materials and methods Mean serum phosphorus (mg/dL) 4.956 2.3 Mean serum uric acid (mg/dL) 5.956 3.2 We performed a retrospective observational study in patients Mean number of HD sessions 96 2 admitted to the Institute of Nephrology, Madras Medical College, Chennai with various causes of AKI and renal biopsy showing pigment nephropathy during January 2011 to December 2016. Those patients with lost follow-up of at least software package (v15.0, SPSS Inc., Chicago, IL, USA). P < 0.05 3 months and underlying known renal disease were excluded. was taken as statistical significance. Renal biopsy was done in patients who had persistent oliguria for >7 days and renal failure for >14 days despite supportive treatment. Perls staining for iron was done in all patients and Results immunostaining for myoglobin in selected patients. Detailed history including history of recent trauma, exertion, seizures, The total number of AKI cases over 6 years was 3300, out of infections and intake of alcohol/medications, demographic data which 155 (4.7%) had laboratory evidence of rhabdomyolysis and clinical findings were noted. and 98 patients (2.9%) had evidence of hemolysis. A total of 46 Laboratory investigations included urine analysis, spot urine patients with biopsy-proven pigment cast [26 patients (56%) protein:creatinine ratio, urine myoglobin, plasma free hemoglo- with rhabdomyolysis and 20 patients (44%)] were included with bin, reticulocyte count blood urea, serum creatinine, sodium, mean follow-up of 14 6 5.5 months. Those patients with clinical potassium, calcium, prothrombin time, serum creatine phos- and laboratory evidence of rhabdomyolysis or hemolysis but no phokinase (CPK), Lactate dehydrogenase (LDH) and liver func- demonstrable pigment cast in renal biopsy were excluded from tion tests, treatment details and outcome were recorded. the study. Demographic and clinical data are given in Table 1. All the renal biopsies were subjected to light microscopy Mean serum CPK was 2319 6 690 IU/L and mean serum LDH was with various stains including hemotoxylin and eosin, Periodic 2128 6 890 IU/L. Out of 26 patients with rhabdomyolysis, 8 acid–Schiff, trichrome, Periodic Schiff-methanamine and Perls patients had serum CPK <1500 IU/L and 18 patients had Prussian blue stain. Perls stain for iron confirms hemosiderin >1500 IU/L. Only five patients had severe rhabdomyolysis, as seen in the tubular epithelial cell cytoplasm. In the presence of defined by serum CPK >5000 IU/L, hypoalbuminemia, hyperka- intratubular pigment casts with a globular/ropy appearance, lemia and hypocalcemia. Approximately 20 patients presented myoglobin immunohistochemistry (IHC) was done whenever with hemolysis, of which the most common was rifampicin possible. Hemoglobin IHC was not done due to unavailability. induced (7 patients), followed by sepsis (5), malaria (3), The etiology of rhabdomyolysis and hemolysis was ascertained mismatched blood transfusion/transfusion reaction (3) and by clinical history and laboratory findings. paroxysmal nocturnal hemoglobinuria (PNH) (2). In rifampicin- All the patients received supportive treatment and forced induced hemolysis, the mean duration of anti-tuberculosis alkaline diuresis was given when presenting without volume treatment was 2 weeks; all the patients were on intermittent overload or oliguria. Indications of hemodialysis (HD) were oli- therapy. The etiology of AKI due to rhabdomyolysis and hemol- goanuria, hyperkalemia (>5.5 mEq/L), metabolic acidosis and ysis in our study in comparison with the literature are given in acute pulmonary edema. Table 2. In our study, 26 out 155 rhabdomyolysis patients and 20 AKI was defined as per Kidney Disease Improving Global out of 98 hemolysis patients had pigment casts (P ¼ 0.54). All Outcomes 2012 guidelines as increase in serum creatinine by renal biopsies revealed acute tubular injury in dilated tubules, 0.3 mg/dL within 48 h or increase in serum creatinine to 1.5 swollen tubular epithelial cells with cytoplasmic vacuoles, times from baseline that is known or presumed to have sloughed off epithelial cells forming granular debris, edematous occurred within the prior 7 days or urine volume <0.5 mL/kg/h interstitium and pigment casts (Figure 1) in the tubules. None of for 6 h. Complete recovery of kidney function was defined as a the patients had significant glomerulosclerosis, interstitial decrease in the serum creatinine level to within a normal range. fibrosis or tubular atrophy. Out of 26 patients with evidence of Chronic kidney disease (CKD) was defined as estimated glomer- rhabdomyolysis, myoglobin immunostaining (Figure 2) was ular filtration rate <60 mL/min/1.73 m at 3 months after the done in 18 patients and was found to be positive and all 20 biop- onset of AKI. The presence of rhabdomyolysis was diagnosed by sies with hemolysis revealed Perls stain positivity in cytoplasm. clinical history and elevated serum CPK >390 IU/L (three times In all, two patients had acute interstitial nephritis and two had the normal) and hemolysis by elevated LDH (>420 IU/L), anemia immunoglobulin A deposits in addition to pigment nephrop- (Hb<10 mg/dL) and elevated bilirubin. Data are expressed as athy. There was no significant difference noted in the morphol- mean (6 standard deviation), median (range), numbers or per- ogy of pigment casts due to rhabdomyolysis or hemolyis except centages. The differences in variables between patients with that Perls stain positivity in cytoplasm was seen in all 20 rhabdomyolysis or hemolysis were assessed using the chi- patients with hemolysis but only in 1 patient with rhabdomyol- square test. All calculations were performed using the SPSS ysis. Some minimal lymphocytic interstitial infiltrates were Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/348/4596641 by Ed 'DeepDyve' Gillespie user on 20 June 2018 350 | R. Sakthirajan et al. Table 2. Etiology of rhabdomyolysis and hemolysis causing AKI Common causes Causes in our study (n) Rhabdomyolysis N ¼ 26 Extreme physical exercise/ Snake envenomation (10) seizures Seizures (7) Extreme temperatures Strenuous exercise (5) Trauma/crush syndrome Wasp sting (2) Vascular ischemia Rifampicin induced (2) Drug induced Infections/sepsis Toxins Endocrine disorders Metabolic/electrolyte disorders Hemolysis N¼ 20 ABO-incompatible blood Rifampicin induced (7) Fig. 2. Renal biopsy immunostaining—positive for myoglobin. transfusions Sepsis/DIC (5) Glucose-6-phosphate dehy- Malaria (3) drogenase (G6PD) deﬁciency Mismatched blood transfusion/ Table 3. Variables between AKI due to rhabdomyolysis and Poisoning transfusion reaction (3) hemolysis Snake and insect bites PNH (2) Drug reactions Variables Rhabdomyolysis Hemolysis P-value PNH Number 26 20 Malaria Mean age (years) 41.1 39.2 0.91 Mean CPK (IU/L) 3581 1057 0.002 Mean LDH (IU/L) 1294 2962 0.0001 Mean potassium (mEq/L) 5.2 4.61 0.88 Mean calcium (mg/dL) 8.06 8.03 0.97 Mean phosphorus (mg/dL) 4.6 5.3 0.45 Mean uric acid (mg/dL) 4.7 7.2 0.20 Mean number of HD sessions 9.3 8.6 0.71 Death 0 3 0.05 constituents into the circulation . The mechanisms of renal toxicity by myoglobin, a 17.8-kDa protein, are renal vasocon- striction, formation of intratubular casts and the direct toxicity of myoglobin to kidney tubular cells [3, 4]. Myoglobin is filtered by the glomeruli, gets concentrated along the renal tubules and precipitates with the Tamm–Horsfall protein, a process favored by acidic urine. It appears in the urine only when the renal threshold of 0.5–1.5 mg/dL of myoglobin is exceeded. Tubule Fig. 1. Renal biopsy showing pigment cast in the tubules. obstruction occurs usually at the distal tubules, and direct tubule toxicity occurs in the proximal tubules. Serum CPK is the most sensitive enzyme marker of muscle injury. Though serum noted in 8 out of 26 rhabdomyolysis patients and in 6 out of 20 myoglobin levels peak before serum CPK, it has a rapid and hemolysis patients. All except one patient (97.8%) required HD unpredictable metabolism. The measurement of serum myoglo- and mean number of HD sessions was 9 6 2. A total of three bin has a low sensitivity for the diagnosis of rhabdomyolysis . patients (6.5%) died with sepsis/disseminated intravascular There is no defined threshold value of serum CPK above which coagulation (DIC), all had AKI due to hemolysis etiology. the risk of AKI is markedly increased, although values >5000 U/ Statistical analysis of variables between AKI due to rhabdo- L have been reported to increase the risk of AKI, but only five myolysis and hemolysis is given in Table 3. There was no differ- patients in our study had such high values [6, 7]. ence between AKI due to rhabdomyolysis and hemolysis except Rhabdomyolysis-induced AKI was first described by Meyer-Betz for high CPK in patients with rhabdomyolysis and LDH level in in 1911 . Approximately 10–50% of patients with rhabdomyol- patients with hemolysis. At mean follow-up, five patients (12%) ysis develop AKI, and it contributes to 5–25% of all cases of AKI had progressed to CKD. Out of these, two were due to severe [9, 10]. In our study, rhabdomyolysis contributed to 4.7% of rhabdomyolysis and three due to hemolysis. total AKI. In a retrospective study involving 126 patients with severe Discussion rhabdomyolysis with a 9-year follow-up, the incidence of AKI was 58%. The causes of rhabdomyolysis  include immobili- The causes of pigment-induced nephropathy are rhabdomyoly- zation due to illicit drugs abuse (27.8%), infectious disease sis, intravascular hemolysis and bile pigment nephropathy due (19.8%), trauma (7.1%), stroke (4.8%), surgery (3.2%) and other to cholestasis. Rhabdomyolysis refers to disintegration of stri- (30.2%), whereas it was due to snake envenomation (38%), ated muscle, resulting in the release of muscular cell Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/348/4596641 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Pigment nephropathy | 351 seizures (30%), strenuous exercise (19%), wasp sting (6.5%) and laboratory evidence, immunohistochemistry of pigment casts will rifampicin induced (6.5%) in our study. Death was significantly be helpful in clinching the etiology, though is not essential. higher among patients with AKI, compared with patients with- Snake envenomation is the most common cause of rhabdo- out AKI (19.2% versus 3.6%). The risk factors for AKI include myolysis and rifampicin is the most common cause of hemoly- peak CPK, hypoalbuminemia, metabolic acidosis and decreased sis causing pigment nephropathy in our study. It has a prothrombin time. The mortality rate varied from 3.5% to 22% relatively good prognosis depending on the underlying etiology, [3, 12, 13]. None of our patients with rhabdomyolysis-induced though long-term follow-up is needed to ascertain the burden AKI died. Hyperkalemia, hyperuricemia and hypocalcemia are of pigment-induced nephropathy to CKD incidence in the other common complications of rhabdomyolysis . The main future. step in management remains the early, aggressive repletion of fluids. Administration of sodium bicarbonate, which results in Conflict of interest statement an alkaline urine, was first proposed by Bywaters and Beall, though studies did not show encouraging results [15, 16]. Long- None declared. term survival among patients with rhabdomyolysis and AKI is reported to be close to 80% . References Hemolysis is the second most common cause of pigment nephropathy. Deposits of iron and hemosiderosis in the kidney 1. El-Abdellati E, Eyselbergs M, Sirimsi H et al. 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Clinical Kidney Journal – Oxford University Press
Published: Nov 6, 2017
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