Clinical Nephrology, Vol. 63 – No. 6/2015 (331-337)
Tubular dysfunction in renal transplant patients using sirolimus or tacrolimus Original ©2015 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430 DOI 10.5414/CN108541 e-pub: May 6, 2015
Key words kidney concentrating ability – kidney transplantation – renal tubular acidosis – sirolimus – tacrolimus
Pedro B. Banhara, Renato T. Gonçalves, Pedro T. Rocha, Alvimar G. Delgado, Maurilo Leite Jr, and Carlos P. Gomes Division of Nephrology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Abstract. Background: Tubular dysfunction is prevalent among kidney transplant patients using calcineurin inhibitors, but our knowledge of the tubular effects of mTOR inhibitors is more limited. Methods: 60 kidney transplant outpatients using either the calcineurin inhibitor tacrolimus or the mTOR inhibitor sirolimus were investigated for renal tubular dysfunction. Proximal tubule function was assessed by quantification of albumin and β2-microglobulin, tubular reabsorption of phosphate and fractional excretion of bicarbonate. Distal tubular function was evaluated by water deprivation test and by urinary acidification test using furosemide and fludrocortisone for pH, ammonium and titratable acidity measurements. Results: The prevalence of distal renal tubular acidosis (dRTA) was 17% for both treatment groups. 70% of patients treated with sirolimus and 94% using tacrolimus presented with urine concentrating defect (p = 0.04). Conclusion: Distal RTA and urine concentrating defect were highly prevalent after kidney transplantation both in the sirolimus and tacrolimus treated patients. Acidification test was essential for the appropriate diagnosis of dRTA while dipstick urine specific gravity test was able to detect urine concentrating defect in this population.
Introduction
Received November 27, 2014; accepted in revised form March 2, 2015 Correspondence to Pedro Barcelos Banhara Rua Pereira da Silva, 80/303, Laranjeiras, 22221-140, Rio de Janeiro-RJ, Brazil pedrobanhara@ gmail.com
Calcineurin inhibitors (CNI) have significantly improved renal allograft survival, however the nephrotoxicity induced by these drugs remains the most important alloantigen-independent cause of chronic allograft dysfunction [1]. CNI induced nephrotoxicity may result in renal tubular functional alterations and metabolic disturbances like hyperkalemia, hypomagnesemia and magnesium wasting, distal renal tubular acidosis (dRTA), and hyperuricemia [2]. CNI induced dRTA may be the consequence of a reduced expression of H+-ATPase in the luminal membrane [3].
Renal tubular acidosis (RTA) results from abnormalities in the excretion of an acid load by the kidney leading to disruption of the acid-base balance [4]. There are three main categories of RTA: proximal RTA or type 2, related to reduced reabsorption of HCO3– in the proximal convoluted tubule; dRTA or type 1, caused by an impairment of H+ secretion by the distal tubule resulting in inadequate urine acidification, and type 4, resulting from hypoaldosteronism or tubular resistance to aldosterone [5]. Tacrolimus administration was shown to reduce the rate of H+ secretion by the distal tubule [6], while sirolimus may reduce tubular protein reabsorption [7] and cause hypokalemia by an increased tubular secretion of potassium [8]. Metabolic acidosis after renal transplantation may interfere with mineral metabolism and protein synthesis. Sodium bicarbonate supplementation was shown to slow the rate of decline of renal function and resulted in improvement of nutritional status in patients with chronic kidney disease presenting with low levels of serum bicarbonate [9]. There is evidence that the immunosuppressive agents may induce tubular dysfunction, leading to electrolyte and acid-base disorders that might, in turn, be deleterious to graft survival. The aim of this study was to test for tubular dysfunction in chronic kidney transplant patients on either a sirolimus or tacrolimus based immunosuppressant regimen.
Patients and methods Study population 184 kidney transplant patients treated at the outpatient clinic of the Division of Ne-
332
Banhara, Gonçalves, Rocha, et al.
Table 1. Comparison between the sirolimus and tacrolimus groups. N Age, year Male, n (%) Diabetes, n (%) Urinary concentrating defect, n (%) Post-transplant time, months Previous rejection episodes, n (%) GFR (CKD-EPI), mL/min/1.73 m2 Urine osmolality, mOsm/kgH2O Serum osmolality, mOsm/kgH2O Urine specific gravity Dipstick urine pH Serum bicarbonate, mEq/L Serum anion gap, mEq/L FE-HCO3, (%) Urine anion gap, mEq/L Urinary ACR, mg/mg β2-microglobulin, mg/L 24-hour urine calcium, mg/24 h Na, mEq/L Ca, mg/dL K, mEq/L P, mg/dL Cl, mEq/L Mg, mEq/L Serum albumin, g/dL Serum uric acid, mg/dL 24 h urine protein, mg FE Na, % FE K, % FE Ca, % PRR, % FE Mg, % FE uric acid, %
Sirolimus group 30 48.3 ± 11.8 14 (47) 6 (20) 21 (70) 60 (48 – 72) 7 (23) 69.9 ± 10.4 564 ± 132 287 (284 – 291) 1.015 (1.015 – 1.025) 5.0 (5.0 – 6.0) 20.1 ± 2.1 16.5 (13.3 – 18.1) 0.05 ± 0.06 +25.6 ± 17.9 0.04 (0.01 – 0.14) 0.20 (0.20 – 0.60) 79.0 (64.0 – 113.2) 139 (137 – 142) 9.0 ± 0.6 4.1 (3.9 – 4.4) 3.3 ± 0.6 104 ± 3.7 1.8 ± 0.3 3.8 (3.6 – 4.1) 4.6 (3.8 – 5.3) 179 (109 – 736) 0.9 ± 0.4 8.0 ± 2.7 0.8 ± 0.5 83 ± 7.0 4.1 ± 2.3 9.2 ± 3.4
Tacrolimus group 30 46.7 ± 8.8 13 (43) 6 (20) 28 (94) 103 (32 – 121) 10 (33) 63.6 ± 14.2 473 ± 139 289 (284 – 293) 1.010 (1.010 – 1.015) 5.0 (5.0 – 6.0) 19.8 ± 3.0 17.2 (15.4 – 21.4) 0.07 ± 0.19 +26.7 ± 14.6 0.03 (0.01 – 0.06) 0.40 (0,20 – 1.6) 140.5 (59.5 – 262.5) 140 (139 – 142) 9.3 ± 0.9 4.4 (4.2 – 4.8) 3.5 ± 0.6 102 ± 3.7 1.6 ± 0.2 4.2 (3.9 – 4.3) 6.2 (4.9 – 7.3) 165 (113 – 213) 1.1 ± 0.7 9.6 ± 4.6 1.2 ± 0.8 75 ± 17.5 6.7 ± 3.4 8.4 ± 4.1
p N/A 0.55 1.00 0.75 0.04 0.02 0.57 0.05 0.013 0.39 0.007 0.71 0.73 0.09 0.58 0.84 0.67 0.20 0.35 0.41 0.22 0.004 0.30 0.13 0.02 0.006 < 0.001 0.25 0.17 0.23 0.09 0.09 0.01 0.52
Mean ± SD or median [interquartile range], proportions where appropriate. GFR = glomerular filtration rate; CKD-EPI = chronic kidney disease epidemiology collaboration; FE = fractional excretion; ACR = albumin creatinine ratio; iPTH = intact parathyroid hormone; PNA = protein equivalent of total nitrogen appearance; PRR = phosphate reabsorption rate; N/A = non applicable.
phrology at Universidade Federal do Rio de Janeiro, Brazil, were evaluated from May 2011 to August 2012. 60 asymptomatic patients with CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) [10] estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73 m2 and proteinuria 10% defined proximal tubular acidosis [5]. Fractional excretion of electrolytes and uric acid were also performed. Distal tubular function was evaluated using urinary acidification test for dRTA and urine osmolality for assessment of concentrating ability. Urinary acidification test was performed after 12 hours of water restriction followed by acute oral administration of 0.1 mg fludrocortisone and 40 mg furosemide [11]. An arterial blood sample was collected for blood gas analysis and serum osmolality before drug administration. Urine samples were collected at 0, 1, 2, 3, and 4 hours. Urine samples were used for urinary fasting dipstick analysis (pH and specific gravity) (0 h), osmolality (0 h), gas analysis (0 – 4 h), spectrophotometry analysis of urinary ammonium (NH4+) (0 and 4 h), and neutralization reaction with sodium hydrox-
ide for titratable acidity (TA) measurements (0 and 4 h). dRTA was diagnosed with findings of sustained urinary pH > 5.5 associated with the failure of NH4+ and TA excretion to increase after 4h of the acidification test. Urinary osmolality
Tubular dysfunction in renal transplant patients using sirolimus or tacrolimus Original ©2015 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430 DOI 10.5414/CN108541 e-pub: May 6, 2015
Key words kidney concentrating ability – kidney transplantation – renal tubular acidosis – sirolimus – tacrolimus
Pedro B. Banhara, Renato T. Gonçalves, Pedro T. Rocha, Alvimar G. Delgado, Maurilo Leite Jr, and Carlos P. Gomes Division of Nephrology, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Abstract. Background: Tubular dysfunction is prevalent among kidney transplant patients using calcineurin inhibitors, but our knowledge of the tubular effects of mTOR inhibitors is more limited. Methods: 60 kidney transplant outpatients using either the calcineurin inhibitor tacrolimus or the mTOR inhibitor sirolimus were investigated for renal tubular dysfunction. Proximal tubule function was assessed by quantification of albumin and β2-microglobulin, tubular reabsorption of phosphate and fractional excretion of bicarbonate. Distal tubular function was evaluated by water deprivation test and by urinary acidification test using furosemide and fludrocortisone for pH, ammonium and titratable acidity measurements. Results: The prevalence of distal renal tubular acidosis (dRTA) was 17% for both treatment groups. 70% of patients treated with sirolimus and 94% using tacrolimus presented with urine concentrating defect (p = 0.04). Conclusion: Distal RTA and urine concentrating defect were highly prevalent after kidney transplantation both in the sirolimus and tacrolimus treated patients. Acidification test was essential for the appropriate diagnosis of dRTA while dipstick urine specific gravity test was able to detect urine concentrating defect in this population.
Introduction
Received November 27, 2014; accepted in revised form March 2, 2015 Correspondence to Pedro Barcelos Banhara Rua Pereira da Silva, 80/303, Laranjeiras, 22221-140, Rio de Janeiro-RJ, Brazil pedrobanhara@ gmail.com
Calcineurin inhibitors (CNI) have significantly improved renal allograft survival, however the nephrotoxicity induced by these drugs remains the most important alloantigen-independent cause of chronic allograft dysfunction [1]. CNI induced nephrotoxicity may result in renal tubular functional alterations and metabolic disturbances like hyperkalemia, hypomagnesemia and magnesium wasting, distal renal tubular acidosis (dRTA), and hyperuricemia [2]. CNI induced dRTA may be the consequence of a reduced expression of H+-ATPase in the luminal membrane [3].
Renal tubular acidosis (RTA) results from abnormalities in the excretion of an acid load by the kidney leading to disruption of the acid-base balance [4]. There are three main categories of RTA: proximal RTA or type 2, related to reduced reabsorption of HCO3– in the proximal convoluted tubule; dRTA or type 1, caused by an impairment of H+ secretion by the distal tubule resulting in inadequate urine acidification, and type 4, resulting from hypoaldosteronism or tubular resistance to aldosterone [5]. Tacrolimus administration was shown to reduce the rate of H+ secretion by the distal tubule [6], while sirolimus may reduce tubular protein reabsorption [7] and cause hypokalemia by an increased tubular secretion of potassium [8]. Metabolic acidosis after renal transplantation may interfere with mineral metabolism and protein synthesis. Sodium bicarbonate supplementation was shown to slow the rate of decline of renal function and resulted in improvement of nutritional status in patients with chronic kidney disease presenting with low levels of serum bicarbonate [9]. There is evidence that the immunosuppressive agents may induce tubular dysfunction, leading to electrolyte and acid-base disorders that might, in turn, be deleterious to graft survival. The aim of this study was to test for tubular dysfunction in chronic kidney transplant patients on either a sirolimus or tacrolimus based immunosuppressant regimen.
Patients and methods Study population 184 kidney transplant patients treated at the outpatient clinic of the Division of Ne-
332
Banhara, Gonçalves, Rocha, et al.
Table 1. Comparison between the sirolimus and tacrolimus groups. N Age, year Male, n (%) Diabetes, n (%) Urinary concentrating defect, n (%) Post-transplant time, months Previous rejection episodes, n (%) GFR (CKD-EPI), mL/min/1.73 m2 Urine osmolality, mOsm/kgH2O Serum osmolality, mOsm/kgH2O Urine specific gravity Dipstick urine pH Serum bicarbonate, mEq/L Serum anion gap, mEq/L FE-HCO3, (%) Urine anion gap, mEq/L Urinary ACR, mg/mg β2-microglobulin, mg/L 24-hour urine calcium, mg/24 h Na, mEq/L Ca, mg/dL K, mEq/L P, mg/dL Cl, mEq/L Mg, mEq/L Serum albumin, g/dL Serum uric acid, mg/dL 24 h urine protein, mg FE Na, % FE K, % FE Ca, % PRR, % FE Mg, % FE uric acid, %
Sirolimus group 30 48.3 ± 11.8 14 (47) 6 (20) 21 (70) 60 (48 – 72) 7 (23) 69.9 ± 10.4 564 ± 132 287 (284 – 291) 1.015 (1.015 – 1.025) 5.0 (5.0 – 6.0) 20.1 ± 2.1 16.5 (13.3 – 18.1) 0.05 ± 0.06 +25.6 ± 17.9 0.04 (0.01 – 0.14) 0.20 (0.20 – 0.60) 79.0 (64.0 – 113.2) 139 (137 – 142) 9.0 ± 0.6 4.1 (3.9 – 4.4) 3.3 ± 0.6 104 ± 3.7 1.8 ± 0.3 3.8 (3.6 – 4.1) 4.6 (3.8 – 5.3) 179 (109 – 736) 0.9 ± 0.4 8.0 ± 2.7 0.8 ± 0.5 83 ± 7.0 4.1 ± 2.3 9.2 ± 3.4
Tacrolimus group 30 46.7 ± 8.8 13 (43) 6 (20) 28 (94) 103 (32 – 121) 10 (33) 63.6 ± 14.2 473 ± 139 289 (284 – 293) 1.010 (1.010 – 1.015) 5.0 (5.0 – 6.0) 19.8 ± 3.0 17.2 (15.4 – 21.4) 0.07 ± 0.19 +26.7 ± 14.6 0.03 (0.01 – 0.06) 0.40 (0,20 – 1.6) 140.5 (59.5 – 262.5) 140 (139 – 142) 9.3 ± 0.9 4.4 (4.2 – 4.8) 3.5 ± 0.6 102 ± 3.7 1.6 ± 0.2 4.2 (3.9 – 4.3) 6.2 (4.9 – 7.3) 165 (113 – 213) 1.1 ± 0.7 9.6 ± 4.6 1.2 ± 0.8 75 ± 17.5 6.7 ± 3.4 8.4 ± 4.1
p N/A 0.55 1.00 0.75 0.04 0.02 0.57 0.05 0.013 0.39 0.007 0.71 0.73 0.09 0.58 0.84 0.67 0.20 0.35 0.41 0.22 0.004 0.30 0.13 0.02 0.006 < 0.001 0.25 0.17 0.23 0.09 0.09 0.01 0.52
Mean ± SD or median [interquartile range], proportions where appropriate. GFR = glomerular filtration rate; CKD-EPI = chronic kidney disease epidemiology collaboration; FE = fractional excretion; ACR = albumin creatinine ratio; iPTH = intact parathyroid hormone; PNA = protein equivalent of total nitrogen appearance; PRR = phosphate reabsorption rate; N/A = non applicable.
phrology at Universidade Federal do Rio de Janeiro, Brazil, were evaluated from May 2011 to August 2012. 60 asymptomatic patients with CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) [10] estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73 m2 and proteinuria 10% defined proximal tubular acidosis [5]. Fractional excretion of electrolytes and uric acid were also performed. Distal tubular function was evaluated using urinary acidification test for dRTA and urine osmolality for assessment of concentrating ability. Urinary acidification test was performed after 12 hours of water restriction followed by acute oral administration of 0.1 mg fludrocortisone and 40 mg furosemide [11]. An arterial blood sample was collected for blood gas analysis and serum osmolality before drug administration. Urine samples were collected at 0, 1, 2, 3, and 4 hours. Urine samples were used for urinary fasting dipstick analysis (pH and specific gravity) (0 h), osmolality (0 h), gas analysis (0 – 4 h), spectrophotometry analysis of urinary ammonium (NH4+) (0 and 4 h), and neutralization reaction with sodium hydrox-
ide for titratable acidity (TA) measurements (0 and 4 h). dRTA was diagnosed with findings of sustained urinary pH > 5.5 associated with the failure of NH4+ and TA excretion to increase after 4h of the acidification test. Urinary osmolality
