Reversibility of Cyclosporin Nephrotoxicity After Three Months' Treatment

Chapman, Jeremy R.; Harding, Nigel G. L.; Griffiths, David; Morris, Peter J.

doi:10.1016/s0140-6736(85)91902-6

Cited by 115 publications

(33 citation statements)

References 18 publications

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“…CsA has numerous side effects, of which nephrotoxicity [2,3] and hyperuricemia [4 ]are the most important. As many as 50% of patients taking CsA become hyperuricemic [5,6,7] and approximately 10% develop gout [8].…”

Section: Introductionmentioning

confidence: 99%

Use of Uric Acid-Lowering Agents Limits Experimental Cyclosporine Nephropathy

Mazali

Johnson²,

Mazzali³

2011

Nephron Exp Nephrol

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Background: Hyperuricemia frequently complicates cyclosporine (CsA) therapy. Previous studies have shown that hyperuricemia exacerbates interstitial and vascular lesions in the cyclosporine model. We tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity. Methods: CsA nephropathy was induced by administering CsA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CsA group). The effect of preventing hyperuricemia was determined by concomitant treatment with a xanthine oxidase inhibitor, allopurinol (CsAALP), or with a uricosuric, benzbromarone (CsABENZ), in drinking water. Control groups included vehicle-treated rats. Results: CsA-treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with allopurinol or benzbromarone limited renal disease, with reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis, in association with restoration of VEGF expression. Both drugs provided comparable protection. Conclusions: An increase in uric acid exacerbates CsA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. The similar protection observed with both drugs suggests that the effect is associated more with lowering uric acid levels than the antioxidant effect of allopurinol.

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Section: Introductionmentioning

confidence: 99%

Use of Uric Acid-Lowering Agents Limits Experimental Cyclosporine Nephropathy

Mazali

Johnson²,

Mazzali³

2011

Nephron Exp Nephrol

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“…The use of uricosurics in these patients could be questioned because (a) reduced GFR [5,6] and (b) impaired tubular handling of uric acid due to CsAinduced proximal tubular dysfunction [7][8][9][10][11] could potentially impair their effect. The present data, however, demonstrate an excellent efficacy of benzbromarone in lowering plasma uric acid within 1 week in all patients with a creatinine clearance > 25 ml/min.…”

Section: Discussionmentioning

confidence: 99%

Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

Zürcher¹,

Bock²,

Thiel³

1994

Nephrology Dialysis Transplantation

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Abstract.Patients on cyclosporin A (CsA) often develop hyperuricaemia and gout. In transplant patients the use of uricosuric drugs for treating hyperuricaemia may be preferable to allopurinol because of the known interaction of the latter with azathioprine. We therefore prospectively studied the uricosuric efficacy of 100 mg benzbromarone (Bbr;Desuric®) daily in 25 CsA-treated renal transplant patients with stable graft function and hyperuricaemia (> 359 umol/1 for females, >491 umol/1 for males).Benzbromarone decreased plasma uric acid from 579± 18 umol/1 to 313±24 umol/1 (mean + SEM; P< 0.001) and thereby normalized plasma uric acid in 21 of 25 patients. The remaining four patients had creatinine clearances between 21 and 25 ml/min, the lowest of the entire study group. Mean fractional clearance of uric acid increased from 5.4 ±0.4% to 17.2 ±1.0% (i><0.001). The relative decrease of plasma uric acid closely correlated with baseline creatinine clearance (r = 0.67; P<0.001). CsA trough values were not influenced. None of the patients experienced any significant side-effects. As an unexpected find-ing, urinary uric acid excretion increased from 2082+ 175 umol/24 h to 3233 ±232 umol/24 h after 4 weeks' treatment with benzbromarone.In conclusion, benzbromarone normalized plasma uric acid in all CsA-treated renal transplant recipients with a creatinine clearance > 25 ml/min. Due to its excellent efficacy and lack of significant side-effects, benzbromarone appears to be preferable to allopurinol in CsA-treated renal transplant recipients with a creatinine clearance over 25 ml/min.

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“…CsA alone in clinical studies at a dose of 10 mg/kg/day provided insufficient immunosuppression; thus a midpoint dose of 17.5 mg/kg/day was used in subsequent trials, revealing both immunosuppressive efficacy and acute nephrotoxicity when CsA was withdrawn abruptly at 3 months and replaced by the then conventional therapy of azathioprine and steroids (3). An improvement in renal function was seen in this study, with the serum creatinine dropping by around 50-60 umol/L within a week of conversion in most patients.…”

Section: Acute Cni Nephroxicitymentioning

confidence: 99%

“…The electron photomicrograph of the ischemic glomerulus became a useful emblem for illustration of CsA nephrotoxicity. That this was not the whole answer using therapeutic blood levels was illustrated by the clinical recognition of the tubular damage seen on histology (8) and the elevation of uric acid blood levels (3,9). The question raised in the 1980s was whether or not the reversibility of renal impairment seen at 3 months would become irreversible with time.…”

Section: Chapmanmentioning

confidence: 99%

Chronic Calcineurin Inhibitor Nephrotoxicity—Lest We Forget

Chapman

2011

American Journal of Transplantation

140

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Calcineurin inhibitor (CNI) nephrotoxicity was recognized in Cambridge in the late 1970s. The vasoconstrictor impact of cyclosporine (CsA) and to a lesser extent tacrolimus, in both acute and chronic settings, results from a decrease in vasodilators and increase in vasconconstrictors while direct tubular toxicity results from blockade of mitochondrial permeability transition pores and inhibition of prolyl isomerase. A biopsy of native kidneys of recipients of CNIs reveals nephrotoxicity as the most common pathological diagnosis with chronic CNI toxicity and hypertension the primary problems. A long-term study of randomized clinical trials with up to 20 years of follow-up shows inferiority of both renal function and graft survival for continuous CsA compared to either CsA withdrawal or continuous azathioprine and prednisolone. Pathological hallmarks of chronic CNI nephrotoxicity include stripped interstitial fibrosis, arteriolar hyalinosis and glomerular sclerosis, but with the exception of nodular arteriolar hyalinosis the findings are non specific. The model for chronic renal allograft loss must be multifactorial with both immune and nonimmune factors operating dependent upon an individual's risk factors for cell and/or antibody-mediated rejection, CNI nephrotoxicity and recurrent disease. Better outcomes will require early diagnosis and individualization of therapy dependent upon the dominant mechanisms impacting each patient. The revisionist view put forward by some senior, experienced and thoughtful individuals, challenges the concept of chronic CNI nephrotoxicity as an important clinical entity. By implication, the view that appears to be promoted is as follows: we need not fear-prolonged exposure to CNIs, and in seeking better long-term solutions for transplant recipients, we have forgotten alloimmunity. It is thus apparent that we must revisit the data and again question the basis for chronic CNI nephrotoxicity in current clinical practice. This contribution to the debate will focus on the evidence that CNIs are nephrotoxic and that their impact needs to be limited if we are to improve long-term outcomes after transplantation, leaving others to promote the contrary perspective and perhaps also to reflect on the largely unproven impact of the steroid avoidance and other minimization strategies so prevalent today.

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Reversibility of Cyclosporin Nephrotoxicity After Three Months' Treatment

Cited by 115 publications

References 18 publications

Use of Uric Acid-Lowering Agents Limits Experimental Cyclosporine Nephropathy

Use of Uric Acid-Lowering Agents Limits Experimental Cyclosporine Nephropathy

Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

Chronic Calcineurin Inhibitor Nephrotoxicity—Lest We Forget

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