Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies

Fervenza, Fernando C.; Fitzpatrick, Peter M.; Mertz, Jim I.; Erickson, Stephen B.; Liggett, Scott; Popham, Sandy; Wochos, Daniel N.; Synhavsky, Arkady; Hippler, Steven; Larson, Timothy S.; Bagniewski, Stephanie M.; Velosa, Jorge A.

doi:10.1093/ndt/gfh079

Cited by 103 publications

(62 citation statements)

References 16 publications

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“…When lower levels of proteinuria are present we recommend discontinuation of SRL only if proteinuria increases during follow up. In our clinical experience and others, 11,12 SRL can worsen preexisting proteinuria. Thus, if upon discontinuation of SRL proteinuria does not normalize an evaluation for the causes of the proteinuria should be undertaken.…”

Section: Clinical Commentary Wwwjasnorgsupporting

confidence: 54%

Significance and Management of Proteinuria in Kidney Transplant Recipients

Amer

Cosio

2009

Journal of the American Society of Nephrology

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Section: Clinical Commentary Wwwjasnorgsupporting

confidence: 54%

Significance and Management of Proteinuria in Kidney Transplant Recipients

Amer

Cosio

2009

Journal of the American Society of Nephrology

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“…In human primary glomerular disease, mTOR inhibition has been tried in more advanced disease states. In parallel to chronic allograft nephropathy, introduction of mTOR-based treatment was associated with acceleration of proteinuria and decline in renal function in some patients, but was at least to some degree beneficial in others (1,6,11). With regard to the relatively early start of mTOR inhibition in this experimental study, the early preventive use of mTOR inhibitors in chronic primary human glomerulopathies has not been determined yet.…”

Section: Discussionmentioning

confidence: 91%

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

Krämer

Wang-Rosenke²,

Scholl³

et al. 2008

American Journal of Physiology-Renal Physiology

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-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. Am J Physiol Renal Physiol 294: F440-F449, 2008. First published December 19, 2007 doi:10.1152/ajprenal.00379.2007.-Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg ⅐ kg Ϫ1 ⅐ body wt Ϫ1 ) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. KruskalWallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (Ϫ38%), systolic blood pressure (Ϫ16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (Ϫ61 and Ϫ24%), transforming growth factor-␤1 overexpression (Ϫ41 and Ϫ47%), collagen I deposition (Ϫ53 and Ϫ65%), cell proliferation (Ϫ90 and Ϫ76%), and leukocyte number (macrophages Ϫ52 and Ϫ53%; lymphocytes Ϫ58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine Ϫ0.68 mg/dl, urea Ϫ66.7 mg/day, and creatinine clearance ϩ0.13 ml ⅐ min Ϫ1

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“…However, the association of tacrolimus and sirolimus increased delayed graft function rate by threefold in kidney transplant recipients (15) and caused acute graft failure in living donor kidney recipients (21). Furthermore, sirolimus can be nephrotoxic to the native kidney as reported in patients with chronic glomerulopathies (22). Sirolimus nephrotoxicity is due to direct tubular damage and, to a lesser degree, to glomerular damage.…”

Section: Diabetes Who Received Islet Transplantation Alone and The Edmentioning

confidence: 99%

Kidney Function After Islet Transplant Alone in Type 1 Diabetes

et al. 2007

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OBJECTIVE -Islet transplantation alone is an alternative for the replacement of pancreatic endocrine function in patients with type 1 diabetes. The aim of our study was to assess the impact of the Edmonton immunosuppressive protocol (tacrolimus-sirolimus association) on kidney function. RESEARCH DESIGN AND METHODS-Nineteen patients with type 1 diabetes and metabolic instability received islet transplantation alone and immunosuppressive therapy according to the Edmonton protocol. Serum creatinine (sCr), creatinine clearance (CrCl), and 24-h urinary protein excretion (UPE) were assessed at baseline and during a follow-up of 339 patientmonths.RESULTS -After islet transplantation we observed 1) sCr within the normal range in all but two patients in whom sCr increased immediately after islet transplantation, and despite withdrawal of immunosuppression, patients progressed to end-stage renal disease (ESRD); 2) CrCl remained within the normal range for those patients who had normal baseline values and decreased, progressing to ESRD in two patients with a decreased baseline CrCl; and 3) 24-h UPE worsened (Ͼ300 mg/24 h) in four patients. In the two patients who progressed to ESRD, the worsening of 24-h UPE occurred immediately after islet transplantation. In one patient 24-h UPE worsening occurred at 18 months, and, after withdrawal of immunosuppression, it returned to the normal range. In another patient 24-h UPE increased at 24 months and remained stable while immunosuppression was continued.CONCLUSIONS -In type 1 diabetic patients receiving islet transplantation alone, the association of tacrolimus and sirolimus should be used only in patients with normal kidney function. Alternative options for immunosuppressive treatment should be considered for patients with even a mild decrease of kidney function. Diabetes Care 30:1150 -155, 2007T he Diabetes Control and Complications Trial has shown that in patients with type 1 diabetes, intensive diabetes treatment reduces incidence and delays progression of long-term complications (1). The Epidemiology of Diabetes Intervention and Complications (EDIC) study, a follow-up of the original Diabetes Control and Complications Trial cohort, has shown a sustained effect of intensive diabetes treatment on the development and progression of nephropathy and macrovascular disease (2). Furthermore, the EDIC study has shown that patients with type 1 diabetes with some endogenous Cpeptide reserve have a lower risk of progression of retinopathy and neuropathy (2). However, the benefits of intensive diabetes treatment come with the price of severe hypoglycemia and increased body weight (1).Several studies have reported a high rate of insulin independence and normalization of blood glucose and A1C levels after either pancreas or islet transplantation (3-7). In patients with type 1 diabetes, pancreas or islet transplantation has improved kidney graft survival (8,9), whereas the positive impact of pancreas transplantation on the native kidney has been counterbalanced by the nephrotoxicity of immun...

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Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies

Abstract: Rapamycin can cause nephrotoxicity in some patients with chronic glomerulopathies. Whether the toxicity is solely related to rapamycin, due to the combination of proteinuria and rapamycin, or other unknown factor use is presently undetermined.

Cited by 103 publications

References 16 publications

Significance and Management of Proteinuria in Kidney Transplant Recipients

Significance and Management of Proteinuria in Kidney Transplant Recipients

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

Kidney Function After Islet Transplant Alone in Type 1 Diabetes

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