Nephrotoxicity of cyclosporin A. A lithium clearance and micropuncture study in rats

Dieperink, Hans; Leyssac, P. P.; Starklint, H; Kemp, E

doi:10.1111/j.1365-2362.1986.tb01310.x

Cited by 46 publications

(21 citation statements)

References 24 publications

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“…It has been proposed that an increase in proximal tubular reabsortion rate should be a mechanism in CsA-induced hypertension [18], but, as demonstrated in the present study, no elevation in APR occurs in CsA-treated patients. This is in accordance with previous studies performed in animals, RTx, non-transplanted patients, and healthy volunteers [2, 3, 4, 16, 17]. …”

Section: Discussionsupporting

confidence: 79%

“…These changes in renal function have been found to occur within a few hours after the CsA peak blood concentration [2, 3, 4]. Chronic treatment with higher CsA doses in transplanted and nontransplanted humans and in rats is also accompanied by increased FPR [16, 17, 19]. This increase in FPR seems to be secondary to the CsA-induced preglomerular vasoconstriction and subsequent hypoperfusion and decline in GFR.…”

Section: Discussionmentioning

confidence: 99%

“…The hyperuricaemia in CsA-treated patients has also been attributed to an effect of CsA on renal tubular function [12, 13, 14]. Using the lithium clearance method, some studies have tried to evaluate whether CsA affects proximal and distal tubular reabsorption rates of sodium and water [2, 3, 4, 15, 16, 17, 18, 19, 20, 21], but the results are conflicting. We have previously shown that a few hours after the CsA peak blood concentration, a transient decrease in renal clearance of lithium (C Li ) and an increase in fractional proximal tubular reabsorption (FPR) of sodium and water occurs in parallel with the decrease in GFR in both healthy volunteers and RTx chronically receiving CsA [2, 3, 4].…”

Section: Introductionmentioning

confidence: 99%

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Glomerular and Tubular Function in Renal Transplant Patients Treated with and without Ciclosporin A

Hansen¹,

Fogh‐Andersen²,

Leyssac

et al. 1998

Nephron

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The present study evaluated whether chronically administered low-dose (<5 mg/kg) ciclosporin A (CsA) affects renal haemodynamics and tubular function in renal transplant recipients (RTx) when studied at nadir CsA blood levels. The renal clearance of lithium was used as an index of proximal tubular outflow of sodium and water. Effective renal plasma flow, glomerular filtration rate, and renal clearance of lithium were studied in 67 stable non-diabetic RTx and 44 healthy controls. Forty-eight of the RTx were treated with CsA, prednisone, and azathioprine. Nineteen were treated exclusively with prednisone and azathioprine. In RTx with a good graft function (serum-creatinine <125 µmol/l), no specific CsA-induced renal haemodynamic and tubular dysfunctions were evident. In CsA-treated RTx with a slightly reduced renal function (serum creatinine 125–180 µmol/l) a decrease in fractional proximal tubular reabsorption was found. The renal clearances of urate and magnesium were comparable between RTx treated with or without CsA, and a significant correlation between glomerular filtration rate and renal clearance of urate was found. CsA-treated RTx had a significantly higher blood pressure, independent of glomerular filtration rate and segmental tubular function. In conclusion, at nadir CsA blood levels, no specific CsA-induced tubular dysfunction evaluated by the renal lithium clearance method could be demonstrated in RTx receiving chronically low-dose CsA. The hyperuricaemia commonly seen in RTx seems to be mainly caused by the reduced glomerular filtration rate.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glomerular and Tubular Function in Renal Transplant Patients Treated with and without Ciclosporin A

Hansen¹,

Fogh‐Andersen²,

Leyssac

et al. 1998

Nephron

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“…Acute renal dysfunction may occur within the first few weeks or months of initiating therapy and is usually reversible fol lowing ciclosporin dosage adjustment [10][11][12], However, the impact of protracted pathophysiologic factors could lead to irreversible kidney injury [9,13,20], Drug-induced tubular injury [36,37] and increased renal vascular resistance [38,39] have been suggested as possible primary pathogenetic mechanisms. Recently, there has been considerable interest in ciclosporin-induced renal hemodynamic changes as probable factors contributing to the observed alterations in renal function and morphology [13,[40][41][42][43]. Several mechanisms have been proposed to explain the decreased renal blood flow associated with ciclosporin administration including in creased sympathetic nervous activity [38,44], activation of the renin-angiotensin system [45][46][47], increased renal thromboxane A2 production [48][49][50], and altered produc tion of prostacyclin-stimulating factor [51].…”

Section: Discussionmentioning

confidence: 99%

Evolution of Ciclosporin Nephrotoxicity in Patients Treated for Autoimmune Uveitis

Austin¹,

Palestine²,

Sabnis³

et al. 1989

Am J Nephrol

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Among 73 patients treated with ciclosporin (CS) for autoimmune uveitis, a 50% elevation of serum creatinine was observed in 37% within 3 months of starting CS and in 25% after more than 6 months of relatively uncomplicated therapy. Sequential renal function and histologic evaluations were performed in 17 patients to further characterize the nephrotoxic effects of long-term CS therapy. Inulin clearance remained essentially unchanged in 12 patients despite CS dosage reductions in the majority. In 2 such patients, repeat renal biopsy specimens revealed evidence of progressive irreversible kidney injury even though renal function was stable. Inulin clearance decreased substantially in 3 patients; in 1 case a follow-up renal biopsy showed increased severity of chronic histologic change. For 2 patients, the inulin clearance more than doubled after CS dosage reduction; and in 1 of those cases, repeat renal biopsy showed no evidence of progressive renal scarring. Overall, the morphologic attributes of irreversible kidney injury (designated by a chronicity index including glomerular sclerosis, tubular atrophy and interstitial fibrosis) were increased in 3 of 6 follow-up renal biopsy specimens. Histologic alterations of renal arterioles, including hyaline change, were observed in all CS-treated patients. The hyaline change of arterioles was either extensive in the first renal biopsy specimen or became extensive in the second biopsy in the 3 cases manifesting an increased chronicity index on the follow-up renal biopsy. Thus, parenchymal injury can progress in some cases despite CS dosage reduction and stable renal function; renal arteriolar histologic change is a prominent finding in these patients. Patients that exhibit a substantial improvement in renal function after dosage reduction may experience a more favorable course.

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“…This pressor effect may be inhibited by sympathetic ct-blockade with pra zosin or by denervation [38]. CS can reduce renal blood flow by up to 50% when given acutely [39,40], and flow to heart, lungs and liver may also be reduced [41], A further effect of CS might be the retention of so dium. Certainly CS may be responsible for sodium reten tion in the maintenance phase of CS therapy [42], but suggestions that this in turn determines the hypertensive tendency remain speculative [43].…”

Section: Discussionmentioning

confidence: 99%

Hypertensive Exercise Responses in Ciclosporin-Treated Normotensive Renal Transplant Recipients

Scott¹,

Hay²,

Higenbottam³

et al. 1990

Nephron

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Although many patients taking ciclosporin (CS) for the long term develop hypertensive side effects, a proportion do not. We have studied the blood pressure response to graded upright bicycle exercise while continuously recording the metabolic rate in 18 normotensive renal transplant recipients whose mean age was 30.8 years (range 16–54). Nine were treated with CS alone and 9 with azathioprine and a steroid, prednisolone (AzS). Both groups performed a progressive exercise test, with work increasing by 25 W every 4 min from rest. All patients completed a workload of at least 75 W during the test. A group of 8 normal subjects whose mean age was 29 years (range 19–44) were exercised with the same protocol. The CS group had a significantly higher mean systemic blood pressure at both 50 and 75 W (124 and 132 mm Hg, respectively), compared with the AzS group (103 and 108 mm Hg; p < 0.01). The blood pressure response to exercise in the AzS group was similar to that observed in the normal group. This was despite a higher metabolic rate at each stage of work in the AzS group as compared with the CS or normal groups. Despite being normotensive at rest, renal transplant patients who are treated with CS have evidence of a vasopressor effect, with systemic vascular resistance inappropriately high for exercise, implying reduced compliance of the vascular bed.

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Nephrotoxicity of cyclosporin A. A lithium clearance and micropuncture study in rats

Cited by 46 publications

References 24 publications

Glomerular and Tubular Function in Renal Transplant Patients Treated with and without Ciclosporin A

Glomerular and Tubular Function in Renal Transplant Patients Treated with and without Ciclosporin A

Evolution of Ciclosporin Nephrotoxicity in Patients Treated for Autoimmune Uveitis

Hypertensive Exercise Responses in Ciclosporin-Treated Normotensive Renal Transplant Recipients

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