Cyclosporine Nephropathy Research Articles

Reversibility of chronic cyclosporine nephropathy in rats after withdrawal of cyclosporine.

Renal interstitial inflammation is an important factor in the pathogenesis of chronic cyclosporin A (CsA) nephropathy. We studied the expression of the chemoattractant osteopontin (OPN) and the relationship between OPN expression and tubulointerstitial injury in a rat model of chronic CsA nephropathy. Chronic CsA nephropathy was induced in Sprague-Dawley rats by administering CsA (15 mg/kg sc) for 5 wk and then withdrawing it for 5 or 10 wk. Renal function, histopathology (arteriolopathy, ED-1-positive cells, and tubulointerstitial fibrosis), renin-angiotensin system (RAS) activity, and OPN expression were observed during the follow-up period. Renal function deteriorated in CsA-treated rats, with the development of typical histopathology and activation of RAS. After CsA withdrawal, these parameters were significantly reversed (all P < 0.05). The upregulation of OPN mRNA and protein expression seen in CsA-treated rat kidneys was decreased 5 wk after CsA withdrawal and was further decreased after 10 wk. Of note, OPN mRNA expression correlated with the number of infiltrating macrophage (r = 0.651, P < 0.01) and tubulointerstitial fibrosis (r = 0.729, P < 0.01). These findings suggest that OPN expression and macrophage infiltration decrease after long-term CsA withdrawal in rats with established chronic CsA nephropathy, and this is closely associated with recovery from renal injury.

Effects of cyclosporine in osteopontin null mice

Osteopontin (OPN) is a macrophage adhesive and cell survival factor that is up-regulated in tubules in tubulointerstitial disease. We have previously reported that rats with cyclosporine (CsA) nephropathy have increased tubular osteopontin that correlates with the infiltration of macrophages and interstitial fibrosis. This study tested the hypothesis that the absence of OPN would ameliorate CsA nephropathy. OPN knockout (-/-) and wild type (+/+) mice were fed a low salt diet (Na+ 0.01%) for one week and then received daily CsA injections (30 mg/kg, SC) until sacrifice at two weeks. Afferent arteriolopathy, tubulointerstitial injury, macrophage infiltration, collagen III deposition, transforming growth factor-beta (TGF-beta) expression, and tubular and interstitial cell proliferation and apoptosis were evaluated. Wild type mice developed early features of CsA nephropathy, with arteriolar hyalinosis and cortical and tubulointerstitial fibrosis. Despite comparable CsA levels, OPN-/- mice had less arteriolopathy (15 vs. 24%, P < 0.05), a 20% reduction in cortical macrophage infiltration (P < 0.05), and 20% reduction in interstitial collagen deposition (P < 0.05). OPN-/- mice also showed less cortical interstitial cell proliferation but no differences in tubular cell proliferation or apoptosis. OPN+/+ mice also developed some neurotoxicity, consisting of ataxia, and this was associated with increased mortality at two weeks. OPN partially mediates arteriolopathy, early macrophage recruitment and fibrosis in murine CsA nephropathy. OPN also may be involved in CsA associated neurotoxicity.

Transforming growth factor-beta1 and tumor growth factor-beta-inducible gene-H3 in nonrenal transplant cyclosporine nephropathy.

Cyclosporine nephropathy (CyAN) is a major limiting factor in the otherwise successful widespread use of cyclosporine in solid organ transplant. Transforming growth factor-beta1 (TGF-beta1) has been implicated as an important fibrogenic cytokine in the development of this disease. TGF-beta-inducible gene-H3 (beta(ig)-H3) is a TGF-beta1- induced gene product, which acts as a marker for biologically active TGF-beta1. This study reports TGF-beta1 gene expression and beta(ig)-H3 tissue distribution in non-renal allograft CyAN. Renal tissue from nine patients who had developed CyAN after successful heart or heart-lung transplantation and from four kidneys removed for tumour were analyzed for TGF-beta1 gene expression beta(ig)-H3 protein with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. TGF-beta1 gene expression was increased in CyAN compared to nephrectomy (P<0.0001). Beta(ig)-H3 protein expression was identified in distal convoluted tubular epithelium and parietal glomerular epithelium in CyAN, and not in nephrectomy samples. Expression of TGF-beta1 mRNA was significantly higher in renal tissue from patients not receiving angiotensin converting enzyme inhibitor (ACEI) therapy for hypertension (P<0.05). These findings support the hypothesis that TGF-beta1 is an important cytokine in the development of CyAN, independent of its role in chronic rejection in renal allografts.

Long-term effects of chronic cyclosporine nephropathy on outcome of renal allografts

Long-term effects of chronic cyclosporine nephropathy on outcome of renal allografts

Subclinical Renal Injury Induced by Transient Cyclosporine Exposure is Associated with Salt-Sensitive Hypertension

Cyclosporine use is highly associated with the development of salt-sensitive hypertension. We hypothesized that subtle renal injury induced by cyclosporine could lead to salt sensitivity. Cyclosporine nephropathy was induced by treatment for 4 weeks with cyclosporine (15 mg/kg/day) on a low sodium (0.05%) diet, followed by stopping cyclosporine and placement on a high sodium (4%) diet for 4 additional weeks. Control groups included a group treated with cyclosporine (15 mg/kg/day) on a normal salt diet in which nephropathy does not develop, and a vehicle-treated group. A fourth group received half-dose of cyclosporine (8 mg/kg/day) on a low sodium diet, which results in mild nephropathy. Biopsies were obtained at the end of the cyclosporine administration (4 week) and at sacrifice (8 week), and blood pressure and renal function were measured. Rats treated with cyclosporine for 4 weeks on a low sodium diet developed classic features of tubulointerstitial disease and arteriolopathy; these changes were absent in the cyclosporine/normal salt group and in the vehicle group. At 4 weeks, all groups were switched to a high salt diet; only the rats with nephropathy developed hypertension. The degree of hypertension correlated closely with the degree of tubulointerstitial injury (r=0.85) and with the severity of the arteriolopathy (r=0.9) (p<0.0.1). Importantly, renal function (creatinine clearance) was normal in all groups at 8 weeks, documenting that the hypertension could not be attributed to cyclosporine-mediated alterations in glomerular filtration rate (GFR). One mechanism by which cyclosporine induces hypertension is the induction of subtle renal microvascular and tubulointerstitial disease. This mechanism is not dependent on GFR and may persist even after the cyclosporine is discontinued.

Immunohistochemical analysis of renin activity in chronic cyclosporine nephropathy in childhood nephrotic syndrome.

Although the pivotal role of activation of the intrarenal renin-angiotensin system (RAS) has been demonstrated in the rat model of chronic cyclosporine (CyA) nephropathy, it is still unclear whether intrarenal RAS activation is responsible for chronic CyA nephropathy in humans. Therefore, the distribution of renin in formalin-fixed, paraffin-embedded renal biopsy specimens obtained from 26 children who had idiopathic nephrotic syndrome (NS) and who were treated with long-term moderate-dose CyA was examined with the use of immunohistochemistry with rabbit polyclonal anti-human renin antibody. Nineteen patients had steroid-dependent NS, and 7 had steroid-resistant NS. However, CyA treatment led all of the latter patients into complete remission. All of the patients underwent renal biopsies at the start and the end of CyA treatment. In the pre-CyA specimens, immunoreactivity to renin was detected mainly in those parts of arterioles within the anatomically well-defined juxtaglomerular apparatus. In the post-CyA specimens, it was also detected in those parts of the vessels upstream from the juxtaglomerular apparatus. Moreover, the ratio of the number of renin-positive cells to the number of glomeruli (histologic renin index) increased significantly with long-term CyA treatment (from 1.26+/-0.24 to 4.30+/-0.40, P<0.0001). Eleven of the post-CyA specimens showed mild or moderate CyA-associated arteriolopathy (CAA), whereas 15 showed no CAA. The histologic renin index was significantly higher in specimens with CAA than in those without CAA (5.16+/-0.59 versus 3.67+/-0.48, P = 0.031). Seven CAA-positive patients underwent repeat biopsies 6 to 12 mo after discontinuing the CyA. Their specimens showed an improvement in the CAA and significantly lower histologic renin index compared with the post-CyA (from 4.18+/-0.69 to 2.10+/-0.25, P = 0.018). Eleven of the post-CyA specimens showed mild to moderate interstitial fibrosis, and 15 showed no fibrosis. There was no significant difference in immunoreactivity to renin between the specimens with interstitial fibrosis and those without. However, patients with interstitial fibrosis had significantly longer periods of heavy proteinuria during CyA therapy, because of either steroid-resistant NS or frequent relapses of NS (83+/-18 versus 35+/-12 d, P = 0.030). These findings indicate that long-term CyA treatment for idiopathic NS in children may stimulate renin production in arterioles. They also suggest that CyA-stimulated intrarenal RAS activation is responsible for the development of CAA and that CyA-induced interstitial fibrosis is potentiated by long-term heavy proteinuria and is at least partly independent of CyA-stimulated intrarenal RAS activation.

THE ROLE OF RENAL SYMPATHETIC NERVES IN EXPERIMENTAL CHRONIC CYCLOSPORINE NEPHROPATHY

Sympathetic nervous system hyperactivity has been postulated to play a major role in the intense intrarenal vasospasm and hypertension provoked by cyclosporine. It has been argued that the denervated renal allograft may be partially protected from the tubulointerstitial fibrosis associated with chronic cyclosporine administration compared with innervated kidneys in extrarenal transplantation. Utilizing a model of chronic cyclosporine nephropathy in which striped fibrosis develops in the uninephrectomized salt-depleted rat, the effect of renal denervation on renal structure and function was examined. Sprague-Dawley rats maintained on a low-salt diet underwent uninephrectomy and contralateral renal denervation or sham denervation, followed by cyclosporine 15 mg/kg daily by injection. After 21 days, glomerular filtration was markedly depressed and linear zones of tubular atrophy and interstitial fibrosis had developed compared with vehicle-treated control animals (P<0.001). However, there was no significant difference in either renal function or structure between denervated and sham-operated animals treated with cyclosporine. We conclude that renal sympathetic neural hyperactivity is not important in the development of chronic cyclosporine nephropathy.

Inhibition of the matrix metalloproteinase system in a rat model of chronic cyclosporine nephropathy

Chronic cyclosporine A (CsA)-induced nephropathy is histologically characterized by tubular lesions, the interstitial recruitment of inflammatory cells, arteriolopathy and focal interstitial fibrosis. Recent studies show that the intrarenal inhibition of matrix degradation and recruitment of monocytes/ macrophages into the kidney plays a critical role in the development of renal interstitial fibrosis. We examined the expression of components of the matrix metalloproteinase (MMP) system and plasminogen activator inhibitor type-1 (PAI-1) in kidneys from rats injected daily s.c. during three weeks with CsA (10, 15 or 20 mg CsA/kg body wt) or vehicle solution. In all CsA-treated rats, serum creatinine levels were significantly elevated compared to control levels. The extent of CsA-induced atrophy was not influenced by the dosage during a three-week CsA treatment. The administration of CsA did not significantly increase total cortical interstitial collagen deposition, whereas alpha-smooth muscle actin expression was significantly increased in all CsA-treated rats. Analysis of the different subpopulations of inflammatory cells recruited into the chronically injured kidney revealed a marked influx of macrophages into fibrotic cortical foci of CsA-treated rats. The number of cortical macrophages was highest in the group receiving the highest CsA dose. PAI-1 antigen, present in proximal tubular lysosomes in kidneys from all experimental groups, stained very intensely in atrophic tubules in CsA-treated rats. Both stromelysin and interstitial collagenase mRNA were expressed in the kidneys of control rats, but their message transcription remained unaltered after CsA treatment. In contrast, the expression of tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1) was significantly increased after CsA treatment. TIMP-1 mRNA was undetectable in renal sections from sodium-depleted vehicle-treated animals using the in situ hybridization (ISH) technique. ISH of selected renal sections of CsA-treated rats identified the cells responsible for the increased TIMP-1 message transcription after CsA administration, mainly as interstitial cells and also as visceral and parietal epithelial cells. These results suggest that the locally increased expression of TIMP-1 rather than a decrease of matrix metalloprotease expression, contributes to the development of CsA-induced focal interstitial fibrosis in the rat.

Morphological studies of baseline needle biopsies from living donor kidneys: light microscopic, immunohistochemical and ultrastructural findings.

Fifty-seven consecutive living donors (31 women and 26 men aged 20.7-72.3 years, mean 50.6 years) were subjected to needle biopsy during nephrectomy, immediately before removal of the kidney. By light microscopy, semiquantitative scoring (0-3) was performed for arteriosclerosis, arteriolar hyalinosis (hyalin arteriolosclerosis), glomerulosclerosis, interstitial mononuclear cell infiltration, and interstitial fibrosis/tubular atrophy. Whereas vascular changes were striking in many biopsies (arteriosclerosis grades 2-3: 28/54 cases, arteriolar hyalinosis grades 2-3: 15/55 cases), glomerular and tubulointerstitial changes were mostly low grade. The morphological changes tended to be more pronounced in middle-aged and older individuals, but, in particular, vascular changes were seen also in the younger age group. Immunofluorescence microscopy revealed glomerular granular staining for IgM in 52.7% of the cases, IgA in 9.1%), IgG in 1.8%, and C3 in 12.7%. The main ultrastructural finding was glomerulosclerosis; one case with diffuse glomerular IgA showed distinct dense deposits, and one case showed similar dense deposits without IgA deposition. Arteriolar wall deposition of C3 was found in 58.2% of the cases, and IgM in 10.9%. Especially C3 occurred both with arteriolar hyalinosis and in arterioles without light microscopic alterations. The observation of significant vascular changes in baseline biopsies is relevant especially in the differential diagnosis of chronic rejection and cyclosporine nephropathy. The immunohistochemical findings strongly indicate the occurrence of immunoglobulins and complement factor C3 in both glomeruli and arterioles without clinical or morphological signs of renal disease. The possible pathophysiological significance of such deposits remains, however, uncertain.

Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner

Cyclosporine is a potent immunosuppressant know to selectively suppress specific cytochrome P450 (P450) isoforms following chronic therapy in the rat. Cyclosporine undergoes significant hepatic metabolism in the rat, primarily due to P450 3A isoforms. Hence, alterations in hepatic metabolism of cyclosporine may lead to changes in drug pharmacokinetics or pharmacodynamics. The purpose of this study was to examine the temporal effect of chronic cyclosporine dosing on P450 protein expression and metabolic activity in a rat model of chronic cyclosporine nephropathy. Adult male rats were administered cyclosporine 15 mg/kg/day or vehicle 1 ml/kg/day by subcutaneous injection for up to 28 days. To examine whether or not metabolic activity recovered following drug removal, additional rats were administered cyclosporine for 28 days followed by vehicle for up to an additional 15 days. Hepatic P450 protein expression and microsomal metabolic activity were measured by Western blot analysis and in vitro steroid hydroxylation, respectively. Cyclosporine trough levels progressively increased over the 28 days period and were still measurable for up to 15 days after discontinuation. Immunoblot analysis indicated that chronic cyclosporine treatment suppressed P450 3A2 expression and in vitro steroid hydroxylation in a time-dependent manner. Fifteen days following discontinuation of cyclosporine dosing, hepatic metabolic activity and microsomal P450 3A2 levels returned to near pre-dosing levels. We conclude that the time-dependent P450 suppression by cyclosporine may at least partially explain the variability in cyclosporine pharmacokinetics. These studies support the hypothesis that hepatic isoforms other than P450 3A2 may be responsible for cyclosporine metabolism during chronic treatment in the rat.

Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis

Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis

Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis

Recently we developed a model of cyclosporine nephropathy in rats characterized by tubulointerstitial (TI) injury, macrophage infiltration, and progressive interstitial fibrosis [1, 2]. To determine if the TI injury accompanying cyclosporine A (CsA) nephropathy was associated with accelerated apoptosis and ischemia, we treated rats for five weeks with CsA with or without losartan (to block angiotensin II type 1 receptor), or hydralazine/furosemide (H/F) (protocol #1). In protocol #2, rats received CsA with or without L-NAME (to block nitric oxide) or L-arginine (to provide a precursor to nitric oxide formation). Cyclosporine A treated rats had increased apoptosis of tubular and interstitial cells documented by PAS, propidium iodide staining, TUNEL assay, and electron microscopy compared to vehicle treated controls. Macrophages containing apoptotic cells could be confirmed by TUNEL/ED-1 doublestaining and colocalized in areas of TI injury. Animals treated with CsA + losartan had a statistically significant decrease in apoptosis (TUNEL + cells/mm2) when compared to CsA treated animals (6.0 vs. 19.9, P < or = 0.0001). The decrease in apoptosis in the CsA + H/F group was not statistically significant. Animals treated with CsA + L-NAME had a statistically significant increase in apoptosis compared to the CsA treated animals (12.3 vs. 6.4, P = 0.001). L-arginine administration with CsA resulted in a decrease in tubulointerstitial apoptosis versus CsA treated animals, however, this did not reach statistical significance. The addition of L-arginine did result in a significant reduction in interstitial fibrosis (P < 0.0001). Regression analysis revealed a significant correlation between apoptosis and interstitial fibrosis in both protocols. (CsA vs. CsA + losartan r = 0.63, P < 0.0001; CsA vs. CsA + L-NAME r = 0.83, P < 0.0001). We conclude that CsA nephropathy is associated with a marked increase in apoptosis of tubular and interstitial cells. Cyclosporine A induced apoptosis is partially mediated by angiotensin II and nitric oxide inhibition, suggesting a role for renal ischemia in this process, and CsA induced apoptosis correlates with interstitial fibrosis.

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy.

Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.

Angiotensin II blockade decreases TGF-β1 and matrix proteins in cyclosporine nephropathy

Angiotensin II (Ang II) is implicated in fibrosis but the precise mechanism of this effect remains unclear. In a model of chronic cyclosporine (CsA) nephropathy, we previously showed that TGF-beta1 plays a role in CsA-induced tubulointerstitial fibrosis and arteriolopathy by stimulating extracellular matrix (ECM) protein synthesis and inhibiting ECM degradation through increasing the synthesis of plasminogen activator inhibitor (PAI)-1. We hypothesized that Ang II contributes to fibrosis by inducing TGF-beta1. Salt-depleted rats were given placebo, CsA alone, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide, CsA + losartan (AT1 receptor antagonist) or CsA + enalapril (Ang converting enzyme inhibitor) and were sacrificed at 7 and 28 days. All treated groups achieved similar blood pressures and glomerular filtration rates. The lesion of chronic CsA nephropathy was ameliorated by concomitant therapy with losartan or enalapril at 28 days, a phenomenon not observed in the other treatment groups. Similarly, Ang II blockade resulted in decreased expression of TGF-beta1 and PAI-1 by Northern and ELISA. Similarly, the expression of ECM proteins directly influenced by TGF-beta decreased with Ang II blockade. These results suggest that CsA-induced fibrosis in this model is independent of renal hemodynamics and is mediated, at least partly, through Ang II induction of TGF-beta1 expression.

Sodium depletion enhances fibrosis and the expression of TGF-β1 and matrix proteins in experimental chronic cyclosporine nephropathy

The major limitation to the clinical use of cyclosporine (CsA) is renal toxicity. In the past, the lack of an animal model of chronic CsA nephropathy has hampered the study of its pathogenesis. Rats given CsA and placed on a low sodium diet (LSD) develop a histology similar to human lesions of chronic CsA nephropathy, a phenomenon not observed in animals on a normal sodium diet (NSD). We have previously shown that transforming growth factor-β1 (TGF-β1) is involved in the CsA-induced renal fibrosis in rats on a LSD. We hypothesized that sodium depletion is critical to the increase in TGF-β1 expression, which, in turn, results in excessive matrix accumulation. Pair-fed rats were placed on a NSD or LSD, treated with CsA or vehicle, and killed at 7 or 28 days (N = 4 to 6 in each group). All rats achieved similar blood pressure control, and all CsA-treated rats achieved similar CsA blood levels. However, while CsA did not affect creatinine clearance in rats on a NSD, it lowered creatinine clearance in rats on a LSD ( P < 0.01). Cyclosporine-induced tubulointerstitial fibrosis and arteriolopathy was observed at 28 days only in the rats on a LSD ( P < 0.05). In addition, peripheral renin activity was increased only in the rats on a LSD ( P < 0.01), while it remained normal in the rats on a NSD. In addition, CsA-treated rats on a LSD developed a progressive increase in the mRNA expression of TGF-β1 and the matrix proteins biglycan and type I collagen at 7 and 28 days. Most of the changes were seen at 28 days ( P < 0.001 for TGF-β1, P < 0.01 for biglycan and type I collagen). On the other hand, CsA treatment in rats on a NSD did not affect the mRNA expression of TGF-β1 and matrix proteins. Most of the changes in the immunofluorescence deposition of the glycoproteins tenascin and fibronectin EDA+ were in the tubulointerstitium and vessels of the kidneys of rats on a LSD and were mostly significant at 28 days, in accordance with the characteristic histology of chronic CsA nephropathy. The mRNA expression of plasminogen activator inhibitor-1, a protease inhibitor involved in matrix degradation and stimulated by TGF-β1, was observed only in kidneys of rats on a LSD ( P < 0.01). Since sodium depletion elevates peripheral renin activity, our experiments suggest a role for the renin-angiotensin system in the expression of TGF-β1 and matrix proteins in CsA-induced renal fibrosis of rats on a LSD.

Heparin Decreases Blood Pressure and Response to Exogenous Endothelin but Does Not Protect Against Chronic Experimental Cyclosporine Nephropathy

Cyclosporine nephrotoxicity is caused by renal arteriolar vasoconstriction and tubulointerstitial fibrosis. Endothelin has been proposed as a major mediator of these phenomena. Heparin inhibits vascular smooth muscle cell proliferation and lowers blood pressure by regulating endogenous endothelin I production. In a model of chronic cyclosporine nephrotoxicity in the rat, animals were treated with cyclosporine alone, cyclosporine plus heparin, and heparin alone for 28 days. Independent experiments determined that these doses of heparin resulted in a marked decrease in responsivity to exogenous endothelin. Despite this, there were no beneficial effects on renal structure or function in this animal model of chronic cyclosporine nephrotoxicity. Thus, the role of endothelin in the pathogenesis of the chronic tubulointerstitial changes and arteriolopathy in this model is probably minor.

Cyclosporine nephropathy: clinical, histological, and functional aspects

Cyclosporine nephropathy: clinical, histological, and functional aspects

Chronic cyclosporine nephropathy: The Achilles' heel of immunosuppressive therapy

Chronic cyclosporine nephropathy: The Achilles' heel of immunosuppressive therapy

“Recurrence” of cyclosporine nephropathy in a heart transplant recipient

CYCLOSPORINE has led to major improvements in the outcome of solid organ transplantation. 1 However, renal dysfunction and end-stage renal disease (ESRD) have been reported in patients receiving cyclosporine. 1-3 We report a case of a heart transplant recipient who developed ESRD attributable to cyclosporine nephropathy that, subsequently, developed similar lesions after a kidney transplantation from a living-related donor.

Cytotoxics, cyclosporine and membranous nephropathy.

Membranous nephropathy remains the most common underlying cause of adult-onset nephrotic syndrome. Most patients with the idiopathic variant do well, with 10-year renal survival in a quite tight range of 70-90%. This indolence in the disease process and the spontaneous remission rate of 15-30% are the major factors that have prevented a uniform opinion from developing regarding therapy. The best long-term results come from the studies of an Italian group which used a regimen of chlorambucil and prednisone. Their most recent publication showed an impressive improvement in renal survival at 10 years from 62% in their untreated group to 90% in their treated group. The perceived risk: benefit ratio in the asymptomatic patient, however, has prevented the application of this approach to the average patient with idiopathic membranous nephropathy. The only randomized controlled study to use pulsed cyclophosphamide plus prednisone showed no benefit compared with the use of steroids alone. In contrast to the best cytotoxic trials, the application of cyclosporine treatment has been largely limited to patients at high risk of progression. Cyclosporine's efficacy in the short term is unquestioned, and a recent randomized controlled trial suggests an improved long-term preservation of renal function. Its costs, risks and long-term benefits require continuing assessment.