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Background The use of cyclosporin A (CsA) is hampered by the development of nephrotoxicity including hypertension, which is partially dependent on renal sodium retention. To address this issue, we have investigated in vivo sodium reabsorption in different nephron segments of CsA-treated rats through micropuncture study coupled to expression analyses of sodium transporters. To translate the findings in rats to human, kidney-transplanted patients having CsA treatment were enrolled in the study. Methods Adult male Sprague–Dawley rats were treated with CsA (15 mg/kg/day) for 21 days, followed by micropuncture study and expression analyses of sodium transporters. CsA-treated kidney-transplanted patients with resistant hypertension were challenged with 50 mg furosemide. Results CsA-treated rats developed hypertension associated with reduced glomerular filtration rate. In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption in the proximal tubule but enhanced sodium reabsorption in the thick ascending limb of Henle's loop (TAL). Expression analyses of sodium transporters at the same nephron segments further revealed a reduction in Na+-H+ exchanger isoform 3 (NHE3) in the renal cortex, while TAL-specific, furosemide-sensitive Na+-K+-2Cl− cotransporter (NKCC2) and NHE3 were significantly upregulated in the inner stripe of outer medulla. CsA-treated patients had a larger excretion of urinary NKCC2 protein at basal condition, and higher diuretic response to furosemide, showing increased FeNa+, FeCl− and FeCa2+ compared with both healthy controls and FK506-treated transplanted patients. Conclusion Altogether, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ~50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted. [ABSTRACT FROM AUTHOR]

Background Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology. Methods Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT–PCR) were assessed. Results Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells. Conclusions Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling. [ABSTRACT FROM AUTHOR]

Podocytes play a key role in maintaining the blood–urine barrier for high-molecular-weight proteins. They are considered to be terminally differentiated, and podocyte loss cannot be compensated by regenerative proliferation. Various diseases leading to podocyte damage and loss result in proteinuria and cause nephrotic syndrome. Therefore, direct therapeutical strategies to protect podocytes in disease situations are a logical concept to prevent disease or to delay disease progression. Acquired podocytopathies like idiopathic focal segmental glomerulosclerosis and minimal change disease are historically considered as immunological diseases. Therefore, immunosuppressive agents such as steroids and calcineurin inhibitors are the commonly used treatment strategies. However, the causative disease mechanisms behind these treatment strategies remain elusive. Recent evidence shows that immunosuppressive agents, in addition to the effect on the immune system, directly influence the unique structure and function of podocytes. In this context, the actin cytoskeleton of the podocyte and cytokines such as vascular endothelial growth factor play a pivotal role. In this review, we summarize the direct effects on podocytes obtained in vivo and in vitro after treatment with calcineurin inhibitors, mTOR inhibitors and glucocorticoids. These direct effects could play a key role in the treatment concepts of podocytopathies with an important impact on the long-term renal function in patients with pharmacological immunosuppression. [ABSTRACT FROM AUTHOR]

Background. Prednisone is a major factor of bone loss after kidney transplantation. The role of hyperparathyroidism and immunosuppressors is less clear. [ABSTRACT FROM PUBLISHER]

Background. Among renal allograft recipients, there is a considerable variability in cyclosporin A (CsA) trough levels. Some of the CsA metabolites are pharmacologically active. The variability of polyclonal CsA trough levels may contribute to the fact that long‐term renal allograft survival is still not satisfactory. In a retrospective, single‐centre study, we investigated the influence of the variability of polyclonal CsA trough levels on long‐term renal allograft function. [ABSTRACT FROM PUBLISHER]

Background. The pathogenesis of chronic cyclosporin A (CsA) nephrotoxicity is largely unknown. In this study we examined whether CsA produces cell death through necrosis or apoptosis of either cultured human proximal tubular epithelial cells (PTEC) or the porcine tubular cell line LLC‐PK1. [ABSTRACT FROM PUBLISHER]

Background. Cardiovascular disease (CVD) is a major cause of death in renal transplant recipients (RTR). Suppression of fibrinolysis plays a role in the progression of atherosclerosis. Accelerated progression of atherosclerosis and fibrinolytic system suppression has been observed in RTR. Despite many years of intensive research, the reason for impaired fibrinolysis in this patient population is not fully understood. Thrombin‐activatable fibrinolysis inhibitor (TAFI) is a recently discovered glycoprotein combining coagulation and fibrinolysis. This study was conducted to evaluate concentrations of TAFI, markers of thrombin generation, endothelial injury, and some standard laboratory parameters in RTR receiving triple immunosuppressive drug regimen. [ABSTRACT FROM PUBLISHER]

Background. Glucose intolerance is an untoward side effect of some immunosuppressive and anti‐hypertensive drugs. The primary aim of the present prospective observational study was to test the hypothesis that tapering off prednisolone and cyclosporin (CsA) the first year after transplantation may have beneficial effects on glucose tolerance in renal transplant recipients. [ABSTRACT FROM PUBLISHER]

Background. A single oral dose of cyclosporin‐A (CsA) transiently reduces renal plasma flow (RPF) and glomerular filtration rate (GFR) in transplant patients and, in some patients, chronic administration of CsA leads to renal impairment and fibrosis. Based on experimental studies, several mediators including free radicals have been proposed to account for CsA‐nephrotoxicity. We have previously reported that administration of the antioxidant vitamin E in a rat model of chronic CsA‐nephrotoxicity reduces renal fibrosis and maintains renal function. [ABSTRACT FROM PUBLISHER]

Background. The oral formulation of cyclosporin A (CsA)—Sandimmun—has a highly variable absorption. The development of a CsA microemulsion—Sandimmun Neoral—resulted in increased bioavailability, and decreased variability of absorption. The first oral formulation (Sandimmun) interacted with numerous other drugs and grapefruit juice. Several of these interactions might be explained by decreased pre‐systemic metabolism by a cytochrome‐enzyme (e.g. CYP3A4) located in the enteral mucosa, and/or via the P‐glycoprotein‐mediated decreased transport of CsA back from enterocytes into the gut lumen. The purpose of this pharmacokinetic study was to investigate the interaction between Sandimmun Neoral and grapefruit juice. [ABSTRACT FROM PUBLISHER]

Background. Hyperlipidaemia is an important risk factor for cardiovascular disease in renal transplant recipients. The aim of this study was to test the efficacy and possible drug–drug interactions of the new HMG‐CoA reductase inhibitors (statins) atorvastatin and cerivastatin in cyclosporin A (CsA)‐treated renal transplant patients. [ABSTRACT FROM PUBLISHER]

Background. Both mycophenolate mofetil (MMF) and azathioprine (AZA) are immunosuppressive drugs that inhibit purine synthesis. In theory, MMF selectively inhibits lymphocyte proliferation, while AZA has well-known effects on red blood cells and thrombocytes as well. In renal transplant recipients we replaced CsA therapy by MMF in an attempt to reduce the immunosuppressive load 1 year after kidney transplantation. During this study we observed the effect of MMF on haematological parameters such as haemoglobin (Hb), leukocytes, and thrombocytes. [ABSTRACT FROM PUBLISHER]

Background.Cardiovascular disease is now the major cause of death in renal transplant patients. This study aimed to assess the prevalence of cardiovascular disease in stable renal transplant patients as compared with the general background population, and to assess risk factors for cardiovascular disease in this patient group. [ABSTRACT FROM PUBLISHER]

Background.Immunosuppressive treatment with cyclosporin A (CsA) improves the survival of renal allografts, but is associated with renal vasoconstriction and hypertension. Previous reports suggest that the calcium-channel blockers nifedipine and amlodipine may improve graft function in CsA-treated patients. We have compared the effects of amlodipine (5-10 mg once daily) and nifedipine retard (10-40 mg twice daily) on renal function and blood pressure in renal transplant recipients treated with CsA. [ABSTRACT FROM PUBLISHER]

Despite intensive investigation, a pathophysiological role for the endogenous vasoconstrictor peptide endothelin (ET) remains elusive. The kidney is particularly sensitive to the effects of ET, which are mimicked by the administration of cyclosporin A (CsA), and animal models suggest a role for ET in the vasoconstricive effects of CsA. Using a recently validated novel fluorescent quantitative RT-PCR assay to enable the direct study of human renal biopsies, we have quantified mRNA for the two known ET receptor subtypes ETA and ETB in cortical tissue from three groups of patients: renal transplant recipients on CsA (n=7), those with native renal disease (n=5) and normal controls (n=7). Median mRNA levels (amol/μg total RNA) were 0.024, 0.17 and 0.2 respectively for ETA and 0.57, 0.64 and 0.96 for ETB. These values indicate significant downregulation of ETA (P=0.003) but not ETB (P=0.104) mRNA in the transplant group. These results provide the first demonstration of a perturbation in the human ET system at tissue level in a pathophysiological situation, and suggest that the deleterious renal vasoconstrictor effects of CsA might be ameliorated by selective ETA receptor antagonism in the future. This study also illustrates the feasibility of ex vivo analysis of human diagnostic material at the molecular level. [ABSTRACT FROM PUBLISHER]

Background. This study investigated the relationships between cyclosporin A (CsA) blood levels and episodes of renal allograft rejection and nephrotoxicity following renal transplantation, with the aim of establishing whether CsA profiles provided more useful information than single CsA blood levels in respect of these relationships. Methods. One hundred and sixty-two profiles were performed over 16 months in 40 patients and analysed retrospectively. Blood samples were taken at 0, 2, 4, 6 and 8 h after the morning CsA dose. Rejection episodes were diagnosed by renal biopsy and CsA nephrotoxicity by a fall in serum creatinine 1 week after a cut in CsA dose. Results. The mean area under the curve (AUC) was lower for profiles performed at the time of rejection (3821 h.ng/ml) than that of a matched group of non-rejecting profiles (5479 h.ng/ml; P≤0.02). An AUC above 6400 h.ng/ml significantly discriminated rejection from non-rejection, whereas pre-dose and peak CsA concentrations did not have such discriminating cut-off values. A comparison of CsA-toxic and non-toxic profiles showed that there were no significant differences between mean CsA concentrations nor between the mean AUCs of these groups. Conclusion. We conclude that basing CsA dosing on CsA profiles could help to avoid some early episodes of rejection without increasing the risk of nephrotoxicity. [ABSTRACT FROM PUBLISHER]

Thrombotic microangiopathy (TMA) can be a late complication of bone marrow transplantation (BMT). A patient is described in whom the haemolytic uraemic syndrome developed 10 months after BMT and who died of E. coli sepsis while on maintenance haemodialysis. The literature is reviewed, regarding clinical presentation, incidence, pathogenesis and therapy. TMA can be observed, after an interval of 3–12 months, in about 6–26% of patients following BMT. Reported cases vary considerably in clinical severity, from mild presentations to severe TMA with high mortality rates despite intensive therapy. Important pathogenetic roles are ascribed to the conditioning total body irradiation and the use of cyclosporin A, but other factors may be involved as well. Next to supportive therapy, plasma exchange and the use of ACE inhibitors may be of value in treating BMT-associated TMA. [ABSTRACT FROM PUBLISHER]

Background. The synthetic prostacyclin analogues have been proposed to protect against cyclosporin A (CsA) nephrotoxicity. The present study investigated the effect of infusion of the prostacyclin analogue iloprost on the acute CsA-induced renal hypoperfusion and hypofiltration in stable renal-transplant recipients. Methods. The study included 10 stable renal-transplant recipients with good graft function (s-creatinine 90–170 umol/1). Renal function and the acute renal haemodynamic and tubular response to an oral CsA-dose (Sandimmun Neoral, 3 mg.kg−1) were investigated with an infusion of iloprost (1 ng.kg−1.min−1) or placebo on 2 separate days. After an overnight fast, seven 30-min renal clearance periods were performed, two before infusion, three during infusion, and two recovery periods. An additional control clearance study without CsA intake or iloprost/placebo infusion was done in eight of the patients. Results. CsA ingestion decreased ERPF and GFR significantly with a maximum decline at the end of the clearance study. Iloprost infusion abolished the CsAinduced decrease in ERPF, but had no effect on the CsA-induced decrease in GFR, leading to a significant decline in FF. Renal clearance of lithium (CLi), used as an index of proximal tubular outflow, decreased in parallel with GFR after CsA intake, with no additional effects of iloprost. Iloprost infusion decreased blood pressure and increased heart rate. Conclusion. Infusion of iloprost causes systemic and renal vasodilatation, but has no effect on the CsA-induced decrease in GFR and CLi in stable renal transplant recipients. [ABSTRACT FROM PUBLISHER]

Cyclosporin A (CsA) can reduce proteinuria in various forms of human and experimental glomerulonephritis. This antiproteinuric effect of CsA may be the consequence of diminution of immunological damage, a drug-induced decrease of GFR, or changes in permselectivity of the glomerular basement membrane (GBM). We studied the antiproteinuric effect of CsA in the heterologous phase of a passively induced anti-GBM nephritis in the mouse. This passive model characterized by acute exudative glomerular lesions and a dose-dependent albuminuria. Rabbit anti-mouse GBM antibodies were administered intravenously in C57B110 mice at day 4, after 3 days of pretreatment with either CsA (75 mg/kg body weight) (=15) or olive oil (OO, controls, =15) orally. CsA did not influence the severity of the histological lesions. Albuminuria was substantially reduced by CsA (CsA 1.6±1.8; OO 5.6±3.2 mg/18 h; <0.002). There was considerable concomitant reduction of the GFR by CsA, as measured with a Cr-EDTA single-shot plasma clearance technique before (day —1) and during treatment (day 4): GFR ratio day 4/day—1 for CsA, 0.4±0.1; for OO controls, 1.1±0.6; <0.01. This drug-induced decrease of GFR was prevented by simultaneous treatment with phenoxybenzamine (PB) twice daily 45 μg orally for 4 days (GFR ratio day 4/day—1 for PB and CsA, 0.9±0.4; controls (PB and OO), 1.0±0.4; =NS). Although the CsA-induced GFR reduction was prevented, CsA still reduced albuminuria significantly (PB and CsA, 2.2±1.8; controls (PB and OO), 5.6±1.8 mg/18 h; =0.003). Therefore the antiproteinuric effect of CsA in this model seems to result not only from a reduction of the GFR but also from reduction of the permselectivity of the GBM for proteins. [ABSTRACT FROM PUBLISHER]

The renal effects of low-dose cyclosporin A (CsA) treatment in severe psoriasis was investigated in 10 patients treated with a mean CsA dose of 3.23 (range 1.94–4.10) mg/kg/day for 12 months. The psoriasis area and severity index was reduced by 63–76%. Ambulatory GFR (iothalamate-I) ERPF (hippuran-), RVR and MAP were examined at 3-months intervals. A control renal biopsy was performed shortly before treatment start and a second biopsy was taken after 12 months of therapy. GFR was slightly but significantly reduced after 6 and 9 months; after 12 months the decrease was not significant (121.0±7.6 versus 115.2±7.8 ml/min/l.73M >0.10). After 12 months serum creatinine increased from 82±4 to 94±7 μmol/litre (<0.05 while an insignificant increase of ERPF was seen and FF decreased from 0.29±0.01 to 0.26±0.01 (<0.05). MAP remained unchanged. GFR and serum creatinine correlated significantly within each 3-month interval. A slight interstitial fibrosis was seen in the second biopsy in 4 of 10 patients receiving a mean CsA dose of 3.2–4.1 mg/kg/day. In three of these patients a concomitant rise in serum creatinine was seen. In conclusion, low-dose CsA was associated with reversible fall in GFR and potentially progressive structural changes not always accompanied by corresponding functional alterations. One should consider reducing the daily dose of CsA to 3.0 mg/kg body- weight or less in CsA therapy up to 1 year. [ABSTRACT FROM PUBLISHER]

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 μmol/l for females, >491 μmol/l for males). Benzbromarone decreased plasma uric acid from 579±18 μmol/l to 313±24 μmol/l (mean±SEM; <0.001) and thereby normalized plasma uric acid in 21 of 25 patients. The remaining four patients had creatininc 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% (<0.001). The relative decrease of plasma uric acid closely correlated with baseline creatinine clearance (=0.67; <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 μmol7sol;24 h to 3233 ±232 μmol/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 creati nine clearance over 25 ml/min. [ABSTRACT FROM PUBLISHER]

In a prospective, randomized and placebocontrolled study we evaluated the influence of treatment with the calcium-channel blocker diltiazem on the course and results of cadaveric kidney transplantation in 39 graft recipients. The grafts were reperfused with Euro-Collins solution containing diltiazem 20 mg/l. All recipients except those in chronic treatment with a calcium-channel blocker received preoperatively a bolus of diltiazem or placebo 0.3 mg/kg and in all an infusion of diltiazem or placebo 3 mg/kg/24 h was started preoperatively. After that, diltiazem or placebo was given orally for 3 months. Donors were not treated. Immunosuppressive therapy consisted of prednisone, azathioprine and CsA. There were no significant differences between the groups concerning donor or recipient characteristics, HLA-mismatching, and ischaemic time. Thrombosis leading to graft loss occurred in 3 recipients (diltiazem:2, placebo:1) and one graft was lost due to septicaemia (diltiazem). For the remaining 35 grafts no beneficial effect of treatment with diltiazem was found for the rate of delayed graft function, the rate of rejections, time to first rejection, whole blood CsA concentration, or graft function. The CsA dose needed to reach target whole blood concentration was significantly less in the diltiazem group. In conclusion, our results do not indicate any beneficial effects of treatment with diltiazem in cadaveric kidney transplantation, except a reduction of costs because of a significant reduction of the CsA dosage. [ABSTRACT FROM PUBLISHER]

Cyclosporin (CsA) induces autophagolysosomes in proximal tubules. A major lysosomal function is degradation of cell proteins. Cathepsin B and L are marker enzymes for the activity of lysosomal protein degradation. Therefore we measured cathepsin activities in microdissected proximal tubule segments and urine from rats treated with CsA, 30 mg/24 h by gavage for 42 days. Cathepsin activity was increased in proximal tubule by 117% and in 24-h urine by 37% compared to controls. Unchanged values of serum cathepsin activity and of proteinuria excluded increased glomerular filtration or decreased tubular absorption as major source of urine cathepsins. Therefore urine cathepsin excretion reflected tubular cathepsin activity. Urine cathepsin excretion was also measured in patients without renal disease treated with CsA for multiple sclerosis (MS). It was increased by 59% in patients with CsA serum values > 120 ng/ml compared to MS patients without CsA or with serum CsA < 120 ng/ml. Urine cathepsin excretion increased linearly with serum CsA (). The data suggest that cathepsin activity is increased in proximal tubules of CsA-treated patients. Hence CsA may stimulate protein degradation in proximal tubules of men and rats. [ABSTRACT FROM PUBLISHER]

We report here for the first time that human renal proximal tubular cells secrete endothelin, clear evidence of de-novo endothelin synthesis by these cells and the effect of cyclosponn A (C5A) on endothelin synthesis both in short-term (24 h) and medium-term (5-day) culture. Human renal cortical epithelial cells were cultured and shown to possess proximal tubular characteristics. These cells produced endothelin in culture in a time- dependent manner, as measured by radioimmunoassay (291.6± 51.4 pg/well/24 h). Furthermore, endothelin production by these cells was significantly decreased by up to 80% by cycloheximide (1051.8± 54.9 pg/mg cell protein/24 h versus 253.2± 12.6 pg/mg cell protein/24 h), showing that these cells actively synthes ize endothelin. In short-term culture (24 h), CsA signi ficantly inhibited endothelin synthesis at a medium concentration of 10,000 ≥g/I. No change in endothelin synthesis was seen at lower CsA concentrations. In contrast, over a 5-day period, a non-significant increase in endothelin synthesis was observed at CsA concentra tions of 2000 ≥g/I (152.5±20.4%); however, cell growth was significantly decreased at this concentration (71.33±6.39%). Using a newly developed two-site immunoradiometric assay specific for endothelin-l (ET-1), we demonstrate that ET-1 is the major endo thelin isoform produced by human renal proximal tubular cells. [ABSTRACT FROM PUBLISHER]

Functional and morphological cyclosporin A (CsA) nephropathy has been attributed to a CsA-induced constriction of the afferent glomerular arteriole. Calcium-channel blockade with nifedipine prevented the development of short-term functional nephrotoxicity in CsA-treated rats. This study investigated whether the calcium antagonist felodopine a structural analogue of nifedipine which reduces renal tubular fractional sodium reabsorption could prevent both short- and long-term functional and long-term morphological CsA nephropathy. In short-term experiments four groups of Spraque-Dawley rats (n = 39) were given CsA (either 0 or 12.5 mg/kg per day by daily gastric intubation for 2 weeks) and felodipine (0 or 30 mg/kg per day) in the diet. In long-term experiments rats (n = 39) were given CsA (12.5 mg/kg per day for 16 weeks) and felodipine (0 or 30 mg/kg per day in the diet). Renal function was investigated with clearance methods (inulin lithium and sodium) and kidney morphology was studied by light-microscopy. In short-term experiments CsA treatment reduced GFR (730 versus 1181 μl/min per g kidney weight (KW) P<0.05) and C< (130 versus 271 μl/min per gKW P<0.02). Felodipine decreased proximal fractional reabsorption (PFR) (67.5% versus 71.4% p<0.05) and increased C (15.9 versus 8.4 μl/min per gKW p<0.02) as compared to controls. In CsA-treated rats felodipine increased C (1260 versus 730 μl/min per gKW p<0.05) and C (319 versus 130 μlsol;min per gKW P<0.02). Also in long-term experiments felodipine given to CsAtreated rats increased C (1361 versus 956 μl/min per gKW p<0.05) and C (246 versus 146 μl/min per gKW p<0.05). Felodipine did not reduce the number of collapsed basophilic tubules or the amount of interstitial fibrosis in the kidneys from CsA-treated rats. In conclusion short- and long-term co-treatment with felodipine and CsA reduced functional CsA nephrotoxicity. Felodipine was unable to prevent CsA-induced morphological damage to the kidneys. [ABSTRACT FROM PUBLISHER]

The renal effects of the calcium-channel antagonist isradipine were evaluated in cyclosporin A (CsA)-treated renal allografted patients more than 5 months after transplantation. Twelve patients withstable renal function were given placebo for 2 weeks and en isradipine 1.25 mg × 2 for 1 week and 2.5 mg × 2 for the next 3 weeks in an open trial. The CsA dose wasunchanged during the study. Isradipine did not interfere with the pharmacokinetics of CsA as both whole blood trough and peak levels were unchanged. Isradipine reduced mean arterial blood pressure (MAP) from 117.0 ± 1.8 to 106.3 ± 1.9 mmHg (P<0.01). The renal effects were studied during water diuresis 1–3 h after drug intake. Para-aminohippurate clearance (CPAH)increased from 256.4 ± 21.5 to 291.5 ± 26.3 ml/min (P<0.05), renal vascular resistance was reduced by 21.5% (P<0.01) and inulin clearance (CIn) was unchanged. Fractional proximal reabsorption, calculatedfrom lithium clearance (CLi), was reduced by 11.9% (P<0.01) by isradipine. Isradipine also reduced proximal reabsorption of sodium (APRNa) and increased distal sodium delivery (DDNa). Distal sodium reabsorption (ADRNa) and free-water clearance (CH2O) were significantly increased. Urinary excretion of enzymes and proteins was unchanged by isradipine [ABSTRACT FROM PUBLISHER]

The purpose of this study was to investigate possible additive effects of calcium antagonists on the cyclosporin A (CsA)–induced inhibition of cellular immunity. Human T–cells were isolated using standard methods and stimulated with phytohaemagglutinin (PHA, n=8), the monoclonal antibody OKT3 (n=6), or mixed lymphocyte reaction (MLR, n=5). Verapamil, nifedipine, nimodipine or diltiazem were added (5 × 10−7 − 5 × 10−5 M) to the cultures, either alone, or in combination with CsA (62.5, 125, and 250 ng/ml). 3H–thymidine uptake was measured to estimate the proliferative responses and dose response curves were constructed for the Ca antagonists and their combinations with CsA. A 50% inhibition of T–cell proliferation in the different stimulation assays was achieved with 3.2 × 10−5−5.3 × 10−5M verapamil, 2.5 × 10−5−4.3 × KT5 M nifedipine, 3.7 × 10−6− 5 × 10−6 M nimodipine, and >5 × 10−5 M diltiazem. In combination with CsA a dosedependent additive inhibitory effect of the Ca antagonists on T–cell proliferation was observed. This effect was less pronounced in the OKT3 assay, intermediate after PHA stimulation and most pronounced in MLR. Even in low concentrations, which correspond to therapeutic serum concentrations, Ca antagonists have an additive inhibitory effect in MLR. We conclude that Ca antagonists exert a dose-dependent inhibitory effect on T-cell proliferation. A combination of CsA with verapamil, nifedipine, nimodipine, or diltiazem is more effective than each drug given alone. This additive effect of Ca antagonists and CsA may possibly contribute to a better graft survival in clinical transplantation. [ABSTRACT FROM PUBLISHER]

In a previous study we demonstrated that cyclosporin-treated renal transplanted patients have a reduced 1,25(OH)2D3 synthesis in comparison with azathioprine-treated transplanted patients. To assess the impact of this defect on intestinal calcium transport we compared the plasma calcium variation and the urinary calcium excretion in 14 cyclosporin-treated and in 12 azathioprine-treated patients, in fasting conditions and 4 hours after an oral calcium load (1 g). In ten cyclosporin patients we also correlated cyclosporin plasma values with plasma 1,25(OH)2D3 values before and after a 25(OH)2D3 oral load.After the oral calcium load, plasma and urinary calcium increased significantly in the azathioprine group, while remaining unchanged in the cyclosporin group. A negative correlation between plasma concentrations of cyclosporin and the increment in 1,25(OH)2D3 after 25(OH)D3 oral load was also observed. Thus, our data suggest that cyclosporin impairs 1-alpha hydroxylase activity and alters the response to an oral calcium load. [ABSTRACT FROM PUBLISHER]

Of 1041 renal allograft transplantations performed in our centre, 142 (13.6%) were carried out with ABO-minor-incompatible kidneys. Anti-recipient ABO antibodies were found in two of 34 patients treated with cyclosporin. These two cases of severe but self-limited haemolysis due to anti-A1 and anti-B, respectively, are reported in detail. Among 108 azathioprine-treated patients no evidence of the disorder was found.The condition should be suspected in any recipient with an unexpected reduction in haematrocrit or other signs of haemolysis after ABO-minor-incompatible organ transplantation. [ABSTRACT FROM PUBLISHER]

Ninety-four renal allograft recipients receiving cyclosporin A (CsA) immunosuppression for up to 4 years were examined for the presence of viral warts, keratoses, and skin cancers. They were compared with a group of 68 recipients on azathioprine who had been matched for duration of immunosuppression and other factors that might influence the occurrence of these lesions. No difference in prevalence of these tumours was found. Viral, bacterial, and fungal infections and other disorders of the skin related to immunosuppression were also noted. Apart from hypertrichosis, which occurred more frequently in the CsA group, no differences were observed. In view of the importance of duration of immunosuppression, the relative effects on the skin of the two drugs will not become apparent until CsA has been in general use for a much longer period of time. In the early stages, however, there appear to be no differences in the dermatological side-effects between CsA- and azathioprine-treated patients. [ABSTRACT FROM PUBLISHER]

In a prospective randomized trial, 57 renal transplant patients received sequential immunosuppression consisting of lymphocytoglobulin (ALG), aza-thioprine, and steroids for 14 days (group A) and another 57 patients for only 2 days (group B). In each case therapy was continued with cyclosporin A and steroids. The purpose of this study was to find the most favourable time to switch over to continuous cyclosporin A therapy with avoidance of its nephro-toxic side-effects during the perioperative phase. As a consequence of ALG intolerance, conventional immunosuppression had to be changed in group A after a mean of 7.8 days, as opposed to 2.1 days in group B. The patients receiving a prophylactic therapy with ALG, azathioprine, and steroids for 14 days (group A) had to be dialysed at a significantly greater frequency than patients with an early start to cyclosporin A (group B) from the second to the fourth week. Patient survival rates 1 and 2 years after transplantation of group A (95 and 92%) and group B (96 and 92%) were not distinct, and there was no significant difference in graft survival rates of group A (79 and 79%) and B (89 and 82%) after the same time. A delayed start of cyclosporin A after 14 days showed no further advantage but rather a significantly greater frequency of dialysis; thus the early onset of cyclosporin A treatment post-transplant is preferable. [ABSTRACT FROM PUBLISHER]

We have developed a simple method of sample collection which allows the measurement of cyclosporin (CsA) to be made from blood obtained from a finger stab and collected onto filter paper. CsA concentrations estimated from blood spots and venous samples obtained at the same time showed good correlation. This method has various practical applications: peak and trough blood CsA concentrations (as well as profiles) may be routinely measured from samples collected by patients at home; it may be of particular value in children and other patients with poor venous access. [ABSTRACT FROM PUBLISHER]

In a study designed to test the long-term nephrotoxic effects of cyclosporin A (CyA), 11 of 13 rats given CyA, 25 mg/kg per day for 8 months, developed cataract. None of the 15 rats given CyA 12.5 mg/kg per day, nor of the controls given vehicle only (n=10), developed this lesion. In a subsequent study, 15 rats were given CyA 25 mg/kg per day, 15 were given 12.5 mg/kg per day, and 10 controls were given the vehicle only. After 16 weeks, three rats of the group on CyA 25 mg/kg per day had developed cataract. The SPF Sprague—Dawley rats were maintained on a controlled breeding diet (Ewos R3). Perforating eye lesions or infections were not observed, but one rat without opacity of the lens had antibodies against sialodacryoadenitis virus. Thus, in the rat, high-dose CyA has significant cataractogenic effects when administered for 15%—25% of the rat life-span. [ABSTRACT FROM PUBLISHER]