Switch from cyclosporine A to mycophenolate mofetil in nephrotic children

Nephrotoxicity is a well-known adverse effect of cyclosporine A (CyA) treatment in children with steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome (NS). We analyzed nine children (age: 3.3–15.7 years, two girls) with SD or SR NS who experienced a significant decrease in their GFR under CyA treatment as measured by inulin clearance (C_IN). Mycophenolate mofetil (MMF) was introduced progressively until doses of 1 g/1.73 m² twice daily were reached. CyA treatment was stopped after introduction of MMF and oral steroids were reduced if possible. After a median follow up of 261 days, no adverse effects of MMF such as diarrhea or hematological anomalies occurred in our patients. After switching from CyA to MMF, those children with SD NS remained in remission without proteinuria and those with SR NS did not show any significant changes in their residual proteinuria. The serum protein level did not change significantly in any of the children analyzed. GFR increased from a mean of 76.9±4.8 to 119.9±5.9 mL/1.73 m² per min (P<0.001). Oral steroid treatment could be reduced from a median [range] prednisone dose of 0.85 [0.26–2.94] mg/kg/d pre-MMF to 0.29 [0–1.1] mg/kg per day (P=0.026), and blood pressure decreased moderately after CyA withdrawal, but the difference did not reach statistical significance. We conclude that a switch from CyA to MMF seems to be safe for children with SDNS and SRNS in terms of side effects as well as disease control, at least in the short term. Interruption of CyA treatment lead to rapid amelioration of kidney function in these children, often associated with steroid sparing, which may lead to additional benefit for growth velocity, blood pressure and physical appearance.     

Angiotensin converting enzyme inhibitors for reduction of proteinuria in children with steroid-resistant nephrotic syndrome

The effects of angiotensin converting enzyme inhibitors (ACEI) on proteinuria, renal function, and serum proteins were evaluated in six children with steroid-resistant nephrotic syndrome and proteinuria of 3–15 g/24h (277±47 mg/m² per hour). Following ACEI, proteinuria decreased from 7,408±2,385 (mean±SEM) to 3,746±1,395 mg/24 h (P<0.05). Creatinine clearance was 87.8±22.6 before and 96.4±23.6 ml/min per 1.73 m² after ACEI. In two patients, inulin and para-aminohippuric acid clearances were normal before and after ACEI, together with parallel reductions of urine protein of 50% and 46%. Clearance of total protein was reduced by 56% following ACEI, compared with reduction in the clearance of gamma globulin by 58% and albumin by 39.5%. No significant change was seen in blood pressure, serum albumin, or total protein following ACEI. After ACEI, diuretic doses were able to be reduced or eliminated in three patients. Reduction of proteinuria was sustained during a followup period of 11–20 months in three patients. ACEI may be of benefit in the clinical management of children with steroidresistant nephrotic syndromes, allowing reduction in diuretic requirements.     

Frequently relapsing nephrotic syndrome: treatment with mycophenolate mofetil

Long-term treatment with cyclosporin A (CyA) of children with frequently relapsing steroid-sensitive nephrotic syndrome (SSNS) carries the risk of nephrotoxicity. We have analyzed renal function in 23 children with SSNS during CyA therapy. Repeated measurements of glomerular filtration rate (single-shot ⁵¹Cr-EDTA clearance) showed a decline from 131±21 ml/min per 1.73 m² to 116±27 ml/min per 1.73 m² at last follow-up. Similarly, effective renal plasma flow (simultaneous ¹²³I-hippurate clearance) was correlated with duration of CyA treatment, and showed a decline from 980±318 ml/min per 1.73 m² to 724±242 ml/min per 1.73 m². In a pilot study we investigated the effect of mycofenolate mofetil (MMF) in 7 children with a median age of 12.7 years [6 with minimal change nephrotic syndrome (MCNS), 1 with focal segmental glomerulosclerosis (FSGS)] with signs of nephrotoxicity because of long-term CyA therapy. Only 1 patient with SSNS showed a relapse during MMF therapy. In the patient with FSGS, MMF was started in addition to CyA, resulting in complete remission for a follow-up of 28 months. This preliminary study demonstrates that children with MCNS treated with CyA may be successfully converted to MMF without major side effects. In all cases, including FSGS, MMF had a beneficial effect on renal function. These data should be confirmed by a prospective randomized clinical trial.     

Plasmapheresis therapy for rapidly progressive Henoch-Schönlein nephritis

Six Japanese children with rapidly progressive Henoch-Schönlein purpura nephritis (HSPN) received multiple drug therapy combined with plasmapheresis (PP). After five courses of PP, multiple drug therapy, including methylprednisolone and urokinase pulse therapy, oral prednisolone, cyclophophamide, dipyridamole, and warfarin was given. At presentation, urine protein excretion and histological indices of the mean activity and chronicity were 245±101 mg/m² per hour, 6.6±1.2, and 1.5±1.3, respectively. After 6 months of therapy, urinary protein excretion had decreased significantly (P<0.001). The activity index decreased significantly at the second renal biopsy performed at a mean interval of 4.3 months after the first (2.8±1.4, P<0.05), while the chronicity index did not change. At the most recent observation, all showed clinical improvement. Two patients had normal urine, three had proteinuria of <20 mg/m² per hour, one had proteinuria of >20 mg/m² per hour, and none had renal insufficiency. Although this case series is without controls, our treatment protocol may be of benefit to children with rapidly progressive HSPN.     

Effects of growth hormone on kidney function in pediatric transplant recipients

Recent evidence suggests that treatment with recombinant human growth hormone (rhGH) after a successful kidney transplant improves the growth rate of children with short stature. We prospectively investigated eight children (6 boys, 2 girls), focusing on acute rejection episodes and changes in serum creatinine levels during rhGH treatment. The children (mean age 11.6±3.4 years) received rhGH daily (0.04–0.05 mg/kg subcutaneously). Seven patients completed at least 12 months (20±8 months) of rhGH treatment. Their mean serum creatinine level was 1.3±0.7 mg/dl 12 months before, and increased to 3.4±4.2 mg/dl after 12 months of rhGH treatment, but did not achieve statistical significance (P=0.06). Their mean calculated glomerular filtration rate was 58±20 ml/min per 1.73 m² 12 months before, and decreased to 38±21 ml/min per 1.73 m² 12 months before, and decreased to 38±21 ml/min per 1.73 m² after 12 months of rhGH treatment, but did not achieve statistical significance (P=0.08). Of the seven patients, two developed acute rejection after 5 and 6 rejection-free years; three lost their grafts and returned to dialysis. These preliminary observations describe untoward renal events in children receiving rhGH treatment after a kidney transplant.     

Low-dose cyclosporin A therapy in cadaver renal transplantation in children

Fifty-one pediatric patients undergoing a first cadaveric kidney transplantation were followed for at least 2 years after grafting. They were divided into two groups: those treated with methylprednisolone plus azathioprine (AZA) and those treated with methylprednisolone plus low-dose cyclosporin A (CyA; median dose 109 mg/m² per day ≙ 3.4 mg/kg per day after 1 year). The steroid dosage given was significantly lower in the second group. The 4-year graft survival rate was 68% for the AZA group and 78% for the CyA group. Renal function did not differ significantly in the two groups; after 1, 2, and 3 years, the median 24-h creatinine clearance was 79, 69, and 51 ml/min/1.73 m², respectively, for the AZA group and 78, 63, and 68 ml/min/1.73 m², respectively, for the CyA group. Linear growth was similar in the two groups. We conclude that in pediatric patients the results of low-dose CyA immunosuppression do not differ significantly from those obtained with AZA in terms of graft survival, renal function, or growth.     

Long-term renal allograft function under maintenance immunosuppression with cyclosporin A or azathioprine

In order to evaluate long-term renal graft function, 149 cyclosporin A and prednisolone (CyA/P)-treated renal transplant recipients were compared with 119 azathioprine and prednisolone (Aza/P)-treated patients. Only patients who had a functioning graft for at least 1 year and who were maintained on their initial immunosuppressive protocol were included. The minimum follow-up period was 4 years. Renal graft function was estimated by yearly determinations of serum creatinine and creatinine clearance. The CyA/P-treated patients had a significantly higher serum creatinine and a significantly lower creatinine clearance at every point in time posttransplantation than Aza/P-treated patients (P<0.001). The evolution of renal graft function, as reflected in the line of regression for serum creatinine and creatinine clearance versus time, was estimated for each individual patient. There was an almost stable renal function, as assessed by the median of the slopes of the regression line for serum creatinine versus time in both groups. The median increase in serum creatinine was only 1.4 mol/l per year for Aza/P-treated patients and 2.4 mol/l per year for CyA/P-treated patients (difference NS). The median decline in creatinine clearance was 2.18 ml/min per 1.73 m²/year in the Aza/P group and 1.07 ml/min per 1.73 m²/year in the CyA/P group (P=0.05). In patients with a functioning graft for at least 5 years, creatinine clearance remained unchanged in both groups during the study period. In conclusion, renal graft function, as assessed by measurements of serum creatinine and creatinine clearance, remained essentially unchanged for at least 5 years after transplantation, regardless of the immunosuppressive protocol used. Thus, these data do not indicate a progression with time of the nephrotoxicity observed in CyA-treated patients.     

Does Everolimus Associated With a Low Dose of Cyclosporine in Long-Term Cardiac Transplant Recipients Improve Renal Function? Initial Experience

Background

Cyclosporine (CsA) renal toxicity is a well-known side effect. Various immunosuppressive strategies have been developed to minimize renal insufficiency. The use of everolimus associated with low levels of CsA can be an alternative strategy.

Methods

From October 2007 to April 2008, everolimus was started with a lower dose of cyclosporine (trough levels from 109.3 ± 27.5 to 93.7 ± 30.1 ng/mL after 45 days) in 21 cardiac transplant recipients (18 male and 3 female patients, mean age 56.4 ± 10.7 years). Pre-everolimus therapy creatinine levels, creatinine clearances, and glomerular filtration rates were 1.9 ± 0.9 mg/dL, 54.2 ± 18.1 mL/mins and 44.3 ± 16.5 mL/min/m², respectively.

Results

We observed a significant reduction in creatinine levels (from 1.9 ± 0.9 to 1.4 ± 0.3 mg/dL, P = .022) as well as a significant improvement in creatinine clearances (from 54.2 ± 18.1 to 69.0 ± 19.0 mL/min, P = .020) and glomerular filtration rates (from 44.3 ± 16.5 to 57.1 ± 16.3 mL/min/m², P = .010) after 7 days of everolimus therapy. Upon univariate analysis patient age, pretransplantation creatinine clearance, creatinine clearance after everolimus introduction, glomerular filtration rate at 45 days, and time from transplantation were associated with renal improvement. Upon multivariate analysis, only creatinine clearance at 7 days was related to the renal improvement.

Conclusions

These preliminary data suggested that everolimus with a low dose of CsA may be safe and effective to reduce CsA-related renal insufficiency among selected, heart transplant patients.     

Effect of cyclosporin A on glomerular filtration rate in children with minimal change nephrotic syndrome

Cyclosporin A (CyA) is now commonly used in the management of children with steroid-dependent nephrotic syndrome. In order to assess nephrotoxicity related to CyA therapy, we measured glomerular filtration rate (GFR) on 123 occasions in 24 children with minimal change nephrotic syndrome receiving CyA. GFR was estimated from the plasma clearance of⁵¹chromium-EDTA every 3 months during CyA therapy of up to 27 months duration. There was a significant reduction in GFR after 3 months of CyA therapy [118±33 (SD) to 93±24 ml/min per 1.73 m²] but no further fall thereafter, although the reduction in GFR was sustained for the duration of CyA therapy. This reduction in GFR appeared to be reversible upon cessation of CyA, but careful monitoring of renal function is necessary in such patients to prevent the development of longer term nephrotoxic sequelae.     

Renal handling of uric acid under cyclosporin A treatment

The renal handling of uric acid during cyclosporin A (CyA) treatment was investigated by clearance studies using 24-h urine collections in 28 paediatric renal transplant recipients (CyA group), and the results were compared with those of 19 renal transplanted children treated with azathioprine and prednisolone (AZA group), 35 children with chronic renal failure (CRF) and 10 children with normal renal function (N group). Serum uric acid levels were significantly higher in the CyA group (567±156 mol/l) compared with the AZA group (378±98), the CRF group (415±119) and the N group (290±68). Mean uric acid clearances in each group measured 3.9±2.8 ml/min per 1.73 m² (CyA), 5.6±3.4 (AZA), 4.0±2.2 (CRF) and 8.4±3.7 (N). Calculation of the net tubular uric acid reabsorption per millilitre glomerular filtration rate revealed a significantly increased value of 0.53±0.15 mol/ml in the CyA group (P<0.01) compared with 0.34±0.08, 0.29±0.15 and 0.27±0.07 mol/l for the AZA, CRF and N groups respectively. We therefore conclude that CyA treatment is associated with an increased net tubular reabsorption of uric acid, which may lead to hyperuricaemia.     

Long-term effects of levamisole treatment in childhood nephrotic syndrome

The effects of levamisole treatment on long-term outcome were evaluated in a retrospective study of frequently-relapsing (FRNS, n =15), steroid-dependent (SDNS, n =13), and steroid-resistant (SRNS, n =6) nephrotic syndrome in 34 children (21 boys, 13 girls, mean age 5.0±3.4 years) during a 60-month follow-up period. The definition of frequent relapses was 4 relapses per year. The current relapse was treated with prednisolone 60 mg/m² per day for 4 weeks, then with 40 mg/m² every other day for 4 weeks, after which the dose was tapered by 10 mg weekly. From the beginning of the 5th week, levamisole was introduced at a dose of 2 mg/kg per day. The duration of levamisole treatment was 17±7 months. Before starting levamisole treatment the mean level of proteinuria was 2.17±1.34 g/day and the relapse rate was 4.41/year. By the end of levamisole therapy, proteinuria had fallen to 0.142±0.211 g/day and the relapse rate to 0.41/year. No relapse occurred in 23 of the 34 patients during levamisole treatment. In the 24-month follow-up period after the discontinuation of levamisole, 28 children remained in total remission, while 6 had relapses. The cumulative steroid dose before levamisole therapy was 7,564.4±3,497.1 mg/year and following the introduction of levamisole 1,472.9±1,729.9 mg/year ( P <0.0001). We observed reversible neutropenia in 5 patients, but no other side effects were seen. Our findings suggest that in FRNS and SDNS levamisole significantly reduces both the relapse rate and the cumulative steroid dose; therefore, it could be recommended for these patients. In SRNS patients it has also some benefit because proteinuria and the cumulative steroid dose could be reduced significantly.     

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

Cyclosporine (CyA) has made a great impact on 1-year allograft survival, however, after years, renal function deteriorates, possibly due to chronic toxicity. Recently, Mycophenolate mofetil (MMF) was introduced as a non-nephrotoxic immunosuppressant that might be effective in chronical transplant arteriolopathy. We therefore started MMF at a dose of 600 mg/m² b. i. d. in 18 pediatric renal transplant recipients (10.8 ± 3.9 (SD) years of age at transplantation, 11/18 with a history of rejections) with biopsy-proven chronic arteriolopathy and other signs of CyA toxicity at a mean follow up time of 6.2 ± 2.7 (range 2.3–11.8) years after transplantation. One month prior to conversion, mean serum creatinine was 171 ± 96 μmol/l, lower than at the time of conversion (188 ± 100 μmol/l, P = 0.003, paired t-test). At last follow-up (median 13.7 months, range 5.0 to 25.0 months) after conversion, mean serum creatinine decreased significantly to 127 ± 69 μmol/l (P = 0,0003, paired t-test). The CyA dosage was reduced from a mean of 150 ± 39 mg/m2 per day to 59 ± 13 mg/m² per day in 7 patients, and CyA was discontinued in 11 patients after a median period of nine months (range 1–18 months). After a median period of 21 days, a pharmacokinetic profile was performed in all patients. The mean MMF dose was 1117 ± 319 mg/m² per day (range 675–1774 mg/m² per day). The mean Mycophenolic acid (MPA) trough concentration was 4.0 ± 2.0 μg/ml, range 1.4–7.9 μg/ml. Mean 12 h MPA AUC was 70.6 ± 28.1 (range 31.9–127) μg × h/ml. Except for one patient with diarrhea associated with a high AUC, and for one patient with a steroid-sensitive rejection episode after 566 days, no other patient experienced side effects or a rejection episode. Prednisolone was left unaltered at 2–4 mg/m² per day. We conclude that MMF allows safe reduction of CyA with markedly better graft function, suggesting that chronical CyA-toxicity partially accounts for deteriorating allograft function. Received: 20 April 1999 Revised: 9 January 2000 Accepted: 15 March 2000     

Prediction of high-degree steroid dependency in pediatric idiopathic nephrotic syndrome

Most patients with idiopathic nephrotic syndrome are steroid-responsive, but about 50% relapse and often become steroid-dependent and exposed to long-term steroid complications. The aim of this study was to determine predictive risk factors for steroid and/or cyclosporine A (CyA) dependence. In France, steroid responsiveness is defined as remission after 1 month of oral prednisone (60 mg/m² per day) and—in the case of persistent proteinuria on day 30—three methylprednisolone pulses (MPP; 1 g/1.73 m² on days 1, 3, and 5). Thirty-five steroid-responsive children, followed between 1999 and 2006, were included in this study. Median age at diagnosis was 4.9 years. All patients initially received prednisone 60 mg/m² per day. Twenty-four of the 35 patients were steroid-dependent, with 12 requiring MPP. Of the latter 12 patients, 83.3% were treated with CyA during follow-up; in comparison, only 16.7% of the patients who did not receive MPP required CyA during follow-up (chi-square test, P = 0.001). T risk for steroid dependence was 100% in our cohort if remission was achieved after day 20. Patients who need MPP are at high risk to require CyA to achieve disease control. By identifying these children, we could use adequate immunosuppressive drugs earlier and reduce morbidity related to steroids and multiple relapses.     

The Na+-excreting efficacy of indapamide in combination with furosemide in massive edema

Background Massive systemic edema is often observed in patients with severe nephrotic syndrome, including diabetic nephropathy. Although furosemide, a loop diuretic, is often administered to these patients, some patients do not respond to this treatment, still showing massive edema.Methods The efficacy of indapamide which has a thiazide-like effect on distal convoluted tubules in combination with furosemide, was evaluated in eight patients with massive edema, in regard to both Na⁺ excretion and diuresis. Indapamide 2 mg was administered once a day, in the morning, to patients in whom it was considered that furosemide treatment of 40–120 mg a day for 1 week was ineffective.Results Urinary Na⁺ excretion was markedly increased, from 83.7 ± 82.2 mEq/day to 140.7 ± 33.8 mEq/day after 1 week of the combination therapy compared with furosemide alone (P < 0.01); urine volume was also increased, from 1070 ± 230 ml to 1359 ± 296 ml after 1 week of the combination therapy (P < 0.05). In this context, body weight was significantly decreased, from 57.2 ± 12.3 kg to 53.4 ± 12.8 kg, after the combination therapy (P = 0.01). Indapamide in combination with furosemide was well tolerated, and no significant changes in serum levels of creatinine and potassium were observed.Conclusions This combination therapy appears to be effective in patients with massive edema, as it increased diuresis, and achieved potent Na⁺ excretion.     

Post-transplant conversion from cyclosporin to azathioprine: effect on cardiovascular risk profile

The benefits of long-term cyclosporin (CyA) therapy are not yet established and must be weighed against its toxicity. We studied cardiovascular risk factors in 25 patients who received a kidney transplant between 1985 and 1989 and in whom CyA was discontinued. The protocol for discontinuing CyA involved starting azathioprine (Aza) and then weaning CyA over 6 weeks without changing the prednisone dose. Parameters collected from the patients' charts 3 months before (pre) and 3 months after conversion (post) and at the most current follow-up (cur) included serum creatinine, cholesterol, blood pressure, and anti-hypertensive medication. The severity of the hypertension was graded, based on a hypertension index reflecting the nature and dose of the anti-hypertensive medication. Of the 25 patients in whom CyA was discontinued, 2 experienced a rejection episode during conversion and were switched back to CyA; 1 patient had a rejection episode after conversion but remained on Aza. Converted patients demonstrated improved renal function (1/Cr pre 0.69±0.20, post 0.84±0.23, P<0.05), lower serum cholesterol levels (pre 6.8±1.0, post 5.8±1.2, P<0.05), lower mean arterial pressure (pre 111±14, post 102±8, P<0.05) and a lower hypertension index (pre 2.45±2.77, curr 1.62±1.70, P<0.05). Although conversion may carry some risk of acute rejection, it improves graft function and the cardiovascular risk profile significantly.     

Cyclosporine A treatment in patients with Alport syndrome: a single-center experience

Limited and discordant data are available on cyclosporine A (CsA) treatment for proteinuria in Alport syndrome (AS). To address this lack of consistent data, we have studied 15 AS patients (14 males; mean age 15.3?±?6.0 years) treated with CsA. Patient selection criteria included a urinary protein/creatinine ratio ≥1 mg/mg and a creatinine clearance >40 ml/min/1.73 m². CsA treatment was started at an initial dose of 5 mg/kg/day and subsequently adjusted to reach target C2 levels of 500 ng/ml. Renal function, proteinuria, and blood pressure were monitored. Blood pressure was treated to avoid the administration of angiotensin converting enzyme or angiotensin receptor blockers for the first 2 years of therapy. The average follow-up was 3.5 years. Five patients had chronic renal failure at the beginning of treatment, of whom three and one reached end-stage renal failure within 1 and 3 years, respectively. In the remaining 11 patients, the glomerular filtration rate declined by 11?±?6% within 6 months, but remained stable thereafter. Proteinuria decreased by 63?±?21% from baseline, but returned nearly to baseline after 2.5 years of follow-up. Based on these results, we suggest that CsA is effective in reducing proteinuria in patients with Alport syndrome but that this effect is temporary. Our data do not support the use of CsA therapy for proteinuric patients with AS, particularly if they have chronic renal failure.     

Anaphylactoid purpura: Characteristics of 16 patients who progressed to renal failure

Renal insufficiency occurs in at least 1.5% of children with anaphylactoid purpura (AP). We reviewed the records of 16 children who developed end-stage renal disease (ESRD group) secondary to AP and matched them for age, era of onset, renal histology, and clinical severity at onset with 16 children who has AP but whose creatinine clearance returned to and remained normal (recovery group). We reviewed creatinine clearances at 1, 3, 5, and 10 years after onset. A creatinine clearance >70 ml/min per 1.73 m² was present in 50% of the patients in the ESRD group at 3 years and in 25% at 5 years after onset. In contrast, all patients in the recovery group had a creatinine clearance >70 ml/min per 1.73 m² by 3 years (7 of 16 had a creatinine clearance >125 ml/min per 1.73 m²) and all were normal 95–125 ml/min per 1.73 m²) by 5 years. Thus, the presence of an increased creatinine clearance (>125 ml/min per 1.73 m²) at 3 years predicted recovery, while failure to reach a creatinine clearance of >70 ml/min per 1.73 m² at 3 years predicted progression to ESRD. There was no evidence of recurrent systemic AP or nephritis in the 14 patients who underwent renal allograft transplantation. We conclude that long-term evaluation of patients over many years is required to identify those who will progress to ESRD from AP and that recurrence of AP in the renal transplant is uncommon.     

Rapamycin Reduces Proteinuria and Renal Damage in the Rat Remnant Kidney Model

Rapamycin is an immunosuppressive drug used to prevent acute allograft rejection in solid organ transplantation. It shows less nephrotoxicity than calcineurin inhibitors. We evaluated the effect of rapamycin in rats undergoing 5/6 nephrectomy, a model of proteinuric and progressive renal failure. Fourteen days after surgery rats were randomized either to receive rapamycin or to remain untreated (control). Rats were humanely killed on day 91; serum creatinine, creatinine clearance, and proteinuria were assessed. Renal sections were stained with periodic acid-Schiff to evaluate glomerular volume (Gv), glomerulosclerosis (GS) and tubulointerstitial damage (TIS); we evaluated GS and TIS by Sirius red staining (SR). Epithelial-to-mesenchymal transition (EMT) was assessed by immunohistochemistry. Rapamycin affected neither serum creatinine nor creatinine clearance; it reduced Gv (controls, 5.9 ± 3.1 × 10⁶; rapamycin, 1.3 ± 0.7 × 10⁶ μm³) and proteinuria (control, 349 ± 146; rapamycin, 56 ± 27 mg/24 h; P < .05); rapamycin ameliorated GS (control, 78 ± 7; rapamycin, 36 ± 7%; P < .05; SR: control, 13.2 ± 3.5; rapamycin, 3.8 ± 1.0%; P < .05), and TIS (control, 3.25 ± 0.5; rapamycin, 1.0 ± 0.1; P < .05; SR: control, 29 ± 3; rapamycin, 11 ± 3%; P < .05). Rapamycin reduced αSMA (control, 3.25 ± 0.5; rapamycin, 1.0 ± 0.1; P < .05), VIM (control, 3.5 ± 0.6; rapamycin, 1.0 ± 1.4; P < .05), and CD68⁺ cells infiltration (control, 110 ± 43; rapamycin, 24 ± 1 cells; P < .05). Rapamycin slows the progression of renal damage in the rat remnant kidney and may represent a novel approach to the treatment of chronic kidney disease.     

Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506

This prospective study investigated hypertension and renal vasoconstriction developing during the 1st year after renal transplantation in patients randomly allocated to treatment with FK 506 (n = 28) or CyA (n = 13). Starting doses were 0.2–0.3 mg/kg per day for FK 506 and 5–8 mg/kg per day for CyA; doses were subsequently adjusted to trough levels (5–15 ng/ml for FK 506 and 100–150 ng/ml for CyA). We compared 24-h ambulatory blood pressure measurement, antihypertensive treatment, serum creatinine, and resistance index (RI), measured by Doppler ultrasound at the level of the interlobar artery. Until month 2 of treatment, FK 506-treated patients had a significantly lower RI (8 %) and better renal graft function, as evidenced by significantly lower serum creatinine values. Some 13 % of FK 506-treated patients, compared to 70 % of CyA-treated patients (P < 0.01), needed additional antihypertensive drugs after transplantation to keep blood pressure stable. FK 506 treatment, at the above-mentioned dosages, was associated with a significantly higher number of infections (urinary tract infection, pyelonephritis, and pneumonia). We conclude that CyA produces greater renal vasoconstriction and systemic hypertension than FK 506, as reflected in higher renal interlobar artery RI values and a greater need for antihypertensive treatment. After 2 months of treatment and a reduction in CyA trough levels, the renal effects (i. e., lower RI and lower creatinine values), but not the systemic hypertensive effects, disappear. Received: 25 March 1997 Received after revision: 25 September 1997 Accepted: 8 October 1997     

Aggressive treatment of severe idiopathic focal segmental glomerulosclerosis

 When focal segmental glomerulosclerosis (FSGS) has reached the stage of chronic renal insufficiency, further progression is usually considered inevitable. African-American patients are believed to exhibit a particularly aggressive form of FSGS. We have treated five African-American patients, aged 11–18 years, with FSGS and reduced renal function using intensive intravenous methylprednisolone protocol, combined with chlorambucil in three cases. All patients had a pretreatment creatinine clearance of less than 50 ml/min per 1.73 m². Three patients responded with normalization of creatinine clearance and serum albumin levels and had no or only minimal proteinuria at latest follow-up. One patient showed no improvement and one patient progressed to end-stage renal disease. These findings indicate, for the first time, that even severe FSGS may respond to aggressive methylprednisolone with or without alkylating agent treatment, and that African-American race does not preclude a favorable response. Received: 12 June 1998 / Revised: 17 November 1998 / Accepted: 18 November 1998