The Renal Safety Profile of Fluvastatin: Results of a Pooled Analysis

A pooled analysis was designed to evaluate the effects of fluvastatin on the kidney, in terms of renal adverse events, laboratory abnormalities, and renal function over time. An analysis of adverse events was performed on data from 30 completed clinical trials of fluvastatin in 11,815 patients. An analysis of renal function was also performed on data from patients who participated in long-term studies >6 months in treatment duration. Creatinine clearance was calculated using the Cockcroft-Gault formula. Mean creatinine clearance values were in the normal to near-normal range at baseline. Changes in creatinine clearance and serum creatinine from baseline were similar in fluvastatin-treated patients and placebo-treated patients. In the all-fluvastatin group, mean creatinine clearance (±standard deviation) increased from 87.8 (±42.8) mL/min at baseline to 89.4 (±41.2) mL/min at endpoint. In the placebo group, mean creatinine clearance (± standard deviation) increased from 87.7 (± 43.9) mL/min at baseline to 88.7 (±41.4) mL/min at endpoint. In the all-fluvastatin group, mean serum creatinine (± standard deviation) decreased from 1.14 (±0.20) mg/dL at baseline to 1.11 (±0.20) mg/dL at endpoint. In the placebo group, mean serum creatinine (±standard deviation) decreased from 1.15 (±0.22) mg/dL at baseline to 1.12 (±0.22) mg/dL at endpoint. The incidence of renal adverse events was low and comparable between the fluvastatin and placebo treatment groups. This pooled analysis demonstrates that fluvastatin treatment across the approved daily dose range of 20 mg to 80 mg does not adversely affect creatinine or creatinine clearance over time in dyslipidemic patients.     

Beneficial effects of fluvastatin on progressive renal allograft dysfunction

To assess the time-dependent changes in renal function in relation to antioxidant and lipid-lowering effects of fluvastatin in hyperlipidemic renal transplant recipients, 20 patients were treated with fluvastatin 40 mg/d for 12 months, after failure of a dietary program. Plasma malondialdehyde (MDA) levels and lipid profiles were evaluated in relation to serum creatinine and calculated creatinine clearances 18 months before and during the fluvastatin treatment. Mean baseline lipid values were: total cholesterol 318 mg/dL, triglycerides 212 mg/dL, LDL cholesterol 219 mg/dL, HDL cholesterol 58 mg/dL, apolipoprotein A 176 mg/dL, and apolipoprotein B 145 mg/dL. During 12 months of treatment, fluvastatin produced consistent and significant reductions in total and LDL cholesterol (-18.4% and -24.1%), triglycerides (-17.7%), and apolipoprotein B (-22.7%) as well as an increase in HDL cholesterol (12.3%) and apolipoprotein A (9.2%). Plasma MDA levels decreased by 41.8% (from 3.5 +/- 0.3 to 1.8 +/- 0.1 nmol/mL, P =.00002). Creatinine clearance, which had been declining at a rate of 0.32 mL/min/month during the previous 18 months before treatment, progressively improved during treatment, giving a positive slope of the creatinine clearance, which increased by 0.35 mL/min/month, (P =.016; 53.3 +/- 4.2 mL/min vs 49.8 +/- 4.1 mL/min pretreatment). Multiple linear regression analysis revealed that MDA was the parameter most closely associated with the variability in creatinine clearance. In conclusion, renal transplant patients with lipid abnormalities display renoprotective activity of fluvastatin, possibly due to its lipid-lowering and antioxidant effects.     

No detrimental effect on renal function during long-term use of fluvastatin in renal transplant recipients in the Assessment of Lescol in Renal Transplantation (ALERT) study

BACKGROUND: Concerns have recently been raised regarding a potential harmful effect of statins on renal function. This study investigated the effect of fluvastatin treatment on renal function in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) trial. METHODS: ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40-80 mg daily (n = 1050) or placebo (n = 1052) on cardiac and renal outcomes in renal transplant recipients over a follow-up period of five to six years. The incidence of graft loss, changes in serum creatinine, calculated creatinine clearance and proteinuria, and the incidence of renal adverse events (AEs) were assessed in both treatment groups. RESULTS: Fluvastatin treatment in ALERT had no significant effect compared with placebo on renal function, assessed by serum creatinine (overall adjusted mean +/- SEM: fluvastatin, 175.4 +/- 2.20 micromol/L; placebo, 172.7 +/- 2.20 micromol/L; p = 0.39), creatinine clearance (fluvastatin, 55.3 +/- 0.30 mL/min; placebo, 55.8 +/- 0.30 mL/min; p = 0.26) or proteinuria (fluvastatin, 0.58 +/- 0.03 g/24 h; placebo, 0.53 +/- 0.03 g/24 h; p = 0.31). There were no significant differences between treatment groups when the 283 patients suffering graft loss were excluded from the analysis. Fluvastatin also had no detrimental effect on creatinine clearance or proteinuria in the subgroup of 340 diabetic patients without graft loss in ALERT. No notable differences in the rate of renal or musculoskeletal AEs were observed between fluvastatin and placebo groups. CONCLUSIONS: Fluvastatin had no detrimental effect on renal function, or the risk of renal AEs, in renal transplant recipients with or without diabetes enrolled in ALERT. Fluvastatin treatment for the prevention of cardiac events may therefore be used without fear of jeopardizing renal function.     

The plasma creatinine concentration is not an accurate reflection of the glomerular filtration rate in stable renal transplant patients receiving cyclosporine

We studied 31 stable renal cadaver kidney transplant patients receiving cyclosporine (CyA) and prednisone for immunosuppression to determine what reduction in true glomerular filtration rate (GFR) was reflected by their mild elevation in plasma creatinine concentration (1.8 +/- 0.11 mg/dL). We measured both the creatinine clearance (60 +/- 4.32 mL/min/1.73 m2) and the true GFR using Technetium 99m-DTPA (44 +/- 2.72 mL/min/1.73 m2). The creatinine clearance overestimated true GRF by a mean of 38%, indicating that this percentage of creatinine reached the urine by tubular secretion rather than glomerular filtration. A similar degree of overestimation was found in a separate group of 14 patients receiving imuran for immunosuppression. In 23 patients receiving CyA in whom the serum creatinine concentration was less than 2.0 mg/dL, the mean DTPA clearance was 49.5 +/- 2.83 mL/min/1.73 m2. In stable renal transplant patients receiving CyA, a serum creatinine concentration at, or close to, the upper limit of the normal range may reflect markedly impaired renal function.     

Treatment of atherosclerotic ostial renal artery stenosis with the intravascular stent

Traditional approaches to revascularization for atherosclerotic ostial renal artery stenosis (RAS) have been suboptimal because of the invasiveness and relatively high perioperative morbidity and mortality of surgery and the low rates of success and long-term patency with percutaneous renal angioplasty (PTRA). We report our 5-year (1991 to 1996) experience with the intravascular stent (Palmaz stent; Johnson & Johnson, Miami Lakes, FL) for the treatment of ostial RAS in 129 patients (63 men, 66 women) and 148 arteries. The mean age of the patients was 71+/-10 years; 98% were hypertensive and 57% had renal dysfunction. Angiographic characteristics of RAS were unilateral in 78%, bilateral in 15%, and single kidney in 7%. The technical success rates were 98% for stent versus 11% for PTRA in the ostial location. The stent restenosis rate (angiographic) was 14% at 8+/-5 months. Systolic and diastolic blood pressures were as follows: baseline, 158+/-3 and 84+/-2 mm Hg; 6 months, 149+/-3 and 81+/-2 mm Hg; 12 months, 149+/-3 and 79+/-2 mm Hg; and 24 months, 135+/-3 and 79+/-2 mm Hg. Follow-up values were significantly lower than baseline (P < 0.05). The number of medications for hypertension initially decreased from 2.2+/-0.1 at baseline to 1.6+/-0.1 and 1.8+/-0.1 at 1 and 3 months, respectively (P < 0.05). By 6 months, however, the number of medications had increased and was not significantly different from before stent placement. Renal function was stable in the group as a whole: Cockroft-Gault creatinine clearance (C-G CrCl) at baseline was 40+/-2 mL/min; at 6 months, 36+/-3 mL/min; at 12 months, 39+/-3 mL/min; and at 24 months, 39+/-4 mL/min. When stratified by degree of renal function, values were similarly stable. Patients with a baseline serum creatinine level of 2 mg/dL or less had C-G CrCl values as follows: baseline, 53+/-3 mg/dL; 6 months, 43+/-4 mg/dL; 12 months, 46+/-4 mg/dL; and 24 months, 52+/-5 mg/dL. Those with a baseline serum creatinine level greater than 2 mg/dL had C-G CrCl values as follows: baseline, 26+/-2 mg/dL; 6 months, 31+/-4 mg/dL; 12 months, 32+/-6 mg/dL; and 24 months, 23+/-3 mg/dL. Of eight patients who were dialysis dependent, four (50%) recovered renal function with a mean serum creatinine level of 2.3+/-0.5 mg/dL at 15+/-6 months (range, 9 to 24 months). Stent placement for the treatment of atherosclerotic ostial RAS has a high success rate and a low rate of restenosis. Control of hypertension improves in most patients. Renal function stabilizes or improves in the majority of patients, even those with severe renal failure. These favorable outcomes are maintained long term.     

The clinical status of cadaveric renal transplant patients treated for 10 year with cyclosporine therapy

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.     

Percutaneous nephrolithotomy requiring multiple tracts: comparison of morbidity with single-tract procedures

PURPOSE: To compare the morbidity of percutaneous nephrolithotomy (PCNL) requiring multiple percutaneous tracts with that of procedures requiring a single tract for calculus clearance. PATIENTS AND METHODS: Data from 20 patients undergoing PCNL through two or more percutaneous renal tracts over a 1-year period were compared with a contemporary cohort of 20 patients undergoing PCNL requiring a single tract. The mean stone size was 2157 mm(2) v 423 mm(2) (P < 0.0001), the baseline serum creatinine concentration was 1.67 mg/dL v 1.13 mg/dL (P < 0.05), and the baseline hemoglobin concentration was 11.8 g/dL v 13.4 g/dL (P < 0.05) in the multiple- and single-tract groups, respectively. RESULTS: All single-tract and 95% of multiple-tract patients were rendered stone free. The mean drop in hemoglobin was similar in the two groups (2.3 g/dL for single tract v 2.1 g/dL for multiple tracts; P = 0.55). Complications occurred in two patients in each group. Four multiple-tract patients required blood transfusion. The need for transfusion correlated with lower preoperative hemoglobin and higher preoperative serum creatinine. There was a significant rise in serum creatinine (1.67 mg/dL to 1.91 mg/dL; P < 0.05) and drop in creatinine clearance (76.9 mL/min to 67.2 mL/min; P < 0.05) in the multiple-tract group; this was more pronounced in patients with existing renal insufficiency. No significant change in renal function was seen in the single-tract group. CONCLUSIONS: Monotherapy with PCNL utilizing multiple percutaneous tracts is highly effective in the treatment of staghorn and other large-volume renal calculi. Blood loss and complication rates with such an aggressive approach are comparable to those of PCNL incorporating a single percutaneous tract for more straightforward calculi.     

Clinical evolution in the first 3 months of patients after liver transplantation in maintenance phase converted from mycophenolate mofetil to mycophenolate sodium due to gastrointestinal complications

The enteric-coated mycophenolate sodium (EC-MPS) is a new formulation of mycophenolic acid with a gastro-resistant enteric coating, which releases the drug in the intestine, reducing the incidence of the gastrointestinal (GI) adverse effects. The present work provided a summary of 20 patients with liver transplantation and more than a 1 year of treatment with mycophenolate mofetil (MMF) who, after presentation of GI complications, were converted to EC-MPS. The patients were followed over a 3-month period after beginning EC-MPS treatment. The mean age of the cohort was 53 +/- 10 years and included 75% men. The reasons for transplantation were ethanol cirrhosis (70%), hepatitis C cirrhosis (30%), hepatocarcinoma (5%), and Wilson's disease (5%). At baseline, all patients were being treated with cyclosporine (CsA). CsA doses and levels were reduced during follow-up: baseline dose 179 mg/day versus 143 mg/day at 3 months; levels: 90.4 ng/mL versus 85.8 ng/mL, respectively (P = .017). The administered dose of EC-MPS was 720 mg/day in all cases. The GI complications at baseline were: diarrhea 60% (92% moderate-severe), abdominal discomfort 60% (58% moderate), abdominal pain 45% (44% moderate-severe), gas 40% (38% moderate-severe), nausea 20% (25% moderate), and dyspepsia 20% (mild). After 3 months of EC-MPS treatment, only two patients (10%) displayed moderate diarrhea. The renal evolution was favorable, serum creatinine was reduced, and 24-hour creatinine clearance significantly increased (creatinine: 1.78 +/- 1.6 mg/dL at baseline versus 1.30 +/- 0.3 mg/dL at 3 months, P = .002; creatinine clearance: 72.8 +/- 18 mL/min versus 79.6 +/- 13 mL/min, P = .001). Conversion of MMF to EC-MPS in liver transplant recipients solved the GI tolerability problems and improved renal function during the first 3 months, probably due to the concomitant reduction of anticalcineurinic dose.     

Lercanidipine in patients with chronic renal failure: the ZAFRA study

OBJECTIVE: The objective was primary to evaluate the safe use of a new calcium channel blocker, lercanidipine, in patients with chronic renal failure (CRF). The secondary objective was to study the protective effect of calcium channel blocker on renal function in CRF patients previously treated with ACE inhibitors or angiotensin receptor blockers. DESIGN AND METHODS: The study recruited 203 CRF patients (creatinine >1.4 mg/dL for males, creatinine > 1.2 mg/dL for females, or creatinine clearance <70 mL/min). All patients were receiving ACE inhibitors (63.4%) or angiotensin II antagonist (36.6%) therapy, but they had higher blood pressure than recommended for CRF (130/85 mmHg). No patients were under diuretic treatment. Patients were clinically evaluated 1, 3, and 6 months after starting treatment with lercanidipine. Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to the treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection. RESULTS: 175 patients rendered valuable for the study (age 63.9+/-11.9 years, 52.9% males and 47.1% females). Blood pressure (BP) significantly decreased from 162+/-17/93+/-8.3 mmHg to 132+/-12/78+/-6 mmHg. 89.2% of patients showed a significant BP reduction, and 58.1% achieved optimal BP control (<130/85 mmHg). Seven patients (3.4%) showed untoward effects. Not one case of edema was detected, and the prevalence of adverse effects related to vasodilatation was extremely low (three patients, 1.48%). Plasmatic creatinine did not change (1.9+/-0.5 baseline versus 1.9+/-0.6 mg/dL), but creatinine clearance increased at the end visit (41.8+/-16.0 baseline versus 45.8+/-18.0 mL/min, p=0.019). Plasmatic cholesterol also decreased from 221+/-46 to 211+/-35 mg/dL (p=0.001). CONCLUSIONS: Lercanidipine showed a high antihypertensive effect in CRF patients. It has a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, measured through creatine clearance, was detected.     

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.     

Usefulness of Sirolimus as Rescue Therapy in Heart Transplant Recipients With Renal Failure: Analysis of the Spanish Multicenter Observational Study (RAPACOR)

Background

Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity.

Methods

We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min.

Results

Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events.

Conclusions

Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.     

An open-label, pilot study evaluating the safety and efficacy of converting from calcineurin inhibitors to sirolimus in established renal allograft recipients with moderate renal insufficiency

This pilot study was designed to evaluate the safety and efficacy of converting from a calcineurin inhibitor (CI) to a sirolimus (SRL)-based regimen in established renal transplant recipients with moderate renal insufficiency. Sixty renal transplant recipients on CI-based immuno-suppression with a serum creatinine (SCr) between 159 and 265 microM (1.8 and 3.0 mg/dL) and a glomerular filtration rate (GFR) between 30 and 70 mL/min were enrolled. SRL dosing was dependent upon concomitant immunosuppressive therapy. The mean patient age was 45 yr and the mean time from transplant to study enrollment was 60.8 months (range: 7-198). The median SCr was 168 microM (1.9 mg/dL) and the median GFR was 51 mL/min. Twelve months after conversion the patient and graft survival rates were 96.7% and 95%, respectively. The incidence of biopsy-proven acute rejection was 3.3% (two cases reported, Banff grades IA and IB). The median SCr and median creatinine clearance were 168 microM (1.9 mg/dL) and 53 mL/min, respectively. Hyperlipidemia, diarrhea, peripheral edema, rash, and anemia were the most commonly reported adverse events. Patients with moderate renal insufficiency can be converted from CI to SRL-based therapy and maintain renal function over a 1-yr period.     

The effect of sirolimus in the development of chronic allograft nephropathy

PURPOSE: The effect of sirolimus (SRL) in renal function was studied in renal transplant recipients. PATIENTS AND METHODS: We studied 20 patients who underwent live related kidney transplantation 1 to 2 years prior under cyclosporine (CsA) treatment and displayed serum creatinine values between 2 and 3 mg/dL. The patients were randomized into 2 groups prospectively. The calcineurin inhibitors (CNI) group continued taking CsA; the SRL group underwent a switch from CsA to SRL. Biopsies were performed to assess chronic allograft nephropathy (CAN) findings and TGFbeta1 in the transplanted kidneys at the beginning and the end of the study. Creatinine clearance, serum creatinine, and proteinuria values were detected in the beginning as well as at 1, 3, 6, and 12 months later. RESULTS: At the beginning of the study, the creatinine clearance and serum creatinine levels were 52.21 mL/min and 2.05 mg/dL in the CNI group and 47.76 mL/min and 2.13 mg/dL in the SRL group, respectively. At 12 months, these values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Creatinine clearance values between the 2 groups at 12 months were statistically different. Although it was not significant, there was a tendency toward decreases inflammatory infiltration and TGFbeta1 levels in the SRL group compared with the CNI group on the second biopsies. CONCLUSION: Pathologic findings of CAN development, serum creatinine, and creatinine clearance values were ameliorated in the SRL group. We concluded that SRL positively affected long-term graft survival.     

mTOR inhibitors: do they help preserve renal function?

BACKGROUND: Renal function deterioration is one of the main problems facing heart transplant recipients. The mammalian target of rapamycin (mTOR) inhibitors, in combination with or replacing calcineurin inhibitors, may help preserve renal function. The aim of this study was to evaluate the progression of renal function after switching the immunosuppressive regimen. PATIENTS AND METHODS: We studied 23 heart transplant recipients (5.5 +/- 4.5 years since transplantation). An mTOR inhibitor was introduced to replace cyclosporine (everolimus, 65%; sirolimus, 35%). Patient clinical characteristics and renal function were studied after switching. The statistical analysis used Student t test for paired data. RESULTS: The reason for the transplantation was ischemic cardiopathy (52%), dilated myocardiopathy (39%), or other causes (9%). Mean age at time of transplantation was 52 +/- 9 years. Comorbidities were as follows hypertension (43%), insulin-dependent diabetes (22%), hypercholesterolemia (39%), and ex-smokers (70%). The reason for the switch was increased creatinine (65%), appearance of tumors (26%), or others (8%). Previous creatinine level was 1.89 +/- 0.6 mg/dL with clearance of 61.7 +/- 23 mL/min and at the end of follow-up (mean follow-up, 11 +/- 6 months) creatinine level was 2.0 +/- 1.45 mg/dL with clearance of 68.3 +/- 35 mL/min, namely, no significant difference (P = .49 and P = .57, respectively). In the subgroup of patients who switched treatment due to renal dysfunction, initial creatinine level was 2.38 +/- 0.4 mg/dL with clearance of 42.3 +/- 10 mL/min and at the end of follow-up it was 2.28 +/- 0.2 mg/dL and 43.6 +/- 11 mL/min, respectively (P = .68 for creatinine and clearance). CONCLUSIONS: The introduction of mTOR inhibitors to the immunosuppressant regimen may be useful to delay renal functional deterioration caused by calcineurin inhibitors.     

Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy

Radiocontrast-induced nephropathy (RCIN) is a common cause of hospital-acquired acute renal failure and is associated with a high mortality rate. RCIN is potentially preventable, because administration of the radiocontrast agent is predictable, and a high-risk population has been identified. This multicenter, prospective, randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of intravenous atrial natriuretic peptide (anaritide, ANP 4-28) to prevent RCIN. Patients with stable chronic renal failure (serum creatinine greater than 1.8 mg/dL or serum creatinine between 1.5 and 1.8 mg/dL with estimated creatinine clearance of < or = 65 mL/min) were assigned to receive either placebo or one of three doses of anaritide (0.01 microg/kg/min, 0.05 microg/kg/min, or 0.1 microg/kg/min) for 30 minutes before and continuing for 30 minutes after radiocontrast administration. All patients were given intravenous 0.45% saline for 12 hours before the radiocontrast procedure and continuing for 12 hours after the last dose of radiocontrast. Both ionic and nonionic radiocontrast agents were administered. RCIN was defined as either an absolute increase of serum creatinine of > or = 0.5 mg/dL or a percent increase of > or = 25% over baseline. Of the 247 patients who completed the study, 50% had diabetes mellitus. There were no statistical differences in baseline serum creatinine, change in serum creatinine, or the incidence of RCIN. The incidence of RCIN was placebo, 19%; anaritide (0.01), 23%; anaritide (0.05), 23%; anaritide (0.1), 25%. Patients with diabetes mellitus had a significantly greater incidence of RCIN: placebo, 26% versus 9%; anaritide (0.01), 33% versus 13%; anaritide (0.05), 26% versus 21%; anaritide (0.1), 39% versus 8% (diabetic v nondiabetic, P < 0.002). There was no effect in the diabetic or nondiabetic groups by anaritide on the incidence of RCIN. Comparison of the highest-risk group of patients, defined as patients with diabetes mellitus and a baseline serum creatinine > or = 1.8 mg/dL, with the lowest-risk group, defined as patients without diabetes mellitus and a baseline serum creatinine of 1.8 mg/dL or less, did not show a beneficial effect of anaritide administration. In conclusion, administration of intravenous anaritide before and during a radiocontrast study did not reduce the incidence of RCIN in patients with preexisting chronic renal failure, with or without diabetes mellitus.     

Preemptive Living Donor Renal Transplantation: A Single-Center Experience

Renal transplantation is considered preemptive if it occurs before initiation of dialysis. In our experience and in the literature, preemptive transplantation has been shown not only to reduce the costs of renal replacement therapy but also to avoid the long-term adverse effects of dialysis. Preemptive renal transplantation therefore is associated with better survival of both the allograft and the recipient. Our aim was to evaluate the outcomes of preemptive renal transplantation experience at our center. Since 1985, 1385 renal transplantations have been performed at our center. We retrospectively analyzed the 16/1385 recipients (11 male, 5 female) of overall mean age of 28.5 ± 15 years who underwent preemptive procedures. The causes of end-stage renal failure were focal segmental glomerulosclerosis (n = 5), vesicular ureteral reflux (n = 4), Berger disease (n = 2), polycystic renal disease (n = 2), and others (n = 3). Ten patients were adults, the remaining six, children. The mean creatinine clearance and plasma creatinine levels of the recipients before renal transplantation were 13.5 ± 8.5 mL/min and 6.7 ± 2.4 mg/dL, respectively. All renal transplantations were performed from living related donors. The mean preoperative serum creatinine levels, mean glomerular filtration rate, and creatinine clearance rates of the donors were 0.8 ± 0.1 mg/dL, 61.6 ± 6.5 mL/min, and 112.5 12 mL/min, respectively. Two episodes of acute cellular rejection and one of humoral rejection occurred during a mean follow-up of 48.7 ± 14 months (range = 25-76 months). The two patients who experienced graft losses due to humoral rejection or chronic rejection were retransplanted 2 and 48 months thereafter, respectively. At this time all patients are alive with good renal function. In conclusion, our single-center results are promising for preemptive renal transplantation as the optimal, least-expensive mode of treatment for end-stage renal disease.     

20-year experience with elderly donors in living renal transplantation

PURPOSE: This study evaluates the impact of living renal donors (LD) aged 60 years and older on graft performance and patient survival in an old-for-young constellation. PATIENTS AND METHODS: We analyzed 144 consecutive LDs between January 1983 and December 2002 (19 patients 60+/125 controls). RESULTS: Mean donor age in the 60+ group was 63.7 (+/- 2.6) years and 43.7 (+/- 9.0) years for the <60 group. Mean recipient age was 42.4 (+/- 15.2) years versus 32.6 (+/- 15.3) years HLA-A, -B, and DR-mismatches were 3.16 (+/- 1.3) for the 60+ group and 3.13 (+/- 1.7) for the controls (P = NS). Rejection episodes in the first year following LD did not differ (53% versus 33%, P =.25). Mean serum creatinine for 65+ versus <65 after 1, 3, and 12 months was 1.91 +/- 1.2 versus 1.48 +/- 0.85 mg/dL (P =.16), 1.82 +/- 0.89 versus 1.29 +/- 0.35 mg/dL (P <.05) and 1.80 +/- 0.31 versus 1.37 +/- 0.38 mg/dL (P <.05) and mean creatinine clearance at 12 months 62 versus 82 mL/min (P =.06). Censored 1-, 3-, and 5-year graft survival was 100% versus 95% (P = NS), 100% versus 93% (P = NS) and 100% versus 83% (P = NS) with no significant difference in the log-rank test for Kaplan Meier. CONCLUSION: No impact of donor age was found for graft survival but function of the 65+ kidneys at 3 and 12 months was reduced. Living renal donors 60+ are acceptable for carefully allocated recipients.     

Ribavirin dose modification based on renal function is necessary to reduce hemolysis in liver transplant patients with hepatitis C virus infection

Hepatitis C virus (HCV) is currently the most common etiology for liver transplantation (LTx) in the United States. A significant number of patients develop recurrent HCV after LTx. Although there is no completely satisfactory treatment for recurrent HCV, a combination of interferon-α (INF) and ribavirin remains the most widely used. Ribavirin is eliminated through the kidneys and tends to accumulate in the presence of renal dysfunction. The primary side effect of ribavirin is hemolysis. The goal of the present study was to correlate the incidence of hemolysis with renal function in LTx patients with recurrent HCV who were being treated with ribavirin. The incidence of hemolysis and the renal function were examined in 72 liver transplant patients (58 male and 14 female patients) with recurrent HCV receiving INF (3 million units, three times per week) and ribavirin (initial dose of 400 mg twice daily). Patients were grouped according to the decrease in the percentage of hematocrit after the introduction of ribavirin, with their baseline serum creatinine and creatinine clearance calculated using the Cockcroft-Gault formula. The decrease in the percentage of hematocrit after ribavirin treatment was also examined with respect to creatinine clearance as a continuous variable. In addition, for purposes of presentation, patients were analyzed in three groups: creatinine clearance of ≥ 70 mL/min (group A), creatinine clearance < 70 mL/min and ≥ 40 mL/min (group B), and creatinine clearance < 40 mL/min (group C). Forty-five (62.5%) patients experienced a decrease in hematocrit (Hct) ≥15% after starting INF and ribavirin. The mean serum creatinine was 1.3 ± 0.5 mg/dL (median, 1.3) in this group, and the mean calculated creatinine clearance was 71 ± 29 mL/min (median, 66.47). In the 27 patients who did not show a significant decrease (< 15%) in hematocrit, the mean serum creatinine was 1.1 ± 0.3 mg/dL (median, 1.0) and the mean creatinine clearance was 95 ± 39 (median, 96) mL/min (P = .018). On continuous variable of calculated creatinine clearance, there was a trend in the decrease in hematocrit after ribavirin treatment compared with pretreatment (P = .09). However, the rate of hemolysis was significantly different in group A (53.7%), group B (70.8%), and group C (100%) (P = .042). Patients on INF and ribavirin therapy who experienced hemolysis had significantly higher serum creatinine levels and lower creatinine clearances compared with those who did not have hemolysis. The incidence of hemolysis was significantly associated with higher serum creatinine and decreased creatinine clearance. Because ribavirin is eliminated by the kidneys, this observation points to the need for adjustments in the dose of this agent in LTx patients, who tend to have some degree of renal dysfunction, to reduce the incidence of hemolysis. Further pharmacokinetic studies of ribavirin in LTx patients with varying degrees of renal function may allow the development of an algorithm for the safer use of ribavirin in HCV-positive LTx patients. (Liver Transpl 2002;8:1007-1013.)     

Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials.

The incidences of osteoporosis and renal insufficiency increase with age. We studied the influence of renal function on the safety and efficacy of risedronate 5 mg daily in osteoporotic women. Risedronate was safe and effective in osteoporotic women with mild, moderate, or severe age-related renal impairment. INTRODUCTION: The incidences of both osteoporosis and renal insufficiency increase with age; thus, the effect of renal impairment on the safety and efficacy of osteoporosis treatments is a clinical concern. Risedronate is a pyridinyl bisphosphonate well established as safe and effective in the treatment and prevention of osteoporosis. Currently, there is little available information about the effect of bisphosphonate treatment in patients with renal insufficiency. This retrospective analysis was conducted to study the influence of renal function on the safety and efficacy of risedronate in a population of osteoporotic women. MATERIALS AND METHODS: Combined data from nine randomized, double-blind, placebo-controlled phase III risedronate trials were analyzed. The patients in these studies had no markedly abnormal laboratory parameters that were considered clinically significant and no evidence of significant disease. This analysis included patients who received placebo (n = 4,500) or risedronate 5 mg (n = 4,496) for up to 3 years (average duration of exposure, 2 years) and who had renal impairment (creatinine clearance [CrCl] < 80 ml/min). CrCl was estimated by the Cockcroft and Gault method, based on age, weight, and serum creatinine. Patients were categorized as having mild (CrCl >or=50 to <80 ml/min), moderate (CrCl >or=30 to <50 ml/min), or severe (CrCl < 30 ml/min) renal impairment. RESULTS: Of the patients studied, renal impairment at baseline was mild in 48% (mean [range] serum creatinine, 0.9 [0.4-1.6] mg/dl), moderate in 45% (1.1 [0.6-1.9] mg/dl), and severe in 7% (1.3 [0.7-2.7] mg/dl). In both the placebo and risedronate treatment groups, the patients with the most severe renal impairment were older and had more severe osteoporosis. The incidences of overall adverse events and of renal function-related adverse events were similar in the placebo and risedronate 5 mg groups regardless of renal function. Furthermore, evaluation of changes from baseline in serum creatinine revealed no difference in renal function between the placebo and risedronate 5 mg groups in any of the renal impairment subgroups at any time-point. In all three subgroups, risedronate effectively preserved BMD and reduced the incidence of vertebral fractures. CONCLUSIONS: These findings show that risedronate is safe and effective in osteoporotic women with age-related mild, moderate, or severe renal impairment.     

Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism

BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration. METHODS: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.