Does H2-receptor antagonist alter the renal function of cyclosporine-treated kidney grafts?

Histamine-type 2 antagonists (H2-blockers) as represented by cimetidine have been shown to adversely affect renal allograft function, particularly when coadministered with cyclosporine, currently a major immunosuppressant. To determine whether or not a newer and more powerful H2-blocker, famotidine, would produce similar adverse effects, we assessed seven cyclosporine-treated renal allograft recipients with regard to changes in their renal function on or off the H2-blocker over a one-week period. Neither the administration nor withdrawal of famotidine (20-40 mg/day) resulted in any significant changes in serum creatine, BUN, urine output or cyclosporine trough levels, suggesting that famotidine can be safely administered as an H2-blocker to cyclosporine-treated renal allograft recipients.     

Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients

Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well tolerated, and there was no deleterious effect on the immunosuppressive activity of cyclosporine. This drug interaction provides a significant reduction in the costs associated with organ transplantation.     

Serum potassium concentrations in cyclosporine- and azathioprine-treated renal transplant patients

Hyperkalemia was commonly observed in successful renal transplant patients treated with cyclosporine and prednisone. At 1, 3 and 6 months after transplantation, 13 of 50, 9 of 50, and 5 of 50 patients, respectively, had serum concentrations of potassium greater than 5 mEq/1. This contrasts with the finding of hyperkalemia in only 1 of 13 comparable patients treated with azathioprine and prednisone. Mean serum concentrations of potassium at these dates were significantly higher in cyclosporine-treated patients than azathioprine-treated patients. The 2 patient groups had similar mean serum concentrations of chloride, bicarbonate and creatinine, and mean creatinine clearances at 1 and 3 months. Exposure to diuretic agents and antihypertensive agents was similar in the 2 groups. Serum concentrations of electrolytes and renal function data in hyperkalemic and normokalemic transplant patients receiving cyclosporine were similar. These observations suggest an association between cyclosporine administration and hyperkalemia in renal transplant recipients.     

Effects of Nva2-cyclosporine on glomerular filtration rate and renal blood flow in the rat

The effects of Nva2-cyclosporine on glomerular filtration and renal blood flow in rats were studied and compared with those of cyclosporine. An infusion of Nva2-cyclosporine (20 mg/kg) caused a 53% fall in glomerular filtration rate (1.0 +/- 0.08 to 0.47 +/- 0.09; P less than 0.001) and renal plasma flow (3.2 +/- 0.4 to 1.6 +/- 0.4; P less than 0.005). Nva2-cyclosporine when infused in a dose of 10 mg/kg caused a nearly identical fall in inulin clearance and renal plasma flow. By comparison an infusion of cyclosporine (20 mg/kg) caused a 50% decrease in inulin clearance and a fall in renal plasma flow from 2.6 +/- 0.3 to 0.9 +/- 0.3. Nva2-cyclosporine or cyclosporine was given chronically in a dose of 20 mg/kg intraperitoneally for seven days. Cyclosporine produced a 27% fall in creatinine clearance, whereas Nva2-cyclosporine produced a 19% decrease in creatinine clearance (NS). These studies suggest that Nva2-cyclosporine has adverse effects on renal blood flow and glomerular filtration rate similar to those seen with cyclosporine.     

Factors associated with hyperhomocysteinemia after renal transplantation

Recent studies show that clinically stable renal transplant recipients have an increased prevalence of hyperhomocysteinemia (hyperHcy), but the mechanism of this disorder has not yet been elucidated. The aim of the present study was to evaluate the factors associated with hyperHcy after a successful renal transplantation. In 106 stable renal transplant recipients, total serum Hcy level (tHcy), folate, total protein, serum creatinine concentration, creatinine clearance, lipid status, body weight (BW), body mass index (BMI), and body fat (BF) were determined. The mean doses of cyclosporine, prednisolone, and azathioprine (mg/kg/day) were recorded. The mean serum tHcy level was significantly higher in renal transplant patients than in healthy controls (22.02 +/- 8.02 versus 13.0 +/- 3.3 micromol/ L; p < 0.001), and the incidence of patients with hyperHcy was 82%. Comparison of the group of 20 patients with tHcy level <15 micromol/L and the group of 86 patients with tHcy level >15 micromol/L revealed that the latter was significantly older, heavier, had been longer on dialysis before renal transplantation, and had older donors and poorer renal graft function. Significant correlation was found between tHcy level and recipient age, dialysis duration, BW, creatinine clearance, serum creatinine, and folate concentration. However, multivariate analysis indicated that creatinine clearance (p = 0.025) and BW (p = 0.03) were the only determinants of elevated total Hcy level in renal transplant recipients. HyperHcy persists after successful kidney transplantation in the majority of renal transplant recipients, and its appearance is primarily associated with creatinine clearance and body weight.     

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.     

Kidney transplantation without calcineurin inhibitor drugs: a prospective,randomized trial of sirolimus versus cyclosporine

BACKGROUND: Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients. METHODS: We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL. RESULTS: Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine. CONCLUSIONS: Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.     

Effective long-term immunosuppression maintained by low cyclosporine levels in primary cadaveric renal transplant recipients

Nephrotoxicity and cost are the major problems in the use of cyclosporine (CsA) in renal transplantation. Thus, maintenance of CsA levels at the lower limits of the therapeutic range is desirable. The lowest CsA level effective in preventing rejection while avoiding nephrotoxicity has not been defined. We report on 44 primary cadaveric renal transplant recipients treated with a protocol that involved a progressive reduction in the trough CsA levels. CsA was initiated at an oral dose of 15 mg/kg, and this dose was adjusted to achieve serum trough levels, as measured by radioimmunoassay, of 150-200 ng/ml during the first month, 100-150 ng/ml during the second month, 75-100 ng/ml during the third month, and 50-75 ng/ml thereafter. Patient and graft survival at 18 months were 94% and 83.6%, respectively. The mean daily CsA doses were 6.7 +/- 3.1 mg/kg at 6 months, 5.5 +/- 3.2 mg/kg at 12 months, and 4.7 +/- 2.4 mg/kg at 18 months. Corresponding trough serum CsA levels were 94 +/- 59 ng/ml, 64 +/- 22 ng/ml, and 44 +/- 21 ng/ml at 6, 12, and 18 months, respectively. Mean serum creatinine concentrations were 1.8 +/- 0.6 mg/dl at 6 months, 1.7 +/- 0.5 mg/dl at 12 months, and 1.6 +/- 0.5 mg/dl at 18 months. The mean serum creatinine concentration at 18 months was not significantly different from that of 18 conventionally treated primary cadaveric renal transplant recipients (1.6 +/- 0.5 vs. 1.4 +/- 0.4 mg/dl, P = .31). A total of 67% of patients did not have any rejection episodes under this protocol, while 71% of patients never developed CsA nephrotoxicity. No patient was taken off CsA for progressive nephrotoxicity. We conclude that trough serum CsA levels of 50-75 ng/ml, as measured by radioimmunoassay, are sufficient to maintain effective immunosuppression in the long-term management of primary cadaveric renal transplant recipients. These values are much lower than previously recommended, and this approach ameliorates chronic CsA nephrotoxicity.     

Effect of calcium channel antagonists on renal function in hypertensive heart transplant recipients.

Orthotopic heart transplant recipients treated with immunosuppressive regimens based on cyclosporine have a high incidence of hypertension. Cyclosporine-induced nephrotoxicity characterized by afferent glomerular arteriolar vasoconstriction also develops in these patients. Calcium channel antagonists produce afferent glomerular arteriolar vasodilation. Angiotensin-converting enzyme inhibitors (ACEI) dilate the efferent arteriole and have been suggested to decrease glomerular filtration rate in subjects taking cyclosporine. To test the hypothesis that calcium channel antagonists would improve glomerular filtration rate in heart transplant patients receiving ACEI treatment, we reviewed the charts of our patients whose treatment for hypertension had been changed from an ACEI to a calcium channel antagonist. A change in renal function was assessed by the average of serum creatinine level, blood urea nitrogen, and creatinine clearance within 3 months before and after the change from ACEI to calcium channel antagonist. Blood pressure was assessed on two different occasions before and after conversion to calcium channel antagonist. The data were analyzed by a paired Student t test. Serum blood urea nitrogen and creatinine levels decreased significantly when patients were treated with calcium channel antagonists (p < 0.05). Creatinine clearance increased in all patients when the treatment was converted to a calcium channel antagonist (CCA) (ACEI = 56.4 +/- 19.3 ml/min versus CCA = 71.06 +/- 23.77, N = 9; p < 0.005). A 5-mm Hg decrease occurred in mean arterial pressure when treatment was changed from ACEI to calcium channel antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impairment of prednisolone metabolism by cyclosporine treatment in renal graft recipients

Pharmacokinetics of prednisolone were studied in 64 randomly chosen renal transplant patients treated with azathioprine and prednisolone (Aza-Po) or cyclosporine and prednisolone (CsA-Po). Intrinsic clearance for prednisolone was calculated after an oral test dose of 0.5 mg prednisolone/kg bodyweight. In 38 patients on Aza-Po treatment the mean clearance for prednisolone was 0.17 +/- 0.04 1/kg/hr (range 0.11-0.27) and in 39 patients on CsA-Po the mean prednisolone clearance was 0.12 +/- 0.02 (0.07-0.17) (P less than 0.001). Eight patients on CsA-Po were tested on three occasions; prednisolone clearance at 2-4 weeks was 0.13 +/- 0.02 (range 0.11-0.17), at 3-6 months 0.11 +/- 0.01 (0.10-0.12) and at 2-5 years 0.11 +/- 0.02 (0.09-0.14). In 11 patients the treatment was changed from Aza-Po to CsA-Po. The prednisolone clearance then decreased from 0.18 +/- 0.05 1/kg/hr (range 0.13-0.27) to 0.12 +/- 0.03 (0.10-0.16) (P less than 0.001). When the treatment was changed from CsA-Po to Aza-Po in 2 patients the prednisolone clearance increased from 0.12 and 0.10 to 0.17 and 0.12 1/kg/hr, respectively. These data show not only that the prednisolone metabolism is slower in cyclosporine-treated patients but also that this metabolism is retarded when azathioprine is replaced by cyclosporine, and that it is accelerated when cyclosporine is replaced by azathioprine. In the CsA-Po treated patients the prednisolone clearance was also found to be lower after 3-6 months than after less than one month (P less than 0.05) but there has been no further decrease in the prednisolone metabolism after up to more than 4 years of cyclosporine treatment.     

Significance of delayed graft function in cyclosporine-treated recipients of cadaver kidney transplants

Many transplant teams are reluctant to initiate cyclosporine immunosuppression in recipients of cadaver kidney grafts with delayed graft function (DGF). The renal function of cadaver kidney grafts in cyclosporine-treated recipients was compared in 47 recipients with DGF and 57 without DGF. Regardless of initial renal function, all recipients received prednisone, azathioprine, and oral cyclosporine 5 mg/kg/day or its intravenous equivalent. All kidneys were flushed with ice-cold intracellular electrolyte solution and cold-stored for 15-54 hr (mean of 31 hr) prior to transplantation at our hospital between April 10, 1985 and November 30, 1986. Rejection crises were treated with high-dose steroids or OKT3. Cyclosporine was discontinued during courses of OKT3. Recipients with DGF had significantly higher one-month serum creatinine nadirs (2.6 +/- 1.8 mg/dl vs. 1.5 +/- 0.5 mg/dl). Actuarial graft survivals were not significantly different at one year (82.2 +/- 5.5% vs. 82.6 +/- 6.4%, all graft losses included). Mean serum creatinine levels at six months and twelve months after grafting were not significantly different (1.7 +/- 0.4 mg/dl vs. 1.8 +/- 1.2 mg/dl and 2.0 +/- 0.5 vs. 1.7 +/- 0.7 mg/dl, respectively). Delayed graft function following cadaver kidney transplantation does not adversely affect intermediate term function of kidney grafts flushed with intracellular electrolyte solution and cold-stored until transplantation when a low-dose cyclosporine induction protocol is used and cyclosporine is discontinued during OKT3 administration.     

Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rats with renal isograft.

The question of whether pharmacological inhibition of the thromboxane A2 activity prevents cyclosporine-induced chronic renal dysfunction in a Lewis rat model of renal isograft was addressed. Transplanted animals were given a daily oral dose of cyclosporine (20 mg/kg; N = 15), cyclosporine (20 mg/kg) and the thromboxane A2 receptor antagonist GR32191 (3 mg/kg twice daily, by gavage; N = 15), or the vehicle alone (N = 12). Treatments were started the day of kidney transplant, and animals were monitored for 1 year. Cyclosporine-treated animals developed renal insufficiency, as documented by serum creatinine levels of 0.49 +/- 0.09, 0.95 +/- 0.12, and 1.38 +/- 0.15 mg/dL before and after 6 and 12 months of observation, respectively. Cyclosporine and GR32191 used in combination partially but significantly prevented the deterioration of renal function (serum creatinine, basal, 0.52 +/- 0.06; month 6, 0.68 +/- 0.04; month 12, 0.93 +/- 0.10 mg/dL). At the end of the study, GFR, as insulin clearance, was significantly lower in rats given cyclosporine (0.28 +/- 0.09 mL/min/100 g) than in rats given cyclosporine plus GR32191 (0.45 +/- 0.05 mL/min/100 g) or than in vehicle-treated animals (0.56 +/- 0.07 mL/min/100 g). Similar results were obtained for the effective RPF, measured as p-aminohippurate clearance. At the same time points, comparable to whole-blood cyclosporine levels were found in rats receiving cyclosporine alone and in those given cyclosporine plus GR32191. More than 50% of the animals on cyclosporine alone died from uremia before the end of the observation period. By contrast, rats receiving cyclosporine in combination with GR32191 had a prolonged survival.(ABSTRACT TRUNCATED AT 250 WORDS)     

Creatinine clearance after cimetidine administration: is it useful in the monitoring of the function of transplanted kidney?

BACKGROUND: Determination of clearance of endogenous creatinine using its plasma and urinary concentration (standard clearance), Cockroft and Gault formula, or MDRD formula (estimated clearance) is commonly performed for assessment of glomerular filtration rate. Although the evaluation of renal function in this way is useful, it is biased with an error resulting from secretion of creatinine in tubules. This error can be reduced by determining the clearance after administration of cimetidine, which competitively blocks creatinine tubular transport. METHODS: The study was performed in the group of 87 patients after renal transplantation. In this group, estimated clearance and creatinine clearance after cimetidine administration (1000 mg in 75 patients and then 1600 mg in 12 patients with plasma creatinine above 3 mg/dL) were determined. RESULTS: Analysis of mean percentage differences between clearance values after cimetidine administration and estimated clearance shows increasing contribution of creatinine tubular secretion along with plasma creatinine increase in renal transplant recipients. A higher dose of cimetidine resulted in lower clearance values in renal transplant recipients with plasma creatinine above 3 mg/dL. CONCLUSIONS: Creatinine clearance after administration of 1000 mg cimetidine seems to be a useful measure of glomerular filtration rate in renal graft recipients with plasma creatinine concentration below 2.5 mg/L. Higher dose of cimetidine would be needed to effectively block tubular excretion at higher concentrations of creatinine. Establishing an efficient but safe dose of cimetidine for such patients needs further investigations. As we have noticed that creatinine clearance calculated according to MDRD formula was similar to the clearance after administration of cimetidine, we propose a strategy of one GFR measurement at baseline using 24h urine collection after cimetidine administration and follow-up with creatinine clearance calculated from MDRD formula during standard check-up visits.     

Increased serum beta 2 microglobulin during rejection, cyclosporine-induced nephrotoxicity, and cytomegalovirus infection in renal transplant recipients

In 83 renal transplant recipients, serum beta 2 microglobulin (beta 2m) levels were significantly elevated during pretransplant uremia, rejection, cyclosporine-induced nephrotoxicity, and infections. In patients with normal serum creatinine, 74% had elevated serum beta 2m levels. None of the cyclosporine-treated patients had normal levels of beta 2m. Patients with stable renal allograft function receiving cyclosporine showed significantly higher serum beta 2m (P less than 0.001) and serum creatinine (P less than 0.01) levels than azathioprine treated patients. Patients with an irreversible rejection showed significantly higher serum concentrations of beta 2m than patients experiencing a reversible rejection (P less than 0.001). During cytomegalovirus (CMV) infection the serum beta 2m levels were elevated compared with other infections (P less than 0.001), while the serum creatinine was not. However, infected patients had higher serum levels of beta 2m and creatinine than patients with stable renal allograft function (P less than 0.001). Serum beta 2m may therefore be useful in the early diagnosis of CMV infection. To conclude, serum beta 2m levels cannot distinguish between rejection, cyclosporine nephrotoxicity, or infection.     

Six-month clinical outcome of cyclosporine microemulsion formulation (Sigmasporin Microral) in stable renal transplant patients previously maintained on sandimmun neoral

The trial objective was to investigate the feasibility and safety of conversion to a generic microemulsion cyclosporine in stable renal transplant patients premaintained on Neoral. We enrolled 75 patients from seven centers in five Middle Eastern countries monitored them for 6 months after conversion to Sigmasporin Microral. Readings at 0, 0.5, 1, 2, 3, 4.5, and 6 months included cyclosporine blood level, serum creatinine, liver enzymes, lipid profile, blood sugar, blood pressure and adverse events. Patients included 54 men and 21 women of mean age 38.9 +/- 10.7 years at 30.3 +/- 29.3 months post-transplantation maintained on Sigmasporin Microral dose of 2.8 +/- 1.0 mg/kg per day; they were observed to be stable throughout the study period as reflected by the therapeutic blood C(0) level of 181.6 +/- 102.1 and C(2) of 759.2 +/- 384.4. Their absorption profile as represented by C(2)/C(0) was 4.9 +/- 2.8, and C(2)/cyclosporine dose of 282.3 +/- 128.8. An average serum creatinine level of 116.1 +/- 29.5 mumol/L denoted stable graft function and their liver enzymes did not change during the study. No new-onset cases of hypertension, diabetes mellitus, or hyperlipidemia were reported among the patients. Graft function was stable for all patients, except for two incidences of mild acute rejection and two of mild cyclosporine nephrotoxicity; graft and patient survival rates were both 100%. Results of this 6-month study showed that Sigmasporin Microral was effective to maintain stable renal function in kidney transplant patients converted from Neoral with similar safety and tolerability profiles as those reported in the literature.     

Chronic cyclosporine-induced nephrotoxiciy in heart transplant patients: long-term benefits of treatment with mycophenolate mofetil and low-dose cyclosporine

BACKGROUND: Cyclosporine-induced nephropathy is a major limitation in heart transplant patients. Cyclosporine dose reduction may lead to substantial early improvement in renal function. Our aim was to study the long-term benefits of therapy with low doses of cyclosporine plus mycophenolate mofetil in heart transplant patients with drug-induced nephrotoxicity. METHODS: Twenty-five adult heart transplant patients with cyclosporine-related nephrotoxicity (mean posttransplant = 41.7 +/- 25.7 months) were included in the retrospective analysis (22 men, mean age = 58.8 +/- 7.9 years.). Patients were switched from azathioprine to mycophenolate mofetil (1 to 3 g/d), followed by a stepwise reduction in cyclosporine dosage (trough cyclosporine level maintained around 100 ng/mL). Renal function was determined by serial measurements of serum creatinine and glomerular filtration rate at 3-month intervals. RESULTS: With a mean follow-up of 30 +/- 13 months, the baseline creatinine of 2.37 +/- 0.5 mg/dL decreased to 1.59 +/- 0.40 mg/dL (P < .0001). The baseline glomerular filtration rate of 36.77 +/- 10.10 mL/min improved to 54.98 +/- 13.80 mL/min (P < .0001). The cyclosporine level was the unique independent variable associated with renal functional improvement (partial R(2) = 0.4). Within the first 3 months, renal function displayed a rapid improvement after conversion to mycophenolate mofetil (P < .001), reaching a plateau, without further significant improvement over the course of time. CONCLUSIONS: Cyclosporine-induced nephrotoxicity is not a progressive, irreversible disease. Reduction in cyclosporine exposure by addition of mycophenolate mofetil is useful to achieve long-term renal functional improvement, thereby avoiding chronic renal failure. A unique, significant factor associated with this improvement was the reduction in cyclosporine level.     

Anti-CD25 monoclonal antibody sequential immunosuppressive induction therapy in renal transplants with high risk of delayed graft function

There is little experience on the use of monoclonal antibodies that block the high-affinity interleukin-2 receptor (basiliximab and daclizumab) in sequential therapy in renal transplants with risk of delayed graft function. This study sougth to test the efficacy and safety of the substitution of anticalcineurins with two doses of basiliximab or daclizumab in the immediate posttransplant period for recipients at risk of delayed renal graft function. Immunosuppression consisted of steroids, mycophenolate mofetil, and two doses of basiliximab (20 mg/day) on days 0 and 4 posttransplant or daclizumab (1 mg/kg per day) on days 0 and 15 posttransplant. Anticalcineurins were not administered until the beginning of graft function. Among 49 recipients (mean age 63.5 +/- 10.5 years), 40 received a kidney from a donor over 60 years of age, three from a non-heart-beating donor, and six from donors with an acute elevation of serum creatinine to 2.4 +/- 0.86 (1.7-3.7). At a mean follow-up of 14.2 +/- 8.4 months, five patients experienced acute rejection episodes. Only 15 patients needed posttransplant dialysis (2.7 +/- 1.6). In 11 patients, cyclosporine (CsA) was introduced at 6 +/- 2.9 days posttransplant and in 37, tacrolimus on 8.6 +/- 3.6 days posttransplant. The incidence of kidney graft loss was 16.3%. Patient survival was 96%. Thirty-nine recipients are alive with functioning grafts, with mean serum creatinine of 1.4 mg/dL. In conclusion, substitution for anticalcineurins with interleukin-2-receptor blockade in the immediate posttransplant period for patients at risk of delayed graft function minimizes nephrotoxicity and reduces tubular necrosis, without increasing the risk of an acute rejection episode.     

Reversal of chronic cyclosporine nephrotoxicity after heart transplantation-potential role of mycophenolate mofetil.

BACKGROUND: Chronic cyclosporine nephrotoxicity (CCN) after heart transplantation is a progressive condition that may lead to end-stage renal failure. The extent to which CCN is reversible with reduction or withdrawal of cyclosporine therapy is unknown. The aim of this study was to assess the reversibility of CCN and to assess the safety and efficacy of a strategy of cyclosporine dosage reduction, combined with conversion from azathioprine to mycophenolate mofetil (AZA/MMF switch) to maintain immunosuppression. METHODS: An AZA/MMF switch followed by cyclosporine dose reduction was undertaken in 30 heart transplant recipients (23 men, 7 women; mean age, 54 +/- 2 years) with established CCN at a mean of 90 +/- 9 months after transplantation (range, 17-182 months). The mean maintenance MMF dosage was 2.3 +/- 0.1 g/day (n = 28). Mean cyclosporine dosage was decreased from 2.3 +/- 0.2 mg/kg/day before AZA/MMF switch to 1.6 +/- 0.2 mg/kg/day. RESULTS: Three patients (10%) were withdrawn from MMF, 2 because of diarrhea and the third because of severe pneumonia that developed within 2 weeks of AZA/MMF switch. All 3 were restabilized with AZA. One patient (4%) experienced acute rejection 7 months after AZA/MMF switch. This resolved after an oral pulse of prednisolone. Systemic infections occurred in 6 patients within 12 months of AZA/MMF switch. Actuarial survival 1 year after AZA/MMF switch was 86% +/- 6%. One patient died of infection and 3 of other causes. Serum creatinine concentration decreased from 248 +/- 15 micromol/liter before cyclosporine dosage reduction to 193 +/- 11 micromol/liter and 206 +/- 19 micromol/liter at 3 and 12 months after dosage reduction (both p < 0.01 versus baseline, n = 23). Of the 23 patients who remained on MMF at 12 months, a decrease in serum creatinine was documented in 19 (83%). Four patients showed no improvement or showed deterioration in renal function, and three of these progressed to end-stage renal failure. CONCLUSIONS: Chronic cyclosporine nephrotoxicity has a significant reversible component in most patients. A strategy of AZA/MMF switch combined with cyclosporine dosage reduction is generally well tolerated and results in short-term improvement in renal function in most patients. Close vigilance is required during the first 12 months after AZA/MMF switch because both acute rejection and infection may occur.     

Creatinine Clearance after Cimetidine Administration—Is It Useful in the Monitoring of the Function of Transplanted Kidney?

Background. Determination of clearance of endogenous creatinine using its plasma and urinary concentration (standard clearance), Cockroft and Gault formula, or MDRD formula (estimated clearance) is commonly performed for assessment of glomerular filtration rate. Although the evaluation of renal function in this way is useful, it is biased with an error resulting from secretion of creatinine in tubules. This error can be reduced by determining the clearance after administration of cimetidine, which competitively blocks creatinine tubular transport. Methods. The study was performed in the group of 87 patients after renal transplantation. In this group, estimated clearance and creatinine clearance after cimetidine administration (1000 mg in 75 patients and then 1600 mg in 12 patients with plasma creatinine above 3 mg/dL) were determined. Results. Analysis of mean percentage differences between clearance values after cimetidine administration and estimated clearance shows increasing contribution of creatinine tubular secretion along with plasma creatinine increase in renal transplant recipients. A higher dose of cimetidine resulted in lower clearance values in renal transplant recipients with plasma creatinine above 3 mg/dL. Conclusions. Creatinine clearance after administration of 1000 mg cimetidine seems to be a useful measure of glomerular filtration rate in renal graft recipients with plasma creatinine concentration below 2.5 mg/L. Higher dose of cimetidine would be needed to effectively block tubular excretion at higher concentrations of creatinine. Establishing an efficient but safe dose of cimetidine for such patients needs further investigations. As we have noticed that creatinine clearance calculated according to MDRD formula was similar to the clearance after administration of cimetidine, we propose a strategy of one GFR measurement at baseline using 24h urine collection after cimetidine administration and follow-up with creatinine clearance calculated from MDRD formula during standard check-up visits.     

Daily renal hypoperfusion induced by cyclosporine in patients with renal transplantation.

A variety of side effects are associated with the use of cyclosporine, the most relevant of which remains the renal toxicity. We did parallel studies on cyclosporine pharmacokinetics and renal function in patients who had a recent kidney transplant and were given cyclosporine as a part of their immunosuppressive therapy. Seven consecutive renal transplant patients were studied at the end of a month of treatment while on different oral cyclosporine doses (5, 3.5, 2.5, or 1.5 mg/kg, twice a day, respectively). Cyclosporine pharmacokinetics profiles and renal function parameters (GFR and renal plasma flow [RPF], as inulin and p-amino hippurate clearances, respectively) were determined before and over a 12-hr period after each single dose of cyclosporine. Plasma levels and urinary excretion rate of endothelin were also studied before and after the highest cyclosporine dose (5 mg/kg). Mean trough levels, area under the curve values, and maximum concentration of blood cyclosporine were comparable after 5 and 3.5 mg/kg cyclosporine and decreased in a dose-dependent manner after the lower doses (2.5 and 1.5 mg/kg). In the same patients GFR declined on average 63%, 53%, 35%, and 18%, 2-4 hr after maximum cyclosporine concentration was reached. As blood levels of cyclosporine returned to trough, GFR progressively increased to baseline. Similar results were found for RPF; 5 mg/kg cyclosporine did not modify endothelin plasma levels. By contrast, urinary excretion of the peptide increased significantly (P less than 0.01) in the 6 hr that followed cyclosporine administration and returned within the normal range in the subsequent 6 hr. Following each oral administration of cyclosporine, 2-4 hr after peak blood concentration was reached, patients showed renal hypoperfusion, transient and rapidly reversible. This was associated with an increased urinary endothelin excretion rate that was also transient. It is speculated that an excessive renal synthesis of endothelin is the cause of the daily renal hypoperfusion observed in patients with renal transplants given cyclosporine.