Amelioration of chronic renal allograft dysfunction in cyclosporine-treated patients by addition of azathioprine

Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)     

Immunoregulatory mechanisms in cyclosporine-treated renal allograft recipients

Cyclosporine (CsA)-treated recipients of a primary cadaveric (CAD) renal allograft were postoperatively evaluated for their donor and nonspecific immune responsiveness. Recipients with posttransplant (Tx) T helper (TH):T suppressor (TS) cell ratios less than 1.0 (averaged for the first 0-30 post-Tx days) had significantly better one-year serum creatinines (SCr) of 1.8 +/- 0.7 vs. 2.3 +/- 0.6 for recipients with TH:TS ratios greater than 1.0, P less than 0.05. Significantly fewer rejection episodes (30 vs. 57) and immune graft losses (10 vs. 19) were experienced by recipients with TH:TS ratios less than 1.0 vs. greater than 1.0, P less than 0.001 and 0.05, respectively. Recipients with TH:TS ratios less than 1.0 vs. greater than 1.0 displayed significantly lower post-Tx panel mixed lymphocyte culture (PMLC) stimulation indices (SI) of 24 +/- 11 vs. 38 +/- 6, P less than 0.05 and donor MLC SI of 15 +/- 6 vs. 31 +/- 8, P less than 0.05, respectively. Moreover, the post-Tx:pre-Tx donor MLC ratio of 0.58 +/- 0.2 vs. 1.1 +/- 0.32 was significantly lower in recipients with TH:TS ratios less than 1.0 vs. greater than 1.0, P less than 0.05. The suggested donor hyporesponsiveness in recipients with post-Tx TH:TS ratios less than 1.0 was further investigated by studying 46 CsA-treated allograft recipients for their ability to display regulatory T cell or adherent monocyte MLC suppressor activity. With a mean follow-up time of 5 +/- 4 months (range 0.5-14 months) we observed that 46% (21/46) of the patients displayed T cell suppressor activity, including 35% (16/46) with T-donor-specific and 46% (21/46) with T non-specific MLC suppressor activity. Additionally, 59% (27/46) of the patients also displayed nonspecific adherent monocyte MLC suppression. Recipients displaying either T cell or adherent monocyte suppression experienced significantly fewer rejection episodes than patients with no suppressor cell activity (P less than 0.05). Moreover, patients with T cell suppressor activity displayed a significantly lower panel and donor MLC vs. patients not displaying T suppressor activity (P less than 0.05. and 0.05, respectively). Finally, there was a significant correlation between the display of T cell suppressor activity in patients who were matched with their donors at the HLA-DR locus vs. no display of T suppressor activity in those patients unmatched with their donors at the HLA-DR locus.     

Immunopharmacodynamic evaluation of cyclosporine-treated renal allograft recipients

Since the mode of action of cyclosporine (CsA) in man is incompletely understood, there are no monitoring tools to assess immunosuppressive effect in vivo. In vitro CsA inhibits lymphoproliferation in response to allogeneic and mitogenic stimuli, presumably due to reversible suppression of T helper cell generation of interleukin-2. Therefore the present studies examined the immunosuppressive effect of patient sera on a third-party mixed lymphocyte reaction (MLR) as a pharmacodynamic approach to quantify patient responses to CsA administration. Four kinetic patterns of in vitro immunosuppressive activity were discerned: 24/28 (86%) patients showing two cycles of MLR inhibition--namely, a first peak corresponding to absorption of CsA and an independent second peak of immunosuppression (type I), were free of rejection; while 17/23 (74%) patients demonstrating one cycle corresponding to the peak of CsA absorption (type II) suffered rejection episodes (P less than 0.001). In addition, 20 patients generating continuously high levels of in vitro serum activity (type III) were almost all free of rejection, but manifested nephrotoxicity; while two patients showing continuously low levels (type IV) suffered graft loss due to irreversible rejection (P less than 0.01). Thus failure to display either a second peak or continuously high levels of MLR inhibition was associated with a markedly increased incidence of rejection (76% versus 16%). The in vitro functional characteristics of peak-2 were similar to those of CsA, as assessed by the kinetics of inhibition of MLR lymphoproliferation or cell-mediated lympholysis (CML), and by gross chemical properties of partitioning into organic solvents and heat stability. These findings suggest that pharmacodynamic analysis by MLR inhibition not only affords a useful parameter of immunosuppression, but also may provide an in vitro model to dissect the generation and biotransformation of active CsA metabolites.     

Rapamycin in patients with chronic renal allograft dysfunction

PURPOSE: Nephrotoxicity of calcineurin inhibitors (CNI) complicates the management of chronic renal allograft dysfunction. Rapamycin is a promising immunosuppressive agent free of nephrotoxicity. The effect of conversion from CNI to rapamycin in recipients with chronic allograft dysfunction is still unclear. We investigated the effect of rapamycin in patients with chronic allograft dysfunction. METHODS: We conducted a prospective study on kidney transplant recipients with chronic allograft dysfunction. The patients were under classic CNI, mycophenolate mofetil, and prednisolone triple therapy. They had progressive deterioration of the allograft function. They were converted from CNI to rapamycin directly and observed for 6 months. The CNI serum levels before the conversion were within recommended range. Allograft function, clinical features and adverse effects were evaluated before and after the rapamycin conversion. RESULTS: A total of 16 patients were enrolled. Six of them (37.5%) failed to have a smooth conversion because of deterioration of allograft function and intractable adverse effects. Ten patients (62.5%) went through the 6-month observation period with improved graft function. The average reduction of serum creatinine was 27.7% (p < 0.001) in successful conversion. There were no significant differences on age, gender, lipid profile, sugar control, and rapamycin levels between successful and failed conversion. Anemia and diastolic blood pressure were significantly improved after successful conversion. The failed patients had a longer transplantation period (6.1 +/- 4.1 vs. 11.2 +/- 3.4 yr, p < 0.05). Two of them (12.5%) developed bacteria pneumonia. Self-limited diarrhea developed in three patients (18.8%). CONCLUSION: We suggested that conversion from CNI to rapamycin was beneficial in some kidney transplant recipients with chronic allograft dysfunction.     

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.     

Vitamin C improves endothelial dysfunction in renal allograft recipients.

BACKGROUND: Endothelial function is impaired in renal allograft recipients but the effects of antioxidant vitamin therapy on endothelial function in such patients is unknown. METHODS: Thirteen renal allograft recipients were randomized to vitamin C or placebo in a double blind cross-over study design. Flow-mediated endothelium-dependent dilation and glyceryltrinitrate-induced endothelium-independent dilation of the brachial artery were assessed before and 2 h after oral administration of 2 g vitamin C or placebo. RESULTS: Plasma vitamin C levels increased from 33.5+/-17.0 micromol/l to 98.8+/-60.2 micromol/l after treatment (P=0.0001). Endothelium-dependent dilation improved (from 1.6+/-2.6 to 4.5+/-2.5%) after vitamin C administration but was unchanged after placebo (1.9+/-1.5 to 1.8+/-2.5%; P=0.003 for vitamin C vs placebo). There was no significant change in endothelium-independent dilation in response to vitamin C. Vitamin C was also associated with a significant increase in the lag time in dilute serum oxidation (P=0.001). CONCLUSIONS: Vitamin C acutely improves flow-mediated, endothelium-dependent dilation and increases the resistance of lipoproteins in dilute serum to oxidation in renal transplant recipients.     

Posttransplant diabetes mellitus in cyclosporine-treated renal allograft patients: a case-control study

The incidence and risk factors for the development of posttransplant diabetes mellitus (PTDM) was retrospectively evaluated in cyclosporine-treated renal transplant patients. An incidence of 9.4% was observed over a 10-year period. Weight and body mass index were risk factors identified in a case-controlled study. Age, race, family history of DM, and cyclosporine and prednisone doses were not associated with the development of PTDM. We concluded that the development of PTDM is mainly related to weight. All efforts must be taken to avoid this complication.     

Onset of dialysis encephalopathy in cyclosporine-treated renal allograft recipients

Three patients who developed typical features of dialysis encephalopathy following renal transplantation are presented. No patient had evidence of overt neurological dysfunction pretransplantation. All patients were taking cyclosporine at the time of onset of neurological disease. Two patients died as a result of their neurological condition. The third patient made a satisfactory recovery. Factors responsible for the onset of dialysis encephalopathy in the renal posttransplantation period are discussed. We propose that cyclosporine may have been an important precipitating factor of the neurological syndrome of these patients.     

Immunophenotype of infiltrating cells in protocol renal allograft biopsies from tacrolimus-versus cyclosporine-treated patients

The prevalence of subclinical rejection is lower in patients receiving tacrolimus than in patients treated with cyclosporine. However, it is not known whether this difference is related to the modulation of a specific cell immunophenotype. We perform a two case-one control study in patients treated with tacrolimus (n=44) or cyclosporine (n=22) with a protocol biopsy performed at 4 to 6 months. Immunophenotype of infiltrating cells was evaluated with monoclonal antibodies directed against CD45 (all leukocytes), CD3 (T lymphocytes), CD68 (monocytes/macrophages), and CD20 (B lymphocytes) and expressed as interstitial positive cells/mm(2). The number of interstitial CD45 (290+/-209 vs. 696+/-560; P<0.01), CD3 (121+/-84 vs. 208+/-104; P<0.01), and CD68 (155+/-232 vs. 242+/-280; P<0.05) but not CD20 (137+/-119 vs. 197+/-154) positive cells was lower in tacrolimus-treated patients. T lymphocytes and macrophages interstitial infiltration was reduced in tacrolimus treated patients evaluated with protocol biopsies in comparison to cyclosporine-treated patients.     

Hepatitis B liver disease in cyclosporine-treated renal allograft recipients

To establish the impact of cyclosporine on the development of chronic hepatitis in hepatitis B surface antigen (HBsAg)-positive renal allograft recipients, the incidence and outcome of chronic hepatitis in 20 cyclosporine-treated patients (CsA group) were compared with 13 azathioprine-treated patients (AZA group). All 33 patients had a functioning graft for 2 years or longer. Twenty-nine of the 33 patients were HBsAg-positive prior to the initiation of hemodialysis. The difference in the incidence of chronic hepatitis between these 2 groups was not statistically significant (78.6% in the AZA group vs. 52.4% in the CsA group, P = 0.12). In the CsA group, 3 patients (15%) developed liver cirrhosis, and there was a 5% mortality. The AZA group had a 7.7% mortality, and 4 patients (30.8%) developed liver cirrhosis. Serial serum samples obtained from these 33 HBsAg-positive renal allograft recipients were analyzed for antibody to hepatitis D virus (anti-HD). Anti-HD was found in 3 patients. Two of them developed anti-HD seroconversion after renal transplantation during a mean follow-up of 4 years. All 3 patients developed chronic hepatitis and 2 of them have subsequently developed liver cirrhosis. There was a mortality of 6.1% in 33 HBsAg-positive patients compared with a 5.3% mortality in 57 HBsAg-negative renal allograft recipients. The difference was not statistically significant. We conclude from this study that (1) CsA-treated HBsAg-positive renal allograft recipients have a tendency to develop chronic hepatitis like AZA-treated patients; (2) HBsAg-positive patients have an increased risk of HDV superinfection after renal transplantation, and this may result in rapid progression to liver cirrhosis; (3) HBsAg-positive patients who acquire HBsAg prior to renal transplantation have a low overall mortality, including death due to liver disease, for a mean follow-up of 4 years.     

Renin-angiotensin-aldosterone system and vasopressin in cyclosporine-treated renal allograft recipients

Eleven patients, who had undergone renal transplantation and who had hypertension, aged 19-56 years, were treated with cyclosporine and prednisolone. We measured plasma renin activity, aldosterone and vasopressin (RIAs) at the first, second and third week and again 9 to 12 months after transplantation. Plasma renin activity was in the low-normal range throughout (0.31 +/- 0.05, 0.30 +/- 0.03, 0.32 +/- 0.05 ng/ml/h on short- vs. 0.32 +/- 0.04 ng/ml/h on long-term), aldosterone showed a tendency to decrease (114 +/- 27, 72 +/- 18, 71 +/- 11 pg/ml on short- vs. 54 +/- 23 pg/ml on long-term), whereas vasopressin remained moderately increased during the observation period (10.5 +/- 0.8, 10.4 +/- 1.6, 8.9 +/- 0.6 pg/ml on short- vs. 9.6 +/- 1.0 pg/ml on long-term). We then investigated the reactivity of the renin-system in 5 of the patients by stimulating renin release by captopril. Increases in plasma renin activity were only moderate (0.35 +/- 0.03 vs. 0.66 +/- 0.21 ng/ml/h) and blood pressure dropped only slightly (148 +/- 2.0/98 +/- 1.2 vs. 141 +/- 4.6/95 +/- 4.2 mmHg). Levels of plasma aldosterone were significantly suppressed from a low baseline (46.4 +/- 13.5 vs. 25.3 +/- 6.1 pg/ml, p less than 0.05). The increase in vasopressin was unaffected by captopril (9.6 +/- 1.0 vs. 8.8 +/- 0.4 pg/ml). Our results suggest that in renal transplantation patients with good graft function, the activity of the renin system is unaffected by cyclosporine treatment on short- and on long-term. Vasopressin stimulation does not seem to depend on the renin system and might play a role as a vasoconstrictor in the face of a denervated kidney.     

Serum C-reactive protein concentrations in cyclosporine-treated renal allograft recipients

Acute or persistent elevations in serum C-reactive protein (CRP) concentration have been shown to be of value in diagnosing acute rejection episodes in azathioprine (AZA)-treated renal transplant recipients. To assess whether changes in serum CRP level might assist in differentiating nephrotoxicity from acute rejection in cyclosporine (CsA)-treated renal transplant recipients, we measured changes occurring in serum CRP concentrations in 74 CsA patients in response to transplant operation, acute rejection, cyclosporine nephrotoxicity, and serious infection, and compared these values with changes in AZA patients. Serum CRP concentration rose in response to operation in virtually all patients, regardless of immunosuppressive regimen, from mean baselines of 5.9 +/- 2.7 mcg/ml (AZA) and 6.8 +/- 6.5 mcg/ml (CsA) to mean peak levels of 43.8 +/- 33.4 mcg/ml and 65.1 +/- 39.5 mcg/ml, respectively. CRP rose during 76% of acute rejection episodes in AZA patients by a mean of 29.7 +/- 37.4 mcg/ml. In contrast, in 80% of acute rejection episodes of CsA patients, CRP remained undetectable or failed to rise above a stable, minimally elevated baseline. Similarly, there was no elevation in CRP in 9 of 10 episodes of nephrotoxicity. In 14 CSA patients with serious infections (8 pulmonary, 3 intraabdominal, 3 genitourinary), CRP rose by a mean of 67.7 +/- 50.7 mcg/ml. Thus, although CRP rises significantly with operation or serious infection in CsA patients, CRP fails to rise with nephrotoxicity or acute rejection.     

Posttransplant hyperglycemia. Increased incidence in cyclosporine-treated renal allograft recipients

The incidence of posttransplant diabetes mellitus (PTDM) was compared in two groups of renal allograft recipients. These were all nondiabetic patients who had been transplanted between 1979 and 1987 and received either azathioprine-methylprednisolone (group 1) or cyclosporine-methylprednisolone (group 2) therapy as maintenance immunosuppression. The incidence of PTDM in group 1 was 9.1% vs. 18.6% in group 2 (P less than .05). The mean daily dose of methylprednisolone during the initial 2 months posttransplant was not greater among the PTDM patients of groups 1 or 2. Cyclosporine levels and mean daily CsA doses during the initial 2 posttransplant months were also not different among the CsA-PTDM and euglycemic CsA patients. Posttransplant diabetes mellitus occurred rapidly (less than 2 months) and required insulin therapy in the majority of cases. Increased age (greater than 40 years) was associated with a higher risk for PTDM, however, the greater incidence accompanying increased body weight only approached significance. Patient gender and donor source were not associated with significant risk for PTDM. The development of PTDM was accompanied by a significant decrease in graft survival at 3 years in the entire PTDM population and at 4 years in the CsA-PTDM subgroup. Actuarial patient survival was not adversely affected. The current study suggests that CsA may be diabetogenic when administered with methylprednisolone to renal allograft recipients. The adverse effect on allograft survival requires further investigation. These results may also have important implications for pancreatic and islet cell transplantation.