D. Golden

Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years.

The therapeutic efficacy of cyclosporine (CsA) as an immunosuppressive agent was complemented by a modest, long-term incidence of toxic complications in 402 renal allograft recipients engrafted one to five years prior to analysis. The overall patient and graft survivals at one year were 97% and 84% (actual), and at five years 92% and 67% (actuarial). The immunosuppressive therapeutic index was excellent: only 12% of allografts were lost from rejection, with 5% of patients succumbing to infection. While infections were common, tending to emanate in the urinary tract or to be viral in etiology, they were generally mild and readily controlled. Only four patients displayed malignancies; none succumbed to this cause. The most common toxic complication was hypertrichosis, which was accentuated in pediatric patients. While tremors occurred in 20% of patients, primarily during the first three months, other neuroectodermal complications of parethesias, depression, somnolence, and seizures were rare. Hepatotoxicity, which was noted in 50% of patients, particularly recipients of cadaveric grafts, generally was first seen as a transaminase elevation, at least partially reversible by dose-reduction and abating by the third year. Associated disturbances of cholelithiasis and pancreatitis were occasionally observed. Nephrotoxicity was the only persistent, long-term complication. Hypertension occurred in 72% of patients during the first month, 36% in the second year, and about 15% thereafter. Hyperuricemia, which occurred in about 30% of recipients during the first two years, was occasionally associated with symptomatic gout. The mean serum creatinine level remained elevated throughout the follow-up period at 1.8—1.9 mg/dl, suggesting persistent, but nonprogressive, drug-induced renal injury. The present analysis documents the relative safety of CsA for long-term therapy, and highlights the need for new approaches to ameliorate drug-induced nephrotoxicity.

Causes of graft loss beyond two years in the cyclosporine era

While CsA has improved renal-allograft survival rates in the first 2 years compared with Aza, Terasakis multicenter study (1) failed to show any difference in long-term graft survival in CsA-Pred versus Aza-Pred-treated recipients. The present study examines the long-term graft-survival rates at a single center using CsA immunosuppression and seeks to discern the causes of 58 graft losses among 343 patients with functioning grafts beyond 2 years posttransplantation. The 6-year primary and cadaveric actuarial graft survival at this institution is 59% with a graft half-life of 10 years, which is better than the 40% and 7.7 years, respectively, reported by Terasaki (1) for primary cadaveric recipients on Aza-Pred. It is also better than the 41%, 6-year survival and 5.5-year half-life for primary cadaveric recipients treated with CsA-Pred as reported in the multicenter study. (1) Less experience with the use of CsA may explain the latter comparison. Primary LRD grafts at this institution (2/3 haploidentical) have a 6-year actuarial survival of 77% and a half-life very closely approximating that of HLA-identical LRD grafts under Aza (23.4 years). These results demonstrate that CsA mitigates the effects of HLA incompatibility to reduce graft survival. The most common cause of graft loss beyond 2 years was chronic rejection (36.2%) followed by noncompliance (27.6%). Patient deaths resulted in 13 of the 58 graft losses; most of the deaths were related to cardiovascular diseases. Only 3 patients died from causes that could be attributed to CsA immunosuppression; 2 from sepsis and 1 from viral hepatitis. Acute rejection caused 8.6% of the graft losses on continuous CsA therapy. When immunologic risk factors were analyzed, the entire graft-loss group had a significantly higher proportion of retransplant patients than the graft-survival group (P less than 0.005), suggesting that prior transplantation imposes a higher risk for graft loss not only acutely but long term as well. However, retransplanted patients were significantly less likely to lose their grafts because of noncompliance (P less than 0.005). Male patients were found to be significantly more noncompliant.

The adverse impact of cytomegalovirus infection on clinical outcome in cyclosporine-prednisone treated renal allograft recipients

Cytomegalovirus (CMV) infection was diagnosed in 28% (n=144) of 516 renal allograft recipients treated with cyclosporine-prednisone (CsA-Pred) immunosuppressive therapy. The majority of infections produced either asymptomatic (n=37) or mild-to-moderate (n=75) clinical disease, while 10% were lethal (n=14). Transplantation from a seropositive donor to a seronegative recipient was associated with an increased incidence of (CMV) infection but did not predispose to more severe clinical disease. Similarly, donor source (cadaver [CAD] vs. living-related donor [LRD]), age ≥45 years, and antecedent pulse steroid therapy for the treatment of acute rejection were not correlated with clinically more severe disease. An increase in serum creatinine to ≥25% of preinfection nadir values occurred in association with CMV infection in 106 patients, returning to nadir values or below in 74.5% of these individuals. CMV infection

Stability of renal allograft function associated with long-term cyclosporine immunosuppressive therapy ― five year follow-up

To examine the evolution of renal allograft function in kidney transplant recipients receiving long-term cyclosporine therapy, we evaluated 50 cadaveric and 30 living-related renal transplant recipients having graft survival greater than or equal to 12 months and an opportunity for 5 years of follow-up. Linear analysis of long-term allograft function in each patient was undertaken by plotting reciprocal serum creatinine (1/Crs) values vs. time. Mean follow-up was 49 +/- 18 months. Actual 3-year and 5-year allograft survivals were 83.8% (n = 80) [corrected] and 73.3% (n = 75) [corrected], respectively. Collective analyses of values of 1/Crs measured at yearly intervals and of the slopes of the curves obtained by plotting 1/Crs vs. time for each patient suggested that long-term use of CsA is associated with impaired but generally stable allograft function 1-5 years posttransplant. The aggregate rate of decline of renal allograft function in the study population did not differ from that of a historical control group consisting of 59 renal transplant recipients treated with a conventional prednisone-azathioprine immunosuppressive regimen. Donor source, diabetes, and diastolic hypertension (diastolic BP greater than 95 mmHg in more than half the follow-up readings) were not correlated with a more rapid rate of decline of allograft function as reflected in the slopes of the 1/Crs vs. time curves between 12 months posttransplant and the end of follow-up. In contrast, a significantly greater rate of decline of cadaveric allograft function was observed in patients with 12-month Crs values greater than 2.5 mg% and recipients of greater than 2 HLA-A,B-mismatched cadaveric kidneys. The data do not support an indication for routine conversion from CsA to azathioprine following successful renal transplantation.

The impact of cytomegalovirus infection on seronegative recipients of seropositive donor kidneys versus seropositive recipients treated with cyclosporine-prednisone immunosuppression.

To assess the impact of cytomegalovirus (CMV) infection in D+R- patients treated with eyclosporine (CsA)-prednisone immunosuppression, we compared the incidence of CMV infection, severity of disease, and the 1, 2, and 3-year actual graft and patient survival rates of CMV-infected D+R- patients with R+ patients from a group of 516 renal allograft recipients at our center. CMV infection occurred more frequently in 27/56 D+R- patients (48%) versus 111/376 R+ patients (29%) (P<0.01) and first transplants (47%) vs. 30%, P0.05). There were no significant differences in CMV disease severity between the aggregate D+R- and R+ patient groups and when subgroups of these patients receiving cadaveric donor (CAD), living-related donor (LRD), first, or retransplant allografts were compared.

Complications of Cyclosporin Therapy

Cyclosporin (CsA) therapy has improved the outcome of allotransplants. Because of a relatively selective action on T lymphocytes, CsA therapy causes fewer immunosuppressive complications of infection or malignancy compared to previous chemical agents, which were relatively nonspecific in their spectrum of action on lymphoid versus nonlymphoid cells. Gastrointestinal complaints after oral administration and vasomotor reactions after intravenous administration represent pharmacologic toxicities rarely of major clinical import. Drug-induced complications involve primarily the neuroectodermal, or the mesenchymal hepatic and renal, systems. While the former group of complications are rarely severe, mesenchymal nephrotoxicity poses a major limitation of drug therapy. On the one hand, reductions by 33% of normal renal function in patients treated with CsA for autoimmune disease appear to be reversible on discontinuance of therapy. On the other hand, severe renal dysfunction occurs in transplant recipients, particularly in the presence of concomitant therapy with nephrotoxic drugs. In the kidney transplant setting, numerous factors exacerbate the druginduced injury, including adverse donor procurement conditions, prolonged graft storage, and allograft rejection. Since the clinical and histologic findings in CsA nephrotoxicity tend to be pleiomorphic, no single diagnostic or therapeutic strategy has emerged. However, insights gained through pharmacologic monitoring of renal allograft recipients suggest that the group at increased risk for nephrotoxicity can be identified by elevated serum drug trough levels, increased area under the plasma time concentration curve, prolonged elimination half-life, and heightened pharmacodynamic sensitivity to CsA. Analysis of pharmacologic data in conjunction with clinical results should provide drug regimens of maximal therapeutic index with minimal risk of complications.