Richard Thistlethwaite

BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added. CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Reducing the size of a liver for use in a recipient smaller than the donor is one way to reduce mortality before orthotopic liver transplantation in children because of the scarcity of pediatric organ donors. In this report, we review the results of this approach over the past 2 years, during which we have used reduced-size orthotopic liver transplantation routinely in small children. Forty-nine children underwent orthotopic liver transplantation between September, 1986, and October, 1988; orthotopic liver transplantation with a whole organ (full-size orthotopic liver transplantation) was performed in 36 children, whereas 13 patients received reduced-size orthotopic liver transplantation. In two pairs of patients, the reduced grafts were obtained from single donors, using a "split-liver" procedure. All grafts were implanted in the orthotopic position following total recipient hepatectomy. The preoperative diagnostic categories were not significantly different between groups. Patients receiving reduced-size orthotopic liver transplantation were younger (1.6 +/- 1.5 vs. 4.4 +/- 4.6 years), and a higher percentage were in the intensive care unit prior to transplant (31 vs. 9%). Thirty of 36 (82%) patients receiving full-size orthotopic liver transplantation and 10 of 13 (77%) patients receiving reduced-size orthotopic liver transplantation are alive 3 to 27 months after transplantation. The rates of retransplantation were 24% for full-size orthotopic liver transplantation and 15% for reduced-size orthotopic liver transplantation. Despite the greater complexity of reduced-size orthotopic liver transplantation and the higher frequency of critically ill recipients selected for the procedure, the results of reduced-size orthotopic liver transplantation are comparable with full-size orthotopic liver transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperlipidemia poses a risk for cardiovascular disease in both hemodialysis and renal transplantation patients. Although lipid profiles differ between the 2 populations, we evaluated the possibility that both groups have similar abnormalities of lipoprotein(a) [Lp(a)]. Mean serum Lp(a) and standard error of the mean (SEM) in hemodialysis and transplant recipients was 16.6 +/- 4.7 and 18.3 +/- 3.6 mg/dl, respectively, compared with 10.7 +/- 4.1 mg/dl in healthy controls, p less than 0.05. That serum Lp(a) levels are significantly elevated in dialysis and renal transplantation patients suggests at least 1 common pathogenic mechanism for the high incidence of atherosclerosis in both groups.

OBJECTIVE: Cholesteryl ester transfer (CET) is accelerated in patients with IDDM treated with conventional (subcutaneous) insulin therapy (CIT) and a number of other disorders associated with premature cardiovascular disease. We have shown that in IDDM this disturbance is closely linked to iatrogenic hyperinsulinemia (HI), because it was reversed when insulin was administered by the intraportal (i.p.) route. In this study, we sought to determine whether HI after successful pancreas-kidney transplantation (PKT) has the same adverse effect on CET. RESEARCH DESIGN AND METHODS: CET was measured by both mass and isotopic assays and compared in two groups of euglycemic non-insulin-requiring IDDM PKT patients with either systemically draining allografts and persistent HI or grafts with portal vein anastomoses that were normoinsulinemic (PK-P). A third group of eight nondiabetic kidney transplant (KT) patients receiving the same immunosuppressive drugs served as control subjects. RESULTS: CET in pancreas-kidney transplantation subjects with systemic venous drainage (PK-S) was increased (P < 0.001) to the same level we have reported previously in IDDM patients receiving CIT and was significantly higher (P < 0.001) than in those subjects with PK-P. CET in the PK-P group did not differ from that of the KT control patients. CONCLUSIONS: CET is affected by variations in systemic insulin levels in pancreas transplant patients with allografts that have differing venous drainage. Because high systemic insulin levels are linked to the activation of (ET, euglycemic HI IDDM pancreas allograft recipients may continue to be at high risk for macrovascular complications.