Valganciclovir prophylaxis in patients at high risk for the development of cytomegalovirus disease.

BACKGROUND: Despite advances in antiviral therapies, cytomegalovirus (CMV) remains the leading opportunistic infection in the transplant population. Valganciclovir (VGC), the L-valyl ester prodrug of ganciclovir (GCV), provides an excellent oral alternative to GCV for the prevention of CMV in transplant recipients. We investigated the use of VGC for CMV prevention in high-risk renal and pancreas transplant recipients. METHODS: Patients at high risk for development of CMV disease were defined as either those who had donor positive, recipient-negative serostatus (D+/R-), or those who received antilymphocyte antibody (ALA) therapy for either rejection treatment or induction. A retrospective review was conducted of all kidney and pancreas transplants performed between August 2001 and December 2003. A total of 341 transplants were performed, of which 109 received VGC, and 88 were included in this analysis. RESULTS: The overall incidence of CMV disease was 5.7% (5/88). All of the CMV episodes were in patients who were D+/R- (17.2% [5/29] versus 0% [0/59], P<0.001). Of these patients, all the episodes of CMV were in patients who received VGC prophylaxis for<100 days post transplant (29% [5/17] versus 0% [0/12], P=0.06). The overall incidence of leukopenia was 11% and thrombocytopenia was 7%, with the incidence between the D+/R- group and the ALA group being similar. CONCLUSION: VGC is an effective agent in preventing CMV disease in kidney and pancreas transplant recipients who are at high risk for developing the disease. The optimal length of prophylaxis in D+/R- patients is still undefined, while 3 months of prophylaxis appears to be sufficient in patients who received ALA therapy.

Does treatment of cadaveric organ donors with desmopressin increase the likelihood of pancreas graft thrombosis? Results of a preliminary study.

Desmopressin (DDAVP) is commonly used in cadaveric organ donors to treat diabetes insipidus. The thrombogenic potential of DDAVP is well known. Recent animal data have demonstrated that DDAVP impairs pancreas graft (PG) microcirculation and perfusion. The aim of this study was too evaluate the effect of DDAVP on the incidence of PG thrombosis in clinical pancreas transplantation. A retrospective review of simultaneous kidney-pancreas transplant (SKPT) entered in the Scientific Registry of Transplant Recipients (SRTR) between 10/5/87 and 9/27/02 was performed. Patients were included for analysis if there was definitive documentation as to whether DDAVP was (DDAVP-Y) or was not (DDAVP-N) administered to the donor. Both dose and duration of DDAVP treatment were not recorded by SRTR. A total of 2804 SKPTs were available for analysis. Mean follow-up was 1.75 years (range, 1 month to 8.4 years). A total of 1287 SKPT patients (46%) received a PG from a DDAVP-Y donor. Graft ischemia times, donor and recipient ages, recipient gender distribution, surgical techniques, and immunosuppressive regimens were similar in both groups. The overall incidence of PG thrombosis was 4.3%. The incidence of PG thrombosis in recipients of grafts from DDAVP-Y donors was 5.1% compared to 3.5% in recipients of grafts from DDAVP-N donors (P =.04). Fifty-eight percent of thrombosed PG came from DDAVP-Y donors compared to 42% from DDAVP-N donors (P =.04). We conclude that there appears to be a relationship between donor treatment with DDAVP and PG thrombosis. A prospective study is needed to verify these findings and to determine their clinical significance.

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation.

The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue in kidney-pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. All patients received antibody (Ab) induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-five patients (31%) had SRL substituted for MMF for the following indications: (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2) intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively. Mean follow-up was 3 +/- 2 years overall and 1.2 +/- 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR, 1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL levels; of these, 6 (86%) had mean TAC levels of <4.5 in the month preceding AR. Mean creatinine overall and for the rising creatinine group remained stable. All patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance demonstrated biochemical or clinical improvement. Sirolimus-related infection or other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients can be safely switched to SRL with long-term stabilization of renal function, excellent graft and patient survival, and no increase in SAE. A minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR.

Clinical significance of eosinophils in suspicious or borderline renal allograft biopsies.

AIMS: Renal allograft biopsies play a critical role in renal transplantation. Acute rejection characterized by tubulitis and intimitis is of primary concern. There is an association between eosinophilic infiltrates and irreversible acute rejection; however, the significance of eosinophils in biopsies that fall short of the diagnostic threshold for acute rejection has not been well studied. This report describes clinical course, treatment and long-term outcome of 5 transplant recipients with biopsy histology that showed borderline changes associated with eosinophilic infiltrates. METHODS: Clinical records were selected for review on the basis of biopsy histology satisfying the following criteria: presence of interstitial infiltrates with eosinophils, absence of definitive criteria for acute rejection and absence of findings suggestive of infection or cyclosporine toxicity. RESULTS: All identified biopsies occurred within the first month of transplantation, and histology showed varying degrees of patchy mononuclear cell infiltrates composed of lymphocytes, with eosinophilic infiltrates, but no evidence of acute rejection based on Banff criteria. These patients were taking trimethoprim-sulfamethoxazole and ranitidine at the time of biopsy. Serum creatinine returned to baseline levels in each case after stopping both drugs, and remained stable during the duration of follow-up without any documented episode of acute rejection. No patient received specific therapy for acute rejection. CONCLUSION: This report suggests that independent of decisions on treatment with high-dose steroids or anti-lymphocyte antibody preparations, the management algorithm should include stopping drugs associated with acute interstitial nephritis when non-diagnostic biopsies show eosinophilic infiltrates.

Ranitidine-induced acute interstitial nephritis in a cadaveric renal allograft.

Ranitidine frequently is used for preventing peptic ulceration after renal transplantation. This drug occasionally has been associated with acute interstitial nephritis in native kidneys. There are no similar reports with renal transplantation. We report a case of ranitidine-induced acute interstitial nephritis in a recipient of a cadaveric renal allograft presenting with acute allograft dysfunction within 48 hours of exposure to the drug. The biopsy specimen showed pathognomonic features, including eosinophilic infiltration of the interstitial compartment. Allograft function improved rapidly and returned to baseline after stopping the drug.

Diurnal cyclosporine dosing optimizes exposure and reduces the risk of acute rejection after kidney transplantation.

Acute rejection (AR) following transplantation may be due to episodic subtherapeutic cyclosporine (CsA) levels related to diurnal variation of hepatic drug metabolism. We postulated that asymmetrical dosing of CsA based on individualized pharmacokinetic profiles would optimize drug exposure and decrease the risk of AR. We prospectively treated all patients undergoing kidney transplantation with a diurnally split dose of CsA microemulsion given q 12 hours (3.5 mg/kg q a.m., 3.0 mg/kg qPM). Morning doses were adjusted to reach a day-time area under the concentration curve (AUC) of 7,800 ng hour/ml (utilizing 2 hour and 6 hour levels) and evening doses were adjusted to a morning trough of 300 ng/ml. Patients received high-dose steroids tapered to 20 mg prednisone by day 6. CsA was started within 36 hours and mycophenolate mofetil (1000 mg q 12 hour) was added on day 3 in most patients and continued for 3 months. Only one patient received antibody induction. Thirty kidneys (67% cadaveric) were transplanted into 28 adult patients (50% African American, 57% men). Therapeutic targets were reached in all patients prior to discharge and maintained during the study period. At 3 months follow-up, there was not a single episode of documented AR and mean creatinine was 1.5 +/- 0.1 mg/ml. Twelve patients required biopsy for allograft dysfunction; however no histological evidence of AR or CsA-toxicity was identified and the creatinine normalized in each case without altering immunosuppression. Patients continued to require increased CsA doses in the AM compared to the PM (P<0.05) throughout the study to maintain target levels. Diurnal dosing of CsA based on individual pharmacokinetic profiles optimizes CsA exposure and reduces the risk of AR during the first 3 months after transplantation.

Association of hypertension with beta2- and alpha2c10-adrenergic receptor genotype.

The adrenergic receptors have been implicated in the pathogenesis of essential hypertension. We hypothesized that hypertension is associated with variants at the beta2-adrenergic receptor locus and at one of the alpha2-adrenergic receptor loci. In unrelated individuals, we measured untreated blood pressure and characterized each subject as hypertensive or normotensive. We then used genomic DNA to identify beta2- and alpha2c10-adrenergic receptor restriction fragment length polymorphisms. In 175 subjects (49 percent with hypertension, 55 percent black), both hypertension and race were associated with genotype at the beta2 locus (chi2 for hypertension = 11, P = .004, chi2 for race = 8.8, P = .012). The association with hypertension persisted in each race group separately (blacks only: chi2 = 9.6, P = .008; whites only; chi2 = 14.2, P = .001). This association persisted in a logistic model that controlled for race (P = .01). Genotype was also significantly associated with baseline systolic, diastolic, and mean arterial blood pressures (P = .05, .01, and .02, respectively). These data suggest that the beta2-adrenergic receptor gene is a candidate gene for hypertension in blacks and whites. We also genotyped subjects at the alpha2-adrenergic receptor coded on chromosome 10. There was no association between hypertension and genotype at the alpah2c10 locus in the total group or in blacks, but there was significant association in whites (chi2 = 6.7, P = .03). These data suggest that the beta2- and alph2c10-adrenergic receptor genes may contribute, in a race-specific manner, to the inheritance of essential hypertension. Linkage studies in related individuals are needed to confirm these findings.

Renovascular hypertension in blacks.

To define the clinical characteristics of renovascular hypertension (RVH) and determine the clinical usefulness of captopril stimulated peripheral renin and postcaptopril renography in blacks at risk for RVH, 79 clinically selected hypertensive blacks were evaluated. Unstimulated (U-PRA), captopril stimulated (S-PRA) peripheral renin, and postcaptopril renography (PC-RENO) were obtained. All subjects underwent conventional renal arteriography. Renal artery stenosis (RAS) was present in 14 of 79 (18%) patients. Renovascular hypertension (RVH) was found in 7 of 79 (9%) patients. S-PRA had a sensitivity and specificity of 38% and 86% respectively to detect RAS; and a sensitivity and a specificity of 17% and 85% respectively to detect RVH. PC-RENO had a sensitivity and a specificity of 64% and 58% respectively to detect RAS; and a sensitivity and a specificity of 67% and 58% respectively to detect RVH. This study suggests that RAS occurs in 18% of clinically selected hypertensive blacks. RVH was present in 9% of this population. Captopril stimulated peripheral renin and postcaptopril renography are not useful as screening tools for the diagnosis of renovascular disease in blacks. Blacks at high risk should be evaluated with angiography.