Robert A. Grossman

Nontraumatic Rhabdomyolysis and Acute Renal Failure

Abstract Rhabdomyolysis with myoglobinuria from nontraumatic causes was the sole identifiable explanation for acute renal failure in 15 patients during a three-year period. Myoglobinuria resulted f...

Association of Hepatitis C with Posttransplant Diabetes in Renal Transplant Patients on Tacrolimus

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.

Effect of Towne Live Virus Vaccine on Cytomegalovirus Disease after Renal Transplant: A Controlled Trial

OBJECTIVE To test the efficacy of vaccination with the Towne live attenuated cytomegalovirus vaccine. DESIGN A double-blind, randomized, placebo-controlled trial in candidates for renal transplantation. The cytomegalovirus serologic status of both recipients and donors were determined, and the recipients were followed for periods of 6 months to 7 years after transplant. SETTING A university transplant center. PATIENTS The analyses were made on 237 patients who were given either vaccine or placebo, received renal transplants, and were followed for at least 6 months. INTERVENTION Subcutaneous inoculation with Towne live attenuated virus or with placebo. MAIN OUTCOME MEASURES The presence of cytomegalovirus infection was defined by virus isolation and antibody tests. If infection occurred, a prearranged scoring system for cytomegalovirus disease was used to objectify disease severity. RESULTS The vaccine was well tolerated, and there were no discernible long-term adverse effects. Recipients who were originally seropositive did not clearly benefit from vaccination. Protective efficacy was analyzed in the group at highest risk for cytomegalovirus disease; recipients who were seronegative at the time of vaccination and who received a kidney from a seropositive donor. Compared with placebo recipients, vaccinated patients in this group had significantly less severe cytomegalovirus disease, with a significant reduction in disease scores (P = 0.03) and 85% decrease in the most severe disease (95% CI, 35% to 96%), although infection rates were similar. Graft survival at 36 months was improved in vaccinated recipients of cadaver kidneys (8 of 16) compared with unvaccinated recipients (4 of 16) (P = 0.04). CONCLUSIONS Previous vaccination of seronegative renal transplant recipients with live cytomegalovirus results in reduction of disease severity mimicking the action of naturally derived immunity.

Mycophenolic Acid Area under the Curve Values in African American and Caucasian Renal Transplant Patients Are Comparable

The possibility of an effect of ethnicity on the pharmacokinetics of mycophenolic acid, the immunosuppressive metabolite of the prodrug mycophenolate mofetil, was studied over 90 days following renal transplantation in African American (n = 13) and Caucasian patients (n = 20). Since renal dysfunction and time after transplant surgery are two factors known to alter mycophenolic acid pharmacokinetics, two‐way analysis of variance of the data at each time point with ethnicity and renal function status as covariates was used to evaluate the possibility of an ethnicity effect on the pharmacokinetic parameters. No statistically significant difference based on ethnicity was detected for the primary pharmacokinetic parameters, abbreviated mycophenolic acid area under the concentration‐time curve (MPA AUC), or the predose trough concentration on study days 4,7,14,28, or 90. A statistically significant decrease in MPA AUC and increase in oral apparent clearance were observed in renally impaired patients regardless of ethnicity on days 4, and 4 and 7, respectively. The suggested mechanism for these differences is uremia‐induced increased MPA free fraction, leading to a temporary increased clearance for this restrictively cleared drug.

Comparison of open, laparoscopic, and hand-assisted approaches to live-donor nephrectomy

Background. Minimally invasive donor nephrectomy has become a favored procedure for the procurement of kidneys from live donors. The optimal minimally invasive surgical approach has not been determined. In the current work, we compared the outcome of kidneys procured using the traditional open approach with two minimally invasive techniques: the standard laparoscopic procedure and a hand-assist procedure. Methods. The function of live-donor kidneys procured by open versus minimally invasive procedures was compared (procedures compared were the traditional open donor nephrectomy [ODN], the standard laparoscopic [LAP] approach, and the hand-assisted [HA] laparoscopic technique). The length of donor operation, donor length of stay in the hospital, surgical complications, and cost of hospitalization for three groups of patients were assessed in a series of 150 live-donor nephrectomies. Results. We found that both minimally invasive procedures yielded kidney allografts with excellent early function and a minimum of complications in the donor. The open procedure was associated with a reduced operative time but increased donor length of stay in the hospital. Resource utilization analysis revealed that both minimally invasive techniques were associated with a slight increase in costs compared with the open procedure, despite a shorter hospital stay. Conclusions. Minimally invasive donor nephrectomy is safe and effective for procuring normally functioning organs for live-donor transplantation. Of the two minimally invasive approaches examined, the hand-assisted technique was found to afford a number of important advantages, including facilitating teaching of residents and students, that it is more readily mastered by transplant surgeons, and that it may provide an additional margin of safety for the donor.

The role of pretransplant immunity in protection from cytomegalovirus disease following renal transplantation.

To determine the extent to which pretransplant immunity resulting from natural infection protects against cytomegalovirus (CMV) disease, we analyzed CMV serology on 153 kidney donor and recipient pairs and followed transplant patients to determine incidence and severity of CMV disease. The overall incidence of CMV disease was 22%. Significant differences occurred in CMV disease incidence and severity, depending on the immune status of the kidney donor and recipient. Among recipients of kidneys from seropositive donors, immunity offered significant protection from CMV disease, reducing its incidence from 61% in nonimmune to 24% in immune patients (P less than 0.01). Pretransplant immune patients also had fever CMV-related complications. Among recipients of kidneys from seronegative donors, pretransplant immunity conferred a significant risk of CMV disease; immune patients had a 20% incidence of CMV disease compared with 2% in nonimmune patients (P less than 0.02). Disease was generally mild in all patients receiving kidneys from CMV infection had a 3-fold higher incidence of CMV disease than patients with reactivation infection (P less than 0.01). The incidence of CMV disease was similar in immune patients, whether they received a kidney from a seropositive or a seronegative donor. However, an important observation was that disease was significantly more severe in immune patients receiving a kidney from a seropositive donor (P less than 0.05). This indicates that if kidneys from seropositive donors are selected for use only in seropositive recipients, this places the immune patient at a higher risk for severe CMV disease. We conclude that pretransplant immunity offers a significant advantage to patients receiving kidneys from seropositive donors.

Live Cytomegalovirus Vaccination of Renal Transplant Candidates: A Preliminary Trial

Significant morbidity and mortality are associated with primary cytomegalovirus infections in renal-transplant recipients. In the hope that immunity to cytomegalovirus could safely be established before transplantation, we vaccinated 12 seronegative renal-transplant candidates with the Towne 125 strain of live human cytomegalovirus. Before transplantation, there were no significant reactions except for erythema and induration at the site of inoculation. All vaccinees seroconverted, and the three patients tested acquired a cytomegalovirus-specific cellular immune response. Ten vaccinees underwent transplantation: Nine have completed at least 3 months of follow-up, and eight retain functioning allografts up to 1 year later. Although cytomegalovirus was isolated from six patients after transplantation, the restriction endonuclease patterns of the viral DNA of four of these isolates differed significantly from those of the vaccine strain. Therefore, it appears that the vaccine strain did not become latent in the host, at least in a form that could be reactivated.

Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients.

Renal transplant recipients experience a greatly increased frequency of neoplastic skin lesions, including aggressive squamous cell carcinomas. Recent reports suggest that high doses of systemic retinoids may exert a chemotherapeutic and chemoprophylactic effect. Similarly, topical retinoid, especially tretinoin, has also been shown to be anti-tumoragenic in various settings. Because of the serious toxicity of high-dose systemic retinoid, a protocol was developed that combined topical tretinoin with low-dose etretinate (10 mg daily) for the treatment of frequently occurring dysplastic skin lesions in renal transplant recipients. Seven patients elected to receive combined tretinoin and etretinate therapy, and 4 were treated with tretinoin alone. Clinical evaluations were performed monthly. By 3 months of therapy, 9 of 11 patients exhibited at least a 25% decrease in the number of neoplastic growths. After 6 months, 6 of 8 evaluable patients, including 2 of 3 individuals receiving tretinoin alone, exhibited at least a 50% decrease. Three of 4 patients on the combined regimen and 2 of 3 receiving tretinoin alone for at least 9 months, exhibited a significant decrease in the rate of development of new squamous cell cancers. At the start of treatment, epidermal specimens were almost completely devoid of Langerhans cells (CD1+ cells). Their density increased greatly and in proportion to the duration of therapy. Long term topical tretinoin with or without low-dose oral etretinate seems to be an effective regimen to suppress the development of new tumors and to reduce the numbers of existing lesions in renal transplant recipients.

Percutaneous transluminal angioplasty. The procedure of choice in the hypertensive renal allograft recipient with renal artery stenosis.

A retrospective review of 547 renal transplants performed over a six-year period revealed allograft renovascular hypertension secondary to RTAS in 39 (7.1%) patients. Percutaneous transluminal angioplasty (PTA) resulted in immediate cure or improvement in 76% of the patients, increasing to 83% in patients with functioning kidneys at a mean follow-up period of 30 months (1–72 months). The renal artery stenosis (RTAS) was equally distributed between living-related and cadaver kidney recipients and did not appear to be more prevalent in end-to-end or end-to-side anastomoses. The blood pressures fell from pre-PTA levels of 167 ± 22 mmHg systolic to 141 ± 23.7 post-PTA and 102 ± 11 mmHg diastolic pre-PTA to 88 ± 12 mmHg post-PTA (P < 0.01). Of 25 cured or improved patients, 24 are on significantly less hypertensive medication. Two patients died of causes unrelated to the PTA and only one patient lost a kidney because of the procedure. Compared with operation, PTA is a safer and more effective procedure for the initial treatment of RTAS.

24-Week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course

Background. Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among kidney recipients. The highest risk of CMV infection occurs in CMV-naïve recipients of kidneys from seropositive donors (D+/R−). Optimal CMV prophylaxis is not established. This prospective cohort study compared the safety and efficacy of prophylaxis with 12 versus 24 weeks of oral ganciclovir. Methods. We prospectively administered 24 weeks ganciclovir to 31 D+/R− recipients. The control group comprised 39 patients transplanted in the immediately preceding era who received a 12-week course of prophylaxis. All patients received cytolytic therapy within the first month, as well as a tacrolimus-based maintenance regimen. A logistic regression model was fit to examine the relationship between 24 weeks ganciclovir prophylaxis and the odds of developing CMV infection by one year. Results. Groups were matched, though the 12-week cohort had more delayed graft function than their 24-week counterparts (45% vs. 29%, P=0.04). CMV infection occurred in 31% and 7% patients in the 12-week and 24-week groups, respectively (P≤0.01). Mean time to development of CMV infection was 17.5±2.2 weeks in the 12-week, and 22.0±10.0 weeks in the 24-week, groups (P=0.79). Both 24 weeks ganciclovir prophylaxis (O.R. 0.15, 95% C.I. 0.03–0.91, P=0.04) and delayed graft function (O.R. 4.49, 95% C.I. 1.67–36.56, P<0.01) were associated with CMV infection. Conclusions. Oral ganciclovir prophylaxis for 24 weeks is associated with a lower risk of symptomatic CMV disease than a 12-week course in high risk D+/R− kidney recipients.