Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist

Methylmalonic acidurias are a heterogeneous group of inborn errors of branched-chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut°, cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients.     

Combined Lamivudine and Hepatitis B Immunoglobulin for the Prevention of Hepatitis B Recurrence after Liver Transplantation: Long-Term Results

For the prevention of recurrent hepatitis B virus (HBV) infection after liver transplantation (LT), the efficacy of hepatitis B immunoglobulin (HBIg) has been largely demonstrated. The aim of this pilot study was to determine if the addition of lamivudine to HBIg in the prevention of HBV recurrence after LT could be more effective. Sixty HBsAg-positive/HBV DNA-negative patients underwent LT from October 1990 to December 2001. All 60 patients received intravenous HBIg to maintain serum anti-HB levels above 500 IU/L, indefinitely. Since 1997, 17 patients have received combined oral lamivudine (150 mg/day) and HBIg, and were compared with the historical cohort of 43 patients. In the historical control group, the recurrence rate was 10/43 (23%) after a 98-month median follow-up. Five patients died from HBV-related liver disease. After a 30-month median follow-up, none of the 17 patients in the combined prophylaxis group experienced HBV recurrence, and HBV DNA was undetectable by PCR in at least three serum samples per patient. HBV recurrence was significantly lower when compared with the historical control group (10/43 vs. 0/17, p < 0.01). Our results suggest that combined lamivudine and HBIg can avoid the recurrence of HBV infection in patients who are HBsAg-positive/HBV DNA negative before LT.     

Training the academic nephrologist for the new millennium

Physician-scientists play a key role in bringing basic science advances anticipated in the new millennium to the bedside. However, the existence of such individuals is in jeopardy, the reasons for which are summarized in first part of this article. Solutions to this problem are suggested and specific recommendations are directed at government and private agencies, industry, trainees, mentors, and academic institutions. Time is short and decisive action needs to be taken if we are to reap the full rewards of medical knowledge in the 21st century.     

Preeclampsia: pathophysiology and practice considerations for the consulting nephrologist.

Abnormal placental implantation presumed to be secondary to maternal genetic susceptibility or immune maladaptation is considered to be fundamental to the pathogenesis of preeclampsia. The reduced placental perfusion resulting in placental ischemia is hypothesized to cause the known endothelial dysfunction, which leads to the clinical manifestations of this disease. Oxidative stress is a postulated linking factor, an aberration that possibly has its genesis via cytokines released from the abnormally implanted and perfused placenta. Clearly the maternal pathophysiologic changes that subsequently produce what is recognized as preeclampsia are present long before the disease makes its clinical appearance.     

Significance of Hepatitis B Virus Genotype in Liver Transplantation for Chronic Hepatitis B

Hepatitis B virus (HBV) genotype influences chronic hepatitis B disease profile but its relevance in liver transplantation (LTx) is not known. HBV genotype was identified by direct sequencing from pre-transplant sera of 119 patients who underwent LTx using lamivudine prophylaxis (genotype A,1; B,43; C,74; D,1). The baseline characteristics and outcome of 43 genotype B and 74 genotype C patients were compared. Genotype B patients had significantly more pre-transplant acute flare, worse liver functions and higher model for end-stage liver disease score. Fewer genotype B patients had HBeAg (13% vs. 32%; p=0.017), but HBV DNA seropositivity (by bDNA assay) was comparable (26% vs. 23%; p=0.727). The 3-year graft survival was 83% for genotype B and 89% for genotype C (p=0.2). The rate of HBsAg clearance or seroreversion was the same. The cumulative rate of viral breakthrough due to lamivudine-resistant mutants at 3 years was 4% for genotype B and 21% for genotype C (p=0.017). Liver biopsy after viral breakthrough showed recurrent hepatitis B in 7 of 10 genotype C patients, including 2 with fibrosing cholestatic hepatitis, and no histologic recurrence in 2 genotype B patients. In conclusion, HBV genotypes B and C are associated with different patterns of end-stage liver diseases that required transplantation, and genotype C may carry a greater risk and severity of recurrence due to lamivudine-resistant mutants.     

Hepatitis B and hepatitis C: occupational considerations for the anesthesiologist

Anesthesiologists routinely are exposed to occupational hazards, such as hepatitis B and C, which are potentially lethal. The development of a vaccine has virtually eliminated the hazard for hepatitis B, if the anesthesiologist undergoes a successful vaccination series. There is no vaccine for hepatitis C, which ultimately leads to liver failure and hepatocellular carcinoma. The most likely transmission source to anesthesiologists is their accidental exposure to the blood of patients infected with hepatitis C (2% of the US population). Early diagnosis and pharmacologic treatment of hepatitis B and C can significantly diminish or even cure these diseases.     

Hepatitis B immune globulin: the US experience

The increasingly aggressive use of hepatitis B immune globulin (HBIg) in liver transplantation for hepatitis B infected patients has led to a great improvement in this procedure by lowering the incidence of allograft infection. In this article, major US studies on the use of HBIg are reviewed, including clinical results, clinical failures and problems, and the remaining information still needed for optimal therapy. Several major clinical findings have resulted from these studies. (1) With a high dose of HBIg and continuous use of this agent, it is possible to prevent recurrence in hepatitis B virus DNA-positive patients. (2) It is difficult to predict the required post-transplant dose of HBIg or the recurrence of hepatitis B in allografts. (3) While passive immunization of HBIg can help achieve successful transplants of patients suffering from hepatitis B cirrhosis, there are two typical patterns of failure: allograft infection with wild-type hepatitis B virus in the early perioperative period and with a mutant virus more than 6 months post-transplantation. These problems appear to arise only in patients with pre-transplant viral replication. (4) Combination therapy of HBIg and lamivudine seems promising for further improvement of liver transplantation. (5) There are still unanswered questions concerning the combination strategy: optimal timing, patient selection, duration of therapy, and the risk of viral mutations and adverse events. In addition, the role of changing immunosuppression protocols in improving transplantation of hepatitis B infected patients has not been determined.