Richard E. Neiberger

Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children

OBJECTIVE. Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS. Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function. OUTCOME. There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor δ-aminolevulinate. CONCLUSIONS. In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.

Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate.

OBJECTIVE. The purpose of this research was to report results on long-term administration of dichloroacetate in 36 children with congenital lactic acidosis who participated previously in a controlled trial of this drug. PATIENTS AND METHODS. We conducted a randomized control trial, followed by an open-label study. Data were analyzed for each patient from the time they began treatment through May 2005. RESULTS.Subject exposure to dichloroacetate totaled 110.42 years. Median height and weight increased over time, but the standardized values declined slightly and remained below the first percentile. There were no significant changes in biochemical metabolic indices, except for a 2% rise in total protein and a 22% increase in 24-hour urinary oxalate. Both the basal and carbohydrate meal-induced rises in lactate were blunted by dichloroacetate. The median cerebrospinal fluid lactate also decreased over time. Conduction velocity decreased and distal latency increased in peroneal nerves. Mean 3-year survival for all of the subjects was 79%. CONCLUSIONS. Oral dichloroacetate is generally well tolerated in young children with congenital lactic acidosis. Although continued dichloroacetate exposure is associated with evidence of peripheral neuropathy, it cannot be determined whether this is attributable mainly to the drug or to progression of underlying disease.

Sodium Thiosulfate Treatment for Calcific Uremic Arteriolopathy in Children and Young Adults

In adult patients with ESRD, calcific uremic arteriolopathy (CUA) is an uncommon but life-threatening complication. No effective therapy exists, although anecdotal case reports highlight the use of sodium thiosulfate (STS), a calcium-chelating agent with antioxidant properties. CUA is rare in children, and STS use has not been reported. The objective of this study was to determine the influence of STS treatment on three patients with CUA in a pediatric chronic dialysis unit. The patients were between 12 and 21 yr of age; two were male; and primary diagnoses were obstructive uropathy, renal dysplasia, and calcineurin nephrotoxicity. Time from ESRD to CUA diagnosis was 1, 9, and 20 yr. Diagnosis was made by tissue biopsy and three-phase bone scan. Pain was the presenting symptom. Initial treatment included discontinuation of calcitriol and use of non-calcium-based phosphate binders and low-calcium dialysate concentration. STS dosage was 25 g/1.73 m(2) per dose intravenously after each hemodialysis session. For optimization of removal of calcium deposits, patient three received a combination of STS and continuous venovenous hemofiltration for the first 10 d. All patients demonstrated rapid pain relief. Within weeks, skin induration and joint mobility of the extremities improved. Radiographic evidence of reduction in the calcium deposits occurred within 3 mo of initiation of STS. The only complication was prolonged QT interval in one patient as a result of hypocalcemia, who was resolved by use of a higher dialysate calcium concentration. STS seems well tolerated in children and young adults with CUA and has mild adverse effects. For determination of its efficacy, optimum dosage, duration of therapy, and dialysis modality, controlled trials are needed.

Long-term safety of dichloroacetate in congenital lactic acidosis

We followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or respiratory chain complexes I (1 patient), IV (3 patients) or I+IV (1 patient) who received oral dichloroacetate (DCA; 12.5 mg/kg/12 h) for 9.7 to 16.5 years. All subjects originally participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean ± SD: 23.5 ± 10.9 years). Subjects were either normal or below normal body weight for age and gender. The 3 PDC deficient patients did not consume high fat (ketogenic) diets. DCA maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, electrolyte, renal and hepatic status remained stable. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 3 patients, although symptomatic worsening of peripheral neuropathy did not occur. We conclude that chronic DCA administration is generally well-tolerated in patients with congenital causes of lactic acidosis and is effective in maintaining normal blood lactate levels, even in PDC-deficient children not consuming strict ketogenic diets.

Intermediate‐dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy

Abstract:  BK virus allograft nephropathy (BKVAN) is a rising complication in kidney transplant recipients. Reducing immunosuppression has been the initial form of therapy in most cases, but is not always associated with improvement in graft function. Anti‐viral therapy with low‐dose cidofovir (0.25–0.42 mg/kg/dose) has been used successfully in some patients, but dose‐related nephrotoxicity has limited its use. We present our experience with 3 kidney transplant recipients diagnosed with BKVAN who received intermediate‐dose cidofovir (0.75–1.0 mg/kg/dose) without probenecid, and without concomitant nephrotoxicity. Three female patients, ages 8, 19 and 20 yr, presented with elevated serum creatinine (SCr) values, BK virus stain positive on renal biopsy and high plasma BK viral loads. As a result of viral loads being >2 million copies/ml in two patients and a lack of response to reduction in immunosuppression in the third, we initiated therapy with low‐dose cidofovir. Because of persistent positive BK stain and positive plasma viral load, we then administered intermediate‐dose cidofovir, without probenecid, for several subsequent doses (seven to 15 infusions till date). All patients tolerated the intermediate‐dose cidofovir with no significant rise in SCr during the course of the infusions. The most recent SCr values in all three patients were improved from those at the initial diagnosis of BKVAN. All three patients showed a marked drop in BK viral loads when on intermediate‐dose cidofovir, with complete clearing of viremia in two patients. In our experience, intermediate‐dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.

Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy

Abstract:  BKVAN has emerged as a major morbidity in kidney transplant recipients. Among treatment options is cidofovir, which can be nephrotoxic. We previously reported that intermediate dose cidofovir could be used without significant nephrotoxicity. We present extended results of the same treatment protocol in a larger cohort and with longer follow up. Diagnosis of BKVAN was based on detection of BK viral DNA from plasma and renal allograft biopsy tissue. All patients received cidofovir (0.25–1 mg/kg/dose) every 2–3 wk. Total number of cidofovir doses ranged from 1 to 18 (mean 8). This report includes eight patients, aged 5–21 yr, treated with intermediate dose cidofovir. Median follow‐up was 11 months (range 4–32). Mean fall in reciprocal of serum creatinine (1/sCr) from baseline at BKVAN diagnosis was 64% (range 28–120%). A time‐series plot of plasma BK virus PCR and 1/sCr showed marked reduction in viral loads without significant deterioration in 1/sCr from the initial value at BKVAN diagnosis. In this larger series with extended follow up, intermediate dose cidofovir without probenecid for the treatment of BKVAN continues to show stabilization of renal function without progression to renal failure.

Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients

Araya CE, Garin EH, Neiberger RE, Dharnidharka VR. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients.
Pediatr Transplantation 2010: 14: 145–150.

Cat scratch disease and acute rejection after pediatric renal transplantation

Abstract: Cat scratch disease (CSD) can lead to unexplained fever, generalized lymphadenopathy and organomegaly in immunocompetent individuals. CSD has rarely been reported in immunocompromised transplant recipients, where its clinical features would mimic the more common post‐transplant lymphoproliferative disease (PTLD). We report three cases of CSD seen recently in children who had received prior kidney transplants. The three children were between 7 and 9 yr old, and had received kidney transplants 2–4 yr prior, with stable renal function. In each case, there was unexplained fever with either lymphadenopathy or organomegaly. The diagnosis of CSD was suggested by a history of new cats being introduced into each household and confirmed in all cases by the serological presence of a significant titer (> 1 : 64) of IgM antibodies to Bartonella henselae. Tests for other bacterial infections, cytomegalovirus and Epstein–Barr virus infections were negative. All the patients showed a clinical improvement with anti‐microbial therapy. In patients A and B, the CSD was associated with an acute rejection episode shortly after diagnosis. The rejection episodes were reversed by intravenous steroid pulse therapy. Only four cases of CSD have been previously reported following solid organ transplantation. Acute rejection following CSD has not been previously reported. CSD should be included in the differential diagnosis of fever in the post‐transplant setting, especially where PTLD is suspected.

Kidney function in long-term pediatric survivors of acute lymphoblastic leukemia following allogeneic bone marrow transplantation.

Renal dysfunction may occur in survivors of bone marrow transplantation (BMT). The renal function of children who have survived 5 to 10 years after BMT has not been reported. Bone marrow transplantation was performed in 55 children with acute lymphoblastic leukemia less than 18 years of age at the University of Florida between September 1983 and October 1992. All received a uniform conditioning regimen of high-dose cystosine arabinoside and fractionated total body irradiation. Twenty-three are currently surviving. The survival average period following transplantation is 79 +/- 6.6 (SD) months. The longest survival is 129 months after BMT. We retrospectively examined data evaluating kidney function prior to transplantation, within 150 days after transplantation, and at each childs most recent clinic visit (1.7 to 10 years after transplantation). We were able to collect follow-up data regarding renal function for 17 survivors. Two children (11%) have renal dysfunction in the form of hypertension, glucosuria, and hematuria. One of them had acute renal insufficiency during the first 100 days following BMT. An unexpected finding was the presence of hyperfiltration in 10 patients. In conclusion, in this homogeneous group of children, allogenic BMT did not lead to significant long-term renal dysfunction.

The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis

In 27 of 28 children with congenital lactic acidosis, cerebrospinal fluid lactate was higher than venous blood lactate. The mean +/- SEM difference between these variables was 2.4 +/- 0.3 mmol/L (P =.0001). Girls or patients with pyruvate dehydrogenase deficiency had higher cerebrospinal fluid lactate concentrations than boys or patients with respiratory chain defects or mitochondrial DNA mutations.