Plasma oxalate levels in prevalent hemodialysis patients and potential implications for ascorbic acid supplementation.

OBJECTIVES: Ascorbic acid (AA) supplementation may increase hemoglobin levels and decrease erythropoiesis-stimulating agent dose requirement in patients with end stage renal disease (ESRD). While plasma AA levels >100µM may be supratherapeutic, levels of at least 30µM may be needed to improve wound healing and levels may need to reach 70µM to optimize erythropoiesis. Of concern, oxalate (Ox), an AA metabolite, can accumulate in ESRD. Historically, if plasma Ox levels remain ≥30µM, oxalosis was of concern. Contemporary hemodialysis (HD) efficiencies may decrease the risk of oxalosis by maintaining pre-HD Ox levels <30µM. This study focuses on the plasma Ox levels in HD patients. DESIGN AND METHODS: A prospective, observational study of 197 HD patients with pre-HD AA levels and pre-HD and post-HD Ox levels. RESULTS: Mean plasma Ox levels decreased 71% during the intradialytic period (22.3±11.1µM to 6.4±3.2µM, P<0.001). In regression analysis, pre-HD plasma AA levels ≤100µM were not associated with a pre-HD plasma Ox level≥30µM, even if ferritin levels were increased. Pre-HD plasma Ox levels ≥20 or ≥30µM were not associated with lower cumulative 4-year survival. CONCLUSIONS: Pre-HD plasma AA levels up to 100µM in HD patients do not appear to be associated with an increased risk of developing secondary oxalosis, as the corresponding pre-HD plasma Ox level appears to be maintained at tolerable levels.

Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis.

BACKGROUND AND OBJECTIVES: The efficacy of folic acid therapy to lower homocysteine (Hcy) levels in an effort to reduce cardiovascular disease (CVD) risk in patients with ESRD or advanced chronic kidney disease (ACKD; creatinine clearance, <30 ml/min) remains inconclusive. We conducted a meta-analysis of relevant randomized trials to further examine this issue. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This meta-analysis included 3886 patients with ESRD/ACKD from seven qualified randomized trials using folic acid therapy and with CVD reported as one of the end points. RESULTS: When pooling the seven trials, folic acid therapy reduced the risk of CVD by 15% (RR, 0.85; 95% CI, 0.76 to 0.96; P = 0.009). A greater beneficial effect was observed among those trials with a treatment duration >24 months (RR, 0.84; 95% CI, 0.72 to 0.98; P = 0.02), a decrease in Hcy level >20% (RR, 0.83; 95% CI, 0.73 to 0.95; P = 0.007), and no or partial folic acid fortification (RR, 0.80; 95% CI, 0.65 to 0.99; P = 0.04). The beneficial effect also was seen when Hcy levels decreased >20%, even in the presence of folic acid fortification (RR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. CONCLUSIONS: Folic acid therapy can reduce CVD risk in patients with ESRD/ACKD by 15%. A greater beneficial effect was observed among those trials with no or partial folic acid fortification or a decrease in Hcy level >20% regardless of folic acid fortification.

The primary hyperoxalurias.

The primary hyperoxalurias (PHs) are rare autosomal-recessive inborn errors of metabolism. In the most severe form (type 1), recurrent kidney stones and progressive nephrocalcinosis lead to the loss of kidney function, accompanied by systemic oxalosis, and often requires dialysis and/or transplantation. The variety of genetic mutations leading to PH increasingly are being defined, resulting in the ability to diagnose most patients accurately via minimally invasive means. During and after definitive diagnosis, supportive therapies with pyridoxine supplementation, urinary crystallization inhibitors, and hydration should be used, but have varying success. Emerging information about the renal tubular and intestinal transport of oxalate is leading to increasing evidence to support the use of oxalate-degrading bacteria (probiotics) and enzymes in the treatment of PH. Organ transplantation historically has offered the only potential cure for PH, and may include kidney-alone, combined liver-kidney, or pre-emptive liver-alone transplantation. Exciting new approaches in the treatment of type 1 PH, however, are under investigation. These include the restoration of defective enzymatic activity through the use of chemical chaperones, hepatocyte cell transplantation, or enzyme replacement by recombinant gene therapy. These novel approaches illustrate the goal for the ideal treatment of PH: correcting the genetic defect without exposing patients to the life-long risks associated with organ transplantation.

Hyperoxaluria and systemic oxalosis: current therapy and future directions.

Excessive urinary oxalate excretion, termed hyperoxaluria, may arise from inherited or acquired diseases. The most severe forms are caused by increased endogenous production of oxalate related to one of several inborn errors of metabolism, termed primary hyperoxaluria. Recurrent kidney stones and progressive medullary nephrocalcinosis lead to the loss of kidney function, requiring dialysis or transplantation, accompanied by systemic oxalate deposition that is termed systemic oxalosis. For most primary hyperoxalurias, accurate diagnosis leads to the use of therapies that include pyridoxine supplementation, urinary crystallisation inhibitors, hydration with enteral fluids and, in the near future, probiotic supplementation or other innovative therapies. These therapies have varying degrees of success, and none represent a cure. Organ transplantation results in reduced patient and organ survival when compared with national statistics. Exciting new approaches under investigation include the restoration of defective enzymatic activity through the use of chemical chaperones and hepatocyte cell transplantation, or recombinant gene therapy for enzyme replacement. Such approaches give hope for a future therapeutic cure for primary hyperoxaluria that includes correction of the underlying genetic defect without exposure to the life-long dangers associated with organ transplantation.

Short-term reduction in bone markers with high-dose simvastatin.

The effect of statins on bone mass and fracture rates is uncertain. Therefore, we investigated whether statin therapy acutely altered bone turnover as measured by changes in bone serum markers (bone-specific alkaline phosphatase, osteocalcin, and type I collagen N-telopeptide cross-links). Fasting blood samples were obtained from 55 (M/F 39/16) healthy nonsmoking adults (mean +/- standard deviation: age, 50.4+/-7.5 years; body mass index, 27.8+/-4.9 kg/m(2)) with low-density lipoprotein cholesterol concentrations between 3.38-4.90 mmol/l. Subjects were randomized to four possible 8-week treatment regimens: placebo (n =14), pravastatin 40 mg/daily (n =12), simvastatin 20 mg/daily (n =14) or simvastatin 80 mg/daily (n =15). High-dose simvastatin (80 mg/daily) produced a significant reduction in bone-specific alkaline phosphatase as compared with other treatment regimens (p =0.009). However, there were no changes in urinary N-telopeptide cross-links, a sensitive marker of bone resorption. Short-term use of high-dose simvastatin lowers the level of the serum bone marker bone-specific alkaline phosphatase, which suggests the possibility of reduced bone turnover.

Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne.

BACKGROUND: Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE: The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS: In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS: There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS: A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.

Synthesis of vitamin D in skin after burns.

Severe burn injury is associated with vitamin D deficiency, low bone turnover, and abnormalities in calcium homoeostasis. Patients do not routinely receive vitamin D supplementation and sun exposure is currently not controlled. By analysis of skin biopsy samples for vitamin D3 precursors after exposure to ultraviolet B light we found that the conversion of 7-dehydrocholesterol to previtamin D3 was reduced in children a mean of 14 months after the burn. Low serum 25-hydroxyvitamin D concentrations were also found. We conclude that vitamin D supplementation is necessary after burn injury.

L-carnitine treatment of anemia.

Recombinant human erythropoietin (rHuEPO) and iron supplementation have had a profoundly positive impact on the anemia of patients with chronic kidney disease. However, a significant number of patients remain hyporesponsive to rHuEPO, with hemoglobin values less than target levels. A suboptimal response to rHuEPO is associated with complications that can reduce quality of life and increase morbidity, mortality, and costs. There are a number of other metabolic derangements associated with uremia that can impact on the production and survival of red blood cells. Dialysis-related carnitine disorder is a functional metabolic deficiency, common in chronic dialysis patients, that can have a negative impact on erythrocyte production and survival. This article reviews the role of L-carnitine in the pathogenesis and adjunctive treatment of anemia associated with kidney failure. After a comprehensive database search, primary and secondary reports were analyzed. Laboratory studies examining the influence of carnitine on red blood cell function and clinical trials of L-carnitine in dialysis patients support the use of L-carnitine in the setting of rHuEPO hyporesponsiveness. Consensus groups, including the National Kidney Foundation-Kidney Disease Outcome Quality Initiative (K/DOQI), consider the use of L-carnitine for hyporesponsive rHuEPO-dependent anemia a promising application of this therapy, recommending an empiric trial of L-carnitine in these patients.

Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology.

Children with cholestatic liver disease have been thought to develop hepatic osteodystrophy resulting from vitamin D and calcium malabsorption, resulting in secondary hyperparathyroidism and osteomalacia or rickets. However, treatment with vitamin D has not always proven successful in improving the bone disturbance. The aim of our study was to determine the role of vitamin D deficiency in the pathogenesis of hepatic osteodystrophy. We studied five patients, three female and two male, ages 0.9-19 yr, with biopsy-proven chronic cholestatic liver disease and previously low serum levels of vitamin D despite oral intake of vitamin D preparations. Patients were admitted to the Clinical Research Center for 8 days for sunlight deprivation and ultraviolet light substitution and for determinations of serum 25-hyroxyvitamin D(25(OH)) D2 and -D3, osteocalcin, and type I collagen telopeptide (ICTP), the last two being markers of bone formation and resorption, respectively. Samples were taken on admission, at discharge, and 1 month later. Results demonstrated low serum levels of osteocalcin and normal circulating levels of ICTP. Admission serum 25(OH)D2 levels were uniformly low or undetectable and remained so. Admission levels of circulating 25(OH)D3 were normal or low and did not rise during ultraviolet light therapy or subsequent resumption of oral vitamin D therapy and remained low 1 month later. These results indicate that in the face of low-normal to low total 25(OH)D levels, the low osteocalcin and normal ICTP levels suggest that decreased bone formation and not increased bone resorption is the main determinant of bone loss in a subset of children with chronic cholestatic liver disease.

Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied.