Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A.

The AE1 gene encodes band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytosis. We report here novel AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D. AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A, rescued both AE1-mediated Cl- transport and AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.     

Immune-mediated hemolytic anemia in pediatric renal transplantation

The aim of the study was to demonstrate clinical course of the first reported cases of PLS in pediatric kidney transplantation and therapeutic outcome for such condition using a combination of high-dose corticosteroid and tacrolimus. We report a single case (a nine-year-old Thai boy) with end-stage kidney disease secondary to obstructive uropathy developed immune-mediated hemolytic anemia from the PLS at second week after a pre-emptive living-related kidney transplantation. The alloimmune hemolysis was a result of anti-B antibodies, derived from blood group O-donor lymphocytes. Using a combination of high-dose corticosteroid and a substitution of cyclosporin with tacrolimus, there was no further hemolysis although the anti-B antibodies remained detectable until the eighth week post-transplantation. An impairment of the graft function because of hemoglobinuria was resolved after the hemolysis was stopped. The alloimmune hemolysis caused by PLS in pediatric kidney transplantation could be controlled with a combination of high-dose corticosteroid and tacrolimus.     

Significantly Reduced Acid Detection at 10 Centimeters Compared to 5 Centimeters above Lower Esophageal Sphincter in Patients with Acid Reflux

Ambulatory pH monitoring of the esophagus is carried out by positioning a pH sensor 5 cm above the lower esophageal sphincter (LES). There are several techniques to locate the LES, and each method has a different margin of error. This work used dual pH sensors to monitor simultaneously at two different levels (5 and 10 cm above the LES) in order to establish the possible magnitude of error that could arise from inaccurate placement of a pH probe. Thirty-four patients with symptoms of gastroesophageal reflux (GER) were studied. They were grouped as 20 patients with pathological reflux (GER group) and 14 patients with physiological reflux, based on a reflux score derived by Johnson and DeMeester for distal esophageal pH monitoring. When the reflux scores were compared, the difference between the two monitoring levels was statistically significant in the GER group ( p < 0.001) but not in the physiological reflux group ( p = 0.09). In the GER group, the difference in the Johnson and DeMeester score accounted for a change in clinical diagnosis in nine of the 20 patients if the pH probe was placed at 10 cm above the upper margin of LES. Proximal reflux episodes (10 cm above LES) were preceded by distal reflux episodes (5 cm above LES) in 97% (878/901) of cases. Accurate probe placement is essential in the diagnosis of GER.     

Pediatric kidney transplantation in Thailand: experience in a developing country

From July 1996 to November 2006, 46 patients received kidney transplants at five pediatric centers in Thailand. The male-female ratio was 1.9:1. The primary causes of end-stage renal disease (ESRD) included hypoplastic or dysplastic kidney, chronic glomerulonephritis, reflux nephropathy, pyelo nephritis or interstitial nephritis, focal segmental glomerulosclerosis, and rapidly progressive glomerulonephritis. Mean (SD) age at onset of ESRD was 10.1 (3.1) years, and at transplantation was 11.1 (2.9) years. Preemptive transplantation was performed in 2 patients. Cadaveric donors were used in 67.4% of procedures. Induction of immunosuppression with interleukin (IL)-2 monoclonal antibody was used in 41.3% of the patients. At 1 year posttransplantation, maintenance therapy included corticosteroids in 100% of patients, cyclosporine in 81.6%, tacrolimus in 15.8%, azathioprine in 31.6%, and mycophenolate mofetil in 57.9%. Standardized height z scores at transplantation and last follow-up (mean [SD], 40.0 [28.3] months) remained the same at -1.9. Mean (SD) serum creatinine level at the last follow-up was 1.3 (0.8) mg/dL. Patient survival at 1 and 5 years was 96% and 88%, respectively. Graft survival at 1 and 5 years was 98% and 84%, respectively. The medical expenses at 1, 6, and 12 months were US$601, US$464, and US$384 per month, respectively. The Thai per gross domestic product per capita was US$758 per month. Medical expenses were paid by the government in 44.2% of cases, charity foundations in 39.5%, and the patients' parents in 16.3%. Although the causes, management, and outcomes of ESRD were not different from those in other countries, access to treatment and medical expenses may be substantial barriers in developing countries.     

Combined renin angiotensin blockade in childhood steroid‐resistant nephrotic syndrome

Background: Reduced proteinuria results in delayed deterioration of renal function and remission of proteinuria predicts a good long‐term prognosis in steroid‐resistant nephrotic syndrome (SRNS). The aim of this study was to analyze the effects of the combined angiotensin‐converting enzyme inhibitor and angiotensin II receptor blocker in reducing proteinuria in SRNS. Methods: A prospective study of eight patients with SRNS was conducted at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University from September 2003 to December 2007. Enalapril was given at 0.1 mg/kg/day and was increased by 0.1 mg/kg/day every 4 weeks up to 0.6 mg/kg/day (maximum 40 mg/day) and 1 mg/kg/day of losartan was added for 4 weeks and stepped up to 2 mg/kg/day (maximum 100 mg/day) for another 4 weeks. Results: There were five boys (62.5%) and three girls (37.5%). The mean age at diagnosis was 8.3 ± 4.1 years (range 2.05–13 years) and age at enrollment was 11.7 ± 3.8 years (range 6–16 years). Renal histology revealed seven focal segmental glomerulosclerosis and one immunoglobulin M nephropathy. The results showed significant reduction on mean spot urine protein : creatinine ratio from 9.6 ± 2.3 to 3.6 ± 1.6 (P < 0.05) and 24‐h urine protein from 182.8 ± 59.6 to 28.7 ± 8.2 mg/m²/h (P < 0.05). Urine protein reduction ratio at the end of the study was 50% (P= 0.08). Serum cholesterol, albumin, potassium, blood pressure and renal function had no significant change. No clinical and laboratory side‐effects were reported. Conclusion: Combined high‐dose angiotensin II receptor blocker to high‐dose angiotensin‐converting enzyme inhibitor therapy is safe and effective in reducing proteinuria in childhood SRNS. However a large‐scale study should be conducted to validate this result.     

Alternative method of positioning the pH probe for oesophageal pH monitoring.

The most reliable method of positioning a pH probe for oesophageal pH monitoring is to use manometry to determine the upper margin of the lower oesophageal sphincter and to place the probe 5 cm above this point. Manometry is expensive, however, requires special equipment and training, and is not widely available. An alternative cheaper way of determining the site of the lower oesophageal sphincter has been evaluated. A fine bore nasogastric tube with a latex balloon at its tip was inserted transnasally into the stomach. The balloon was inflated with 10 ml of water and the tube withdrawn until resistance was met. The distance from the nose (in cm) was noted and compared with the upper margin of the lower oesophageal sphincter as determined by oesophageal manometry. The manometric distance agreed closely with the balloon distance minus 1 cm (bias 0.29 cm; 95% CI of bias, 0.03 to 0.55 cm; 2 SD, limits of agreement, 1.58 cm). We conclude that where oesophageal manometry is not available, balloon localisation is a suitably accurate way of identifying the lower oesophageal sphincter.     

Renal tubular dysfunction in α-thalassemia

Shortened red cell life span and excess iron cause functional and physiological abnormalities in various organ systems in thalassemia patients. In an earlier study, we showed that beta-thalassemia patients have a high prevalence of renal tubular abnormalities. The severity correlated with the degree of anemia, being least severe in patients on hypertransfusion and iron chelation therapy, suggesting that the damage might be caused by the anemia and increased oxidation induced by excess iron deposits. This study was designed to define the renal abnormalities associated with alpha-thalassemia and to correlate the renal findings with clinical parameters. Thirty-four pediatric patients (mean age 8.2+/-2.8 years) with Hb H disease or Hb H/Hb CS were studied. Ten patients (group 1) were splenectomized, with a mean duration post splenectomy of 3.5+/-1.4 years; 24 patients (group 2) had intact spleens. The results were compared with 15 normal children. Significantly higher levels of urine N-acetyl-beta- d-glycosaminidase, malondialdehyde (MDA), and beta(2)-microglobulin were found in both groups compared with normal children. An elevated urine protein/creatinine ratio was recorded in 60% of group 1 and 29% of group 2. Two patients (5.9%), 1 in each group, had generalized aminoaciduria. We found proximal tubular abnormalities in alpha-thalassemia patients. Increased oxidative stress, possibly iron induced, may play an important role, since urine MDA levels were significantly increased in both groups of patients.