Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients.

BACKGROUND: Distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene encoding the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) has a high prevalence in some tropical countries, particularly Thailand, Malaysia, the Philippines and Papua New Guinea (PNG). Here the disease is almost invariably recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations. METHODS: We have collected and reviewed our own and published data on tropical dRTA to provide a comprehensive series of clinical and epidemiological studies in 78 patients. RESULTS: Eight responsible SLC4A1 mutations have been described so far, four of them affecting multiple unrelated families. With the exception of the mutation causing South-East Asian ovalocytosis (SAO), none of these mutations has been reported outside the tropics, where dRTA caused by SLC4A1 mutations is much rarer and almost always dominant, resulting from mutations that are quite different from those found in the tropics. SLC4A1 mutations, including those causing dRTA, may cause morphological red cell changes, often with excess haemolysis. In dRTA, these red cell changes are usually clinically recessive and not present in heterozygotes. The high tropical prevalence of dRTA caused by SLC4A1 mutations is currently unexplained. CONCLUSION: A hypothesis suggesting that changes in red cell metabolism caused by these mutations might protect against malaria is put forward to explain the phenomenon, and a possible mechanism for this effect is proposed.

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.

Pediatric kidney transplantation: Siriraj Hospital experience.

We reported six children with end stage renal disease (ESRD) who received kidney transplantation in our unit from 1996 to 2000. They were 5 boys and 1 girl and their mean age was 9.7 +/- 2.7 years (range 6.8 to 13.2). Etiologies of ESRD were congenital anomalies (3 patients), chronic glomerulonephritis (2 patients), and rapidly progressive glomerulonephritis (1 patient). Prior to the transplantation, chronic peritoneal dialysis was used in 5 patients, including one who had to switch to hemodialysis due to chronic exit site infection and 1 had preemptive kidney transplantation. All children received a kidney from living-related donors, 4 from their fathers, 1 from his mother, and 1 from his elder brother. Triple immunosuppressive drug therapy (prednisolone, azathioprine, and cyclosporine A) was initially given to all patients. Serum creatinine returned to normal within the first week in all patients and 4 patients were discharged home by the end of the second week post operation. Immediate complications included severe hypertension (all patients), ureteral leakage (2 patients), neutropenia (3 patients) and nephrotic syndrome (1 patient). Azathioprine was discontinued in 2 patients due to persistent neutropenia. Cyclosporine A was discontinued in 1 patient due to hepatotoxicity, this patient was maintained on mycophenolate mofetil and prednisolone. Serum creatinine levels at last follow-up (mean 24.3 +/- 19.0 months, range 8-55) were normal in 5 patients and slightly increased (1.5 mg/dl) in one. Five patients returned to school full time within 1 year after kidney transplantation. Height standard deviation score improved markedly as early as 6 months post transplant. The cost of maintenance of the immunosuppressive drugs was similar to adults, i.e. 6,859.1 +/- 1,151.8 Baht per month at 6 months post kidney transplantation. We concluded that kidney transplantation can be performed successfully in selected Thai children with very good results and similar cost of treatment as for adults.

Chronic renal failure in Thai children: etiology, cost, and outcome.

We studied the epidemiology, cost and outcome of chronic renal failure (CRF) in Thai children by sending questionnaires to all university hospitals, all government general service hospitals and all pediatric nephrologists in the country. A total of 238 cases (107 from 8 university hospitals and 131 from 70 government general service hospitals) were diagnosed from 1996 to 1998. Mean age of the patients was 8.3 +/- 4.9 yr, male to female ratio was 1.4:1. Congenital KUB anomalies (obstructive uropathy and hypo/dysplasia) were the main causes of CRF in these patients, especially in the under five age group. Only a small number of patients received renal replacement therapy (chronic dialysis and kidney transplant) and the mortality rate was 18.7 per cent in university hospitals. Renal transplantation was performed in only 5 patients in 2 pediatric units and another 2 patients in adult renal units. The outcome of renal transplantation in this small group of patients was very satisfactory. The cost of CRF treatment in children was comparable to adults. The main problems in the management of CRF in Thai children included the lack of experienced personnel, lack of equipment and funding. We conclude that in order to improve the care of CRF in Thai children, a training program for health personnel and budget allocation should be established.

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.

Renal pathology and long-term outcome in childhood SLE.

Renal histology is increasingly used as a guide for therapy and prognosis in SLE but data in children are few and/or short-term. We assessed renal histological features in 19 children with SLE to determine whether these features are useful in predicting long-term outcome. Mean age at biopsy was 10 +/- 1.7 years old, male to female ratio was 1:2.8. Fourteen patients (73%) had diffuse proliferative lupus nephritis. Renal histology was evaluated using an activity index (AI) and chronicity index (CI). Clinical assessment of renal function at biopsy and outcome were graded according to urinalysis and serum creatinine. Renal function at biopsy correlated well with AI (p < 0.001) but not CI. At short-term follow-up (30 months), 3 patients had died from sepsis and another 2 reached end-stage renal disease. CI predicted poor clinical outcome, i.e. death or renal failure (p < 0.005) but AI did not. At long-term follow-up (mean 92.1 +/- 26.8 months) only one more patient reached end-stage renal disease. In others renal function assessment showed improvement or were stable. Neither CI nor AI correlated with clinical outcome. We conclude that although AI correlates well with renal function at biopsy and CI with short-term prognosis, neither can predict long-term outcome. Treatment may have altered the natural course of disease in these patients.

Renal tubular function in beta-thalassemia.

Studies of the renal involvement in thalassemic syndromes have been varied and few. This study was designed to define the renal abnormalities associated with beta-thalassemia and to correlate the renal findings with clinical parameters. One hundred and four beta-thalassemic children with various disease severity were studied. The patients were divided into three groups: 48 with severe anemia [hematocrit (Hct) < 25%], 31 on a hypertransfusion program and desferrioxamine treatment, and 25 with moderate anemia (Hct > 25%). The results were compared with 15 normal children. Significantly higher levels of proteinuria and low molecular weight proteinuria were found in all patients compared with normal children. Aminoaciduria was detected in one-third of patients. Thalassemic patients had significantly lower morning urine osmolarity, higher urine N-acetyl-beta-D-glucoseminidase and malondialdehyde (MDA, an indicator of lipid peroxidation). Patients with severe anemia had significantly higher low-molecular weight proteinuria and MDA, and lower urine osmolarity than those with moderate anemia. Our data confirmed the high frequency of renal abnormalities in beta-thalassemia patients and indicated some degree of proximal tubular dysfunction. Severity of the abnormalities correlated with the degree of anemia and were least severe in patients on hypertransfusion and desferrioxamine therapy. This suggested that the damage might be caused by anemia and increased oxidation induced by excess iron deposits.

Randomized controlled trial of dexamethasone in infectious croup.

Infectious croup is a common and an important cause of upper airway obstruction in young children. Despite its frequency and potentially serious nature, there is still no definite conclusion regarding the beneficial effect of corticosteroid. A randomized controlled study on the effects of dexamethasone in infectious croup was conducted at the Department of Pediatrics, Ramathibodi Hospital between January 1985 and September 1986. Thirty-two patients, 2-37 months old, were included in this study. Fourteen patients received dexamethasone (0.5 mg/kg/dose daily for 3 days) and eighteen patients were the control group. The dexamethasone group had significantly lower croup scores at 48 hour (p < 0.05), shorter hospital course (p < 0.005) and lower incidence of endotracheal intubation (p < 0.05) than the control group. Five patients in the control group required endotracheal intubation. Complications included four episodes of pneumonia, one episode of sepsis, and one bacterial tracheitis. Pneumonia and sepsis occurred only in the control group. We concluded that dexamethasone therapy decrease the severity of infectious croup and the risk of complications.

Renal failure in two patients with Wolfram syndrome.

We describe a Thai family with three children, two of whom presented with Wolfram syndrome, which is a rare syndrome characterised by diabetes insipidus, diabetes mellitus, optic atrophy, deafness and urinary tract dilatation. A girl and her younger brother had insulin-dependent diabetes mellitus at 11 years old with early onset of renal impairment, proteinuria and hypertension. Urinary tract dilatation was demonstrated in both patients. Kidney biopsies were compatible with diabetic nephropathy. Both children also had bilateral sensorineural hearing loss. Optic atrophy with severe loss of vision was detected in the girl and bilateral cataract in her brother. Both patients were HLA DR2 positive. At 16 years old, her creatinine clearance was 16 ml/min/1.73 m2. Her brother's creatinine clearance was 25 ml/min/1.73 m2 at 13 years old. We conclude that renal function should be evaluated in patients with Wolfram syndrome and the cause of renal failure in these patients may be rapid and severe diabetic nephropathy.

Adrenal function after prednisolone treatment in childhood nephrotic syndrome.

Nephrotic syndrome in children is a very common disease in Thailand. Most of the patients respond well to oral prednisolone treatment but side effects of the drug especially adrenal insufficiency remains a threat to all. We studied the adrenal function by studying the response to ACTH stimulation test in 14 Thai children, nine girls and five boys, with idiopathic nephrotic syndrome: immediately, 3, 6 and 9 months after discontinuation of oral prednisolone treatment. Average age on entry to the study was 104.4 months (25-183 months). Prednisolone was given every day for 29 days (6-64 days) then every other day for 542 days (178-1,562 days). Side effects of steroid treatment were gross obesity BMI > 30 (one patient), moderate hypertension (one patient), and marked cushingoid features (two patients). ACTH stimulation tests were normal in 64 per cent of patients within 7 days, 64 per cent at 3 months, 73 per cent at 6 months, and 90 per cent at 9 months after discontinuation of oral prednisolone. We suggest that adrenal insufficiency has to be considered in all children on prolonged prednisolone unit at least 9 months of treatment-free period.

Middle aortic syndrome: clinical and radiological findings.

Eight patients with the middle aortic syndrome are described. They were aged 2 months to 14 years at diagnosis; follow up was one to 11 years. Clinical presentations included asymptomatic hypertension (n = 5), severe headache, nose bleed, and chest pain (n = 1), and cardiac failure (n = 1). All had severe hypertension requiring multiple drug treatment. Diminished peripheral pulses were not helpful in the diagnosis, which is made on aortography. Associated clinical findings were Williams' syndrome (n = 3) and appreciable eosinophilia (n = 3). The differential diagnosis includes Takayasu's arteritis, fibromuscular dysplasia, and neurofibromatosis. Blood pressure was adequately controlled by medical treatment in six patients. Surgical angioplasty was performed in two. One patient remained normotensive without drug treatment 21 months after operation; the other died of sepsis and uncontrollable haemorrhage in the postoperative period. Medical treatment is satisfactory in most cases: surgery should be reserved for those in whom blood pressure cannot be controlled without unacceptable side effects of drug treatment. Although rare, the middle aortic syndrome should be considered in the differential diagnosis of hypertension when commoner causes have been excluded. Aortography is necessary for diagnosis.