New insights into the pathogenesis of distal renal tubular acidosis

The diagnosis and classification of distal renal tubular acidosis (distal RTA) have traditionally been made on the basis of the renal response to physiologic maneuvers, providing only indirect information on the underlying pathophysiology. In the past several years significant advances have been made in our understanding of the molecular basis of distal H+/HCO3- secretion and absorption, at the level of individual transporters. With these advances, a new era of classifying disorders of distal acidification at the molecular level has arrived. In this article we review the cellular and molecular basis of normal acidification mechanisms in the distal nephron. We also review the recent information on the molecular basis of derangements in these mechanisms which lead to distal RTA.     

Pathogenesis of renal calculi in distal renal tubular acidosis. Possible role of parathyroid hormone

Elevated circulating levels of immunoreactive parathyroid hormone (PTH), hypercalciuria and renal calculi were found in 3 patients with distal renal tubular acidosis (RTA). Treatment with alkali resulted in a fall of PTH toward normal and a reduction in urinary calcium, but the frequency of urolithiasis was unchanged. In one patient in whom prolonged follow-up was possible, a subtotal parathyroidectomy was performed. This was followed by virtual cessation of stone formation despite persistence of the acidification defect. This study suggests that RTA may be associated with secondary hyperparathyroidism and that the consequent elevation in PTH may play a contributory role in the pathogenesis of renal calculi.     

Dimercaptosuccinic acid distribution in renal tubular acidosis

A 99Tcm dimercaptosuccinic acid (DMSA) scan performed after a urinary tract infection demonstrated an unusual pattern of isotope uptake, promoting further investigations leading to a diagnosis of renal tubular acidosis secondary to nephropathic cystinosis. This is known to affect isotope imaging but a unique feature in this undiagnosed case was the uncorrected metabolic acidosis, which had further altered the distribution of the DMSA. It is noteworthy because other patients referred for imaging with renal disease may also have abnormalities of acid base balance.     

Sj?gren's syndrome presenting as hypokalemic paralysis due to distal renal tubular acidosis

A 57-year-old woman presented with a flaccid paralysis, muscle tenderness, and respiratory depression. Laboratory results demonstrated severe hypokalemia with hyperchloremic metabolic acidosis and abnormally acidified urine. The urinary anion gap was positive in the presence of acidemia, thus establishing the diagnosis of distal renal tubular acidosis (DRTA). The patient fully recovered after potassium and alkali replacement. Further investigation revealed Sj?gren's syndrome as the underlying cause of DRTA.     

Incomplete distal renal tubular acidosis coinherited with a mutation in the band 3 (AE1) gene

BACKGROUND: Band 3 (anion exchanger 1, AE1) is one of the most abundant proteins of the erythrocyte membrane. We have previously characterized twenty AE1 gene defects underlying spherocytic haemolytic anaemia with band 3 deficiency. Since AE1 is also expressed in the intercalated cells of renal cortical collecting ducts where it is thought to participate in urine acidification, we asked whether the spherocytogenic AE1 mutations also affect the regulation of urine acidity. METHODS: We examined 10 patients from seven unrelated families with hereditary spherocytosis with band 3 deficiency using the short urine acidification test with CaCl2 administration at a dose of 0.2 g/kg b.w. To asses the ability of the nephron to secrete protons, 400 ml of NaHCO3 were infused over a period of 2 h. RESULTS: While we detected no significant abnormalities in eight patients, we have diagnosed incomplete distal renal tubular acidosis (dRTA) in two patients from one family whose urinary pH 5 h after CaCl2 administration were 6.56 and 6.89. Administration of bicarbonate in these two patients resulted in high urinary HCO3- concentration. The patients carry the previously characterized mutation band 3PRIBRAM that encodes a C-terminally truncated band 3 containing only the cytoplasmic domain and the first three putative transmembrane segments. CONCLUSIONS: This finding shows an association of a band 3 defect with abnormal urinary acidification perhaps secondary to Cl-/HCO3- exchange in the basolateral membrane of alpha-intercalated cells of cortical collecting ducts.     

Distal renal tubular acidosis presenting with rhabdomyolysis

Severe hypokalemia is an uncommon cause of rhabdomyolysis. We describe a patient, 28-year-old woman, with distal renal tubular acidosis (DRTA) who developed severe hypokalemia and rhabdomyolysis. Muscle biopsy shows focal muscular necrosis mainly in type II muscle fibers and mild macrophagic reaction. After correcting the acidosis with oral administration of alkalinizing salts, clinical and laboratory improvement was seen. This clearly establish a causal relationship between the positive acid balance, hypokalemia and the muscular manifestation in DRTA.     

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.     

Thyrotoxicosis and renal tubular acidosis presenting as hypokalaemic paralysis

We report a case of oesophageal disease as the first manifestation in a patient with CREST syndrome. A 46-year-old man with achalasia-like syndrome developed CREST syndrome 4 years later. A pneumatic dilatation of the cardia was performed. After pneumatic dilatation the dysphagia and regurgitation disappeared but the patient developed reflux oesophagitis. Four years after diagnosis of oesophageal disease he presented with a clinical picture of CREST syndrome. An acute ileus and constipation developed later. After receiving medical therapy with omeprazole and cisapride the patient is free of oesophageal symptoms and bowel movements are normal. Oesophageal disease is common in patients with limited and diffuse scleroderma, but to our knowledge achalasia-like syndrome has not been previously described as the first manifestation of the systemic disease.     

Siblings with congenital renal tubular acidosis and nerve deafness

The suppression of hyperinsulinism with diazoxide (300 mg/d during 30 days) in a young woman with PCOS and hirsutism, hyperinsulinism and insulinoresistance was followed by a modification of plasma androgens. Testosterone (T) and free testosterone (fT) were reduced after ten days and then increased but always remained below the baseline level. DHEAS had increased 200% by day 10, and 3 alpha-adiol G to three times its basal value by day 20. These modifications were constant during the treatment. fT decrease was secondary to reduction of hyperinsulinism which was followed by an increase of TeBG and a modest and transient reduction of androgen theca cells production. DHEAS increase was due to hyperinsulinism suppression which stimulated adrenal 17-20 lyase activity. 3 alpha-adiol G increase was concomittant, and can be considered as an index of adrenal androgen secretion.     

A young woman with metabolic acidosis and recently discovered IDDM without ketonuria. A rare autoimmune (?) combination of hypothyroidism, diabetes mellitus and distal renal tubular acidosis

A case of a 29-year-old woman with a multiple autoimmune disorder is reported. She had a history of hypothyroidism since the age of 18. She was admitted to hospital due to hyperglycaemia. At admission she had hyperglycaemia, metabolic acidosis, but no urinary ketone bodies. Further laboratory studies revealed that the acidosis was due to distal renal tubular acidosis rather than diabetic ketoacidosis (although the patient had type 1 diabetes mellitus). Blood tests revealed antibodies to glutamic acid decarboxylase (GAD-65; associated with type 1 diabetes mellitus), thyroid and adrenal tissue, and gastric parietal cells. The patient had not developed pernicious anaemia or Addison's disease. The multiple positive antibody titres in this patient indicate that the diabetes, hypothyroidism and distal renal tubular acidosis are part of an autoimmune syndrome.     

Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene

All affected patients in four families with autosomal dominant familial renal tubular acidosis (dRTA) were heterozygous for mutations in their red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members studied. The mutation Arg589--> His was present in two families, while Arg589--> Cys and Ser613--> Phe changes were found in the other families. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Arg589 mutations had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the Ser613--> Phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activity. We conclude that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.     

Incidence of urolithiasis in northeast Thailand

We performed an anterior spinal fusion using a vascularized fibular bone graft combined with posterior fusion for a patient with severe cervical kyphosis due to neurofibromatosis. The kyphosis was corrected from 85 degrees preoperatively to 38 degrees postoperatively. A vascularized fibular bone graft is a useful surgical procedure in selected patients to obtain successful bony union.     

Renal tubular acidosis in children

Renal tubular acidosis represents a heterogenous group of disorders with various etiologies and mechanisms. The physiopathologic basis of each type of renal tubular acidosis is reviewed, focusing on the laboratory investigations necessary to define the nature of the hyperchloremic renal tubular acidosis. Clinically, the four types of renal tubular acidosis can be associated with complications such as osteomalacia, urolithiasis and failure to thrive. Very often, the chronic administration of alkali results in normal growth and development, and greatly reduces the risk of stone formation or nephrocalcinosis.     

Correction of renal tubular acidosis in carbonic anhydrase II-deficient mice with gene therapy

Carbonic anhydrase II (CAII) deficiency in humans is associated with a syndrome of renal tubular acidosis, osteopetrosis, and cerebral calcification. A strain of mice of CAII deficiency due to a point mutation also manifests renal tubular acidosis. We report here that retrograde injection of cationic liposome complexed with a CAII chimeric gene, using a cytomegalovirus (CMV) promoter/enhancer as an expression cassette to drive human CAII cDNA, into the renal pelvis of CAII-deficient mice results in expression of CAII in the kidney. The levels of both the CAII gene and its corresponding mRNA were highest by day 3 after treatment, diminishing thereafter, but remaining detectable by 1 mo. After gene therapy, CAII-deficient mice restored the ability to acidify urine after oral administration of ammonium chloride. The ability to acidify urine was maintained at 3 wk after gene therapy, and was eventually lost by 6 wk. Immunohistochemistry studies using anti-CAII antibodies showed that CAII was expressed in tubular cells of the outer medulla and corticomedullary junction. The gene therapy was not associated with nephrotoxicity as assessed by blood urea nitrogen levels and renal histology. To our knowledge, this is the first successful gene therapy of a genetic renal disease. Our results demonstrate the potential of gene therapy as a novel treatment for hereditary renal tubular defects.     

Familial cryptogenic fibrosing pleuritis with Fanconi's syndrome (renal tubular acidosis). A new syndrome

We describe two siblings with a progressive unrelenting and unique syndrome of bilateral fibrosing pleuritis of unknown cause occurring in association with Fanconi's syndrome (renal tubular acidosis). The parents of the siblings were second cousins. Both siblings had identical pleural histologic characteristics and identical urinary metabolic defects. This condition resulted in the development of severe respiratory failure in both patients and ultimately the death of the older sibling at the age of 21 years.     

Prevalence of alpha-thalassemias in northern Thailand

The population of northern Thailand has one of the highest frequencies of alpha-thalassemia in the world. However, the available distributional data are controversial. In addition to deletional types of alpha-thalassemia Hb, type Constant Spring should also be taken into consideration in alpha-thalassemia population studies, because it causes clinical alpha-thalassemia in the homozygous state or when present with both alpha-globin genes deleted in trans. We have examined a sample of 215 healthy subjects from four rural districts of Chiang Mai province. Out of these, 77 exhibited anomalies of the alpha-globin genes (alpha alpha/-alpha 3.7 in 36; -alpha 3.7/-alpha 3.7 in 3; -SEA in 30; alpha alpha/alpha CS alpha in 5; alpha alpha alpha anti 3.7 in 3). Therefore, no fewer than 2% of the children in northern Thailand are expected to be born with HbH disease or thalassemic hydrops fetalis. The considerable public health problem of hemoglobinopaties and the increasing acceptance of family planning necessitates facilities for the pre- and postnatal diagnosis of these disorders at the DNA level.