Reversible low-molecular-weight proteinuria in patients with distal renal tubular acidosis

Four patients with untreated renal tubular acidosis had a urinary excretion of low-molecular-weight (LMW) proteins which was restored to normal by alkali therapy. Hypokalaemic proximal tubular damage in untreated patients with distal renal tubular acidosis is believed to be the cause of LMW proteinuria. An examination of urinary excretion of LMW proteins is useful for determining hypokalaemic proximal tubular dysfunction, as well as the efficiency of alkali therapy.     

Atypical presentation of distal renal tubular acidosis in two siblings

Primary distal renal tubular acidosis (dRTA) is an inherited disease characterized by the inability of the distal tubule to lower urine pH <5.50 during systemic acidosis. We report two male siblings who presented with severe hyperchloremic metabolic acidosis, high urinary pH, nephrocalcinosis, growth retardation, sensorineural hearing loss, and hypokalemic paralysis. Laboratory investigations revealed proximal tubular dysfunction (low molecular weight proteinuria, generalized hyperaminoaciduria, hypophosphatemia with hyperphosphaturia, and hypouricemia with hyperuricosuria). There was significant hyperoxaluria and laboratory evidence for mild rhabdomyolysis. Under potassium and alkali therapy, proximal tubular abnormalities, muscular enzymes, and oxaluria normalized. A homozygous mutation in the ATP6V1B1 gene, which is responsible for dRTA with early hearing loss, was detected in both siblings. In conclusion, proximal tubular dysfunction and hyperoxaluria may be found in children with dRTA and are reversible under appropriate therapy.     

Atypical distal renal tubular acidosis confirmed by mutation analysis

In autosomal dominant distal renal tubular acidosis type I (dRTA) impaired hydrogen ion secretion is associated with metabolic acidosis, hyperchloremic hypokalemia, hypercalciuria, nephrocalcinosis, and/or nephrolithiasis. A retardation of growth is commonly observed. In this report we present a family with autosomal dominant dRTA with an atypical and discordant clinical picture. The father presented with severe nephrocalcinosis, nephrolithiasis, and isosthenuria but metabolic acidosis was absent. His 6-year-old daughter, however, suffered from metabolic acidosis, hypokalemia, and hypercalciuria. In addition, sonography revealed multiple bilateral renal cysts but no nephrocalcinosis. Mutation analysis of the AE1 gene coding for the renal Cl^–/HCO₃ ^–- exchanger AE1 displayed a heterozygous Arg589Cys exchange in both patients but not in the healthy family members. This point mutation is frequently associated with autosomal dominant dRTA. Diagnosis of autosomal dominant dRTA is supported in this family by results of AE1 mutation analysis. Received: 13 April 2000 / Revised: 23 June 2000 / Accepted: 26 June 2000     

Clinical and genetic analysis of distal renal tubular acidosis in three Chinese children

Objective: Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine. Growth retardation is a major concern in these children. The disease is caused by defects in at least three genes (SLC4A1, ATP6V0A4, and ATP6V1B1) involved in urinary distal acidification. Several series of dRTA patients from different ethnic backgrounds have been genetically studied, but genetic studies regarding Chinese population is rare. Our aim was to investigate the clinical features and genetic basis of primary dRTA in Chinese children.

Methods: Three unrelated patients with dRTA participated in our study. Next-generation sequencing was performed, and the findings were validated using the Sanger sequencing method.

Results: All patients exhibited hyperchloraemic metabolic acidosis, abnormally high urine pH, hypokalemia, and nephrocalcinosis. Growth retardation was observed in all patients. During the follow-up (range 1–4 years), alkali replacement therapy corrected the systemic metabolic acidosis, and two patients demonstrated normal growth. rhGH therapy was administered to patient-3 at the age of 6?years, and his growth rate was significantly improved (growth velocity 9.6?cm/yr). In total, 5 mutations were identified in our cohort of three patients, and four mutations were novel.

Conclusions: We report the clinical and molecular characteristics of dRTA patients from China. The four novel mutations detected in our study extend the spectrum of gene mutations associated with primary dRTA. Furthermore, our study confirms the effect of early treatment in improving growth for dRTA patient and provides insight into the effects of rhGH on dRTA patients who were diagnosed late and exhibiting a persistent growth delay despite appropriate therapy.     

Acute tubulointerstitial nephritis with uveitis syndrome presenting as multiple tubular dysfunction including Fanconi's syndrome

We describe an 11-year-old male patient with acute tubulointerstitial nephritis with uveitis (TINU) syndrome. He presented with easy fatigability, pallor, nocturia and weight loss. laboratory examination disclosed anaemia, polyclonal hypergammaglobulinaemia, low molecular weight proteinuria, glycosuria, aminoaciduria, proximal and distal renal tubular acidosis, a urine concentration defect and decreased creatinine clearance. The multiple renal tubular dysfunction and slight glomerular dysfunction subsided spontaneously. Bilateral anterior uveitis was manifested 7 months after the onset of the disease. This is the first reported case of TINU syndrome with multiple proximal and distal tubular dysfunction including a complete type of Fanconi's syndrome.     

Proximal renal tubular dysfunction in severe burns

Proximal renal tubular function was studied in 11 patients with severe burn injury. Creatinine clearance was normal or increased in ten patients. Fractional excretion of sodium was less than 1% in ten. Fractional excretion of uric acid and amylase were increased in all but four and two cases, respectively, while absolute clearances of lysozyme and beta 2-microglobulin were increased in all but one patient. Renal threshold phosphate concentration was reduced in four patients. Twenty-four-hour urine glucose excretion exceeded 1 g in five patients, aminoaciduria was noted in eight, and proteinuria, predominantly globulinuria, was present consistently. Metabolic acidosis was seen in one patient, and transient hypokalemia occurred in two. Abnormalities of proximal tubular function were more marked in the five patients with the greatest extent of third-degree burns who died. The cause of proximal tubular dysfunction is not clear and may be related to an adaptive response to severe injury.     

Distal renal tubular acidosis: the value of urinary pH,PCO2 and NH4 + measurements

Distal renal tubular acidosis (dRTA) is not a single disease. The experimental forms of the syndrome are unsatisfactory as models of the naturally occurring disease, not least because they are seldom complicated by nephrocalcinosis, which is present in the majority of patients with spontaneous disease and contributes to the renal tubular defects found in the syndrome. Impairment of minimal urine pH, reduced urine carbon dioxide tension (PCO₂) during passage of alkaline urine, and reduced urinary ammonium (NH₄ ⁺) excretion, have all been advocated as essential criteria for the diagnosis of dRTA. Minimal urine pH, measured during metabolic acidosis, sulphate infusion, or after oral frusemide, is the yardstick against which other criteria should be assessed. A reduced urinaryPCO₂ is commonly found in dRTA but is not specific for the syndrome and may be accounted for by tubular defects other than those involving reduced distal hydrogen ion secretion. NH₄ ⁺ excretion is reduced in most patients with renal acidosis whatever the nature of the underlying renal disease; this function is closely related to nephron mass, and is not specifically impaired in renal tubular disease.     

Permeability defect with bicarbonate leak as a mechanism of immune-related distal renal tubular acidosis

We present a 15-year-old girl with distal renal tubular acidosis (dRTA) appearing in what is probably a very early stage of primary Sj?gren's syndrome. On the basis of tests evaluating renal handling of H+, we attempt to explain the mechanism of the urine acidification disorder. The inability to decrease urinary pH during systemic acidosis, together with the normal increase of urinary carbon dioxide partial pressure (pCO2) values after sodium bicarbonate and neutral phosphate loading, suggest a gradient-type dRTA. The inability to lower urinary pH in response to furosemide, accompanied by markedly increased urinary excretion of NH4, HCO3, Na, and K, points to a collecting tubule permeability disorder with bicarbonate leak to the tubular lumen. This patient had never been exposed to amphotericin B. To our knowledge, immune-related dRTA as a result of a gradient defect with bicarbonate leak into the tubular lumen has not been described.     

Bicarbonate therapy improves growth in children with incomplete distal renal tubular acidosis

Incomplete distal renal tubular acidosis (idRTA) has recently been associated with osteoporosis and growth retardation, attributed to the mild persistent metabolic acidosis. We hypothesized a therapeutic benefit from bicarbonate therapy on growth parameters in children with idRTA. In a study group of 40 surgically treated patients with posterior urethral valve (PUV) and normal estimated glomerular filtration rate, we evaluated the change in height standard deviation scores (SDSs) while they were on bicarbonate therapy in the presence of idRTA and complete distal renal tubular acidosis (dRTA). Age- and gender-matched healthy subjects constituted the control group (n = 55). Incomplete dRTA was evaluated by ammonium chloride acidification. The baseline height SDS of −1.94 ± 0.41 and −5.31 ± 1.95 in the groups with idRTA and complete dRTA, respectively, were significantly lower than that of the controls. After a follow-up period of 24.7 ± 8.3 months on sodium bicarbonate therapy, the idRTA patients had a 66% increase in height SDS compared with 26% and 3% increases in the patients with PUV with complete dRTA and without dRTA, respectively. At the end of follow-up, mean height SDS in the group with idRTA no longer remained significantly lower than that of the controls (P = 0.42). We concluded that bicarbonate therapy improves height SDS in idRTA. This issue needs further validation in larger studies.     

Secretory-defect distal renal tubular acidosis is associated with transporter defect in H(+)-ATPase and anion exchanger-1

Recent progress in molecular physiology has permitted us to understand pathophysiology of various channelopathies at a molecular level. The secretion of H(+) from alpha-intercalated cells is mediated by apical plasma membrane H(+)-ATPase and basolateral plasma membrane anion exchanger-1 (AE1). Studies have demonstrated the lack of H(+)-ATPase immunostaining in the intercalated cells in a few patients with distal renal tubular acidosis (dRTA). Mutations in H(+)-ATPase and AE1 gene have recently been reported to cause dRTA. This study extends the investigation of the role of transporter defect in dRTA by using immunohistochemical methods. Eleven patients with hyperchloremic metabolic acidosis were diagnosed functionally to have secretory-defect dRTA: urine pH >5.5 during acidemia, normokalemia or hypokalemia, and urine-to-blood pCO(2) <25 mmHg during bicarbonaturia. Renal biopsy tissue was obtained from each patient, and immunohistochemistry was carried out using antibodies to H(+)-ATPase and AE1. For comparison, renal tissues from the patients who had no evidences of distal acidification defect by functional studies were used: four with glomerulopathy or tubulointerstitial nephritis (disease controls) and three from nephrectomized kidneys for renal cell carcinoma (normal controls). The H(+)-ATPase immunoreactivity in alpha-intercalated cells was almost absent in all of the 11 patients with secretory-defect dRTA. In addition, 7 of 11 patients with secretory-defect dRTA were accompanied by negative AE1 immunoreactivity. In both disease controls and normal controls, the immunoreactivity of H(+)-ATPase and AE1 was strong in alpha-intercalated cells. In conclusion, significant defect in acid-base transporters is the major cause of secretory-defect dRTA.     

Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis

Primary distal renal tubular acidosis (dRTA) type I is a hereditary renal tubular disorder, which is characterized by impaired renal acid secretion resulting in metabolic acidosis. Clinical symptoms are nephrocalcinosis, nephrolithiasis, osteomalacia, and growth retardation. Biochemical alterations consist of hyperchloremic metabolic acidosis, hypokalemia with muscle weakness, hypercalciuria, and inappropriately raised urinary pH. Autosomal dominant and rare forms of recessive dRTA are known to be caused by mutations in the gene for the anion exchanger AE1. In order to identify a gene responsible for recessive dRTA, we performed a total genome scan with 303 polymorphic microsatellite markers in six consanguineous families with recessive dRTA from Turkey. In four of these there was an association with sensorineural deafness. The total genome scan yielded regions of homozygosity by descent in all six families on chromosomes 1, 2, and 10 as positional candidate region. In one of these regions the gene ATP6B1for the ss1 subunit of the vacuolar H(+)-ATPase is localized, which has recently been identified as causative for recessive dRTA with sensorineural deafness. Therefore, we conducted mutational analysis in 15 families and identified potential loss-of-function mutations in ATP6B1in 8. We thus confirmed that defects in this gene are responsible for recessive dRTA with sensorineural deafness.     

Familial hypophosphatemic rickets with proximal renal tubular acidosis

We have experienced 3 case of familial hypophosphatemic rickets with proximal renal tubular acidosis. Consisting of a family of 2 years old girl, 7 months old girl baby and their father aged 42 years. Roentgenological studies, biochemical tests on blood and renal function tests revealed hypophosphatemia in all these patients. Metabolic acidosis was found only in the 2 girls. Distal renal tubular acidosis was not found to be responsible for the metabolic disorder according to the sodium bicarbonate (NaHCO₃), and ammonium chloride (NH₄cl) load testing. No glycosuria, proteinuria and panaminoaciduris were detected, so that Fanconi's syndrome was ruled out and the diagnosis of hypophosphatemia was made. Based on these 3 cases, future status of untreated patients with this disease could be predicted. The course of this disease can be divided into 3 stages, infant, childfood and adult period.     

Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases

Tubular proteinuria defined by a study of Dent's ( CLCN5 mutation) and other tubular diseases. BACKGROUND: The term "tubular proteinuria" is often used interchangeably with "low molecular weight proteinuria" (LMWP), although the former implies a definite etiology. A specific quantitative definition of tubular proteinuria is needed, and we address this by studying five different renal disorders. METHODS: Tubular proteinuria was assessed by measuring urinary retinol-binding protein (RBP), beta2-microglobulin (beta2M), alpha1-microglobulin (alpha1M), and albumin in 138 patients: 26 affected males and 24 female carriers of the X-linked syndrome "Dent's disease," 6 patients with other Fanconi syndromes, 17 with distal renal tubular acidosis (dRTA), 39 with glomerulonephritis (GN), and 26 with Chinese herbs nephropathy (CHN). RESULTS: RBP was better than beta2M or alpha1M in identifying the tubular proteinuria of Dent's disease. Median urinary RBP levels in mg/mmol creatinine were: affected male Dent's, 18.2, N = 26; carrier female Dent's, 0. 30, N = 24; dRTA, 0.027, N = 17; GN, 0.077, N = 39; and normal adults, 0.0079, N = 61. Elevated urinary RBP (>0.017) and albumin < (10 x RBP) + 2 identified all patients with the LMWP of Dent's disease and clearly distinguished their LMWP from that of dRTA and GN. This is a quantitative definition of tubular proteinuria. Consistent with this definition, 80% of those patients with CHN who had an elevated RBP had tubular proteinuria. Urinary RBP and albumin in carriers of Dent's disease were strikingly correlated over a 100-fold range (R = 0.933). CONCLUSION: The combination of elevated urinary RBP (>0.017) and albumin < (10 x RBP) + 2 (mg protein/mmol creatinine) is a quantitative definition of tubular proteinuria. Furthermore, our findings suggest that a shared defect in tubular RBP and albumin reuptake causes this form of proteinuria.     

Inherited renal tubular acidosis

The past few years have witnessed great progress in elucidating the molecular basis of inherited renal tubular acidosis. Consistent with the physiologically defined importance of multiple gene products in urinary acidification, heritable renal tubular acidosis is genetically heterogeneous. Autosomal dominant distal renal tubular acidosis has been associated with a small number of mutations in the AE1 Cl-/HCO3- exchanger although the pathophysiologic mechanisms behind these mutations remain unclear. Rarely, autosomal recessive distal RTA is caused by homozygosity or compound heterozygosity for the loss-of-function mutation AE1 G701D. A larger proportion, often accompanied by hearing loss, is associated with mutations in the ATP6B1 gene encoding the 58 kDa B1 subunit of the vacuolar H+-ATPase. Mutations in the gene encoding the Na+/HCO3- cotransporter, NBC1, have recently been identified in proximal renal tubular acidosis with corneal calcification.     

Distal renal tubular acidosis and ovalocytosis: a case report

A 23-year-old man presented with osteoporosis, revealed by femoral fractures, and a history of nephrolithiasis, short stature, metabolic acidosis, hypokalemia and ovalocytosis, a red blood cell abnormality common in malaria endemic regions. Biological investigations led to the diagnosis of type 1 distal renal tubular acidosis (dRTA). Ovalocytosis and dRTA may co-exist in the same patient, since both can originate in mutations of the anion-exchanger 1 (AE1) gene, which codes for band 3, the bicarbonate/chloride exchanger, present in both the red cell membrane and the basolateral membrane of the collecting tubule alpha-intercalated cell.     

Familial distal renal tubular acidosis with neurosensory deafness: early nephrocalcinosis

Nephrocalcinosis was observed in 3 children of one family with distal renal tubular acidosis (dRTA). At presentation, all 3 patients had failure to thrive, rickets, hyperchloremic metabolic acidosis, hypokalemia, hypophosphatemia and hypercalciuria. At a later age, sensorineural hearing impairment was detected. Nephrocalcinosis was diagnosed in the index case at the age of 5 years, when a plain abdominal roentgenogram was first made; in the younger brother and sister, nephrocalcinosis was detected earlier at the age of 4 months and 5 weeks, respectively. All 3 patients required large doses of alkali (7.5-9.5 mEq/kg body weight/day) during infancy and early childhood to correct the acidosis and to prevent progression of the nephrocalcinosis. Contrary to the current notion that in children with dRTA, nephrocalcinosis is observed only after the age of 3 years, it appears that in some instances nephrocalcinosis may develop in early infancy. The occurrence of nephrocalcinosis at a very young age may be a manifestation of a severe genetically transmitted variant of dRTA and emphasizes the need for early diagnosis and optimal treatment of these patients from the first days of life.     

A study of immune responses to Tamm-Horsfall glycoprotein in the sera of patients with renal tubular acidosis

Antibody to Tamm-Horsfall glycoprotein in the sera of patients with distal renal tubular acidosis (dRTA) was measured by radioimmunoassay, as well as in samples of normal human serum. Normal human serum contains small amounts of IgG capable of interacting with Tamm-Horsfall glycoprotein. Appropriate assays were carried out on antiserum raised in rabbits against human Tamm-Horsfall glycoprotein serially diluted with normal human serum. Corrections were applied for the presence of interfering substances in serum. The amounts of antibody found in samples of normal and patient sera were not significantly different, although some of the patients were diagnosed as having immune as opposed to familial dRTA. Studies of cell-mediated immunity to Tamm-Horsfall glycoprotein was found not to differentiate between the normal and patient samples. dRTA does not appear to be associated with immune responses to Tamm-Horsfall glycoprotein.     

Asymptomatic low molecular weight proteinuria: a report on 5 cases

In children with asymptomatic proteinuria, a high proportion of low molecular weight (LMW) proteins is an indicator of tubular malfunction. In a routine screening program covering the last 15 years and involving 280,000 children, aged between 3 and 19 years, we have identified 5 boys with LMW proteinuria. In 4 of these, renal biopsy was histologically normal on the first presentation. Follow-up for 4-16 years showed normal growth curves, but further evidence of tubular dysfunction appeared: glycosuria and hypophosphatemia in 2 patients; one of them had also aminoaciduria and rising serum creatinine (greater than 1.2 mg/100 ml). Another patient had only increased serum creatinine. The other two, still less than 13 years old, show so far no other abnormality than persistent LMW proteinuria. It is suggested that early identification of LMW proteinuria may presage gradual development of progressive tubular dysfunction with age and that such patients should be followed up indefinitely.     

Disequilibrium pH and bicarbonate reabsorption: relevance to the pathogenesis of distal renal tubular acidosis.

An augmented renal capacity to reabsorb bicarbonate (RHCO3) has been noted in patients with distal renal tubular acidosis (dRTA), and construed as evidence that the basic defect in dRTA is abnormal distal tubular permeability. According to this interpretation, the absence of a disequilibrium pH due to a back-leak of H2C03 permits increased distal H+ secretion and results in an increased RHCO3. To test this assumption, we have evaluated the effect of acute elimination of the disequilibrium pH by carbonic anhydrase infusion. The results establish that this maneuver doses not cause a rise in RHCO3. Thus, the elevated value of RHC3 described in dRTA cannot be the consequence of increased back-diffusion of H2CO3 and is more likely due to coexisting extracellular volume depletion and/or postassium deficiency.     

Glomerular function and urine acidification in chronic renal diseases

Intravenous sodium bicarbonate (NaHCO3) infusion test was performed in 26 patients with chronic glomerulonephritis (CGN) and 16 with distal renal tubular acidosis (dRTA) in order to evaluate urinary acidifying capacity in chronic renal diseases. Comparative studies with glomerular filtration were planned, so that the patients with CGN were divided by creatinine clearance (Ccr) into 3 groups (G-I greater than or equal to 70, 30 less than or equal to G-II less than 70, G-III less than 30 ml/min). Proximal tubular bicarbonate (HCO3) reabsorption rate increased in CGN as Ccr decreased. Urine to blood carbon dioxide tension gradient (U-B PCO2) was above 30 mmHg in controls and below 20 mmHg in dRTA. In patients with CGN, urine HCO3 concentration (UHCO3) did not increase during NaHCO3 loading as Ccr decreased. However, U-B PCO2 rose above 20 mmHg, when UHCO3 was above 50 ml/min. Fishberg concentrating test was also performed in 15 patients with CGN and 6 with dRTA so that the relationship between urinary concentrating ability and urine acidification might be evaluated. While both functions were decreased in dRTA, U-B PCO2 in alkaline urine remained above 20 mmHg in CGN associated with moderate renal dysfunction (Ccr greater than or equal to 30 ml/min) despite decreased maximal urine osmolality. Intravenous furosemide (FM) injection test was carried out in 8 patients with chronic renal failure (CRF) and 3 with dRTA. Minimal urine pH fell below 5.5 and net acid excretion (NAE) increased in controls, whereas these responses were not seen in dRTA. In CRF, urine pH generally decreased below 5.5 and those who had a similar response to FM as dRTA, seemed to have more severe disturbance of the distal acidification. In conclusion, U-B PCO2 in alkaline urine and lowered urine pH in FM loading appeared to be a useful index of distal tubular acid excretion in patients with renal dysfunction. In CGN with moderate renal dysfunction (Ccr greater than or equal to 30 ml/min), urinary acidifying capacity remained normal in comparison with decreased urine concentrating ability.