Diagnosis Of dRTA Research Articles

S2581 Distal (Type I) Renal Tubular Acidosis Associated With Primary Sclerosing Cholangitis

INTRODUCTION: Distal Renal Tubular Acidosis (dRTA) is associated with conditions such as Sjogren's syndrome, lupus, rheumatoid arthritis, primary biliary cholangitis, autoimmune hepatitis, Wilson disease and other conditions. We present a case of a 25-year-old man with primary sclerosing cholangitis (PSC) presenting with dRTA. CASE DESCRIPTION/METHODS: A 25-year-old man with a history of decompensated cirrhosis due to primary sclerosing cholangitis complicated by encephalopathy, esophageal varices presented to the hospital with worsened hepatic encephalopathy. His serum chemistries revealed hypokalemia and non-anion gap metabolic acidosis [serum sodium 140 mEq/L (normal: 136-145), serum potassium 3.3 mEq/L (normal: 3.5-5.1), serum chloride 116 mEq/L (normal: 98-107), serum bicarbonate 16 mEq/L (normal: 22-32), serum albumin 2.3 g/dl (normal: 3.4-5), bilirubin 37.4 mg/dl (normal < 1), alkaline phosphatase 151 U/L (normal: 45-117), aspartate aminotransferase 222 U/L (normal: 15-37), alanine aminotransferase 128 U/L (normal: 16-61)]. Work up was initiated to evaluate the cause of non-anion gap metabolic acidosis. In absence of fistula, ileal conduit, diarrhea, contributing medications, hyperparathyroidism or saline administration with urinary pH 6.0, urine osmolal gap 15, urinary sodium 84 mEq/L, normal urine uric acid and amino acid excretion, a diagnosis of dRTA in the setting of PSC was made. Acidosis was corrected by supplementation of bicarbonate. Encephalopathy responded to lactulose/rifaximin administration. Patient underwent liver transplantation for decompensated cirrhosis which was curative in resolving his dRTA. DISCUSSION: Distal type I renal tubular acidosis (dRTA) may be hereditary, associated with autoimmune diseases (Sjogren, lupus, rheumatoid arthritis and others), chemotherapy drugs or toluene intoxication. In GI realm, dRTA has traditionally been associated with primary biliary cholangitis, autoimmune hepatitis and Wilson disease. Putated mechanisms for its pathogenesis involve gene mutation in hereditary forms, antibodies against vacuolar H+-ATPase, carbonic anhydrase II enzymes in autoimmune forms, direct toxic effect of bilirubin on the renal tubules in cholestatic conditions. Correction of acidosis should be accomplished using potassium citrate – potassium bicarbonate tablets as they contain more mEq of bicarbonate per tablet than commonly used sodium bicarbonate. This abstract helps raise awareness amongst fellows and practicing gastroenterologists in recognizing PSC as a cause of dRTA.

Novel compound heterozygous ATP6V1B1 mutations in a Chinese child patient with primary distal renal tubular acidosis: a case report

BackgroundDistal renal tubular acidosis (dRTA) is a heterogeneous disorder characterized by normal anion gap metabolic acidosis. Autosomal recessive dRTA is usually caused by mutations occurring in ATP6V1B1 and ATP6V0A4 genes,encoding subunits B1 and a4 of apical H+-ATPase, respectively. The heterogeneous clinical manifestations of dRTA have been described in different ethnic groups harboring distinct mutations. Most of the reported cases are from Europe and Africa. At present, the prevalence of primary dRTA is still poorly elucidated in Chinese population.Case presentationA 2-year and six-month-old female patient was hospitalized because of recurrent hypokalemia, hyperchloremic metabolic acidosis and growth retardation. Laboratory investigations presented a normal anion gap hyperchloremic metabolic acidosis, hypokalemia, and inappropriate alkaline urine. Renal ultrasound indicated bilateral nephrocalcinosis. Bilateral sensorineural hearing loss (SNHL) was confirmed with moderately severe (45 dB) on the left ear and severe (80 dB) on the right ear, which was accompanied with enlarged vestibular aqueduct (EVA) on both sides. According to these findings, a diagnosis of dRTA was made. To identify the pathogenic gene mutation, all coding regions of ATP6V1B1 and ATP6V0A4 gene, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. The splicing variants were verified in peripheral blood leucocytes of the patient by RT-PCR. As a result, two novel heterozygous mutations in ATP6V1B1 were identified in the child. One mutation was a successive 2-nucleotide deletion in exon 2(c.133-134delTG), which caused a marked nonsense mediated mRNA decay. The other was a guanine to adenine substitution of the first nucleotide of intron 8(c.785 + 1 G > A), which led to the exclusion of exon 8. After treatment with sodium citrate, potassium citrateand citric acid, metabolic acidosis and hypokalemia were corrected, but her hearing decreased gradually during the 2 years and had to accept the use of bilateral hearing aids.ConclusionsWe described two novel dRTA associated mutations in ATP6V1B1 identified in a Chinese child patient accompanying with SNHL and EVA. Our study will help to expand the understanding of this rare disease in Chinese population.

Tubular dysfunction in renal transplant patients using sirolimus or tacrolimus

Tubular dysfunction is prevalent among kidney transplant patients using calcineurin inhibitors, but our knowledge of the tubular effects of mTOR inhibitors is more limited. 60 kidney transplant outpatients using either the calcineurin inhibitor tacrolimus or the mTOR inhibitor sirolimus were investigated for renal tubular dysfunction. Proximal tubule function was assessed by quantification of albumin and β2-microglobulin, tubular reabsorption of phosphate and fractional excretion of bicarbonate. Distal tubular function was evaluated by water deprivation test and by urinary acidification test using furosemide and fludrocortisone for pH, ammonium and titratable acidity measurements. The prevalence of distal renal tubular acidosis (dRTA) was 17% for both treatment groups. 70% of patients treated with sirolimus and 94% using tacrolimus presented with urine concentrating defect (p=0.04). Distal RTA and urine concentrating defect were highly prevalent after kidney transplantation both in the sirolimus and tacrolimus treated patients. Acidification test was essential for the appropriate diagnosis of dRTA while dipstick urine specific gravity test was able to detect urine concentrating defect in this population.

Why is hypercalciuria absent at diagnosis in some children with ATP6V1B1 mutation?

We try to explain why hypercalciuria is absent at diagnosis in some children with an ATP6V1B1 mutation. A 5-month-old girl presented with distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Direct sequencing of the ATP6V1B1 genes disclosed a new homozygous mutation (452 delT) in exon 13. In particular, an absence of hypercalciuria and a normal level of parathyroid hormones were noted. After alkaline therapy, the signs of nephrocalcinosis improved on ultrasound during follow-up. After a review of the literature regarding patients with ATP6V1B1 gene mutations, a young age seemed to be an important factor for normocalciuria. The probable mechanism of normocalciuria and a dynamic mode of calcium excretion in patients with dRTA is proposed. The determinant factors include the degree of systemic acidosis, urine pH, genetic polymorphisms, age, dietary factors, and volume status. Low sodium intake may be a major determinant of normocalciuria in these patients. It is suggested that hypercalciuria is usually absent at diagnosis of dRTA in young infants. Blood pH, plasma bicarbonate concentration, urinary citrate levels, and growth catch-up may be better indicators of adequate alkali therapy in normocalciuric children. Volume contraction, low salt content in infant formula, and alkaline urine in young infants are likely to account for the increased calcium reabsorption.

Diagnosis, treatment and follow-up in a patient with Nephrocalcinosis due to distal renal tubular acidosis

AbstractTen years ago, a 73 year-old patient presented at our unit with a right nephritic colic and elevated serum creatinine (2.1 mg/dl). This was the first time that the patient had consulted for a urology workup. An abdominal X-ray was performed in which we observed a severe bilateral nephrocalcinosis with right ureteral lithiasis. One of the causes of nephrocalcinosis is distal renal tubular acidosis (dRTA), in that sense the patient presented metabolic acidosis (pH 7.25) together with normopotassaemia (4.4 meq/L) and normochlorine (105 mEq/L). A 24-hour urine test detected citrate (55 mg/dl), calcium (12 mg/dl) and pH of 6.5. A diuretic renogram showed the right relative renal function as 91.2% and left relative renal function as 8.8%. A test with bicarbonate and acetazolamide was performed, confirming a diagnosis of dRTA because the urinary CO2 pressure was 32 mmHg (normal, greater than 70 mmHg). Treatment with potassium citrate and increased intake of liquids was prescribed. Consequently, the patient’s serum creatinine normalized, her blood pH rose to 7.35 and urinary citrate increased to 154 mg/dl. After 10 years of treatment with potassium citrate the patient remains stable. We believe that in these patients it is crucial to carry out an alkalizing treatment: patients with dRTA cannot acidify the urine because a defect in the permeability of the tubule membrane prevents secretion of H+. It is important to administer potassium citrate continuously to improve blood pH, increase urinary citrate and reduce the risk of calcium phosphate crystallization.

Distal renal tubular acidosis: molecular and clinical aspects.

The traditionally descriptive classification of DRTA disorders is being refined as molecular defects are identified. Diagnosis of DRTA is easy: Hyperchloremic acidosis should arouse suspicion, and confirmation can be obtained by measuring urinary pH and ammonia excretion. Treatment is also relatively straightforward and readily corrects all manifestations of the acidification defect.

CO-EXISTENCE OF DISTAL RENAL TUBULAR ACIDOSIS (dRTA) AND NEPHROGENIC DIABETES INSIPIDUS (NDI) IN TWO PATIENTS: IMPLICATIONS FOR THE PATHOGENESIS OF DISTAL RENAL TUBULAR ACIDOSIS

dRTA was documented in 2 females (Case 1 - 14 yrs, Case 2 - 8 mo). The diagnosis of dRTA was based upon a urine pH of 6.9 for each case during an acute metabolic acidosis (blood pH 7.01 and 7.14), a normal HCO3 threshold (fractional HCO3 excretion 4.7 and 3.4%) and a low urine minus blood PCO2 gradient in alkaline urine (U-B PCO2 2 and 3). The diagnosis of NDI was suspected because of polyuria, persistent hypotonic urine and confirmed when investigated in detail. Maximum spontaneous urine osmolality (U Osm) for Case 1 and 2 were 139 and 93 mOsm/kg and increased slightly after infusion of antidiuretic hormone to 180 and 122 mOsm/kg respectively. 2 controls given a similar infusion achieved U Osm's >800 mOsm/kg. Thus our cases have a distal nephron which is impermeable to water and also dRTA with a low U-B PCO2. The low U-B PCO2 can be due to an increased permeability of the distal nephron to H+ in acid urine and H2CO3 in alkaline urine. However our cases had a distal nephron with reduced permeability to H2O and dRTA. Therefore unless there is a selective increased permeability to H2CO3 and H+ but decreased permeability to water, the low U-B PCO2 observed in these cases is more compatible with a failure of H+ secretion in the distal nephron. Animal studies supporting this will be presented.