Distal Renal Tubular Acidosis Research Articles

Neonatal Onset Distal Renal Tubular Acidosis: Description of Two Novel Variants on the ATP6V0A4 Gene and Review of the Literature on Associated Extrarenal Manifestations

AbstractDistal renal tubular acidosis (dRTA) is an extremely rare disease that affects the distal tubule's ability to excrete proton cations, acidify urine, and maintain the acid–base balance. The clinical presentation of dRTA typically includes normal anion gap metabolic acidosis with decreased serum bicarbonate levels, hypokalemia, hypercalcemia, nephrocalcinosis, and alkaline urine. Hereditary causes of dRTA include pathogenic variants in ATP6V1B1, ATP6V0A4, SLC4A1, FOXI1, and WDR72 genes, which encode different transmembrane proteins on the apical surface of type A intercalated cells in the distal tubule. Variants in these genes lead to various defects in the function of the encoded proteins and can also account for extrarenal manifestations of dRTA due to the expression of these proteins in other organs, such as the stria vascularis of the inner ear. However, the literature on extrarenal manifestations, associated renal complications of hereditary dRTA, and appropriate investigations, and follow-up for patients with dRTA is scarce. In this article, we present a challenging case of neonatal-onset dRTA and contribute two novel variants of the ATP6V0A4 gene and a novel phenotype associated with a pathogenic variant on ATP6V0A4 to the scientific community. We also review the existing literature on hereditary causes of dRTA, with emphasis on associated renal and extrarenal complications.

Renal Tubular Acidosis: Recognition and Treatment Strategies

Renal tubular acidosis (RTA) is a group of kidney disorders characterized by impaired renal acidification, leading to disturbances in acid-base balance. This review article provides a comprehensive overview of RTA, including its epidemiology, pathophysiology, clinical presentation, and diagnosis. Three main types of RTA are discussed: distal RTA (Type 1), proximal RTA (Type 2), and hyperkalemic RTA (Type 4). Each type’s underlying causes and mechanisms are explored, highlighting the importance of accurate diagnosis for appropriate management. Diagnostic approaches involving clinical evaluation, laboratory tests, and specialized renal function studies are described in detail. The treatment strategies for each type of RTA are outlined, emphasizing the importance of correcting the acid-base imbalance and managing associated electrolyte abnormalities. Lifestyle modifications and pharmacological interventions are discussed, including alkali supplementation and potassium regulation. Finally, the need for further research and prospective studies to enhance our understanding of RTA and improve therapeutic interventions is emphasized. Advancements in diagnosis

Dry eyes, dry mouth & dormant limbs - A case series

Hypokalemic paralysis is a rare complication of distal renal tubular acidosis from any cause. Those cases diagnosed to have primary Sjogren’s syndrome is rare. Renal tubular acidosis caused by tubulointerstitial nephropathy is an extra glandular manifestation of primary Sjogren’s syndrome. We report three cases of flaccid quadriparesis diagnosed to have hypokalemia due to distal renal tubular acidosis and on furthur evaluation turned out to be Sjogren’s syndrome.

A report of three cases of patients with tubulointerstitial nephritis with IgM-positive plasma cells, treatment, and serum-IgM as a sensitive marker for relapse

BackgroundTubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is a newer disease about which there are many unclear points. Glucocorticoid therapy is effective in many cases of IgMPC-TIN; however, relapse during glucocorticoid tapering has been reported. Relapse and its treatment are poorly defined.Case PresentationCase 1 was a 61-year-old man with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. He was diagnosed with IgMPC-TIN accompanied by Fanconi syndrome and distal renal tubular acidosis (d-RTA). Prednisolone (PSL; 30 mg daily, 0.45 mg/kg/day) treatment was highly effective, and PSL was gradually tapered and discontinued after 1 year. However, 1 month after PSL discontinuation, therapeutic markers were elevated. Therefore, PSL (10 mg daily, 0.15 mg/kg/day) was administered, and the markers indicated improvement.Case 2 was a 43-year-old woman referred for renal dysfunction and proteinuria. Laboratory data revealed that she had primary biliary cholangitis (PBC), d-RTA, and Fanconi syndrome. A renal biopsy showed accumulation of IgM-positive plasma cells in the tubulointerstitium without any glomerular changes. A diagnosis of IgMPC-TIN was made and the patient was started on PSL (35 mg daily, 0.6 mg/kg/day). Therapeutic markers decreased immediately and PSL was discontinued after 1 year. Three months later, the proteinuria and Fanconi syndrome worsened. PSL treatment was restarted (20 mg daily, 0.35 mg/kg/day) and markers indicated improvement.Case 3 was a 45-year-old woman with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. The patient had PBC, Sjögren syndrome, d-RTA, and Fanconi syndrome, and the diagnosis of IgMPC-TIN was made. The patient was started on PSL (30 mg daily, 0.4 mg/kg/day) and disease markers decreased immediately. However, when PSL was tapered to 15 mg daily (0.2 mg/kg/day), the patient’s serum IgM levels increased; therefore, we maintained the PSL at 15 mg daily (0.2 mg/kg/day).ConclusionWe report three cases of relapsed IgMPC-TIN associated with reduction or discontinuation of glucocorticoid therapy. In these cases, elevation of serum IgM preceded that of other markers such as urinary β2-microglobulin, proteinuria, and glycosuria. We recommend monitoring serum IgM levels while tapering glucocorticoids; a maintenance dose of glucocorticoid should be considered if relapse is suspected or anticipated.

P87 Therapeutic outcomes in xanthoma disseminatum with cladribine: a long-term experience of six patients from a tertiary care institute

Abstract Xanthoma disseminatum is a rare, non-Langerhans-cell histiocytosis with systemic involvement that has limited treatment options and response. Cladribine has been previously reported in few case reports and a single case series to induce long-term remission of cutaneous lesions. The aim was to study the treatment outcomes in a long-term follow-up of patients with xanthoma disseminatum, treated with cladribine. This was an ambispective case series of six patients diagnosed with xanthoma disseminatum on the basis of clinical and histopathological features. All patients were treated with monthly cycles of cladribine (2-chlorodeoxyadenosine) 0.14 mg kg−1 daily for 5 days a month, ranging from two to eight cycles. The follow-up period ranged from 2 months to 4.75 years. There were four males and two females in our series, with mean (SD) age of 25.3 (13.1) years (range 9–48). Disease duration at presentation ranged from 1.5 to 8 years. All patients presented with skin-coloured to yellowish-brown papules in a periorbital, perioral and flexural distribution. Four of six (67%) patients had mucosal involvement. All but one patient had associated diabetes insipidus. Half the patients had bone involvement, and two showed extensive infiltrates in the brain causing neurological symptoms. Patients receiving at least three cycles (n = 5) reported a mean improvement of 72% in cutaneous lesions at the end of the follow-up period, allowing for the avoidance of tracheostomy in a patient with laryngeal involvement. Imaging (magnetic resonance imaging of the brain, positron emission computed tomography) repeated in four patients after 3–6 cycles showed evidence of significant improvement in extracutaneous disease. Adverse effects were noted in four (67%) patients, including transient leukopenia in three, post-infusion fever in one and proximal renal tubular acidosis in one. All side-effects were resolved after the cessation of therapy and/or with supportive treatment; no serious infections were reported. Cladribine is a purine analogue that has an antiproliferative effect on histiocytes and lymphocytes, as well as an immunomodulatory action. It has emerged as an effective therapeutic modality for patients with xanthoma disseminatum that necessitates further evaluation for dosage and safety.

#4688 ATP6V0A4 GENE MUTATION-ASSOCIATED NEPHROPATHY

Abstract Background and Aims The ATP6V0A4 gene is localized to chromosome 7q33∼34 and encodes for vacuolar H+-ATPase (V-ATPase) α4 subunit. Decreased V-ATPase function due to mutations in the ATP6V0A4 genes could cause H+ excretion defect of α-intercalated cells in the renal collecting duct, resulting in hereditary distal renal tubular acidosis (dRTA). However, crucially, no gain-of-function mutations in the ATP6V0A4 gene have been reported previously. This study reports a gain-of-function mutation of ATP6V0A4 gene occurred in a 32-year-old male with metabolic alkalosis, hypokalemia and hearing loss, and further explore potential pathogenic mechanisms of this mutation. Method Clinical information was collected from the proband and his family members. Kidney tissue samples were collected for morphological observation and immunohistochemical staining. High-throughput sequencing analyses were done for the proband and his parents. ATP6V0A4 wild-type and mutant plasmids were constructed and used to transfect the 293T cells. After 48 hours of transfection, the expression of ATP6V0A4 was verified using WB analyses and V-ATPase activity was measured by ultraviolet spectrophotometry. Results The proband and his father both suffered from severe hypertension and hearing loss. Blood tests showed hypokalemia, metabolic alkalosis and renal insufficiency. Urinalysis indicated acidic urine. Laboratory tests on admission are shown in Table 1. Renal biopsy suggested malignant hypertensive kidney injury. Whole-exome sequencing demonstrated that the proband carried the heterozygous mutation c.1534G>T; p.V512L in exon 15 of the ATP6V0A4 gene. Sanger sequencing confirmed that the variant was inherited from his father. The immunohistochemical results implied the expression of V-ATPase α4 was significantly higher in renal tissues from proband than that of the control who was diagnosed with minimal change disease (Figure 1B).WB analysis showed 293T cells transfected with ATP6V0A4 mutant plasmids with darker protein bands, suggesting higher expression of V-ATPase α4 (Figure 1D). The cells transfected with mutant ATP6V0A4 plasmids showed significantly higher V-ATPase activity compared with wild-type ATP6V0A4 plasmids transfected cells (Figure 1E). Conclusion The ATP6V0A4 c.1534G>T; p.V512L mutation is a gain-of-function mutation and this result indicates the possibility that this mutation might enhance the normal physiological function of the V-ATPase, and likely contributes to the increased hydrogen ions excretion and thereby to the development of metabolic alkalosis (Figure 1F).

#3320 GENETIC TESTING FOR MOLECULAR DIAGNOSIS OF NEPHROLITHIASIS AND NEPHROCALCINOSIS IN ADULT PATIENTS: A SINGLE-CENTER COHORT

Abstract Background and Aims Hereditary factors represent an important cause of nephrolithiasis which will generate stone disease in adult. Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) for a genetic mutation has become more accessible and the benefits are highlighted by an increasing number of publications. The aim of the paper was to study genetic screening for 36 NL and/or NC patients in order to identify the cases that can be confirmed by mutations in known kidney stone genes. Method Between 2020–2022 we included 35 adult patients with NL/NC with onset on pediatric age or in young adults, plus one of the following criteria: family history for NL/NC, indicative phenotype, recurrent NL. All the patients were diagnosed with NL and/or NC by ultrasound or computed tomography scan. Inform consent was signed and dated before blood samples and we performed genetic testing using nephrolithiasis panel (that include 45 genes) from 2 laboratories. In addition, we performed clinical assessment in a multidisciplinary team, underwent metabolic assessment, and caring out the genealogical tree. Results The study included 18 females and 17 males. The mean age of studied patients was 34.9 ± 10.3 years (range 18 – 54 years), although mean age of NL/NC diagnosis was 19.4 ± 12.0 years (range 0.5 – 34 years). 29 patients presented NL of any type, 12 patients presented both NL and NC, and 3 patients isolated NC. All the patients presented positive family history of NL/NC, 17 (48.5%) patients had pediatric age of onset, 17 (48.5%) patients presented indicative phenotype and 19 (54.2%) recurrent stone disease. Causative monogenic mutations were detected in 25 of 35 NL/NC. We identified 20 deleterious variants in 12 out of 45 analyzed genes. Genetic testing was positive with a definite diagnosis (had pathogenic variant) in 17 (48.6%) of cases, while 3 (8.6%) patients presented likely pathogenic variants, and 5 (14.3%) patients had variants of uncertain significance (VUS). In our cohort, the most common cause of kidney stone disease was cystine nephrolithiasis in 8 (22.8%) patients, followed by hereditary distal renal tubular acidosis in 4 patients, Dent disease in 3 patients, primary hyperoxaluria type 1 in 2 patients, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in 2 patients. Other causes of kidney stone disease included: renal hypouricemia type 1, hereditary hypophosphatemic rickets with hypercalciuria, primary mitochondrial disorders, autosomal dominant familial idiopathic hypercalciuria, Bartter syndrome type 3, and autosomal dominant tubulo-interstitial disease with hyperuricemia. Pathogenic mutations were detected in the following 5 dominant disease genes: SLC7A9 (4 patients), SLC4A1 (3 patients), ADCY10 (1 patient), HNF1B (2 patients), POLG (1 patient). Also, we identified pathogenic mutations in the following 7 recessive disease genes: CLCN5 (3 patients), AGXT (2 patients), CLDN16 (2 patients), SLC3A1 (3 patients), SLC34A3 (1 patient), WDR72 (1 patient), CLCNKB (1 patient). The mean eGFR for the study group was 71.2 ± 37.6 ml/min/1.72 m2. Seventeen patients presented eGFR < 60 ml/min/1.73 m2: seven patients CKD stage 3, four patients CKD stage 4, two patients CKD stage 5, and two patients were with renal replacement therapy. Conclusion Genetic kidney stone disease is an underdiagnosed condition. Although 48.5% of the patients had NL/NC onset on pediatric age, the molecular diagnosis was performed in adulthood, and, for some of them, when they suffer of advanced kidney disease. In our cohort, genetic testing had a high rate of positive molecular diagnosis of NL/NC due to selection criteria. Five of our patients presented VUS, but with disease-specific phenotype. We emphasize the importance of reporting these cases to generate additional evidence that could allow the reclassification of these variants. We conclude that the molecular diagnosis improves patient management, prevent or delay chronic kidney disease, offer possibility of genetic counseling and an extended screening to the family. Thus, our study showed the potential benefits of genetic testing, especially in high-risk groups for stone disease.

#4989 FIRST INTERIM ANALYSIS OF THE INTERNATIONAL DISTAL RENAL TUBULAR ACIDOSIS REGISTRY

Abstract Background and Aims Primary Distal Renal Tubular Acidosis (dRTA) is a rare genetic condition characterized by impaired capacity of A-type intercalated cells to excrete excess of H+ ions. The disease is caused primarily by pathogenic variants in the SLC4A1 gene encoding for the basolateral anion exchanger 1 (AE1) or the ATP6V1B1 and ATP6V0A4 genes encoding for two subunits of the apical proton ATPase. The latter also cause variable degrees of sensorineural hearing loss (SNHL). Additional genes include WDR72 that is associated with amelogenesis imperfecta and FOXI1 that also causes SNHL. To understand better the impact of alkali treatment on the natural history of dRTA, a European prospective registry has been created in collaboration with the ERKNet European Reference Network. Method We present a first interim descriptive analysis of first 182 patients that have been collected from 2019 to 2022. Treatment data are under analysis and are not included. Results To date, mostly paediatric patients (79%) have been included in the registry. A genetic diagnosis was available in 111/182 (61%) of patients and showed the following distribution of underlying genes: ATP6V0A4: 45%, ATP6V1B1: 41%, SLC4A1: 14%. Variants in WDR72 and FOXI1 were reported in one patient each. Overall, we observed no major differences in blood pressure and in urinary/blood parameters, when comparing children vs adults or proton ATPase vs AE1 defects (partially shown in tables 1 and 2). Adult patients were on average diagnosed later, had more frequently nephrolithiasis and higher BMI. In part, differences may reflect selections biases that will be assessed with the collection of longitudinal data. As expected, patients with proton pump defects were diagnosed earlier and had more frequently SNHL. The degree of nephrocalcinosis and the estimated glomerular filtration rates were similar when comparing all groups. None of the patients had developed end stage kidney disease. Conclusion This first report demonstrates successful enrolment of a cohort of patients with dRTA. Enrolment is still ongoing. Longitudinal data will allow assessing the impact of alkali therapy on the long-term outcome.

#6649 SIGNIFICANT CLINICAL IMPROVEMENT OF PAEDIATRIC AND ADULT PATIENTS WITH DISTAL RENAL TUBULAR ACIDOSIS AFTER 6 YEARS OF TREATMENT WITH SIBNAYAL®

Abstract Background and Aims Distal renal tubular acidosis (dRTA) is a rare disease, inherited or acquired, characterized by hyperchloremic metabolic acidosis leading to negative effects on growth, bone and kidney, with growth retardation, rickets in children and osteomalacia in adults, nephrolithiasis and chronic kidney disease. No alkalizing treatment, necessary to control the metabolic acidosis and its consequences in growth, bone and kidney, has been shown, to date, to control the disease in the long term. The aim of this clinical study is to describe a cohort of adult and pediatric dRTA patients treated during 6 years by Sibnayal®, a new prolonged-release alkalizing formulation, in term of metabolic control, growth and long-term complications on bone mineralization and kidney function. Method Thirty patients with genetic dRTA taking Sibnayal®, previously treated with alkalizing standard of care and enrolled in the short-term B21CS study, were followed up for six years on average in a multicenter open-label extension trial (B22CS) to evaluate long-term impact of treatment on standard deviation score (SDS) of height, SDS weight, body mass index (BMI), Z-score spine bone mineral density (BMD), phosphocalcic metabolism (up to 4 years). glomerular filtration rate (GFR), nephrolithiasis, metabolic acidosis control, safety and compliance were also evaluated. Paired t-tests were done from baseline to end of study (EoS) when appropriate. The covariance ANCOVA test was performed to analyze spine BMD Z-score. Data are presented as mean ± standard error of mean. Results Clinical observations in this cohort, after an average of six years of treatment with Sibnayal®, confirmed the adequate control of metabolic acidosis (plasma bicarbonate from 22.0±0;6 mmol/L at baseline to 22.8±0.56 mmol/L at study end). The phosphocalcic metabolism analysis, from baseline to Month 48, demonstrated no significant change on Z-score for age of blood bone alkaline phosphatases, and a significant decrease of Z-score for age of blood phosphorus level (from to -0.5±0.7 to -1.3±1.0, p = 0.03). From baseline to EoS, SDS of height and weight increased significantly (-0.6±1.0 to -0.3±0.9 p = 0.04 and 0.2±1.5 to 0.7±1.4 p = 0.03, respectively), without significant difference in BMI. The spine BMD Z-score, relevant skeletal area for both pediatric and adult patients, underwent a continuous and significant increase of the change from baseline values over 6 years of treatment (difference [95% CI] = 0.404 [0.170; 0.639]). At EoS, spine BMD Z-score was improved in pre- and post-pubertal patients (mean 0.76±0.54 and 0.56±0.22 respectively), while it was stabilized in pubertal patients (mean -0.01±0.39). There was no significant variation of GFR between baseline and EoS. Nephrolithiasis increased slightly according to the increased age of the patient, without surgical intervention for stones removal. Safety and adherence to treatment remained good throughout the study. Conclusion Our data show the positive effect of the long-term treatment with Sibnayal® on growth and spine BMD, nicely improved, in the dRTA patients who participated to this long-term follow-up clinical study. The kidney function is also stabilized in these patients during the follow-up. This is the first report describing the prevention effect on the long-term complications of the distal Renal Tubular Acidosis patients under 6 years of Sibnayal® treatment.

Distal Renal Tubular Acidosis can be the Cause of Hypokalemia in Graves’ Disease: A Rare Association

Distal renal tubular acidosis (dRTA) may rarely occur in the course of autoimmune diseases. We present a patient who was followed up with Graves' disease and vitiligo and who was diagnosed with dRTA upon detection of hypopotasemia. A 9.2-year-old girl presented with complaints of sweating, palpitations, and hand tremors. The patient had vitiligo on examination and was diagnosed with Graves' disease per clinical and laboratory findings. The patient, who received methimazole and was followed up as a euthyroid, was found to have hypokalemia in biochemical examinations performed at the age of 13 years. While investigating the etiology of hypokalemia, the patient was diagnosed with dRTA. Since she had two autoimmune pathologies, it was thought that the dRTA might be of autoimmune origin. Checking serum potassium levels in the follow-up of patients with Graves' disease may allow early diagnosis and treatment of accompanying dRTA.

Abstract #1399358: Treatment of Familial Tumoral Calcinosis with Acetazolamide Plus a Phosphate Binder

Familial tumoral calcinosis is an autosomal recessive disease resulting from fibroblast growth factor 23 (FGF23) deficiency or resistance. Subsequent hyperphosphatemia can lead to painful ectopic calcifications, which are often unsuccessfully managed with surgical intervention. We present a case of a patient with intractable pain due to familial tumoral calcinosis who failed surgical management and was given a trial of acetazolamide in addition to calcium acetate. A 22-year-old female with a history of familial tumoral calcinosis presented for endocrine medical management. In her native country, she developed extensive, painful growths in her left shoulder and hip, for which she underwent surgical tumor debulking. She later developed additional growths in her left elbow and right wrist. Laboratory studies were remarkable for an elevated serum phosphorous level of 7.0 mg/dL (2.5-4.5 mg/dL), parathyroid hormone (PTH) level of 17 pg/mL (15-65 pg/mL), calcium level of 10.1 mg/dL (8.4-10.2 mg/dL) and albumin level of 4.5 g/dL (3.5-5.2 g/dL). FGF23 was found to be markedly elevated at 1,616 RU/mL (44-215 RU/mL). Radiographs of her bilateral shoulders and magnetic resonance imaging (MRI) of her right wrist were consistent with tumoral calcinosis. The patient was reluctant to undergo repeat surgical intervention due to the limited efficacy of her initial procedures. In addition to limiting dietary phosphorous intake, the patient was started on calcium acetate 667 mg three times daily before meals and acetazolamide 250 mg twice daily. Serum phosphorous level subsequently decreased to 6.4 mg/dL. Though she continues to report pain, she has not since developed any new growths. Familial tumoral calcinosis is a rare disease affecting phosphate metabolism. It is caused by inactivating mutations of the FGF23, klotho or GALNT3 genes, resulting in increased phosphate reabsorption in the kidneys. This excess circulating phosphorous binds to serum calcium, causing deposits to build up in soft tissues that can lead to significant discomfort. Given the high rate of recurrence after surgical intervention, medical management is the mainstay of treatment, focusing on limiting dietary phosphorous intake and absorption. Acetazolamide, a carbonic anhydrase inhibitor, has been proposed as an adjunctive treatment modality. By way of inducing a proximal renal tubular acidosis, acetazolamide can potentially augment the solubility of serum calcium-phosphate complexes, thus promoting renal phosphate clearance. This case serves to highlight both a rare diagnosis and it’s limited therapeutic options, as well as the potential efficacy of those therapeutic options in patient care.

Hearing Loss Related to Gene Mutations in Distal Renal Tubular Acidosis

Introduction: Distal renal tubular acidosis (dRTA) is a disease that may develop either primarily or secondarily, resulting from urinary acidification defects in distal tubules. Hearing loss may accompany primary forms of dRTA. This study aims to determine the characteristics of hearing loss due to different gene mutations in patients with dRTA. Methods: Behavioral and electrophysiological audiological evaluations were performed after otolaryngology examination in 21 patients with clinically diagnosed dRTA. Radiological imaging of the inner ear (n = 9) was conducted and results of genetic analyses using next-generation sequencing method (n = 16) were included. Results: Twenty-one patients with dRTA from 20 unrelated families, aged between 8 months and 33 years (median = 12, interquartile range = 20), participated. All patients with ATP6V1B1 mutations (n = 9) had different degrees of hearing loss. There was one patient with hearing loss in patients with ATP6V0A4 mutations (n = 6). One patient with the WDR72 mutation had normal hearing. Large vestibular aqueduct syndrome (LVAS) was detected in 6 (67%) of 9 patients whose radiological evaluation results were available. Conclusions: LVAS is common in patients with dRTA and may influence the type and severity of hearing loss in these patients. The possibility of both congenital and late-onset and progressive hearing loss should be considered in dRTA patients. A regular audiological follow-up is essential for the early detection of a possible late-onset or progressive hearing loss in these patients.

RESPIRATORY FAILURE ASSOCIATED WITH DISTAL RENAL TUBULAR ACIDOSIS IN AN OLDER ADULT WITH SOUTHEAST ASIAN OVALOCYTOSIS AND CONCOMITANT THYROTOXIC ATRIAL FIBRILLATION

Distal renal tubular acidosis (dRTA) is characterized by hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis and metabolic bone disease. It has been associated with Southeast Asian Ovalocytosis (SAO), particularly in malaria endemic region. We present a case of an older adult with dRTA who presented with respiratory failure as a result of hyperchloremic normal anion gap metabolic acidosis, in association with nephrocalcinosis and SAO, however, without hypokalaemia due to concurrent acute kidney injury. Oxygen therapy was able to be weaned off after treatment with alkali supplementation. Distal RTA may be associated with SAO, and early recognition and treatment of dRTA is paramount in preventing complications such as chronic kidney disease, metabolic bone disease and life-threatening respiratory arrest.

The pathophysiology of distal renal tubular acidosis

The kidneys have a central role in the control of acid-base homeostasis owing to bicarbonate reabsorption and production of ammonia and ammonium in the proximal tubule and active acid secretion along the collecting duct. Impaired acid excretion by the collecting duct system causes distal renal tubular acidosis (dRTA), which is characterized by the failure to acidify urine below pH 5.5. This defect originates from reduced function of acid-secretory type A intercalated cells. Inherited forms of dRTA are caused by variants in SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, WDR72 and probably in other genes that are yet to be discovered. Inheritance of dRTA follows autosomal-dominant and -recessive patterns. Acquired forms of dRTA are caused by various types of autoimmune diseases or adverse effects of some drugs. Incomplete dRTA is frequently found in patients with and without kidney stone disease. These patients fail to appropriately acidify their urine when challenged, suggesting that incomplete dRTA may represent an intermediate state in the spectrum of the ability to excrete acids. Unrecognized or insufficiently treated dRTA can cause rickets and failure to thrive in children, osteomalacia in adults, nephrolithiasis and nephrocalcinosis. Electrolyte disorders are also often present and poorly controlled dRTA can increase the risk of developing chronic kidney disease.

Genotype–Phenotype Characteristics of Children with Distal Renal Tubular Acidosis Caused by WDR72 Mutations

Background: Distal renal tubular acidosis (dRTA) can be acquired or inherited. Hereditary types of dRTA are mostly seen in the pediatric population, whereas acquired forms predominate in adults. The diagnosis of hereditary dRTA can be confirmed by genetic testing. Five genes are known to cause the disease: ATP6V1B1, ATP6V0A4, FOXI1, SLC4A1, and WDR72. Most of the children with autosomal dominant forms carry mutations in the SLC4A1 gene, whereas the most common mutation in autosomal recessive type is ATP6V0A4 and ATP6V1B1 genes. Objective: In this systematic review of case reports, we discuss the clinical features and mutation variants of hereditary dRTA due to homozygous pathogenic variations in the WDR72 gene, which has been recently identified. Methods: The PubMed and Google Scholar databases were searched with defined search terms and eligibility criteria independently by different authors. Results: Of five full-text articles retrieved, four were finally included which provided data of 14 individuals, all of which had specific mutations in WDR72 gene. The majority of cases were attributed to individuals of Asian descent (71%) with equal distribution of males and females. The mean age of onset was 4.42 years. Amelogenesis imperfecta (AI) was described in 90% of patients, nephrocalcinosis in 62.5%, polyuria in 55.5%, proximal muscle weakness in 55.5%, and rickets in two patients. Conclusion: In patients exhibiting features such as metabolic acidosis, hypokalemia, AI, polyuria, nephrocalcinosis, and growth retardation, genetic analysis for WDR72 mutation should be considered.

“ABERRANT PRESENTATION OF SJOGREN'S SYNDROME LEADING TO HYPOKALEMIC PERIODIC PARALYSIS – A CASE REPORT”

Tubulointerstitial nephritis (TIN) is the main renal involvement associated with primary Sjögren syndrome (pSS). TIN can manifest as distal renal tubular acidosis (RTA), nephrogenic diabetes insipidus, proximal tubular dysfunction, and others. We present a 50-year-old female with hypokalemic paralysis due to distal RTA(dRTA). She received symptomatic treatment and potassium supplementation with a good response. The evidence suggests that there is an inammatory background and therefore a potential serious affection to these patients, such as hypokalemic paralysis. For pSS-associated Tubulo-interstitial nephritis, we suggest symptomatic therapy with potassium supplementation and corticosteroids combination in treatment.

105 Proximal Renal Tubular Acidosis and Nephrolithiasis in Pregnancy Due to SLC34A1 Gene Mutation

105 Proximal Renal Tubular Acidosis and Nephrolithiasis in Pregnancy Due to SLC34A1 Gene Mutation

Clinical significance of hypouricemia in children and adolescents.

Although hyperuricemia is a widely studied condition with well-known effects on the kidneys, hypouricemia is usually considered a biochemical abnormality of no clinical significance despite the fact that it can be a sign or major finding of serious metabolic or genetic diseases affecting kidney health. In this study, we aimed to investigate and emphasize the clinical significance of hypouricemia. Patients were evaluated retrospectively for persistent hypouricemia defined as serum uric acid concentrations of < 2mg/dL on at least 3 different occasions. According to the blood and urine uric acid (UA) levels, the patients were classified as having hypouricemia due to UA underproduction vs. overexcretion. Demographic, clinical, and genetic characteristics were noted for analysis. Fourteen patients (n = 14; M/F 8/6) with persistent hypouricemia were identified. Hypouricemia due to underproduction was the cause of 42.8% of these cases. All of the patients with a uric acid level of 0mg/dL (n = 4) had hypouricemia due to underproduction. The median serum uric acid level was 0.85 (0-1.6) mg/dL. Isolated hypouricemia and hypouricemia with metabolic acidosis were equally distributed. Among the patients with hypouricemia due to underproduction, the final diagnoses were xanthine dehydrogenase deficiency (n = 5) and alkaptonuria (n = 1). In the overexcretion group, the final diagnoses were nephropathic cystinosis (n = 6), distal renal tubular acidosis (n = 1), and hereditary renal hypouricemia (n = 1). The diagnostic lag was longer for patients with isolated hypouricemia compared to other patients (p = 0.001). Hypouricemia may reflect underlying genetic or metabolic diseases, early diagnosis of which could help preserve kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Sulfate and acid-base balance

It has been acknowledged for years that compounds containing sulfur (S) are an important source of endogenous acid production. In the metabolism, S is oxidized to sulfate, and therefore the mEq sulfate excreted in the urine is counted as acid retained in the body. In this study we show that pH in fluids with constant [Na] and [HEPES] declines as sulfate ions are added, and we show that titratable acidity increases exactly with the equivalents of sulfate. Therefore, sulfate excretion in urine is also acid excretion per se. This is in accordance with the down-regulation of proximal sulfate reabsorption under acidosis and the observation that children with distal renal tubular acidosis may be sulfate depleted. These results are well explained using charge-balance modeling, which is based only on the three fundamental principles of electroneutrality, conservation of mass, and rules of dissociation as devised from physical chemistry. In contrast, the findings are in contrast to expectations from conventional narratives. These are unable to understand the decreasing pH as sulfate is added since no conventional acid is present. The results may undermine the traditional notion of endogenous acid production since in the case of sulfur balance, S oxidation and its excretion as sulfate exactly balance each other. Possible clinical correlates with these findings are discussed.

Мочекаменная болезнь на фоне почечного канальцевого ацидоза.

Introduction. Distal renal tubular acidosis (dRTA) is a rare cause of stone formation in urolithiasis patients according to the conventional wisdom in the urological community. At the same time prevalence of the incomplete dRTA in patients with idiopathic calcium stones is 16.8% (13.6% in men and 25.5% in women) according to the recent studies. Previously, we published a review article, which describes the features of the dRTA etiology and pathogenesis, and presents diagnostic and treatment algorithms. We consider it interesting to present a clinical case in continuation of the previous publication. Clinical case. There are anamnesis data, results of laboratory and instrumental analysis of the patient Zh. with a urolithiasis and renal tubular acidosis are presented. The patient was prescribed a long course of conservative citrate and thiazide diuretics therapy. The patient managed to achieve normalization of the main parameters of blood and urine, stable remission of the disease against the background of ongoing therapy. Conclusions, patients with distal renal tubular acidosis and urolithiasis are quite common in the clinical practice of urologist. Timely diagnosis of the disease and the appointment of adequate therapy can improve the quality of patient's life and reduce the number of stone relapses.