Distal Renal Tubular Acidosis Research Articles

Demographic, Clinical, and Laboratory Characteristics of Children with Renal Tubular Acidosis

This study included patients followed up for primary renal tubular acidosis (RTA) between 1991 and 2012. Clinical characteristics at presentation, physical examination findings, laboratory test results, and treatments were recorded. The patients’ laboratory results, drug doses, height, and weight were recorded every 3 months for the first year of follow-up. Standard deviation scores (Z-scores) of height and weight for age were determined and the patients’ growth rates were evaluated. Of 50 patients followed up for primary RTA, 31 (62%) had distal RTA and 19 (38%) had proximal RTA. The median age at diagnosis was 3 months (range, 1-174 months) for patients with distal RTA and 10 months (range, 2-33 months) for patients with proximal RTA. The median follow-up times in these two groups were 96 months (range, 6-204 months) and 89 months (range, 6-180 months), respectively. Family history of RTA was more common among patients with distal RTA than those with proximal RTA (p=0.013). Nephrocalcinosis and deafness were detected more frequently in the distal RTA group (p=0.001), while ocular pathologies were more common in the proximal RTA group (p<0.001). In patients with distal RTA, older age at diagnosis was associated with lower weight and height Z-scores (p<0.05). Early diagnosis had a positive effect on the growth of patients with primary RTA.

The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis.

In the kidney, the B1 H + -ATPase subunit is mostly expressed in intercalated cells (IC). Its importance in acid-secreting type A ICs is evident in patients with inborn distal renal tubular acidosis and ATP6V1B1 mutations. However, the protein is also highly expressed in alkali-secreting non-type A ICs where its function is incompletely understood. We demonstrate in Atp6v1b1 knock out mice that the B1 subunit is critical for the renal response to defend against alkalosis during an alkali load or chronic furosemide treatment. These findings highlight the importance of non-type A ICs in maintaining acid-base balance in response to metabolic challenges or commonly used diuretics. Non-type A ICs in the collecting duct system express the luminal Cl - /HCO 3- exchanger pendrin and apical and/or basolateral H + -ATPases containing the B1 subunit isoform. Non-type A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type A ICs. The function of B1 in non-type A ICs has remained elusive. We examined the responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide. An alkali load or 1 week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1-/- versus Atp6v1b1+/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non-type A ICs of ex vivo microperfused cortical collecting ducts were reduced, and β2 -adrenergic stimulation of pendrin activity was blunted in ATP6v1b1-/- mice. Basolateral H + -ATPase activity was strongly reduced, although the basolateral expression of the B2 isoform was increased. Ligation assays for H + -ATPase subunits indicated impaired assembly of V 0 and V 1 H + -ATPase domains. During chronic furosemide treatment, ATP6v1b1-/- mice also showed polyuria and hyperchloremia versus Atp6v1b1+/+ . The expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced. Our data demonstrate a critical role of H + -ATPases in non-type A ICs function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H + -ATPase complexes assembly and ability to be stimulated.

Lithium precipitated acute kidney injury: A rare case report

Lithium is known to cause nephrogenic diabetes insipidus, chronic tubule-interstitial nephropathy, and partial distal renal tubular acidosis. We are describing a rare instance of lithium precipitating acute renal injury within a week in a patient receiving long-term nonsteroidal anti-inflammatory drugs (NSAIDs) for medically unexplained symptoms. The patient presented with fluctuating orientation, cerebellar signs, and brisk deep tendon reflexes. Citing associated lithium toxicity discontinuation of lithium and NSAIDs brought back kidney function test to normal. Lithium toxicity was treated with intravascular fluids. We conclude that lithium may precipitate severe but reversible renal failure.

Distal Renal Tubular Acidosis as the Initial Manifestation of Hashimoto Thyroiditis

Distal Renal Tubular Acidosis as the Initial Manifestation of Hashimoto Thyroiditis

Generation of Atp6v1g3-Cre mice for investigation of intercalated cells and the collecting duct.

Kidney intercalated cells (ICs) maintain acid-base homeostasis and recent studies have demonstrated that they function in the kidney's innate defense. To study kidney innate immune function, ICs have been enriched using vacuolar ATPase (V-ATPase) B1 subunit (Atp6v1b1)-Cre (B1-Cre) mice. Although Atp6v1b1 is considered kidney specific, it is expressed in multiple organ systems, both in mice and humans, raising the possibility of off-target effects when using the Cre-lox system. We have recently shown using single-cell RNA sequencing that the gene that codes for the V-ATPase G3 subunit (mouse gene: Atp6v1g3; human gene: ATP6V1G3; protein abbreviation: G3) mRNA is selectively enriched in human kidney ICs. In this study, we generated Atp6v1g3-Cre (G3-Cre) reporter mice using CRISPR/CAS technology and crossed them with Tdtomatoflox/flox mice. The resultant G3-Cre+Tdt+ progeny was evaluated for kidney specificity in multiple tissues and found to be highly specific to kidney cells with minimal or no expression in other organs evaluated compared with B1-Cre mice. Tdt+ cells were flow sorted and were enriched for IC marker genes on RT-PCR analysis. Next, we crossed these mice to ihCD59 mice to generate an IC depletion mouse model (G3-Cre+ihCD59+/+). ICs were depleted in these mice using intermedilysin, which resulted in lower blood pH, suggestive of a distal renal tubular acidosis phenotype. The G3-Cre mice were healthy, bred normally, and produce regular-sized litter. Thus, this new "IC reporter" mice can be a useful tool to study ICs.NEW & NOTEWORTHY This study details the development, validation, and experimental use of a new mouse model to study the collecting duct and intercalated cells. Kidney intercalated cells are a cell type increasingly recognized to be important in several human diseases including kidney infections, acid-base disorders, and acute kidney injury.

Risk Profile of Patients with Brushite Stone Disease and the Impact of Diet.

This study examined the profile of patients and the impact of diet on the risk of brushite stone formation under controlled, standardized conditions. Sixty-five patients with brushite nephrolithiasis were enrolled in the study. Metabolic, dietary, and 24 h urinary parameters were collected under the habitual, self-selected diet of the patients and the balanced mixed, standardized diet. The [13C2]oxalate absorption, ammonium chloride, and calcium loading tests were conducted. All patients had at least one abnormality on the usual diet, with hypercalciuria (84.6%), increased urine pH (61.5%), and hyperphosphaturia (43.1%) being the most common. Absorptive hypercalciuria was present in 32.1% and hyperabsorption of oxalate in 41.2%, while distal renal tubular acidosis (dRTA) was noted in 50% of brushite stone formers. The relative supersaturation of brushite did not differ between patients with and without dRTA. Among all recent brushite-containing calculi, 61.5% were mixed with calcium oxalate and/or carbonate apatite. The relative supersaturation of brushite, apatite, and calcium oxalate decreased significantly under the balanced diet, mainly due to the significant decline in urinary calcium, phosphate, and oxalate excretion. Dietary intervention was shown to be effective and should be an integral part of the treatment of brushite stone disease. Further research on the role of dRTA in brushite stone formation is needed.

An Interesting Case of Sjögren’s Syndrome Presenting with Hypokalemic Quadriparesis and Distal Renal Tubular Acidosis

Abstract Sjögren’s syndrome is well known to masquerade with varied presentations due to its propensity to produce multisystemic and extraglandular disease. We present the case of Sjögren’s syndrome manifesting as new onset, acute quadriparesis. The patient had no articular manifestations suggesting a primary connective tissue disease or obvious sicca symptoms. Laboratory tests revealed severe hypokalemia and metabolic acidosis and antinuclear antibodies profile was positive for anti-Ro/SS-A antibody. Clinical examination revealed long-standing dental caries. A minor salivary gland biopsy showed features of Sjögren’s disease. The patient was started on potassium supplements and immunomodulatory therapy which led to clinical improvement in a week.

Renal tubular acidosis without interstitial nephritis in Sjögren’s syndrome: a case report and review of the literature

BackgroundRenal tubular acidosis is the principal clinical feature associated with tubulointerstitial nephritis in patients with primary Sjögren’s syndrome. Renal tubular dysfunction due to interstitial nephritis has been considered the underlying pathophysiology connecting renal tubular acidosis and primary Sjögren’s syndrome. However, the detailed mechanisms underlying the pathophysiology of renal tubular acidosis in primary Sjögren’s syndrome is not fully understood.Case presentationA 30-year-old woman was admitted with complaints of weakness in the extremities. The patient was hospitalized thirteen years earlier for similar issues and was diagnosed with hypokalemic paralysis due to distal renal tubular acidosis with primary Sjögren’s syndrome. This diagnosis was based on a positive Schirmer's test. Besides, anti-Sjögren’s syndrome-related antigen A was also detected. Laboratory tests indicated distal RTA; however, a renal biopsy showed no obvious interstitial nephritis. Laboratory tests conducted during the second admission indicated distal renal tubular acidosis. Therefore, a renal biopsy was performed again, which revealed interstitial nephritis. Histological analysis of acid–base transporters revealed the absence of vacuolar type H+-ATPases in the collecting duct. The vacuolar type H+-ATPase was also absent in the past renal biopsy, suggesting that the alteration in acid–base transporters is independent of interstitial nephritis.ConclusionsThis case study demonstrates that vacuolar-type H+-ATPases are associated with distal renal tubular acidosis, and distal renal tubular acidosis precedes interstitial nephritis in patients with primary Sjögren’s syndrome.

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.

Respiratory Paralysis in Sjogren’s Syndrome: A Case Report

Introduction: Primary Sjogren’s syndrome (pSS) a systemic autoimmune disease also known as sicca syndrome, primarily affects exocrine glands, particularly the salivary and lacrimal glands, and causes xerostomia and xerophthalmia. Renal involvement in cases of pSS is a rare occurrence. Patients with Sjogren’s syndrome presenting with severe hypokalemia or paralysis are uncommon. Methods: We present a case of a 45-year-old female presenting in our emergency department with hypokalemia-induced quadriparesis resulting from distal renal tubular acidosis due to Sjogren’s syndrome. It was revealed that symptoms of arthralgia and dry mouth had frequently been present for the past few years, with a persistent need for water intake. Results: The patient was given symptomatic treatment during hospitalization and recovered successfully. The report emphasizes that although Sjogren’s syndrome is most often associated with chronic sicca symptoms, it may present for the first time with extraglandular manifestations, which may be life-threatening. Conclusion: Extraglandular forms of Sjogren’s disease can result in severe hypokalemia and paralysis of the limbs and respiratory muscles, which, if ignored, can be deadly for the patient. The course of action for such situations should be early identification and timely treatment because they are treatable and can give patients an asymptomatic and decent quality of life.

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.