Unusual presentation of Sjogren's syndrome.

Sjogren's syndrome is a known cause of renal tubular acidosis (RTA). However, osteomalacia associated with Sjogren's syndrome is rare and seldom reported in literature. We report a case of pseudofractures of both femora due to osteomalacia as a result of RTA secondary to Sjogren's syndrome, which was initially misdiagnosed as a stress fracture. A man in his 30s presented with hip pain and was initially misdiagnosed to have stress fractures because of the 'through and through' extension of the 'fracture' lines at the neck of both femora. The patient had a normal serum biochemistry profile except for elevated alkaline phosphatase levels. On further evaluation, he was found to have distal RTA secondary to Sjogren's syndrome. The patient responded to sodium bicarbonate therapy with clinical, biochemical and radiological improvement. A high index of suspicion for RTA should be kept in a patient with osteomalacia with a normal calcium profile and vitamin D level.

Administration of bicarbonates through percutaneous gastrostomy with continuous nocturnal infusion in a patient with Kearns-Sayre disease: a life changing therapeutical paradigm.

BACKGROUND: Mitochondrial diseases (MDs) are systemic disorders that can affect multiple organs. Renal manifestations, including renal tubular acidosis, are common because kidneys are particularly vulnerable to energy deprivation. Treatment of MDs is often complex and electrolyte replacement can be difficult especially in pediatric patients, because large and repeated amounts of oral supplements are needed but are not well tolerated. CASE PRESENTATION: We describe the case of a girl affected by Kearns-Sayre disease with severe renal tubular acidosis. The management of her metabolic acidosis was challenging because she showed persistent low levels of serum bicarbonates despite a progressive incrementation of oral bicarbonates. Furthermore, as a result to the ingestion of large amounts of alkali, the girl developed an aversion to oral supplementation. After positioning a percutaneous gastrostomy (PEG) and starting enteral administration of bicarbonates (with daily boluses and continuous nocturnal infusion), she finally obtained an adequate electrolyte control, with a significant increase in her quality of life. CONCLUSIONS: In MDs, the combination of nocturnal continuous enteral administration of alkali plus diurnal boluses may represent a valid solution to correct metabolic acidosis. It can also result in an improved patients' quality of life, particularly in pediatric settings, where compliance to oral therapy is often lacking due to the large and repeated amounts of unpalatable bicarbonates solutions required.

Hypocitraturia as a biomarker of renal tubular acidosis in patients with Sjögren's disease.

INTRODUCTION: Sjögren's disease (SD) is an immune-mediated chronic inflammatory disease that affects epithelial tissues, mainly salivary and lacrimal glands. It also presents extraglandular manifestations. The main renal manifestation is tubulointerstitial nephritis (TIN), which can manifest as renal tubular acidosis (RTA). Urinary citrate may be a biomarker of RTA in these patients. The objective of this study was to evaluate whether hypocitraturia is a predictive biomarker of RTA in a sample of patients with SD in a tertiary hospital in southern Brazil. METHODS: All patients with SD who met the inclusion criteria and who participated in the rheumatology outpatient clinic of the Irmandade Santa Casa de Misericórdia de Porto Alegre were included. Demographic, SD, serological and urinary data were obtained. RTA was considered in those patients who persistently presented urinary pH above 5.5 and serum pH below 7.35. Patients who persistently had urinary pH above 5.5 underwent a urinary acidification test with furosemide and fludrocortisone. These patients received 1 mg of fludrocortisone and 40 mg of furosemide and had their urine samples tested 2, 4 and 6 h after taking the medications. The test was stopped at any urine sample with pH 5.5 or less. The variables were expressed as mean and standard deviation or interquartile range. The association between hypocitraturia and RTA was assessed using the chi-square. RESULTS: Forty-two patients were included, 95.2% female with a median age of 61.73 years. The prevalence of complete distal RTA was 4.88%. Twenty-eight patients underwent urine acidification testing. Five patients had hypocitraturia, and two of them had complete distal RTA. The association between hypocitraturia and RTA was statistically significant (p < 0.012), with a sensitivity of 100%, specificity of 91.2% and accuracy of 91.7%. The negative predictive value was 100%. The global renal assessment of the population demonstrated two patients with RTA, one patient with decreased renal function and six patients with proteinuria greater than 0.5 g/24 h. CONCLUSION: The prevalence of RTA in the studied population was 4.88%. Hypocitraturia had high sensitivity and accuracy for the diagnosis of RTA.

Unusual presentation of Sjogren's syndrome during pregnancy: a case report.

BACKGROUND: Pregnancy imposes significant physiological changes, including alterations in electrolyte balance and renal function. This is especially important because certain disorders might worsen and make people more susceptible to electrolyte abnormalities. One such condition is Sjogren's syndrome (SS), an autoimmune disease that can cause distal renal tubular acidosis (dRTA). This case report offers a unique perspective on the intricate physiological interplay during pregnancy, emphasizing the critical importance of recognizing and managing electrolyte abnormalities, particularly in the context of autoimmune disorders such as Sjogren's syndrome. CASE PRESENTATION: We report a case of a 31-year-old pregnant Indian woman at 24 weeks gestation presenting with fever, gastrointestinal symptoms, and progressive quadriparesis followed by altered sensorium. Severe hypokalaemia and respiratory acidosis necessitated immediate intubation and ventilatory support. Investigations revealed hypokalaemia, normal anion gap metabolic acidosis, and positive autoimmune markers for SS. Concurrently, she tested positive for IgM Leptospira. Management involved aggressive correction of electrolyte imbalances and addressing the underlying SS and leptospirosis. CONCLUSION: This case underscores that prompt recognition and management are paramount to prevent life-threatening complications in pregnant patients with autoimmune disease. This report sheds light on the unique challenge of managing hypokalaemic quadriparesis in the context of Sjogren's syndrome during pregnancy.

Pseudohypoaldosteronism and acquired renal aldosterone resistance with hyperkalemic type IV renal tubular acidosis in 2 cats.

This report describes the diagnosis and treatment of aldosterone resistance (AR) and acquired hyperkalemic type IV renal tubular acidosis (RTA) in 2 cats comparable to acquired pseudohypoaldosteronism in people. One cat developed AR from chronic kidney disease after an acute kidney injury and was treated with furosemide per os, which resolved the hyperkalemic RTA. The second cat developed transient AR secondary to a bacterial urinary tract infection associated with urethral catheterization, and treatment with antibiotics resolved the hyperkalemic RTA.

Allogenic hematopoietic stem cell transplantation in an Iranian patient with osteopetrosis caused by carbonic anhydrase II deficiency: A case report.

BACKGROUND: Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic mutations can yield important prognostic and therapeutic implications. Herein, we present the diagnosis and successful application of hematopoietic stem cell transplantation (HSCT) in a patient with osteopetrosis caused by carbonic anhydrase II deficiency (Intermediate osteopetrosis). CASE PRESENTATION: Herein, we describe a 2.5-year-old male patient born to consanguineous parents who presented at 8-month-old with hydrocephaly, brain shunt, and developmental delay. Later at 9 months old, he was found to have eye disorder such as nystagmus, fracture of the elbow, abnormal skeletal survey, normal cell blood count (CBC), and severe hypocellularity in the bone marrow. Further evaluation showed renal tubular acidosis type 2. Whole-exome sequencing revealed a pathogenic homozygous variant in intron 2 of the carbonic anhydrase 2 gene (CA2) gene (c.232 + 1 G>T). The diagnosis of intermediate autosomal recessive osteopetrosis was established, and allogenic HSCT from his mother, a full-matched related donor (MRD), was planned. The conditioning regimen included Busulfan, Fludarabine, and Rabbit anti-thymocyte globulin. Cyclosporine and Mycophenolate Mofetil were used for graft-versus-host-disease prophylaxis. He Engrafted on day +13, and 95% chimerism was achieved. He is currently doing well without immunosuppressive therapy, now 12 months post HSCT, with normal calcium level and improving visual quality and FISH analysis revealed complete donor chimerism. DISCUSSION: HSCT could be a promising curative treatment for intermediate osteopetrosis and can provide long-term survival. Ongoing challenges in various aspects of HSCT remain to be addressed.

Nephrolithiasis Associated with Nephrocalcinosis Is Primarily Composed of Carbonate Apatite.

INTRODUCTION: This study was designed to determine the mineral composition of calculi in nephrocalcinosis with nephrolithiasis, diagnose the underlying disease, and monitor the course of renal function in patients with nephrocalcinosis-nephrolithiasis. METHODS: Renal calculi extruded in a series of 8 patients with nephrocalcinosis were analysed using Fourier transmission infrared spectrometry. In 4 patients, next-generation sequencing using a nephrocalcinosis-nephrolithiasis panel was performed to determine the nature of the underlying disease. In addition, longitudinal analysis of renal function was performed in all patients. RESULTS: Seven patients revealed carbonate apatite as the sole constituent of renal calculi. One patient showed a mixed composition of dicalcium phosphate dihydrate/carbonate apatite at first analysis yet in subsequent episodes also had calculi composed of pure carbonate apatite. Further molecular analysis displayed distal renal tubular acidosis in 2 of 4 patients who consented to sequencing. No known genetic defect could be found in the other two cases. In line with prior reports, decline of renal function was dependent on underlying disease. Distal renal tubular acidosis revealed a progressive course of renal failure, whereas other causes showed stable renal function in long term analysis. CONCLUSION: Nephrocalcinosis with nephrolithiasis is a rare condition with heterogeneous aetiology. Yet mineral composition of renal calculi predominantly consisted of pure carbonate apatite. This uniform finding is similar to subcutaneous calcifications of various origins and might propose a general principle of tissue calcification. Progressive decline of renal function was found in distal renal tubular acidosis, whereas other conditions remained stable over time.

The impact of kidney stone disease on quality of life in high-risk stone formers.

OBJECTIVE: To assess the impact of kidney stone disease (KSD) and its treatment on the health-related quality of life (HRQOL) of high-risk stone formers with hyperparathyroidism, renal tubular acidosis, malabsorptive disease, and medullary sponge kidney. PATIENTS AND METHODS: The Wisconsin Stone Quality of Life questionnaire was used to evaluate HRQOL in 3301 patients with a history of KSD from 16 institutions in North America between 2014 and 2020. Baseline characteristics and medical history were collected from patients, while active KSD was confirmed through radiological imaging. The high-risk group was compared to the remaining patients (control group) using the Wilcoxon rank-sum test. RESULTS: Of 1499 patients with active KSD included in the study, the high-risk group included 120 patients. The high-risk group had significantly lower HRQOL scores compared to the control group (P < 0.01). In the multivariable analyses, medullary sponge kidney disease and renal tubular acidosis were independent predictors of poorer HRQOL, while alkali therapy was an independent predictor of better HRQOL (all P < 0.01). CONCLUSIONS: Among patients with active KSD, high-risk stone formers had impaired HRQOL with medullary sponge kidney disease and renal tubular acidosis being independent predictors of poorer HRQOL. Clinicians should seek to identify these patients earlier as they would benefit from prompt treatment and prevention.

Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?

Metabolic acidosis is a frequent complication in non-transplant chronic kidney disease (CKD) and after kidney transplantation. It occurs when net endogenous acid production exceeds net acid excretion. While nephron loss with reduced ammoniagenesis is the main cause of acid retention in non-transplant CKD patients, additional pathophysiological mechanisms are likely inflicted in kidney transplant recipients. Functional tubular damage by calcineurin inhibitors seems to play a key role causing renal tubular acidosis. Notably, experimental and clinical studies over the past decades have provided evidence that metabolic acidosis may not only be a consequence of CKD but also a driver of disease. In metabolic acidosis, activation of hormonal systems and the complement system resulting in fibrosis have been described. Further studies of changes in renal metabolism will likely contribute to a deeper understanding of the pathophysiology of metabolic acidosis in CKD. While alkali supplementation in case of reduced serum bicarbonate < 22 mmol/l has been endorsed by CKD guidelines for many years to slow renal functional decline, among other considerations, beneficial effects and thresholds for treatment have lately been under intense debate. This review article discusses this topic in light of the most recent results of trials assessing the efficacy of dietary and pharmacological interventions in CKD and kidney transplant patients.

A pH imbalance is linked to autophagic dysregulation of inner ear hair cells in Atp6v1ba-deficient zebrafish.

V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H+ secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H+ transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba-/-) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba-/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba-/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment.

Renal Tubular Acidosis in the Neonate.

See Bonus NeoBriefs videos and downloadable teaching slides Metabolic acidosis can manifest in the neonatal period and cause significant morbidity and mortality in neonates. Preterm infants are at an even higher risk of developing metabolic acidosis. If the acidosis results from a dysfunction of acid-base homeostasis by the renal system, the disorder is known as renal tubular acidosis (RTA). In this review, we will describe renal development and normal acid-base homeostasis by the renal system. We will also discuss the pathophysiology of the different types of RTA, laboratory findings to aid in diagnosis, and treatment considerations. Understanding RTA will help neonatal clinicians recognize and diagnose an infant affected by RTA and initiate treatment in a timely manner.

Nephrolithiasis and/or nephrocalcinosis is significantly related to renal dysfunction in patients with primary Sjögren's syndrome.

OBJECTIVE: The present study compared the clinical features of patients with primary Sjögren's syndrome (pSS) with and without nephrolithiasis and/or nephrocalcinosis to determine factors related to renal dysfunction. METHODS: The clinical features of 68 patients with anti-Sjogren's syndrome antigen A (SSA)/Ro-antibody-positive pSS with and without nephrolithiasis and/or nephrocalcinosis who underwent abdominal computed tomography and/or ultrasonography were retrospectively analysed. RESULTS: Of the 68 patients with anti-SSA-antibody-positive pSS, 23 (33%) had renal nephrolithiasis and/or nephrocalcinosis, whereas 45 (67%) did not. Fourteen (20%) patients had renal dysfunction at diagnostic imaging. Among five patients who underwent renal biopsy, four patients with renal nephrolithiasis and/or nephrocalcinosis were diagnosed with tubulointerstitial nephritis, and one without nephrolithiasis and/or nephrocalcinosis was diagnosed with minimal change nephrotic syndrome. Estimated glomerular filtration rate at diagnostic imaging was significantly lower in patients with than without nephrolithiasis and/or nephrocalcinosis group (P = 0.010). In addition to nephrolithiasis and/or nephrocalcinosis (odds ratio [OR], 3.467; P = 0.045), the gap between serum sodium and chloride concentrations (OR, 10.400; P = 0.012) and increased urinary ß2-microglobulin (OR, 5.444; P = 0.033) were associated with renal dysfunction at the time of diagnostic imaging. CONCLUSION: Nephrolithiasis and/or nephrocalcinosis, normal anion gap metabolic acidosis, and tubulointerstitial damage are associated with renal dysfunction in patients with pSS.

Pembrolizumab-induced Acute Tubulointerstitial Nephritis Accompanying Fanconi Syndrome and Type 1 Renal Tubular Acidosis.

Pembrolizumab, an immune checkpoint inhibitor, is used to treat a variety of refractory malignancies. However, these agents are sometimes associated with immune-related adverse events. A 71-year-old woman received pembrolizumab-integrated chemotherapy to treat her recurrent mandibular gingival cancer. Five months after stopping pembrolizumab, she developed acute tubulointerstitial nephritis associated with Fanconi syndrome and type 1 renal tubular acidosis, which resolved with steroid therapy. We experienced a case of pembrolizumab-induced Fanconi syndrome and type 1 renal acidosis. We recommend follow-up of the tubular function in addition to the renal function even after discontinuation of pembrolizumab.

Kidney manifestations of pediatric Sjögren's syndrome.

Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5-20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6-96.2%), and anti-Ro/SSA (36.4-84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature.

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

SIGNIFICANCE STATEMENT: 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. BACKGROUND: 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. METHODS: We examined the responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide. RESULTS: 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 ß2 -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. CONCLUSIONS: 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.

Distal renal tubular acidosis as presenting manifestation of Wilson disease in a 11-year-old girl.

A 11-year-old girl was referred to the pediatric nephrology services of our hospital for evaluation of vitamin-D-refractory rickets. She was born to second-degree consanguineous parents. On examination, she had wrist widening and bilateral genu varum. She had normal anion gap metabolic acidosis, hypokalemia, and hyperchloremia. The fractional excretion of bicarbonate was 3% and the urine anion gap was positive. She also had hypercalciuria, but no phosphaturia, glucosuria or aminoaciduria. In view of a family history of an elder sister having rigidity with cognitive and speech impairment, an ophthalmic evaluation by slit lamp examination was performed in the index case that revealed bilateral Kayser-Fleischer rings. Serum ceruloplasmin was low and 24-h urine copper was elevated in the index case. Whole exome sequencing unveiled a novel pathogenic variant in exon 2 of the ATP7B gene (chr13: c.470del; Depth: 142x) (homozygous) that resulted in a frameshift and premature truncation of the protein, 15 amino acids downstream to codon 157 (p. Cys157LeufsTer15; NM_000053.4) confirming Wilson disease. There were no mutations in the ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, WDR72 genes or other genes that are known to cause distal RTA. Therapy with D-penicillamine and zinc supplements was initiated. A low dose of 2.5 mEq/kg/day of potassium citrate supplementation normalized the serum bicarbonate levels. This case was notable for the absence of hepatic or neurological involvement at admission. Wilson disease is well known to cause proximal renal tubular acidosis and Fanconi syndrome, with relatively lesser involvement of the distal renal tubules in the literature. However, isolated distal renal tubular involvement as presenting manifestation of Wilson disease (without hepatic or neurological involvement) is rare and can lead to diagnostic confusion.

Association of Familial Hyperkalemia and Hypertension with Proximal Renal Tubular Acidosis and Epileptic Seizures.

INTRODUCTION: Familial hyperkalemic hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension, and hyperchloremic acidosis (HCA). The primary defect is a hyperactive sodium chloride co-transporter, expressed in the renal distal tubule. FHHt is caused by mutation in either WNK1, WNK4, KLHL3, or Cul3. The mechanism of HCA is not completely understood. METHODS: Clinical and genetic data were collected from the largest family with FHHt described in the literature. Urine ammonia was measured in 26 family members. Epilepsy was diagnosed clinically. RESULTS: Of the 85 family members, 44 are affected by the Q565E WNK4 mutation, and 28 are newly described. In genetically engineered mice, urinary ammonium was decreased. In our study, urine ammonium did not change. In 11 unaffected subjects, urine ammonia per creatinine was 8.013 ± 3.620 mm/mm, and in 15 subjects affected by FHHt, it was 8.990 ± 4.300 mm/mm (p = 0.546, not significant). Due to the large family size and prolonged follow-up, rare conditions can be identified. Indeed, two children have genetic generalized epilepsy and one child has migraine. The prevalence of epilepsy is 4.545% (2/44) much higher than in the general population (0.681%). This difference is statistically significant (χ2 with Yates correction = 5.127, p = 0.023). CONCLUSIONS: We provide further evidence that the origin of HCA in FHHt lies in the proximal renal tubule. The association of FHHt with epilepsy leads us to speculate that the raised serum K in susceptible subjects may cause a rise in CSF K, and extracellular cerebral K, leading to epilepsy.

Pediatric Renal Rickets at a Tertiary Center.

We report clinical and etiological profile of 19 children (10 males) with renal rickets managed in the years 2021-2022. Median (IQR) age of presentation was 60 (18-96) months. The commonest cause was renal tubular acidosis (n=8). Genetic analysis revealed the diagnosis in 83% subjects (5 out of 6 tested).