ABSTRACT Cadmium (Cd) accumulates in the renal cortex and impairs phosphate reabsorption in the proximal tubules, leading to increased urinary phosphate excretion and hypophosphatemia. However, the molecular mechanisms underlying Cd‐induced phosphate reabsorption dysfunction remain unclear. In this study, we developed an in vitro evaluation system using an immortalized rat proximal tubule cell line (NRK‐52E) to assess cellular phosphate uptake and examine the effects of Cd. Exposure to subtoxic concentrations of Cd significantly decreased phosphate uptake, while neither cisplatin nor gentamicin did as nephrotoxicants. Cd exposure did not reduce Npt2a or Npt2c expression. Cd exposure caused a marked reduction in mitochondrial membrane potential, ATP production, and the expression of mitochondrial fusion‐related factor OPA1 and respiratory chain components, along with prominent mitochondrial fragmentation. Treatment with inhibitors of OPA1 and the electron transport chain similarly impaired mitochondrial function and reduced phosphate uptake. These findings suggest that Cd‐induced dysfunction of phosphate reabsorption involves OPA1‐dependent mitochondrial fusion defects and mitochondrial dysfunction. This study provides new insights into the molecular mechanisms of Cd nephrotoxicity and demonstrates the potential of this in vitro model for evaluating reabsorption defects akin to Fanconi syndrome.

Cystinosis is a rare autosomal recessive lysosomal storage disorder with an incidence of approximately 1 in 100,000 to 200,000 live births. It is the most common cause of inherited pediatric Fanconi syndrome (FS). Here, we describe the cases of two infants from unrelated families who presented with polyuria and features of proximal renal tubular dysfunction. Although no corneal cystine deposition was observed at presentation, clinical suspicion and genetic analysis confirmed the diagnosis of nephropathic cystinosis. Both patients carried the same pathogenic variant in the CTNS gene, suggesting that it is a hotspot in this region. These patients were managed with oral cysteamine therapy, cysteamine eye drops, and supportive therapy for FS and are currently doing well. Genetic diagnosis plays a crucial role in the early detection of cystinosis, facilitating timely initiation of cysteamine therapy, and should be considered in infants with FS.

Refractory rickets refers to a set of diseases which are identified by a lack of response to therapeutic doses used to treat vitamin D deficiency. A child presenting with refractory rickets can pose a diagnostic dilemma as many kidney diseases have been identified as possible causes. Inherited (e.g., distal renal tubular acidosis, Fanconi syndrome, hypophosphatemic rickets, vitamin D-dependent rickets, nephronophthisis) and acquired tubular disorders [e.g., posterior urethral valves, reflux nephropathy leading to chronic kidney disease (CKD)-mineral bone disorder] may be complicated by refractory rickets. Rarely, chronic liver disease and malabsorption states can also result in refractory rickets. Hypophosphatemia is a feature of both calcipenic as well as phosphopenic rickets. Common features accompanying refractory rickets include polyuria, polydipsia, hypokalemic paralysis, fractures, limb deformities, failure-to-thrive, short-stature, tetany and nephrocalcinosis. A careful history, examination and biochemical evaluation is required to delineate the underlying cause. Using a rational algorithmic approach, it is possible to determine the correct diagnosis in these cases. Consequent upon easy availability of next generation sequencing (NGS), the accurate diagnoses can be promptly made aiding in targeted therapy. Children with refractory rickets need regular follow-up to optimise the biochemical abnormalities, monitor growth and retard the progression of CKD. This article describes the evaluation of a child with refractory rickets using an algorithmic approach, underscores the importance of the necessary blood and urine biochemical tests as well as NGS for identification of the precise etiology of refractory-rickets; and discusses the pathophysiology and management of the most important causes of refractory-rickets.

A 20-month-old boy with severe growth failure and Fanconi syndrome was diagnosed with nephropathic cystinosis, confirmed by corneal deposits and <i>CTNS</i> gene analysis. Despite septic complications, cysteamine therapy successfully stabilised his condition. The case illustrates diagnostic challenges in humanitarian crisis settings and the vital importance of prompt intervention.

Abstract Background The coexistence of tubulointerstitial nephritis (TIN) and uveitis commonly raises suspicion for tubulointerstitial nephritis and uveitis (TINU) syndrome. However, these manifestations may arise from distinct etiologies, making diagnosis challenging. Case presentation: a 30-year-old woman presented with bilateral anterior uveitis and renal impairment. Although TINU was initially suspected, detailed history taking revealed heterochronous mucocutaneous findings compatible with Behçet’s disease, as well as daily ibuprofen use for 4 years. A laboratory evaluation demonstrated Fanconi-type proximal tubular dysfunction. The renal biopsy showed acute TIN with granulomatous inflammation. Given the rarity of TIN due to Behçet’s disease and the absence of systemic activity, ibuprofen-induced TIN was strongly suspected. The renal function improved rapidly after ibuprofen cessation without corticosteroids, whereas uveitis followed a course consistent with Behçet’s disease rather than drug-induced TINU. On the basis of these observations, we constructed a diagnostic approach to differentiate drug-induced TIN, TINU, and systemic inflammatory disease in patients presenting with TIN and uveitis. Conclusions This case demonstrates that TIN and uveitis may originate from separate disease processes. A structured diagnostic approach can help clinicians avoid premature diagnosis of TINU syndrome and correctly identify dual pathology.

Bisphosphonates are commonly used to reduce fracture risk in patients with osteoporosis, in those with malignant metastatic bone disease and for treatment of malignant hypercalcaemia. We present the case of a woman in her 80s admitted with recurrent falls who developed Fanconi syndrome after a single dose of intravenous Zoledronic acid despite normal renal function. In this report, we review the literature exploring nephrotoxicity secondary to Zoledronic acid use, recognizing that there are other reported cases of Fanconi syndrome; however, all in patients with malignancy rather than for osteoporosis. We also present one of the first cases of Fanconi syndrome after just a single exposure to Zoledronic acid in a patient who had normal preceding renal function. This highlights the need to be aware of the possibility of significant nephrotoxicity after a single exposure to Zoledronic acid even without the recognized risk factors of chronic or acute kidney disease.

Mice with the GATM P341L mutations found in patients with Fanconi syndrome have decreased creatine synthesis and enhanced autophagy

Fanconi Syndrome (FS) is a proximal renal tubular dysfunction characterised by the urinary loss of normally reabsorbed substances. Although rare, it may occur as an iatrogenic complication of valproic acid (VPA) therapy in children. The paper reports the case of a 3-year-old boy (Trisomy 21, PEG-fed) treated with VPA for six months. The patient presented with dependent oedema and weight gain. Laboratory tests revealed significant proteinuria (PrU/CrU 5.9 mg/mg), glycosuria, alkaline urinary pH and reduced tubular reabsorption of phosphorus (TRP 64%). Blood tests confirmed metabolic acidosis, hypophosphataemia and hypouricaemia with preserved renal function. The clinical picture is consistent with VPA-induced acquired FS. The pathogenesis is linked to mitochondrial toxicity in the proximal tubule, driven by the inhibition of β-oxidation and depletion of carnitine and coenzyme A. Management involved the gradual discontinuation of VPA and enteral electrolyte supplementation and led to progressive metabolic recovery. This case highlights the necessity of monitoring tubular function in paediatric patients on long-term valproate therapy.

Background: Hypokalemic paralysis is a reversible yet potentially life-threatening cause of acute flaccid weakness. While primary periodic paralysis is well recognised, secondary forms due to renal tubular dysfunction are often overlooked. Fanconi syndrome, a proximal tubulopathy, is an uncommon autoimmune manifestation of Sjögren’s syndrome, which more typically presents with distal renal tubular acidosis (RTA). Its occurrence in a 19-year-old young female is highly atypical and proximal tubular involvement in Sjögren’s is distinctly rare. Case Summary: We describe a 19-year-old female who presented with acute flaccid quadriparesis and severe hypokalaemia. Laboratory evaluation revealed hypophosphatemia, non-anion gap metabolic acidosis and inappropriately alkaline urine. Urinalysis showed phosphaturia, glucosuria and proteinuria, confirming Fanconi syndrome. Electromyography (EMG) demonstrated a myopathic pattern. Strongly positive Anti-Sjögren’s syndrome-related antigen A (Ro) antibody (anti-SSA/Ro) antibodies and polyclonal hypergammaglobulinemia suggested an autoimmune aetiology consistent with renal-limited Sjögren’s syndrome. Targeted correction of electrolytes, vitamin D deficiency and metabolic acidosis led to rapid and complete recovery. The combination of very young age and isolated proximal tubular dysfunction underscores the diagnostic challenge and highlights the importance of considering renal-limited autoimmune disease even without sicca symptoms. Conclusion: This case illustrates a rare presentation of autoimmune Fanconi syndrome manifesting as hypokalemic paralysis in a young female. Anti-SSA/Ro seropositivity and polyclonal hypergammaglobulinemia, despite absent sicca features, should prompt evaluation for renal-limited Sjögren’s syndrome. Early recognition is crucial, as timely metabolic correction results in complete clinical recovery.

A 16-year-old Japanese girl presented to the emergency department with a complaint of increased muscle pain in the thighs and difficulty walking. Laboratory examinations revealed elevated levels of creatine phosphokinase, severe hypokalemia (1.4mmol/L), hyperchloremic metabolic acidosis with a normal anion gap, and a urinary pH of 7.5. The patient was thus diagnosed with hypokalemic rhabdomyolysis due to distal renal tubular acidosis. Furthermore, the patient was diagnosed with Sjögren syndrome based on a high titer of anti-SS-A antibodies, reduced tear production on the Schirmer test, decreased salivary secretion on the Saxon test, and labial salivary gland pathology. Although her muscle symptoms resolved rapidly with fluid and potassium replacement therapy, hypophosphatemia and hypouricemia persisted. The patient was subsequently diagnosed with Fanconi syndrome based on elevated urinary β2-microglobulin and pan-aminoaciduria. Following induction therapy with prednisolone, mycophenolate mofetil was added for maintenance based on renal pathology, which successfully reduced the urinary β2-microglobulin levels. This report describes a case of hypokalemic rhabdomyolysis due to concurrent distal and proximal renal tubular dysfunction in a patient with juvenile Sjögren syndrome. Early detection of renal tubular dysfunction is crucial to prevent life-threatening complications, such as rhabdomyolysis.

Rationale:Adefovir dipivoxil (ADV)-induced Fanconi syndrome associated with hypophosphatemic osteomalacia is an extremely rare disease. Owing to its rarity, it is easily misdiagnosed as cervical spondylotic myelopathy. Here, we present the case of a patient with Fanconi’s syndrome associated with hypophosphatemic osteomalacia that was misdiagnosed as having cervical spondylotic myelopathy.Patient concerns:A 44-year-old Chinese man with a 10-year history of ADV therapy for chronic hepatitis B presented with progressive bilateral lower extremity weakness for more than 6 months. Cervical magnetic resonance imaging revealed disc herniations at C4/5, C5/6, and C6/7, accompanied by spinal cord compression. Laboratory evaluations revealed glucosuria, proteinuria, hypophosphatemia, and impaired renal function. He was misdiagnosed with cervical spondylotic myelopathy and underwent anterior cervical corpectomy decompression and fusion. However, his lower limb weakness failed to improve 10 months after surgery.Diagnosis:On the basis of the patient’s clinical symptoms, along with his long history of oral ADV use, hypophosphatemia, and renal insufficiency, he was diagnosed with adefovir dipivoxil-induced Fanconi syndrome.Interventions:ADV was replaced with entecavir, and the patient was prescribed oral calcitriol 0.25 μg daily and oral calcium carbonate with vitamin D₃ (300 mg calcium and 60 IU vitamin D₃ per tablet) once daily.Outcomes:The patient’s lower limb muscle strength returned to normal after 6 months.Lessons:Fanconi syndrome with hypophosphatemic osteomalacia induced by low-dose adefovir dipivoxil (10 mg/d) is extremely rare. The condition may present with pain, muscle weakness, or numbness, and its nonspecific manifestations can easily lead to a misdiagnosis of cervical spondylotic myelopathy. For patients receiving long-term ADV therapy who develop such symptoms, especially in the presence of cervical disc herniation with spinal cord compression, clinicians should carefully evaluate laboratory findings and physical examination results to exclude the possibility of ADV-induced Fanconi syndrome.

Therapeutic strategies in cystinosis: A focus on cysteamine and beyond.

Rationale:Tubulointerstitial nephritis uveitis syndrome (TINU) is a rare form of acute interstitial nephritis accompanied by uveitis. However, few cases of TINU associated with Fanconi syndrome (FS) have been reported, and the clinical characteristics and optimal management of this rare association remain poorly defined.Patient concerns:In this case report, we aimed to describe 2 cases of TINU associated with FS and their management, emphasizing the importance of recognizing FS as a potential complication in patients with TINU.Diagnoses:Two adult patients with TINU and FS were evaluated. Both presented with renal insufficiency, hypouricemia, hypophosphatemia, hypokalemia, renal glycosuria, low-molecular-weight proteinuria, and uveitis. One patient also had renal tubular acidosis. Renal biopsy revealed acute interstitial nephritis in both cases, with one case additionally showing immunoglobulin A nephropathy.Interventions/outcomes:Systemic and ocular topical corticosteroids were administered, and potassium citrate was used to correct renal tubular acidosis. Renal function, electrolyte levels, and urinalysis results normalized in both patients.Lessons:In patients with TINU and renal tubular dysfunction (such as low-molecular-weight proteinuria, hypophosphatemia, and hypouricemia) the possibility of secondary FS should be considered. Along with corticosteroid therapy, timely treatment of renal tubular acidosis is essential.

BackgroundWest Nile virus (WNV) is a mosquito-borne flavivirus that can cause neuroinvasive disease. Renal involvement is uncommon and acquired Fanconi syndrome has not been previously described in association with WNV.Case presentationAn 81-year-old male from Cyprus presented with fever, headache, disorientation, and signs of meningoencephalitis. Cerebrospinal fluid (CSF) analysis and neuroimaging supported the diagnosis of viral encephalitis. Extensive microbiological testing revealed WNV ribonucleic acid in urine and blood, but not in the CSF. The patient developed persistent hypokalaemia, metabolic acidosis, hypomagnesemia, and hypouricemia, with elevated fractional excretion of these solutes—findings consistent with Fanconi syndrome. Acyclovir was discontinued, and supportive treatment was provided. Renal function and electrolyte levels normalized by day 9. At 2-month follow-up, the patient had fully recovered with normal renal parameters.ConclusionRenal complications of WNV are rarely documented and this case of WNV associated acquired Fanconi syndrome underscores the importance of evaluating kidney function and electrolyte status in WNV-infected patients. Early recognition of tubular dysfunction may prevent complications and improve outcomes.LEARNING POINTSWhile renal complications of West Nile virus (WNV) are documented in rare cases, this is the first reported case of WNV-associated Fanconi syndrome.

Abstract Background and Aims Epithelial cell polarity is crucial for the proper functioning of various organs, including the kidneys. Syntaxin 3, a key molecule in membrane-vesicle fusion, is localized in the apical membrane of proximal tubule epithelial cells (PTECs). Although in vitro studies using other types of epithelial cells besides PTECs have shown the role of syntaxin 3 in regulating apical membrane integrity, its function in epithelial cells in vivo, particularly in PTECs, remains undefined. This study investigated roles of syntaxin 3 in maintaining PTEC apical polarity in vivo and examined renal phenotypes in patients with microvillus inclusion disease (MVID) carrying STX3 mutations. Method Localization of syntaxin 3 in wild-type mice (C57BL/6J) and human kidneys were analyzed by immunofluorescence staining. Blood and urine samples from two patients with MVID carrying STX3 gene mutations were analyzed for Fanconi syndrome-related parameters. Stx3fl/fl mice were crossed with tamoxifen-inducible PTEC-specific Cre-expressing mice to generate Stx3fl/fl;Ndrg1CreERT2/+ mice. Eight-week-old Stx3fl/fl;Ndrg1CreERT2/+ mice were intraperitoneally injected with vehicle (Cont) or tamoxifen (Stx3-cKO). Serum and urine samples were compared between Cont and Stx3-cKO mice one, two, and six months post-induction. To analyze histological changes, mouse kidney tissues were processed for light microscopy and electron microscopy. Expression levels and localization of apical transporters, receptors, and trafficking-associated proteins of PTEC were examined by immunofluorescence staining and western blotting. Receptor-mediated and fluid-phase endocytosis in PTECs were assessed in Cont and Stx3-cKO mice two months post-induction, by injection with various substrates via the orbital vein. Results Syntaxin 3 was localized to the apical membrane of PTECs in both mouse and human kidneys. Stx3-cKO mice exhibited features of Fanconi syndrome, including increased urinary excretion of phosphorus, glucose, amino acids, and low-molecular-weight proteins and metabolic acidosis. Patients with MVID showed similar urinary abnormalities. Stx3-cKO mice exhibited brush border atrophy and vesicle transport stagnation, as evidenced by light microscopy and electron microscopy, and increased subapical localization of trafficking markers Rab11 and vesicle-associated membrane protein 8 as shown by immunofluorescence images. Key transporters and receptors, including sodium-dependent phosphate cotransporter type 2a (NaPi-Iia), sodium-glucose cotransporter 2 (SGLT2), related to b0,+ amino acid transporter (rBAT), megalin, and sodium/hydrogen exchanger 3 (NHE3) showed mislocalization and altered expression. Syntaxin 3 deficiency disrupted the apical expression of ezrin, a crucial protein that links the actin cytoskeleton to the plasma membrane. Both receptor-mediated and fluid-phase endocytosis were impaired in Stx3-cKO mice. Conclusion These results highlight the critical role of syntaxin 3 in maintaining PTEC function and apical polarity, providing new insights into the renal manifestations of MVID and the molecular mechanisms underlying Fanconi syndrome.

Abstract Background and Aims Biallelic, pathological mutations in BCS1L are one of the most common causes of mitochondrial Complex III deficiency. Affected individuals present with a spectrum of multisystemic disorders with variable onset. Among these, proximal renal-tubulopathies are commonly seen. Here, we set out to cultivate renal epithelial cells from a BCS1L mutant patient presenting primarily with renotubular-dysfunction, and to assess their potential as a model of mitochondrial and kidney specific features of their condition. Making use of the European Reference Network on Rare Kidney Diseases (ERKNet), we also aimed to establish a cohort of similar patients to confirm our own and previously published findings. Ultimately, we aim to establish a personalised disease model to further our aetiological understanding of the disease, and in which prospective therapeutics could be tested and affirmed. Method Exome sequencing was performed using the Twist Exome RefSeq capture method. Human urinary Renal Epithelial Cells (huREC) were isolated from fresh subject urine samples and cultivated as monolayers or in matrigel as 3D cystic structures termed tubuloids. Bulk-RNA-sequencing, Western blotting and immunofluorescence were conducted to assess the quantity and subcellular localisations of key mitochondrial markers. Live imaging of mitochondria with Rhodamine 123 was used to assess mitochondrial morphology. The Seahorse Cell Mito-stress test and mitochondrial complex assays were used to assess mitochondrial bioenergetics. Results In an adult female presenting with primary Fanconi Syndrome since the age of 4, exome sequencing identified two pathogenic BCS1L variants in compound heterozygosity (BCS1L NM_004328.5; variants c.-147A>G p.? and c.-166C>T p.(Arg56*)). The patient shows a full spectrum of tubular dysfunction including glycosuria, potassium, phosphate, bicarbonate, and urea wasting, plus low molecular weight protein loss and stage 3b CKD with an eGFR of 35 ml/min/1.73 m2 at 42 years of age. The patient has no cardiac or neurological sequelae. An ERKNet survey involving all 72 pediatric and adult reference centres across Europe, yielded identification of 4 additional patients carrying biallelic pathogenic variants in BCS1L, all of whom showed comparable phenotypic presentation with little to no neurological manifestation, but RTA (4/4), Fanconi Syndrome (4/4), and nephrocalcinosis (2/4). Western Blotting and immunofluorescence confirmed a BCS1L deficiency in patient-huRECs relative to age-sex matched controls. Concurrently, the Seahorse Mito Stress Test demonstrated that BCS1L-mutant huRECs possess reduced total respiratory capacity, relative to controls. Assessment of mitochondrial morphology, mitochondrial complex activities and exome wide gene expression changes are currently in process. 3D tubuloid cultures were also established from patient huRECs, a system that demonstrates enhanced cell polarity and trans-epithelial transport relative to monolayers, for which it is hypothesized respiratory deficiencies may be more pronounced due to enhanced energy requirements. Conclusion 2D- and 3D-cell cultures from a primary Fanconi patient with compound-heterozygous BCS1L-mutations were successfully established from non-invasively acquired urine samples. These cultures emulated key mitochondrial dysfunctions seen in the patient but not in huRECs from healthy controls. In the future, we intend to employ these cells for drug screening purposes against the mitochondrial phenotype. This study acts as a proof of concept for the use of huREC-derived cultures in modelling of rare kidney diseases and mitochondriopathies.

The energy requirement of renal proximal tubular cells depends on mitochondrial fatty acid β-oxidation. Enoyl-CoA hydratase-l-3-hydroxyacyl-CoA dehydrogenase (EHHADH) is a crucial enzyme in mitochondrial fatty acid oxidation, and mutations in EHHADH reportedly cause Fanconi syndrome. Here, we report the case of a 28-year-old Japanese woman with a long-term history of low-molecular-weight proteinuria (LMWP) who exhibited a missense mutation in the EHHADH gene. She was diagnosed with LMWP at 4years of age. The search for the CLCN5 gene was unremarkable, and kidney biopsy revealed no significant tubulointerstitial changes. The LMWP persisted, and glucosuria gradually developed thereafter. Unexpectedly, next-generation sequencing identified a heterozygous missense mutation in the EHHADH gene. Her father, who harbored LMWP, also had the same mutation. Furthermore, immunostaining of the stored kidney specimens showed decreased immunoreactivity for cytochrome coxidase subunit 4 in the proximal tubules, suggesting an underlying mitochondrial impairment.

Abstract Background and Aims Renal involvement in amyloidosis common, however, the occurrence of nephrotic syndrome and tubulopathies are rarely reported in literature. Method We report a case of renal amyloidosis presenting as nephrotic syndrome with concurrent tubulopathy. Results A 62-year old Filipino female was admitted in our institution for a two-month history of worsening anasarca, exertional dyspnea, intermittent abdominal pain, frothy urine, with occasional loose stools, and generalized body weakness. Initial work-up revealed +3 albuminuria, +3 glucosuria, and spot urine protein-creatinine of 57.9 g/day. She also had hypercholesterolemia, hypertriglyceridemia, and hypoalbuminemia. Ultrasound revealed normal-sized kidneys with preserved cortical thickness. She had recurrent hypokalemia, which on work-up revealed a urine potassium-creatinine ratio of 29.7, combined high- and normal-gap metabolic acidosis on arterial blood gas, and urine pH 6.0 which were all consistent with proximal renal tubular acidosis. Renal amyloidosis was eventually confirmed through kidney biopsy revealing diffuse Congo red-positive, apple-green birefringent, acellular mesangial and glomerular capillary loop deposits. She received empiric chemotherapy with cyclophosphamide, bortezomib, and dexamethasone, as well as diuretics and electrolyte replacement, with eventual improvement in her symptoms. Conclusion Deposition of amyloid protein fibrils in the glomerulus can lead to increased capillary permeability, massive proteinuria, and nephrotic syndrome. On the other hand, deposition in the tubules can lead to tubulopathies such as Fanconi syndrome. This case underscores the importance of including amyloidosis in the differential diagnoses for patients presenting with nephrotic syndrome. High clinical suspicion can direct the diagnostic evaluation so that prompt treatment can be instituted and progression to end-stage kidney disease be prevented.

Abstract Background and Aims In his landmark 1953 publication, From Fish to Philosopher, physiologist Homer Smith presented the evolutionary history of renal function as a source of insights for medicine. Seven decades later, it is increasingly clear that the evolutionary story underlying the emergence of renal physiology can provide novel insights into the causes of and potential treatments for renal pathologies. Why are humans vulnerable to renal tubulopathies (RT)? Shouldn't natural selection have favored phenotypes resistant to illness? The evolutionary story of this susceptibility can provide novel insights with salience for research and clinical practice. Importantly, not all traits are adaptive. While natural selection produces adaptive phenotypes, evolutionary trade-offs may lead to both non-adaptive and adaptive characteristics. Emerging phylogenomic methods can help identify potential selective pressures shaping the evolutionary emergence of specific disease vulnerabilities. Here, a novel methodology is used to uncover the origins of RT vulnerability from the dawn of cellular life to modern human kidney. Method This methodology analyses RT gene sets to identify the biologically beneficial processes underlying vulnerability to disease. Gene curation from DisGeNET (v7.0) and MalaCards (v1.14) identified genes for seven RT chosen for their well-characterized genetic bases and relevance to human renal physiology: Fanconi, Bartter, Gitelman, Liddle, Gordon, Distal Renal Tubular Acidosis, and Nephrogenic Diabetes Insipidus. Phylostratigraphic analysis (PhyloFastStrat, v0.2.2) was performed to map the genes’ emergence and adaptations, tracing their origins from cellular life (∼3.6 billion years ago) to Homo sapiens. Gene enrichment analysis (GOEnrichr v3.0) was performed on each set of genes to elucidate their biological, molecular, and cellular roles in renal physiology. Results While analyses encompassed seven RT, evolutionary histories underlying only two, Fanconi and Gitelman, are featured in this abstract. Fanconi syndrome (63 genes) exhibits a distinctive evolutionary trajectory, with early emergence during the cellular organism stage, highlighting the foundational role in solute transport, metabolic homeostasis and waste excretion. As life transitioned to multicellularity, additional genes emerged, particularly during the metazoan stage (∼770 MYA), enabling tissue-specific solute transport. A notable peak in Mammalia (∼220 MYA) reflects functional diversification to terrestrial life adaptations, followed by core gene conservation (Fig. 1). Gitelman syndrome (34 genes) also shows ancient origins, with high initial genes emergence at the cellular organism stage. Key innovations occurred in jawed vertebrates (∼420 MYA), with the development of complex ion transport systems, land-dwelling tetrapods (∼370 MYA), refining mechanisms for electrolyte and water conservation on dry land, and mammals (∼125 MYA), specializing the distal nephron to meet metabolic demands of warm-blooded physiology. A minor uptick in Homo sapiens suggests slight genetic fine-tuning in renal electrolyte handling, potentially reflecting unique human dietary or environmental adaptations (Fig. 2). Conclusion This study highlights the evolutionary trajectory of genes implicated in RT suggesting that vulnerability emerged as an evolutionary trade-off for positive selection for biological processes critical to tubular function. RT vulnerability was linked to several evolutionary milestones including the emergence of ion transport systems, terrestrial adaptations, and tubule refinement. The ancient origins of tubular pathology offer a novel framework for a strengthened understanding of the triggers and natural history of these often enigmatic disorders. This finding is aligned with the prescient premise of Homer Smith's 1953 publication.

Abstract Background and Aims Persistent hypouricemia (HU) (serum uric acid <2.5 mg/dL) is a rare condition. HU due to rare genetic causes, without full-blown Fanconi syndrome (FS) (characterized by glucosuria and hyperuricosuria alongside aminoaciduria, phosphaturia, and renal tubular acidosis), is typically associated with familial renal HU due to SLC12A22 and SLC2A9 variants, as well as xanthinuria linked to XDH and MOCOS variants. Method Nine patients were included. Malnutrition and full-blown FS were excluded. Clinical Exome Sequencing was performed, and pathogenicity of variants were evaluated with 1-SIFT, Polyphen2, and Mutation Taster prediction tools. Results 8 of 9 patients had at least one rare variant as a possible cause of HU. 5 patients had isolated HU, while 3 had both glucosuria and HU without other signs of FS. One patient with recurrent acute kidney injury had a homozygous variant in SLC2A9. Two patients with nephrolithiasis (NL) were diagnosed with xanthinuria type 1 and type 2. The patient with xanthinuria type 2 also had concurrent glucosuria due to additional heterozygous SLC5A2 variant. Homozygous and heterozygous SLC22A12 variants were detected in 2 patients with persistent HU. One patient with glucosuria and HU due to hyperuricosuria had no variants related to HU, but compound heterozygous SLC5A2 variants. The last case had a rare heterozygous FTL (Ferritin-light-chain) variant. This patient had hyperuricosuria. Transcriptomic and single-cell RNA databases showed that FTL has high expression in the proximal tubule, suggesting it may be a candidate gene. Conclusion Genetic HU is rare but often overlooked entity. This study demonstrates, for the first time, the co-occurrence of renal glucosuria and familial renal HU, as well as the coexistence of xanthinuria type 2 and renal glucosuria in two patients. Rare FTL variants have not been previously reported in the literature as a possible cause of renal HU. Our study expands the spectrum of genetic findings of HU. Based on our findings, genetic studies have high diagnostic accuracy and should be used in patients with HU. Additionally, they may identify new candidate genes.