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Tumor-induced osteomalacia (TIO) is an exceedingly rare paraneoplastic condition characterized by hypophosphatemia, osteomalacia, fragility fractures, and fatigue. A 39-year-old man was assessed for hemoptysis, pathological rib fractures, and fatigue, and was found to have a chest mass with lung metastasis. Biopsy of the mass suggested high-grade epithelioid and spindle cell neoplasm. He was initially treated for soft tissue sarcoma with an ifosfamide-based regimen and developed Fanconi syndrome that resolved on cessation of ifosfamide. Serum phosphate remained low. A low tubular maximum reabsorption of phosphate to glomerular filtration rate ratio (TmP/GFR) indicated disproportionate phosphaturia, while a severely elevated fibroblast growth factor-23 (FGF23) level enabled a diagnosis of TIO. He was started on phosphate and calcitriol supplementation. Subsequent next-generation sequencing demonstrated a RET -fusion mutation, leading to reclassification of his malignancy to a sarcomatoid non–small cell lung carcinoma. He was switched to selpercatinib, a targeted RET -kinase inhibitor approved for locally advanced or metastatic RET -fusion–positive solid tumors. This induced tumor remission with subsequent normalization of his FGF23 levels and hypophosphatemia. Despite the presence of a confounding etiology like drug-induced Fanconi syndrome, persistence of hypophosphatemia should prompt a workup of TIO, especially in the presence of a tumor. [ABSTRACT FROM AUTHOR]

Cystinosis is an autosomal recessive lysosomal storage disorder, caused by mutations in the CTNS gene, resulting in an absent or altered cystinosin (CTNS) protein. Cystinosin exports cystine out of the lysosome, with a malfunction resulting in cystine accumulation and a defect in other cystinosin-mediated pathways. Cystinosis is a systemic disease, but the kidneys are the first and most severely affected organs. In the kidney, the disease initially manifests as a generalized dysfunction in the proximal tubules (also called renal Fanconi syndrome). MFSD12 is a lysosomal cysteine importer that directly affects the cystine levels in melanoma cells, HEK293T cells, and cystinosis patient-derived fibroblasts. In this study, we aimed to evaluate MFSD12 mRNA levels in cystinosis patient-derived proximal tubular epithelial cells (ciPTECs) and to study the effect of MFSD12 knockout on cystine levels. We showed similar MFSD12 mRNA expression in patient-derived ciPTECs in comparison with the control cells. CRISPR MFSD12 knockout in a patient-derived ciPTEC (CTNSΔ57kb) resulted in significantly reduced cystine levels. Furthermore, we evaluated proximal tubular reabsorption after injection of mfsd12a translation-blocking morpholino (TB MO) in a ctns−/− zebrafish model. This resulted in decreased cystine levels but caused a concentration-dependent increase in embryo dysmorphism. Furthermore, the mfsd12a TB MO injection did not improve proximal tubular reabsorption or megalin expression. In conclusion, MFSD12 mRNA depletion reduced cystine levels in both tested models without improvement of the proximal tubular function in the ctns−/− zebrafish embryo. In addition, the apparent toxicity of higher mfsd12a TB MO concentrations on the zebrafish development warrants further evaluation. NEW & NOTEWORTHY: In this study, we show that MFSD12 depletion with either CRISPR/Cas9-mediated gene editing or a translation-blocking morpholino significantly reduced cystine levels in cystinosis ciPTECs and ctns−/− zebrafish embryos, respectively. However, we observed no improvement in the proximal tubular reabsorption of dextran in the ctns−/− zebrafish embryos injected with mfsd12a translation-blocking morpholino. Furthermore, a negative effect of the mfsd12a morpholino on the zebrafish development warrants further investigation. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case presentation highlights the need to routinely monitor renal function in patients on Tenofovir Disoproxil Fumarate (TDF) due to its side effect of proximal tubule dysfunction. This is a case presentation of a 50‐year‐old African female who had been on a Tenofovir based regimen for 12 years and developed Fanconi syndrome. She recovered after discontinuation of the Tenofovir Disoproxil Fumarate (TDF). [ABSTRACT FROM AUTHOR]

Fanconi's syndrome (FS) is characterized by type-2 renal tubular acidosis, short stature, and renal rickets, along with glycosuria, aminoaciduria, hypophosphaturia, and urinary bicarbonate wasting. The genetic form of FS has been linked to HNF4A variants. Although additional clinical features such as hearing impairment have recently been associated with HNF4A-linked FS, its ocular manifestation has not been described. Presenting a case of a 5-year-old male child with bilateral progressive corneal opacification and the presence of bilateral greyish-white deposits in the interpalpebral region since infancy. A next-generation sequencing (NGS)-based genetic testing was performed for the child followed by parental genetic testing for the identified variant. Furthermore, relevant works of literature were reviewed related to this condition. Detailed corneal findings showed a bilateral band-shaped keratopathy (BSK) in the patient. Physical and systemic findings showed signs consistent with FS. Sequencing analysis revealed a novel heterozygous c.635C>T, (p.Pro212Leu) variant in the HNF4A gene in the proband and mother, while the father had a normal genotype. Our case highlights the occurrence of BSK in an exceptionally rare manifestation of hereditary FS linked to HNF4A gene variant. The variant exists both in proband and asymptomatic mother. Therefore, the variable penetrance which is known to exist in HNF4A is acknowledged in this context. This report suggests the first documented instance establishing a plausible connection between BSK and HNF4A-associated FS, characterized by the variable penetrance attributed to the HNF4A gene. [ABSTRACT FROM AUTHOR]

Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene that encodes cystinosin, a ubiquitous lysosomal cystine/H+ antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of renal Fanconi syndrome and progressive glomerular and interstitial damage leading to end-stage kidney disease in the second or third decade of life. The exact molecular mechanisms involved in the pathogenesis of renal disease in cystinosis are incompletely elucidated. We have previously shown upregulation of NLRP2 in human cystinotic proximal tubular epithelial cells and its role in promoting inflammatory and profibrotic responses. Herein, we have investigated the role of NLRP2 in vivo using a mouse model of cystinosis in which we have confirmed upregulation of Nlrp2 in the renal parenchyma. Our studies show that double knock out Ctns-/- Nlrp2-/- animals exhibit delayed development of Fanconi syndrome and kidney tissue damage. Specifically, we observed at 4-6 months of age that animals had less glucosuria and calciuria and markedly preserved renal tissue, as assessed by significantly lower levels of inflammatory cell infiltration, tubular atrophy, and interstitial fibrosis. Also, the mRNA expression of some inflammatory mediators (Cxcl1 and Saa1) and the rate of apoptosis were significantly decreased in 4-6-month old kidneys harvested from Ctns-/- Nlrp2-/- mice compared to those obtained from Ctns-/-mice. At 12-14 months of age, renal histological was markedly altered in both genetic models, although double KO animals had lower degree of polyuria and low molecular weight proteinuria and decreased mRNA expression levels of Il6 and Mcp1. Altogether, these data indicate that Nlrp2 is a potential pharmacological target for delaying progression of kidney disease in cystinosis. [ABSTRACT FROM AUTHOR]

Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by cystine buildup in various tissues, including the kidneys. Renal involvement is the primary manifestation, leading to end-stage renal disease (ESRD) if left untreated. Kidney transplantation (KT) in patients with cystinosis has significantly improved their prognosis for the disease outcome. Detailed reports on preoperative and Long-term postoperative management in these patients remain sparse. This report discusses the outcomes of two young adult patients of Middle Eastern descent with cystinosis who underwent KT. The first patient, diagnosed with infantile nephropathic cystinosis treated by cystine-depleting therapy, was operated by KT at the age of 18. The second patient, diagnosed with juvenile cystinosis, underwent transplantation at the age of 35 after being treated with hemodialysis. Our report describes detailed pre- and postoperative managements, including laboratory results, and pharmacological interventions. Both cases highlighted the varying clinical manifestations and disease severity between infantile and juvenile cystinosis. Pre-transplant conditions included renal dysfunction, growth retardation, secondary hyperparathyroidism, anemia, and extrarenal manifestations. Following KT, both patients experienced regained renal function, resolution of extrarenal complications, and normalization of laboratory parameters. Furthermore, both patients showed excellent postoperative outcomes with no acute rejection or allograft-related complications. KT is the treatment of choice for cystinosis patients with ESRD. Long-term follow-up post-transplantation is crucial to maintain good graft function. Further studies may elucidate optimal pre- and postoperative management protocols for this rare condition. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a rare inherited disease due to the mutation of the ATP7B gene, resulting in impaired hepatic copper excretion and its pathological accumulation in various organs such as the liver, the nervous system, or the kidneys. Whereas liver failure and neuropsychiatric disorders are the most common features, less is known about the renal complications. We conducted a review of the literature to define the characteristics and pathophysiology of kidney involvement during WD. This review shed light on strong evidence for direct copper toxicity to renal tubular cells. Excessive tubular copper accumulation might present with various degrees of tubular dysfunction, ranging from mild hydroelectrolytic and acid–base disorders to complete Fanconi syndrome. Proximal and distal renal tubular acidosis also favors development of nephrolithiasis, nephrocalcinosis, and bone metabolism abnormalities. Indirect complications might involve renal hypoperfusion as occurs in hepatorenal or cardiorenal syndrome, but also tubular casts' formation during acute hemolysis, rhabdomyolysis, or bile cast nephropathy. Acute kidney failure is not uncommon in severe WD patients, and independently increases mortality. Finally, specific and long-term therapy by D-penicillamin, one of the most efficient drugs in WD, can cause glomerular injuries, such as membranous nephropathy, minimal-change disease, and, rarely, severe glomerulonephritis. Altogether, our study supports the need for interdisciplinary evaluation of WD patients involving nephrologists, with regular monitoring of tubular and glomerular functions, to provide adequate prevention of renal and bone involvement. [ABSTRACT FROM AUTHOR]

Abstract We present two cases of middle‐aged men who developed Fanconi syndrome and renal dysfunction after consuming “foods with functional claims (FFC)” containing red yeast rice. In the first case, the patient had consumed an FFC for 1 year and another FFC suspected to have contained nephrotoxin for 3 weeks; kidney biopsy performed during the acute phase of renal injury showed severe acute tubular necrosis and tubular cell regeneration. He achieved near‐complete recovery 40 days after the FFC was discontinued. In the second case, the patient had consumed FFC for 4 years and stopped 70 days prior to presentation; kidney biopsy revealed significant tubular recovery, persistent tubular injuries, and interstitial fibrosis. Although the manifestations of Fanconi syndrome subsided, mild renal dysfunction persisted. These cases suggest that FFC with nephrotoxins may induce Fanconi syndrome owing to acute tubular necrosis. Recovery is possible after discontinuing the FFC; while short‐term ingestion of FFC allows for tubular regeneration, its long‐term ingestion may cause irreversible damage and lead to chronic kidney disease. Long‐term follow‐up is crucial for preventing further renal deterioration.

Introduction: The use of immune checkpoint inhibitors has revolutionized cancer treatment, and their application to older people is considered safe by the scientific community. However, immune-related adverse events (irAEs) remain common, and their management poses significant challenges, especially in this population. Case Presentation: We report the case of a fit 82-year-old woman who developed immune-mediated colitis and Fanconi syndrome during treatment with ipilimumab and nivolumab for metastatic melanoma. Treatment consisted of discontinuation of immunotherapy, use of systemic corticosteroids, and second-line immunosuppressants. Despite well-managed treatment, the patient did not recover and died from a gastrointestinal infection. Conclusion: Although studies have shown identical efficacy and safety in younger patients compared to older patients, the consequences of irAEs can potentially be more serious in the older population. The fatal outcome despite well-managed treatment highlights the need to identify predictive factors of immunotherapy-related adverse events in the older population.

Introduction: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. Materials and methods: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. Results: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. Conclusion: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary fructose intolerance or hereditary fructosemia is an autosomal recessive metabolic disorder caused by a loss of function in the aldolase B gene. This disorder affects 1 in 20,000 people, constituting a rare disease with a favorable prognosis through adherence to a fructose-free diet. Despite dietary management, chronic pathology may manifest, underscoring the importance of early diagnosis to mitigate adverse effects. However, early detection of the disease poses significant challenges. Aim: Our aim was to compile pertinent information on the differential diagnosis of this pathology based on patient symptoms, facilitating the development of a diagnostic algorithm for early identification. Methodology: A systematic review adhering to PRISMA guidelines was conducted on empirical studies from PubMed, encompassing a total of 35 studies. Results: Individuals with fructose intolerance may acutely experience postprandial symptoms such as hypoglycemia, vomiting, and abdominal distension. Despite proper treatment, chronic complications such as fatty liver, Fanconi syndrome, growth deficiency, and irritable bowel syndrome may arise. The proposed diagnostic algorithm aims to minimize these adverse processes. Conclusions: Understanding the pathogenesis enables prompt diagnosis and prevention of chronicity. Establishing continuity of care from pediatric to adult medicine is crucial, and disseminating information to non-pediatric endocrinologists is imperative for managing this rare disease. [ABSTRACT FROM AUTHOR]

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption. [ABSTRACT FROM AUTHOR]

Background: Anemia exhibits complex causation mechanisms and genetic heterogeneity. Some cases result in poor outcomes with multisystemic dysfunction, including renal tubulopathy. Early diagnosis is crucial to improve management. Case–diagnosis/treatment: A 21-month-old female patient was admitted with severe anemia. Persistent neutropenia and dysplastic signs suggested myelodysplastic syndrome, but targeted gene panel results were negative. After multiple transfusions, spontaneous hematologic recovery was observed. At 4 years old, she presented failure to thrive, renal Fanconi syndrome, and severe metabolic acidosis. Differential diagnosis included Pearson syndrome (PS), a life-threatening condition associated with mitochondrial DNA (mtDNA), featuring anemia and pancreatic insufficiency. Further analysis revealed a ~ 7.5 kb mtDNA deletion. Until the age of 5, supportive care has been provided, without pancreatic insufficiency. Conclusions: This PS case highlights the importance of genetic testing, even in the absence of typical features. Understanding the nature of mitochondrial disorders enables treatment tailoring and counseling about the prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The use of immune checkpoint inhibitors has revolutionized cancer treatment, and their application to older people is considered safe by the scientific community. However, immune-related adverse events (irAEs) remain common, and their management poses significant challenges, especially in this population. Case Presentation: We report the case of a fit 82-year-old woman who developed immune-mediated colitis and Fanconi syndrome during treatment with ipilimumab and nivolumab for metastatic melanoma. Treatment consisted of discontinuation of immunotherapy, use of systemic corticosteroids, and second-line immunosuppressants. Despite well-managed treatment, the patient did not recover and died from a gastrointestinal infection. Conclusion: Although studies have shown identical efficacy and safety in younger patients compared to older patients, the consequences of irAEs can potentially be more serious in the older population. The fatal outcome despite well-managed treatment highlights the need to identify predictive factors of immunotherapy-related adverse events in the older population. [ABSTRACT FROM AUTHOR]

Lowe syndrome (oculocerebrorenal syndrome of Lowe -- LS) is an ultra-rare, recessive X-linked, multisystem disorder that primarily occurs in males and affects the eyes, nervous system, and kidneys. It is a consequence of mutation of the OCRL gene on chromosome Xq25-26, which encodes phosphatidylinositol 4,5-bisphosphate 5 phosphatase, a protein present in the Golgi complex, lysosomes, and endosomes. The most common symptoms of LS involve congenital cataracts, neurological retardation, and incomplete Fanconi syndrome, ultimately leading to end-stage renal disease between the second and fourth decade of life. The authors present a boy with the intoxication of vitamin D3 and suspicion of congenital cytomegaly eventually diagnosed with LS at the age of 16 months. [ABSTRACT FROM AUTHOR]

Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of various neoplasms. Its main adverse effects include renal damage. A comprehensive review was conducted, including 100 articles from the Scielo, Scopus, and EMBASE databases. Ifosfamide-induced nephrotoxicity is attributed to its toxic metabolites, such as acrolein and chloroacetaldehyde, which cause mitochondrial damage and oxidative stress in renal tubular cells. Literature review found a 29-year average age with no gender predominance and a mortality of 13%. Currently, no fully effective strategy exists for preventing ifosfamide-induced nephrotoxicity; however, hydration, forced diuresis, and other interventions are employed to limit renal damage. Long-term renal function monitoring is essential for patients treated with ifosfamide. Ifosfamide remains essential in neoplasm treatment, but nephrotoxicity, often compounded by coadministered drugs, poses diagnostic challenges. Preventive strategies are lacking, necessitating further research. Identifying timely risk factors can mitigate renal damage, and a multidisciplinary approach manages established nephrotoxicity. Emerging therapies may reduce ifosfamide induced nephrotoxicity. Ifosfamide is a type of chemotherapy used to treat different types of cancers. However, one of its main side effects is kidney damage. Researchers reviewed 100 articles from medical databases to understand how ifosfamide affects the kidneys. The kidney damage is caused by harmful substances produced when ifosfamide is broken down in the body. These substances can harm the cells in the kidneys. Studies have shown that 13% of the patients treated with ifosfamide can die. Currently, there is no perfect way to prevent kidney damage from ifosfamide, but doctors try to protect the kidneys by giving patients plenty of fluids and using other treatments, so it's important for patients who receive ifosfamide to have their kidney function checked regularly. Although ifosfamide is effective against cancer, its potential kidney side effects should be carefully considered by doctors when deciding on the best treatment for each patient. [ABSTRACT FROM AUTHOR]

Key Clinical Message This case presentation highlights the need to routinely monitor renal function in patients on Tenofovir Disoproxil Fumarate (TDF) due to its side effect of proximal tubule dysfunction. Abstract This is a case presentation of a 50‐year‐old African female who had been on a Tenofovir based regimen for 12 years and developed Fanconi syndrome. She recovered after discontinuation of the Tenofovir Disoproxil Fumarate (TDF).

Light-chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains within the proximal tubular epithelial cells, which is usually classified into crystalline and noncrystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Here, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ light chains restricted) and antigen-undetermined MN in a male patient. The patient presented with low-molecular-weight proteinuria, increased serum creatinine levels, and incomplete Fanconi syndrome. To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens, which may enrich our recognition of monoclonal gammopathy of renal significance with synchronous MN.

Abstract Lysinuric protein intolerance (LPI), caused by pathogenic variants of SLC7A7, is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47‐year‐old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets. At the age of 3 years, she demonstrated a failure to thrive. Urinary amino acid analysis revealed elevated lysine and arginine levels, which were masked by pan‐amino aciduria. She was subsequently diagnosed with rickets at 5 years of age and RTA/Fanconi syndrome at 15 years of age. She was continuously treated with supplementation of vitamin D3, phosphate, and bicarbonate. A renal biopsy at 18 years of age demonstrated diffuse proximal and distal tubular damage with endocytosis‐lysosome pathway abnormalities. Distinctive symptoms of LPI, such as protein aversion and postprandial hyperammonemia were not observed throughout the patient's clinical course. The patient underwent a panel‐based comprehensive genetic testing and was diagnosed with LPI. As the complications of LPI involve many organs, patients lacking distinctive symptoms may develop various diseases, including RTA/Fanconi syndrome. Our case indicates that proximal and distal tubular damages are notable findings in patients with LPI. The possibility of LPI should be carefully considered in the management of RTA/Fanconi syndrome and/or incomprehensible pathological tubular damage, even in the absence of distinctive symptoms; furthermore, a comprehensive genetic analysis is useful for diagnosing LPI.

X-linked proximal tubulopathies are rare diseases that predominantly affect men. Women are generally carriers and clinical or biochemical manifestations are usually absent or mild. We present the case of a young woman who presented with a full phenotype of Dent disease type 1 due to a de novo mutation in the CLCN5 gene and a skewed X-chromosome inactivation. Although cases of overt Dent disease type 2 and Lowe syndrome in women have been described in the literature, to our knowledge this is the first case of overt Dent disease type 1. [ABSTRACT FROM AUTHOR]

The article discusses the role of XPR1 in mediating phosphate efflux in cells. While the transporters involved in phosphate uptake are well-known, the identity of the efflux pathway(s) is not fully understood. XPR1 has been proposed as a candidate for this role, and previous studies have shown that XPR1 is involved in phosphate efflux and regulates phosphate homeostasis. However, recent research suggests that XPR1 may not stimulate phosphate efflux and raises questions about its precise activity and expression in different cell types. Further research is needed to better understand the role of XPR1 in phosphate transport. [Extracted from the article]

Abstract Background Tubulointerstitial 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 Presentation Case 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). Conclusion We 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.

BackgroundSystemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations. The symptoms of SLE in children are more atypical than adults. Childhood SLE complicated with Fanconi syndrome is extremely rare and even more difficult to diagnose.Case presentationThis article reports a preschool boy with SLE who presented with renal tubular acidosis, accompanied by weakness in both lower limbs, delayed growth, and malnutrition. It was later found that the patient had the complication of Fanconi syndrome with renal tubular acidosis. Ultimately, renal biopsy confirmed lupus nephritis. The patient was treated with corticosteroid combined with mycophenolate mofetil, hydroxychloroquine, and belimumab. The symptoms of the child were relieved.ConclusionHere we report an extremely rare case of childhood SLE complicated with Fanconi syndrome. There has been no similar clinical report. It is necessary to be alert to the possibility of atypical SLE in children to avoid missed diagnosis and misdiagnosis.

Tubular injury is the main cause of acute kidney injury (AKI) in critically ill COVID-19 patients. Proximal tubular dysfunction (PTD) and changes in urinary biomarkers, such as NGAL, TIMP-2, and IGFBP7 product ([TIMP-2]•[IGFBP7]), could precede AKI. We conducted a prospective cohort study from 2020/03/09 to 2020/05/03, which consecutively included all COVID-19 patients who had at least one urinalysis, to assess the incidence of PTD and AKI, and the effectiveness of PTD, NGAL, and [TIMP-2]•[IGFBP7] in AKI and persistent AKI prediction using the area under the receiver operating characteristic curves (AUCs), Kaplan-Meier methodology (log-rank tests), and Cox models. Among the 60 patients admitted to the ICU with proven COVID-19 (median age: 63-yearold (interquartile range: IQR, 55-74), 45 males (75%), median simplified acute physiology score (SAPS) II: 34 (IQR, 22-47) and median BMI: 25.7 kg/m2 (IQR, 23.3-30.8)) analyzed, PTD was diagnosed in 29 patients (48%), AKI in 33 (55%) and persistent AKI in 20 (33%). Urinary NGAL had the highest AUC for AKI prediction: 0.635 (95%CI: 0.491-0.779) and persistent AKI prediction: 0.681 (95%CI: 0.535-0.826), as compared to PTD and [TIMP-2]•[IGFBP7] (AUCs <0.6). AKI was independently associated with higher SAPSII (HR = 1.04, 95%CI: 1.01-1.06, p = 0.005) and BMI (HR = 1.07, 95%CI: 1.00-1.14, p = 0.04) and persistent AKI with higher SAPSII (HR = 1.03, 95%CI: 1.00-1.06, p = 0.048) and nephrotoxic drug use (HR = 3.88, 95%CI: 1.20-12.5, p = 0.02). In conclusion, in critically ill COVID-19 patients, the incidence of PTD and AKI was relatively high. NGAL was the best urinary biomarker for predicting AKI, but only clinical severity was independently associated with its occurrence. [ABSTRACT FROM AUTHOR]

Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging. In this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period. In conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. Methods: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1–5 and 97 age-matched patients with CKD of other etiology between the ages of 2–17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. Results: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2–6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2–6, 7–12, and 13–17 years). Conclusion: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Light chain proximal tubulopathy (LCPT) is a rare type of monoclonal gammopathy of renal significance. Clinicians should consider LCPT in the differential diagnosis of patients with renal or proximal tubular dysfunction with monoclonal gammopathy. They should confirm diagnosis by renal biopsy and initiate chemotherapy before disease progression. [ABSTRACT FROM AUTHOR]

Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor that has been widely used for the treatment of patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. However, in the HBV monoinfection scenario, only five cases of TDF-associated Fanconi syndrome have been reported thus far, two of them providing a confirmatory kidney biopsy. Here, we describe the case of a 68-year-old woman with chronic hepatitis B (CHB) who developed TDF-induced Fanconi syndrome that reverted after TDF withdrawal from tenofovir alafenamide. Though the overall risk of TDF-associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular functions should be monitored in patients exposed to TDF. [ABSTRACT FROM AUTHOR]

Background Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms: crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described. Methods We conducted a single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005 and 2021. Results The median age was 69.5 years (range 47–80). Ten patients presented with CKD and significant proteinuria (median estimated glomerular filtration rate of 43.5 ml/min/1.73 m2; urine protein:creatinine ratio 328 mg/mmol). Only six patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in seven patients cases and monoclonal gammopathy of renal significance (MGRS) in five patients. A clone was detected in all cases combining serum/urine electrophoresis and free light chain (LC) assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on a combination of CKD without another cause, haematological workup, LC restriction on immunofluorescence and abnormalities on electron microscopy (EM). Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months. Conclusions The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from 'excessive LC resorption without tubular injury'. Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multicentre prospective studies are needed to better define the clinicopathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS. [ABSTRACT FROM AUTHOR]

We report an infant case of transient distal renal tubular acidosis and Fanconi syndrome caused by rotavirus gastroenteritis. A 10-month-old boy was admitted to the hospital because of frequent vomiting, lack of vitality, and dehydration. He was diagnosed with rotavirus gastroenteritis on account of his positive stool rotavirus antigen test. Although he presented with acidemia and severe mixed metabolic acidosis, he also had a urine pH of 6.0, indicating impaired urinary acidification. Therefore, he was diagnosed with distal renal tubular acidosis. On the third day of hospitalization, a relatively low %tubular reabsorption of phosphate level with hypophosphatemia, increased fractional excretion of uric acid with hypouricemia, and high urinary β2-microglobulin levels were observed. Moreover, he was diagnosed with Fanconi syndrome on account of multiple proximal tubular dysfunctions. After remission of rotavirus gastroenteritis, the signs of renal tubular dysfunction improved. This was a case of rotavirus gastroenteritis-caused transient distal renal tubular acidosis and Fanconi syndrome. Severe metabolic acidosis resulted from anion-gap metabolic acidosis due to acute kidney injury by rotavirus gastroenteritis and normal anion-gap acidosis due to renal tubular acidosis. When renal tubular acidosis is associated with a disease that causes anion-gap metabolic acidosis, mixed metabolic acidosis occurs and becomes exacerbated. Furthermore, it is important to consider the complications of renal tubular acidosis in the case of severe metabolic acidosis. [ABSTRACT FROM AUTHOR]

Background: Tenofovir-based regimens remain the first choice for the treatment of human immunodeficiency virus infection and hepatitis B infection. Despite its virologic efficacy and ease of administration, it can lead to significant nephrotoxicity which may not be fully reversible. Case Description: An elderly gentleman on Tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy for 10 years presented with vague symptoms of fatigue, poor oral intake and constipation. He was found to have hypokalemia and a volume depleted status. Detailed evaluation revealed hyperchloremic metabolic acidosis, hypophosphatemia, hypouricemia, proteinuria and amino aciduria consistent with a diagnosis of Fanconi syndrome. He was switched to Abacavir-based regimen, and supplements to correct acidosis and electrolytes were given. At the follow-up visit after a month, his proximal renal tubular injury recovered partially and he was symptomatically better. Conclusion: Patients on long-term therapy with tenofovir should be monitored for proximal renal tubular injury besides estimation of the glomerular filtration rate. Fanconi syndrome may present late after several years of being on TDF therapy. Partial or complete recovery of the renal tubular function occurs after stopping tenofovir. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor 1α (HNF1α) plays essential roles in controlling development and metabolism; its mutations are clearly linked to the occurrence of maturity-onset diabetes of the young (MODY3) in humans. Lysine 117 (K117) to glutamic acid (E117) mutation in the HNF1α gene has been clinically associated with MODY3, but no functional data on this variant are available. Here, we addressed the role of lysine 117 in HNF1α function using a knock-in animal model and site-directed mutagenesis. HNF1α K117E homozygous mice exhibited dwarfism, hepatic dysfunction, renal Fanconi syndrome, and progressive wasting syndrome. These phenotypes were very similar to those of mice with complete HNF1α deficiency, suggesting that K117 is critical to HNF1α functions. K117E homozygotes developed diabetes in the early postnatal period. The relative deficiency of serum insulin levels and the normal response to insulin treatment in homozygous mice were markedly similar to those in the MODY3 disorder in humans. Moreover, K117E heterozygous mutant causes age-dependent glucose intolerance, which is similar to the pathogenesis of MODY3 as well. K117 mutants significantly reduced the overall transactivation and DNA binding capacity of HNF1α by disrupting dimerization. Collectively, our findings reveal a previously unappreciated role of POU domain of HNF1α in homodimerization and provide important clues for identifying the molecular basis of HNF1α-related diseases such as MODY3. Article Highlights: HNF1α K117E homozygous mice exhibited dwarfism, hepatic dysfunction, renal Fanconi syndrome, and progressive wasting syndrome. K117E homozygotes developed diabetes in the early postnatal period. K117E heterozygous mutant causes age-dependent glucose intolerance, which is similar to the pathogenesis of maturity-onset diabetes of the young. K117 mutants significantly reduced the overall transactivation and DNA binding capacity of HNF1α by disrupting dimerization. [ABSTRACT FROM AUTHOR]

The goal of this manuscript is to present and summarize several rare pediatric syndromes (Zellweger syndrome, Kartagener syndrome, Prader-Willi syndrome, Schinzel-Giedion syndrome, Fanconi anemia, Joubert-Boltshauser syndrome, Poretti-Boltshauser syndrome, and Langer-Giedion syndrome) who have been named after luminary "Swiss" physicians (pediatricians, pediatric neurologists, or pediatric radiologists) who recognized, studied, and published these syndromes. In this manuscript, a brief historical summary of the physicians is combined with the key clinical symptoms at presentation and the typical imaging findings. This manuscript is not aiming to give a complete comprehensive summary of the syndromes, nor does it ignore the valuable contributions of many "Swiss" scientists who are not included here, but focuses on several rare syndromes that benefit from imaging data. [ABSTRACT FROM AUTHOR]