Novel Fanconi renotubular syndromes provide insights in proximal tubule pathophysiology.

The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for L-arginine:glycine amidinotransferase (GATM), solute carrier family 34 (type Ii sodium/phosphate cotransporter), member 1 (SLC34A1), enoyl-CoAhydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), hepatocyte nuclear factor 4A (HNF4A), or NADH dehydrogenase complex I, assembly factor 6 (NDUFAF6). We will explore how mutations in these genes revealed unexpected mechanisms that led to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 (SLC34A1). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.

The genetic polymorphisms of XPR1 and SCL34A3 are associated with Fanconi syndrome in Chinese patients of tumor-induced osteomalacia.

PURPOSE: Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia caused by tumors with excess production of fibroblast growth factor 23 (FGF23). Some reports showed that TIO patients had renal Fanconi syndrome (FS) with unidentified mechanism. In this study, we investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and TIO with FS. METHODS: We recruited 30 TIO patients with FS (TIO-FS) as well as 30 TIO patients (TIO-nonFS) without any urine abnormalities matched by age and gender. We collected clinical manifestations and conducted targeted sequencing of SLC34A1, SLC34A3 and XPR1 genes and the association analysis between variants in TIO with FS and phenotypes. RESULTS: TIO-FS group had lower levels of serum phosphate (0.44 ± 0.12 vs. 0.51 ± 0.07 mmol/L, p < 0.05) than TIO-nonFS group. Among the 16 SNPs in SLC34A1, SLC34A3 and XPR1 genes, GG/GC genotypes of rs148196667 in XPR1 and AA/TA genotypes of rs35535797 in SLC34A3 were associated with a reduced susceptibility to have FS. The G allele of rs148196667 in XPR1 decreased the risk of FS. The GGAA haplotype in SLC34A3 and GCT haplotype in XPR1 were associated with a decreased risk for FS. CONCLUSIONS: The polymorphisms of XPR1 and SCL34A3 are associated with TIO patients with Fanconi syndrome. It provides novel insight to the relationship of phosphate transportation and general functions of renal proximal tubules.

Effect of Experimental Fanconi Syndrome on Tubular Reabsorption of Lithium in Rats.

Lithium, administered to patients of bipolar disorders, is mainly excreted into urine, and tubular reabsorption at the proximal tubule is involved in the renal handling of lithium. In this study, we examined the renal excretion of lithium in rats with Fanconi syndrome, characterized by defects of transports of various compounds at the proximal tubules, induced by maleic acid. After maleic acid was intravenously injected, mannitol and lithium chloride were infused in turn. Using samples of plasma and bladder urine during the mannitol infusion, renal parameters were determined. Pharmacokinetic parameters of lithium were obtained using samples during the lithium chloride infusion. Maleic acid decreased creatinine clearance and increased the fractional excretion of glucose and phosphate, suggesting the induction of Fanconi syndrome. In rats with Fanconi syndrome, plasma concentration of lithium was increased, and its renal clearance was decreased. No effect on the fractional excretion of lithium was exhibited. This study represents that the tubular reabsorption of lithium was impaired to the same degree with glomerular filtration in rats with experimental Fanconi syndrome and that the dysfunction of the tubular reabsorption of glucose and phosphate was more severe. It is possible that Fanconi syndrome inhibited the reabsorption of lithium at the proximal tubule and facilitated the reabsorption of lithium from the loop of Henle to the collecting duct.

Bortezomib-based chemotherapy can improve renal and tubular functions in patients with light chain-associated Fanconi syndrome.

Light chain-associated Fanconi syndrome (LCFS) is a disorder of renal proximal tubule due to immunoglobulin light chains. Cases of LCFS are rare and mostly sporadically reported, and treatment of this entity is still controversial. This single-center retrospective study included 22 patients diagnosed with LCFS in Peking Union Medical College Hospital. Monoclonal gammopathy of undetermined significance was diagnosed in 13 patients, and overt multiple myeloma in six patients, with two smoldering myeloma and one Waldenstrom macroglobulinemia. Light chain was mostly kappa type (90.9%). Baseline median estimated glomerular filtration rate was 66 (13-126) ml/min/1.73 m2, with one patient presented as end-stage renal disease. After a median follow-up of 37 months, three patients died. Twelve patients were treated with chemotherapy, including 7 with bortezomib-based regimens. Renal function was significantly improved in the group of patients who received chemotherapy (p = 0.026). Compared with other chemotherapy regimens, patients with bortezomib-based treatment had a better hematological response (p = 0.027) as well as a better proximal tubule outcome (p = 0.015). Chemotherapy likely outweighs supportive treatment in patients with LCFS. Bortezomib-based regimen seems to be a safe first-line therapy for management of those patients.

Salt-Losing Tubulopathies in Children: What's New, What's Controversial?

Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.

[Fanconi-Bickel-Syndrom: a novel genetic disease in Original Braunvieh]. / Fanconi-Bickel-Syndrom: eine bislang unerkannte Erbkrankheit beim Braunvieh.

INTRODUCTION: This case report describes a new genetic disease of the Braunvieh breed in Switzerland. The bovine disorder also occurs in German Fleckvieh, and corresponds to human Fanconi-Bickel syndrome which is an inherited glycogen storage disease caused by mutations of the SLC2A2 gene encoding the glucose transporter GLUT2. This case report describes a single affected Original Braunvieh calf genotyped as homozygous for the FH2-associated SLC2A2 frame shift mutation. The clinical examination showed stunted growth, polyuria and polydipsia, as well as poor claw horn and coat quality. Necropsy revealed a pale cortex of the kidneys and a unilateral renal hypoplasia. Histology showed tubulonephrosis of the proximal tubules with protein- and glucose-rich contents. Glycogen accumulation was not evident in any organ. This finding is different from the reported lesions in two previously described GLUT2-deficient Fleckvieh heifers. In the presented case, growth retardation mainly seems to be associated with renal dysfunction. A direct gene test is available to eliminate the mutant allele from the population.

Renal dysfunction in patients taking fumaric acid esters - a retrospective cross-sectional study.

BACKGROUND: Fumaric acid esters (FAE) have been used for over 30 years in the management of psoriasis. There have been a number of case reports linking the use of FAE with nephrotoxicity, including acute renal injury and Fanconi syndrome. However, one large multicentre retrospective trial showed no evidence of renal dysfunction with FAE. OBJECTIVES/AIMS: The aim of this study was to determine the number of patients in our institution being treated with FAE who developed significant proteinuria or renal dysfunction. METHODS: This was a single-centre retrospective study assessing all patients on FAE who attended for follow-up during an 18-week period between February and June 2015. Demographics, comorbidities, duration and dose of treatment with FAE, proteinuria, renal function and other biochemical serum abnormalities were recorded. RESULTS: One hundred and twenty-seven patients were included in the study. Eighty-two patients had proteinuria detected at some stage during treatment with FAE, and 18 of these had persistent proteinuria (positive in at least three consecutive specimens, 12 weeks apart). Six patients (five female) developed proximal tubular dysfunction (PTD). The risk factors for the development of PTD appear to be lower bodyweight (P = 0.03), higher dose per weight (P = 0.03) and longer duration of treatment (P = 0.03). Renal dysfunction improved on discontinuation or dose reduction in FAE. CONCLUSION: Fumaric acid esters are frequently associated with transient or persistent proteinuria. Significant renal dysfunction is rare and usually reversible on dose reduction or discontinuation of FAE. This study highlights the importance of screening for proteinuria. Higher doses per weight of treatment and longer duration of FAE therapy are likely risk factors for PTD.

Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy.

BACKGROUND AND OBJECTIVES: Nephropathic cystinosis is a lysosomal storage disorder characterized by renal tubular Fanconi syndrome in infancy and glomerular damage leading to renal failure at ∼10 years of age. Therapy with the cystine-depleting agent cysteamine postpones renal failure, but the degree of compliance with this treatment has not been correlated with preservation of kidney function. METHODS: We assessed leucocyte cystine depletion by cysteamine and created the composite compliance score that incorporates the extent of leucocyte cystine depletion, as well as duration of cysteamine treatment, into a single integer. Age at renal failure was used to gauge preservation of renal function, and the Fanconi syndrome index (FSI), a measure of aminoaciduria, was used to assess renal tubular Fanconi syndrome. RESULTS: Age at renal failure varied directly and linearly with the composite compliance score (y = 0.3x +8.8; R(2) = 0.61). The slope indicated that for every year of excellent cystine depletion, nearly 1 year of renal function was preserved. Age at renal failure correlated roughly with mean leucocyte cystine level, but not with mean cysteamine dosage. There was no correlation between the FSI and the composite compliance score. CONCLUSIONS: Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular, but not tubular, function. Oral cysteamine therapy should be given at the maximum tolerated dose, within the recommended limits.

Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys.

Cystinosis, a main cause of Fanconi syndrome, is reproduced in congenic C57BL/6 cystinosin knockout (KO) mice. To identify the sequence of pathogenic and adaptation mechanisms of nephropathic cystinosis, we defined the onset of Fanconi syndrome in KO mice between 3 and 6 months of age and analyzed the correlation with structural and functional changes in proximal tubular cells (PTCs), with focus on endocytosis of ultrafiltrated disulfide-rich proteins as a key source of cystine. Despite considerable variation between mice at the same age, typical event sequences were delineated. At the cellular level, amorphous lysosomal inclusions preceded cystine crystals and eventual atrophy without crystals. At the nephron level, lesions started at the glomerulotubular junction and then extended distally. In situ hybridization and immunofluorescence revealed progressive loss of expression of megalin, cubilin, sodium-glucose cotransporter 2, and type IIa sodium-dependent phosphate cotransporter, suggesting apical dedifferentiation accounting for Fanconi syndrome before atrophy. Injection of labeled proteins revealed that defective endocytosis in S1 PTCs led to partial compensatory uptake by S3 PTCs, suggesting displacement of endocytic load and injury by disulfide-rich cargo. Increased PTC apoptosis allowed luminal shedding of cystine crystals and was partially compensated for by tubular proliferation. We conclude that lysosomal storage triggered by soluble cystine accumulation induces apical PTC dedifferentiation, which causes transfer of the harmful load of disulfide-rich proteins to more distal cells, possibly explaining longitudinal progression of swan-neck lesions. Furthermore, our results suggest that subsequent adaptation mechanisms include lysosomal clearance of free and crystalline cystine into urine and ongoing tissue repair.

Acute metabolic acidosis in a GLUT2-deficient patient with Fanconi-Bickel syndrome: new pathophysiology insights.

Fanconi-Bickel syndrome is a rare autosomal-recessive disorder caused by mutations in the SLC2A2 gene coding for the glucose transporter protein 2 (GLUT2). Major manifestations include hepatomegaly, glucose intolerance, post-prandial hypoglycaemia and renal disease that usually presents as proximal tubular acidosis associated with proximal tubule dysfunction (renal Fanconi syndrome). We report a patient harbouring a homozygous mutation of SLC2A2 who presented a dramatic exacerbation of metabolic acidosis in the context of a viral infection, owing to both ketosis and major urinary bicarbonate loss. The kidney biopsy revealed nuclear and cytoplasmic accumulation of glycogen in proximal tubule cells, a lack of expression of GLUT2, and major defects of key proteins of the proximal tubule such as megalin, cubilin and the B2 subunit of H(+)-ATPase. These profound alterations of the transport systems most likely contributed to proximal tubule alterations and profound bicarbonate loss.

Transient Fanconi syndrome with severe polyuria and polydipsia in a 4-year old Shih Tzu fed chicken jerky treats.

Acquired Fanconi syndrome is characterized by inappropriate urinary loss of amino acids, bicarbonate, electrolytes, and water. It has recently been described in dogs fed chicken jerky treats from China, a new differential diagnosis to the classical inciting infectious diseases (e.g. leptospirosis, pyelonephritis) and toxins. A dog fed exclusively chicken jerky treats purchased in Switzerland was presented to our clinic with severe polyuria, polydipsia and profound electrolyte and acid base disturbances. Other inciting causes of Fanconi syndrome were ruled out. The requirement of a very intensive supportive treatment in this dog stands in contrast to treatment of chronic forms of Fanconi syndrome as described in the Basenji. This intensive therapy and the associated monitoring can be a real challenge and a limiting factor for the prognosis of acquired Fanconi syndrome. Veterinarians should be aware of the risk of excessive feeding of chicken jerky treats.

Inherited secondary nephrogenic diabetes insipidus: concentrating on humans.

The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models.

Acquired Fanconi syndrome associated with prolonged adefovir dipivoxil therapy in a chronic hepatitis B patient.

Adefovir dipivoxil (ADV) is one of the commonly used antiviral agents in the treatment of chronic hepatitis B infection. Nephrotoxicity is dose related and occurred at a daily dosage of >30 mg. However, it is now increasingly recognized that nephrotoxicity can occur at a daily dose of 10 mg. We present a case of acquired Fanconi syndrome in a patient with chronic hepatitis B who had been treated with ADV for 4 years. She presented with progressive muscle weakness and generalized bone pain. The laboratory results showed the feature of proximal renal tubule dysfunction, particularly severe hypophosphatemia. Diagnostic approach to hypophosphatemia and proximal renal tubular dysfunction is discussed. After switching over from ADV to entecavir, her symptoms and laboratory findings returned to normal. Acquired Fanconi syndrome can be associated with ADV at a conventional dosage, and therefore, patients treated with long-term ADV should have regular monitoring of renal function and calcium and phosphate levels.

Treatment of cystinosis with delayed-release cysteamine: 6-year follow-up.

BACKGROUND: Patients with nephropathic cystinosis are required to take 6-hourly immediate-release cysteamine (Cystagon®) to reduce disease progression. This arduous regimen affects quality of life, disrupts sleep, and may result in non-compliance with therapy. Enteric-coated cysteamine bitartrate (EC-cysteamine) was developed as a "proof-of-concept" formulation for twice-daily ingestion. Previous reports have shown this therapy to be effective up to a mean of 14 months. CASE-DIAGNOSIS/TREATMENT: Two subjects (aged 13 and 15 years) received EC-cysteamine for 5-6 years at 60-65 % of their previous total daily dose of immediate-release cysteamine given at 6-h intervals. White blood cell (WBC) cystine levels were monitored every 1-3 months. CONCLUSION: The administration of EC-cysteamine did not result in any change in mean trough WBC cystine levels or any deterioration in the estimated glomerular filtration rate, thyroid, or liver function, suggesting that delayed-release, twice-daily EC-cysteamine is an effective long-term treatment alternative to immediate-release cysteamine given at 6-h intervals.

Nephropathic infantile form of cystinosis about one case.

Cystinosis is the major cause of inherited Fanconi syndrome, and should be suspected in young children with a failure to thrive and with signs of renal proximal tubular damage. This is a study of a case report of cystinosis revealed by a growth failure and chronic dehydration. A 9-month-old boy was referred to our department for evaluation of polyuria and polydipsia. Clinical examination showed dehydration and enlarged wrists and rachitic rosaries. The presence of metabolic acidosis, hypokalemia, hypochloremia with proteinuria, polyuria, and hypercalciuria was suggestive of inherited Fanconi syndrome. The diagnosis of cystinosis was confirmed by an increased leukocyte cystine level.

[Renal glucosuria]. / Glucosurie rénale.

The occurrence of glucosuria in the absence of hyperglycemia is distinctive for renal glucosuria. SGLT2 mutations provoke familial renal glucosuria characterized by persistent glucosuria in the absence of any other renal tubular dysfunction. Renal glucosuria associated with others proximal tubular dysfunctions points to Fanconi syndrome. This generalized dysfunction of proximal tubule needs to be treated and may progress regarding its aetiology to chronic renal failure. The development and study of models of Fanconi syndrome has recently contributed to a better knowledge of the mechanisms implicated in the tubular transport of glucose and low-molecular-weight-proteins. This article reviews these recent developments.

Specific impairment of proximal tubular cell proliferation by a monoclonal κ light chain responsible for Fanconi syndrome.

BACKGROUND: Fanconi syndrome (FS) is a rare renal disorder featuring proximal tubule dysfunction that may occur following tubular reabsorption of a monoclonal light chain (LC), in patients with multiple myeloma. FS may precede the recognition of multiple myeloma by several years. In most cases, crystalline inclusions of monoclonal κ LCs are observed within the lysosomes of proximal tubular cells (PTCs) and probably participate in their functional alteration. METHODS: To investigate the mechanism implicated in proximal tubule dysfunction, we compared the effects of κ LC-CHEB obtained from a patient with myeloma-associated FS to those of control κ LC-BON obtained from a patient without evidence of FS, on the viability and proliferation of two different PTC lines. RESULTS: Our data suggest that the tubular atrophy in myeloma-associated FS does not result from increased apoptosis of PTCs, but from their impaired capacity to proliferate and renew. Indeed, in vitro incubation of cultured PTCs with physiological amounts of the nephrotoxic κ LC-CHEB was sufficient to cause a depression in DNA synthesis and in cell proliferation. This effect was observed neither with control κ LC-BON nor in the absence of κ LC. CONCLUSIONS: The reduced turnover of PTCs may affect tubular repair and regeneration. In addition, the reduced proliferation of myeloma cells producing the same monoclonal κ LC might explain the frequent association of FS with smoldering multiple myeloma.

MYO5B mutations in patients with microvillus inclusion disease presenting with transient renal Fanconi syndrome.

BACKGROUND AND OBJECTIVE: : Microvillus inclusion disease (MVID) is a rare congenital enteropathy associated with brush border atrophy and reduced expression of enzymes at the enterocytes' apical surface. MVID is associated with mutations in the MYO5B gene, which is expressed in all epithelial tissues. Whether organs other than the intestine are affected in MVID is unclear. We report 2 patients with MVID that developed renal Fanconi syndrome while receiving total parenteral nutrition. Renal Fanconi syndrome has been correlated to apical plasma membrane defects in kidney proximal tubular epithelial cells. The aim of the present study was to determine whether MYO5B mutations in these patients correlate with similar apical plasma membrane defects in renal tubular epithelial cells as observed in the intestine. METHODS: : Biopsies from kidney, duodenum, ileum, jejunum, and colon of 2 patients with MVID carrying MYO5B mutations and of age-matched controls were fixed in paraffin and analyzed with immunohistochemistry and transmission electron microscopy. RESULTS: : Structural defects of the brush border and apical recycling endosome organization are observed in enterocytes of all of the segments of the small intestine and colon. MYO5B mutations in patients with MVID with renal Fanconi syndrome do not correlate with aberrant apical plasma membrane morphology or altered apical recycling endosome organization in renal tubular epithelial cells. CONCLUSIONS: : MYO5B mutations have divergent effects on the apical membrane system in kidney and intestinal epithelial cells. Epithelial defects presented in MVID are therefore likely triggered by intestine-specific factors, the identification of which may provide new targets and open avenues for the development of alternative therapeutic strategies to combat this devastating disease.

Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy.

Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV.

Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence.

Tenofovir (TDF) is an effective and widely used treatment for both human immunodeficiency virus (HIV) and hepatitis B virus infection. Although studies suggest that TDF has a low overall toxicity profile and only a modest effect on estimated glomerular filtration rate, numerous case reports have since appeared in the literature describing TDF-associated renal tubular dysfunction, and this is now a significant source of HIV-related referrals to nephrologists. The main target of toxicity appears to be the proximal tubule, and in severe cases, patients can develop renal Fanconi syndrome. We review findings from recent studies in this area performed by ourselves and others and discuss our direct experience as practicing nephrologists. In particular, we discuss: (1) the nature and extent of TDF-associated kidney toxicity in the HIV-infected population, (2) potential underlying mechanisms of toxicity in the proximal tubule, (3) risk factors for developing tubular dysfunction, and (4) suggested strategies to monitor patients on TDF therapy.