Pattern of hereditary renal tubular disorders in Egyptian children.

BACKGROUND: Hereditary renal tubular disorders (HRTD) represent a group of genetic diseases characterized by disturbances in fluid, electrolyte, and acid-base homeostasis. There is a paucity of studies on pediatric HRTD in Egypt. In this study, we aimed to study the pattern, characteristics, and growth outcome of HRTD at an Egyptian medical center. METHODS: This study included children from one month to < 18-years of age with HRTD who were diagnosed and followed up at the Pediatric Nephrology Unit of Sohag University Hospital from January 2015 to December 2021. Data on patients` demographics, clinical features, growth profiles, and laboratory characteristics were collected. RESULTS: Fifty-eight children (57% males; 72% parental consanguinity; 60% positive family history) were diagnosed with seven HRTD types. The most commonly encountered disorders were distal renal tubular acidosis (distal renal tubular acidosis [RTA] 27 cases, 46.6%) and Bartter syndrome (16 cases 27.6%). Other identified disorders were Fanconi syndrome (6 cases with cystinosis), isolated proximal RTA (4 cases), nephrogenic diabetes insipidus (3 cases), and one case for each RTA type IV and Gitelman syndrome. The median age at diagnosis was 17 months with a variable diagnostic delay. The most common presenting features were failure to thrive (91.4%), developmental delay (79.3%), and dehydration episodes (72.4%). Most children showed marked improvement in growth parameters in response to appropriate management, except for cases with Fanconi syndrome. Last, only one case (with cystinosis) developed end-stage kidney disease. CONCLUSIONS: HRTD (most commonly distal RTA and Bartter syndrome) could be relatively common among Egyptian children, and the diagnosis seems challenging and often delayed.

Proximal tubular renal dysfunction among HIV infected patients on Tenofovir versus Tenofovir sparing regimen in western Kenya.

INTRODUCTION: Tenofovir Disoproxil Fumarate (TDF) is the most widely used Anti-Retroviral Therapy (ART) drug due to its potency, safety profile and World Health Organization (WHO) recommendation. TDF causes proximal tubular renal dysfunction (PTRD) leading to Fanconi syndrome, acute kidney injury and chronic kidney disease. Modest rates (2-4%) of TDF related toxicity based on estimated Glomerular Filtration Rate (GFR) have been described, while TDF-induced PTRD has been reported to be 22%. TDF toxicity is more likely among African patients, it is reversible and TDF may be renal dosed in patients with dysfunction. The objective of this study was to assess proximal tubular renal dysfunction, global renal function, and their determinants among patients on TDF versus TDF-sparing regimen. METHODS: This was a cross-sectional study among people living with HIV/AIDS (PLWHA) attending the Academic Model Providing Access to Healthcare (AMPATH) program. The primary outcome of interest in this study was PTRD while the secondary outcome of interest was estimated GFR. PTRD was defined as any two of beta-2 microglobulin in urine, metabolic acidosis, normoglycemic glucosuria and fractional excretion of phosphate. Student's t-test, chi-square and their non-parametric equivalents were used to test for statistical significance. Univariate and multivariate logistic regression analysis was carried out. RESULTS: A total of 516 participants were included in the final analysis, 261 on TDF while 255 were on TDF-sparing regimens. The mean (SD) age of all participants was 41.5 (12.6) years with majority being female (60.3%). The proportion of PTRD was 10.0% versus 3.1% in the TDF compared to TDF-sparing group (P<0.001). Mean estimated GFR was 112.8 (21.5) vs 109.7 (21.9) ml/min/1.73mm3 (P = 0.20) for the TDF compared to TDF-sparing group. TDF users were more likely to have PTRD compared to non-TDF users, adjusted Odds Ratio (AOR) 3.0, 95% CI 1.12 to 7.75. CONCLUSION: There was significant PTRD in the TDF compared to TDF-sparing group without significant difference in estimated GFR. The clinical significance of these findings may not be clear in the short term.

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.

Incidence of renal Fanconi syndrome in patients taking antiretroviral therapy including tenofovir disoproxil fumarate.

The objective of this study was to determine the incidence and predictors of Fanconi Syndrome (FS) in a cohort of patients taking tenofovir disoproxil fumarate (TDF). Clinical records and laboratory investigations from patients receiving TDF between 2002 and 2016 were extracted. FS was defined as normoglycaemic glycosuria and proteinuria and at least one other marker of renal dysfunction. Regression analysis was performed with time to development of FS and the following covariates: ritonavir co-administration, age, gender, co-morbidities (hypertension, hyperlipidaemia, diabetes, viral hepatitis), CD4 cell count nadir and baseline eGFR. One thousand and forty-four patients received TDF without ritonavir and 398 patients with ritonavir. Thirteen cases of FS were identified with a mean duration of exposure of 55 months. The incidence of FS was 1.09/1000PY (0.54-1.63) of TDF exposure (without ritonavir) and 5.50/1000PY (3.66-7.33) of TDF-ritonavir co-administration (p=0.0057). The adjusted hazards ratio for ritonavir co-administration was 4.71 (1.37-16.14, p=0.014). Known risk factors for chronic kidney disease were not associated with development of FS. Ritonavir co-administration, but not other factors, is associated with a greater risk of FS. FS developed late. Known risk factors for chronic kidney disease and length of treatment are not useful for identifying patients most at risk of developing FS in patients taking TDF.

Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use.

AIM: Deferasirox is a new oral iron chelating agent with several cases reporting renal adverse events in recent years. Our aim was to identify the incidence of deferasirox-related Fanconi syndrome (FS) and its risk factors. METHODS: All transfusion-dependent thalassaemic patients who received deferasirox at the outpatient department of the National Taiwan University Hospital (NTUH) from January 2006 to February 2014 were evaluated. RESULTS: This cohort study included 57 patients, and mean age of deferasirox initiation was 18.2 ± 7.7 years. After 6.9 ± 1.8 years of follow-up, 5 in 57 (8.8%) thalassaemic patients had FS. Age of starting deferasirox negatively correlated with incidence of FS (correlation coefficient -0.892, P = 0.008). Other factors were not significantly associated with FS. Serum creatinine level at the start of deferasirox compared to at the end of study or onset of FS did not show significant change (P = 0.277). All the deferasirox-related FS manifested with proximal renal tubular acidosis and hypophosphataemia, which needed specific treatment or withdrawal of deferasirox use. CONCLUSIONS: We recommend that children, especially of young age, who regularly use deferasirox should undergo routine urinalysis and blood testing for early detection of FS.

¿Cuándo debe sospechar un nefrólogo una enfermedad mitocondrial? / When should a Nephrologist suspect a mitochondrial disease?

Las enfermedades mitocondriales, considerando aquellas que afectan a los procesos de la cadena respiratoria (CR) y fosforilación oxidativa mitocondrial (OXPHOS), constituyen un grupo relativamente frecuente dentro de las enfermedades raras que habitualmente tienen afectación multisistémica, una expresión fenotípica muy variable y una base genética compleja. La afectación renal es poco común, siendo el túbulo, y más concretamente su porción proximal, el principal afectado, desarrollándose un síndrome de Toni-Debré-Fanconi completo en las formas más graves. No obstante, en algunos casos existe afectación glomerular, fundamentalmente en forma de glomeruloesclerosis segmentaria y focal (GESF), manifestada por proteinuria e insuficiencia renal. Es importante que el nefrólogo tenga presente la posibilidad de una enfermedad mitocondrial en pacientes con esta forma de afectación renal que presenten datos clínicos acompañantes característicos, sobre todo diabetes mellitus y sordera. En los casos con GEFS, un diagnóstico correcto evitará el uso inapropiado de medicación inmunosupresora. No existen tratamientos específicos para la mayoría de las enfermedades mitocondriales, pero es probable que la intensa investigación actualmente existente sobre estas patologías lleve finalmente a posibilidades terapéuticas eficaces (AU)

Mitochondrial diseases, taking into account those that affect the processes of the respiratory chain (RC) and mitochondrial oxidative phosphorylation system (OXPHOS), make up a relatively frequent group within rare diseases that usually have multisystem involvement, a very variable phenotypic expression and a complex genetic base. Renal involvement is uncommon, with the tubule being the most affected, specifically its proximal portion, developing into full Toni-Debré-Fanconi syndrome in the most serious cases. However, in some cases the glomerulus is involved, fundamentally in focal segmental glomerulosclerosis form (FSGS), expressed by proteinuria and renal failure. It is important that the Nephrologist keeps in mind the possibility of a mitochondrial disease in patients with this type of renal involvement that present clinical data with these characteristics, especially diabetes mellitus and deafness. In cases with FSGS, a correct diagnosis will avoid the inappropriate use of immunosuppressive medication. Specific treatments do not exist for the majority of mitochondrial diseases, but it is likely that the intense research that currently exists for these diseases will eventually produce effective treatment possibilities (AU)

A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a widely used antiretroviral agent with favorable efficacy, safety, and tolerability profiles. However, renal adverse events, including the rare Fanconi syndrome (FS), may occur in a small subset of patients treated for HIV infections. OBJECTIVES: The aim of this study was to identify genetic variants that may be associated with TDF-associated FS (TDF-FS). METHODS: DNA samples collected from 19 cases with TDF-FS and 36 matched controls were sequenced, and genetic association studies were conducted on eight candidate genes: ATP-binding cassette (ABC) transporters ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. The functional effects of a single nucleotide polymorphism (SNP) predicted to alter the transport of tenofovir were then investigated in cells expressing an identified variant of ABCC4. RESULTS: The case group showed a trend toward a higher proportion of rare alleles. Six SNPs in ABCC2 (three SNPs), ABCC4 (one SNP), and OCRL (two SNPs) were associated with TDF-FS case status; however, this association did not remain significant after correction for multiple testing. Six SNPs, present in OCRL (four SNPs) and ABCC2 (two SNPs), were significantly associated with increased serum creatinine levels in the cases, and this association remained significant after multiple test correction (P < 2 × 10). One synonymous SNP in ABCC2 (rs8187707, P = 2.10 × 10, ß = -73.3 ml/min/1.73 m(2)) was also significantly associated with the decreased estimated glomerular filtration rate of creatinine among cases. However, these results were driven by rare SNPs present in a small number of severely affected cases. Finally, a previously uncharacterized, nonsynonymous SNP, rs11568694, that was predicted to alter MRP4 function had no significant effect on tenofovir cellular accumulation in vitro. CONCLUSION: Although no single predictive genetic marker for the development of TDF-FS was identified, the findings from our study suggest that rare variants in multiple genes involved in the renal handling of tenofovir, and/or renal cell homeostasis, may be associated with increased susceptibility to TDF-FS.

Drug-induced renal Fanconi syndrome.

A number of therapeutic drugs are toxic to the kidney proximal tubule (PT) and can cause the renal Fanconi syndrome (FS). The most frequently implicated drugs are cisplatin, ifosfamide, tenofovir, sodium valproate and aminoglycoside antibiotics, and the new oral iron chelator deferasirox has also recently been associated with FS. The incidence of full or partial FS is almost certainly under-estimated due to a lack of appropriate systematic studies, variations in definitions of tubular dysfunction and under-reporting of adverse events. The clinical features of FS are amino aciduria, low molecular weight proteinuria, hypophosphataemia, metabolic acidosis and glycosuria. The most serious complications are bone demineralization from urinary phosphate wasting and progressive decline in kidney function. Commonly used tests for kidney function such as estimated glomerular filtration rate and urine albumin/creatinine ratio are not sensitive markers of PT toxicity; patients at risk should thus be monitored with more appropriate tests, and drugs should be stopped or reduced in dose if toxicity occurs. Substantial recovery of PT function can occur after withdrawal of therapy, but this can take months and chronic damage may persist in some cases.

[Pitfalls of monoclonal gammopathy]. / Les pièges des gammapathies monoclonales.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.

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.

Fanconi syndrome in lymphoma patients: report of the first case series.

BACKGROUND: Fanconi syndrome (FS) is a generalized transport defect in the proximal renal tubule leading to renal losses of phosphate, calcium, uric acid, bicarbonates as well as glucose, amino acids and other organic compounds. It is caused by inherited or acquired disorders including low mass or high mass multiple myeloma. OBJECTIVES: To report the first case series of patients with lymphoma and FS. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients with lymphoma and FS were identified in the nephrology department of two teaching hospitals in Paris, France and Ghent, Belgium. FS was defined by the presence of at least three out of the four following criteria: hypophosphataemia, metabolic acidosis, normoglycaemic glucosuria and hypokalaemia. Patients files were reviewed and relevant data were collected. RESULTS: Eight patients with lymphoma and FS were identified. In six patients, the lymphoma was of the acute T cell leukaemia/lymphoma (ATLL) type, related to human T cell lymphotropic virus 1 (HTLV1) infection. In all patients, FS was severe requiring supplementation. A kidney biopsy performed in a patient with post-transplantation primary renal lymphoma disclosed intense proximal tubule infiltration by lymphomatous cells. In one patient with ATLL, FS features regressed following the successful treatment of lymphoma. CONCLUSION: Patients with lymphoma require careful monitoring for features of FS; lymphoma should also be added to the spectrum of disorders associated to FS. Prospective studies are needed to ascertain the implication of HTLV1 in the genesis of FS.

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Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system.

Tenofovir disoproxil fumarate (TDF) is a commonly used HIV antiretroviral. A relatively uncommon adverse effect of this drug is Fanconi syndrome. What is known about this toxicity, especially in regards to concomitant medication use and outcomes, is limited to isolated case reports and small case series. Therefore, a retrospective review of the FDA Adverse Event Reporting System from 2001 through 2006 was conducted to examine demographics, concomitant medication use, outcomes, and temporal trends in reporting of Fanconi syndrome associated with TDF use. In this large case series of 164 subjects who met the case definition for Fanconi syndrome, the majority (83%) of the subjects received protease inhibitors (PI) with TDF; specifically, 74% of the total received a ritonavir-boosted PI. Didanosine was the most commonly (43%) prescribed nucleoside reverse transcriptase inhibitor (NRTI). The combination of didanosine with boosted PI was frequently observed (34%), and in particular, didanosine plus lopinavir/ritonavir was documented for 22%. Nearly half (46%) of the total were hospitalized. Fracture (2%) and requirement for dialysis (2%) were infrequent while Fanconi syndrome contributed to death in 2% of these subjects. Patients receiving ritonavir-boosted protease inhibitors or didanosine with tenofovir should be closely monitored for development of nephrotoxicity. Although reporting biases and the exclusion of reports with serious confounding conditions likely affected the estimation of outcomes in this case series, severe complications of tenofovir-associated Fanconi syndrome were uncommon.

[Inventory of Fanconi syndrome in Basenji dogs in The Netherlands]. / Inventarisatie van het Fanconi-syndroom bij de Basenji hond in Nederland.

The Fanconi syndrome is a familial disease in the Basenji. Its typical clinical signs are glycosuria and euglycaemia. In the United States, 10% of the Basenji population shows signs of glycosuria. The purpose of this study was to investigate the presence of glycosuria in the Basenji population in The Netherlands. Results showed few dogs to have glycosuria. Furthermore, a hereditary background to Fanconi syndrome in Basenji dogs could not be demonstrated.

The Fanconi-Bickel syndrome: a case of neonatal onset.

A male newborn infant was recognized having Fanconi-Bickel syndrome (FBS) in the neonatal period. The presenting clinical findings were hyperglycemia and polyuria detected during an episode of acute enteritis. Physical examination was normal, biochemical analyses were suggestive of FBS: glycosuria, proteinuria, phosphaturia, generalized aminoaciduria, and increased levels of urinary beta 2-microglobulin, serum glucose and serum alkaline phosphatase. The molecular genetic analysis showed homozygosity for mutations within the gene of the glucose transporter 2 (Glut 2), 1213 C>T. The patient demonstrated improved clinical and metabolic status following institution of diet with frequent small meals and galactose-free-milk as well as pharmacological treatment with phosphate and vitamin alpha-OH-D3. In conclusion, infants showing hyperglycemia and polyuria may be considered having FBS also in the neonatal period. Early institution of adequate caloric intake and replacement of electrolytes and vitamin D may avoid or reduce metabolic complications.

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma.

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 microM (2.0 mg/dL; range, 79.56-327.08 microM [0.9-3.7 mg/dL]) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process.