Proximal Renal Tubular Dysfunction Research Articles

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome

BackgroundFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.MethodsClinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.ResultsHepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3−) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3− and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from − 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.ConclusionsEarly diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Effects of Prolonged Administration of Tenofovir Disoproxil Fumarate-Containing Antiviral Regimen on Renal Function in Low-Risk of Kidney Injury HIV Patients.

This study intended to investigate the impact of long-termtenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine β2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood β2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood β2 microglobulin was statistically significant at month 6 and months 12-30 (P<.05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine β2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P<.05). The abnormal concentration proportion of urine β2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood β2 microglobulin, urine β2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P>.05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine β2 microglobulin levels may be helpful in screening for renal dysfunction.

“A Complex Conundrum”- Fanconi-Bickel Syndrome

Fanconi-Bickel Syndrome (FBS) is a rare form of Glycogen Storage Disease (GSD) type 11 characterised by massive hepatomegaly due to the buildup of glycogen and severe hypophosphatemic rickets due to a proximal renal tubular dysfunction. Since 1940, it has been initially known as hepatorenal glycogenesis with proximal renal tubular dysfunction. It is due to a pathogenic mutation of the GLUT-2 (glucose transporter) gene. Herein, present case report a young toddler who is the firstborn of 3rd-degree consanguinity, presented with rickets, recurrent respiratory tract infections, and hepatomegaly, and was subsequently diagnosed with FBS with the help of genetic studies, showing a mutation in the GLUT-2 gene. With less than 200 cases reported so far, this child represents a unique case with recurrent respiratory infections and developmental delay as presentations along with rachitic features.

Proximal Renal Tubular Dysfunction Induces Severe Hypocalcemia in the Elderly.

Proximal Renal Tubular Dysfunction Induces Severe Hypocalcemia in the Elderly.

Tenofovir-induced hypophosphatemic osteomalacia: how do bone mineral density, trabecular bone score and proximal hip geometry change with treatment?

Tenofovir-induced osteomalacia secondary to proximal renal tubular dysfunction is not an uncommon complication known to occur. A 46-year-old woman was referred for the evaluation of osteoporosis which was diagnosed elsewhere. She had polyarthralgia, bony pains and proximal muscle weakness of 1 year duration. She was diagnosed to have HIV infection and was on antiretroviral therapy that consisted of tenofovir, lamivudine and efavirenz for the past 12 years. She had attained menopause 5 years back. On examination, she had bone tenderness, proximal myopathy and painful restriction of movement of her lower limbs. Investigations showed features of renal tubular acidosis, hypophosphatemia and raised alkaline phosphatase that were suggestive of osteomalacia. X-ray of the pelvis showed diffuse osteopenia and an MRI of the pelvis done showed multiple insufficiency fractures involving the head of femur on both sides. Following this, her tenofovir-based regimen was changed to abacavir, efavirenz and lamivudine with addition of neutral phosphate supplements and calcitriol. On follow-up after 6 months, she had significant improvement in her symptoms as well as in the bone mineral density at the lumbar spine (33.2%), femoral neck (27.6%), trabecular bone score (13.2%) and reduction in the buckling ratio at the narrow neck (6.3%), inter-trochanteric region (34%) and femoral shaft (28.8%). Tenofovir-induced osteomalacia is encountered in individuals on prolonged treatment with tenofovir. Treatment consists of changing to a non-tenofovir-based regimen, as well as supplementation of phosphate and calcitriol. Treatment results in remarkable improvement in symptoms and most densitometric indices. Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections. Tenofovir-related hypophosphatemic osteomalacia is related to proximal tubulopathy and is not an uncommon occurrence. Treatment mandates changing to a non-tenofovir-based regimen with supplementation of neutral phosphate and calcitriol. Treatment results in a significant improvement in bone mineral density, trabecular bone score and hip geometric parameters.

ODP336 Nephrogenic Diabetes Insipidus and Fanconi Syndrome Induced by Ifosfamide in a Patient with Femur Osteosarcoma. A Case Report

Abstract Background Fanconi syndrome and diabetes insipidus are rare adverse effects of ifosfamide. They usually present with high cumulative doses of this medication. They are mainly related to type II proximal renal tubular dysfunction. These complications typically present with severe polydipsia and polyuria accompanied by glycosuria, proteinuria, and some electrolyte abnormalities including hypokalemia, hypophosphataemia, and non-anion gap metabolic acidosis. Clinical case: A 15-year-old male with, a diagnosis of metastatic osteoblastic osteosarcoma in the right distal treated with ifosfamide three years prior to this hospitalization, was admitted to the emergency department complaining of 3 episodes of vomiting, 6 days history of increase volume of the right lower limb and fever. On admission, blood pressure of 80/50 mm Hg, heart rate of 110 beats / minute, respiratory rate of 30 breaths / minute, axillary temperature of 38.3 ° C. It was evident phlogosis at level of the proximal third of the right lower limb. CBC revealed pancytopenia (WBC 5 x10 9 L, Hb 6.8 g/dL, platelets 25×10 3 /mm 3) and ABG and CMP were compatible with mild metabolic acidosis normal AG (pH 7.285, K 1.9 meq / L, Na 156 meq / L, lactate: 0.9 meq / L, HCO3: 17 meq / L). A diagnosis of sepsis was made and the patient was started on meropenem 2g IV every 8 hours, vancomycin 1 g IV every 12 hours, filgastrim 120 ug/daily and one unit of packed RBC. Patient improved after 5 days over the course of his hospitalization. However, on the 18 th day after his hospital admission, he developed a new episode of polyuria, associated with hypocalcemia (7 mg/dL), hypokalemia (2 mEq/L), hypomagnesemia (0.95 mg/dL), hypophosphatemia (0.9 mg/dL) and metabolic acidosis (pH 7.2, bicarbonate 15 mEq/L). Urine analysis revealed glucosuria and proteinuria. Desmopressin test did not showed increase urinary osmolarity thus nephrogenic diabetes insipidus and Fanconi syndrome were diagnosed due to the multiple laboratory abnormalities and sign/symptoms. Patient received electrolyte replacement and ifosfamide was stopped from his chemotherapy regimen. After this, patient recovers and he was discharge at 25 th day of his admission. Conclusion : Ifosfamide causes tubular cell dysfunction leading to both nephrogenic diabetes insipidus and Fanconi syndrome. These complications might event present several years after receiving this chemotherapeutic agent. Full electrolyte repletion and hydration are the gold standard for management The present case report emphasizes the importance of the prevention of nephrotoxicity associated with ifosfamide, since its presentation could increase poor outcomes in patients receiving chemotherapy regimens that include ifosfamide. Presentation: No date and time listed

Proximal tubular dysfunction related to tenofovir in people living with HIV/AIDS: a pharmacogenetic study.

The purpose of this case-control study was to verify the association between single nucleotide polymorphisms (SNPs) in genes encoding drug transporters related to tenofovir disoproxil fumarate (TDF) and proximal renal tubular dysfunction (PRTD), and the association between PRTD and clinical characteristics. The 'cases' met the diagnostic criteria for PRTD, determined by the presence of two or more of the following abnormalities: non-diabetic glycosuria, metabolic acidosis, increased uric acid and phosphorus excretion, decreased tubular phosphorus reabsorption and β2-microglobulinuria. We analyzed eight SNPs in ABCC2, ABCC4, ABCC10 and SLC28A2 genes. Genotyping was performed using real-time PCR. Of the 204 people living with HIV, 38 (18.6%) met the criteria for diagnosis of PRTD and 131 were male (64.2%), with a mean age of 49 years and a history of previous antiretroviral therapy for an average of 5 years. In the multivariate analysis, older individuals, TDF use, protease inhibitor, antihypertensives and anticonvulsants were associated with a risk of developing PRTD. Increased excretion of β2microglobulin was associated with the A/G genotype of rsCC8187710 from ABCC2 ( P = 0.003) and the following genotypes of ABCC4 SNPs: A/G from rs1059751 ( P = 0.023), G/G from rs1059751 ( P = 0.030) and C/C of rs3742106 ( P = 0.041). The increase in the fraction of excreted phosphorus was associated with the C/T genotype of SNCC rsP40037 from ABCC2 ( P = 0.0041). The results indicate an important relationship between SNPs associated with these markers and changes in proximal renal tubule function, and thus support their use as biomarkers for the early detection of PRTD risk.

Abstract 19: A case of fragility fractures due to hypophosphatemic osteomalacia and adult Fanconi syndrome

Background: Fanconi syndrome is attributed with renal proximal tubular dysfunction leading to the wasting of phosphate, amino acids, glucose, and bicarbonate. This result in hypophosphatemic osteomalacia and fragility fractures.Case Presentation: A 38-year-old male presented with increasing bony pains, proximal muscle weakness and fragility fractures of long bones. On evaluation he was detected to have hypophosphatemia, hypokalaemia, metabolic acidosis with normal anion gap, renal phosphate wasting with low with TMP/GFR. His serum parathormone, 25 hydroxyvitamin D, 1, 25- dihydroxyvitamin D, fibroblast growth factor 23 (FGF-23) levels were normal. Serum Protein Electrophoresis was normal. X-Ray showed loozers zone and fractures. He was treated with oral supplements of calcium, bicarbonate, calcitriol and phosphate. After treatment patient's fractures were healed, he regained muscle strength and was able to ambulate with support.Conclusion: This case describes presentation of pathological fractures due to type 2 (proximal) renal tubular acidosis with Hypophosphatemic osteomalacia.

Exposure to Arsenic in the Air and 15-F2t-Isoprostane in Urine in a Sub-population of Inhabitants of a Copper Smelter Region

Most studies on arsenic toxicity have been conducted among populations exposed to arsenic contained in drinking water. Relatively little research concerns effects of airborne arsenic. The aim of this study was to determine whether there is an association between urinary 15-F2t-isoprostane (u15-F2t-IsoP) levels in relation to renal function (urinary creatinine and N-acetyl-β-d-glucosaminidase––uNAG) and urinary arsenic (uAs) in inhabitants from copper smelter impact zone. The secondary purpose of the analysis was to assess utility of a potential association between uAs and u15-F2t-IsoP as a biomarker of systemic oxidative stress. Urinary 15-F2t-IsoP, NAG, and creatinine were measured in 967 urine samples collected from 649 adult women (51.9 ± 13.2 years old) and 318 adult men (53.8 ± 14.9 years old). Total uAs concentration was measured in 918 samples using HPLC-ICP-MS. Arsenic species, such as inorganic arsenic, methylarsonic acid, dimethylarsinic acid, and arsenobetaine, were measured in urine collected from 255 participants with uAs exceeding the upper norm. Data were analyzed using multivariate linear regression and logistic regression models. In the studied population urinary creatinine was positively associated with uAs. A positive linear correlation (p < 0.0000) between lg(uAs) and u15-F2t-IsoP was found both for normal and elevated uAs. A positive linear correlation was observed also between lg(ΣuAs) and u15-F2t-IsoP (p < 0.0000). In the logistic regression model, after adjustment for confounders, elevated uAs was the only predictor of increased u15-F2t-IsoP (OR = 1.31, 95% CI 1.08–1.59, p < 0.01). Cigarette smoking was associated with renal proximal tubular dysfunction only in people with uNAG concentration above 75th quartile. In the studied population chronically exposed to airborne arsenic, increase in urinary arsenic is associated with renal dysfunction and systemic oxidative stress. Urinary 15-F2t-isoprostane may be useful in the monitoring of health status in populations exposed to airborne arsenic.

Hypophosphatemia is an independent risk factor for AKI among hospitalized patients with COVID-19 infection

Background This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. Methods In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. Results In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14–1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. Conclusion The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.

Tubular Injury Causing Protracted Glycosuria Following Withdrawal of a Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor: A Possible Role in the Development of Protracted Hypoglycemia and Ketoacidosis.

We herein present the case of a 45-year-old diabetic woman who developed diabetic ketoacidosis following the administration of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The patient had been diagnosed with diabetes three years previously and was being treated with multiple daily injections of insulin. Metformin hydrochloride and dapagliflozin were added seven months and 11 months later, respectively. Her clinical course was uneventful until the onset of influenza. She then discontinued insulin and oral medications voluntarily. On arrival at the hospital, she was found to be in a state of ketoacidosis, and promptly received insulin and saline infusion. In retrospect, the initial amount of glucose infused was insufficient, and the hypoglycemia was thought to have been prolonged. This phenomenon may also have affected her long-term urinary glucose excretion. Her urinary L-type fatty acid-binding protein (L-FABP) level was found to be markedly elevated (48.8 μg/g·Cr, reference value < 8.4 μg/g·Cr) as was her urinary β2-microglobulin level (9,230 μg/L, reference value < 230 μg/L). Patients with SGLT-2 inhibitor-associated diabetic ketoacidosis often exhibit protracted hyperglycosuria, in which acute proximal renal tubular dysfunction is considered to be etiologically implicated.

Renal proximal tubulopathy in an HIV-infected patient treated with tenofovir alafenamide and gentamicin: a case report

BackgroundThe nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances.Case presentationHere we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved.ConclusionThis is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.

Lowe syndrome – Old and new evidence of secondary mitochondrial dysfunction

The oculocerebrorenal syndrome of Lowe (LS) is a rare, progressive, multisystemic X-linked disorder caused by mutations in OCRL gene. Patients classically present with ocular abnormalities including bilateral congenital cataracts and glaucoma, intellectual delay, severe generalized hypotonia with absent tendon reflexes, and proximal renal tubular dysfunction. Congenital bilateral cataracts and hypotonia are present at birth in almost all patients, while other classical symptoms develop gradually with variable severity. Consequently, differential diagnosis in infant period in these patients can be broad including other rare metabolic and neurologic disorders.Herein we present a 4.5 year old boy with Lowe syndrome caused by mutation of OCRL gene, NM_000276.4:c.643C > T; p.(Gln215*), initially diagnosed as having mitochondriopathy due to alteration of mitochondria on electron microscopic examination in different tissues and decreased values of mitochondrial energy metabolism measurements in muscle. No pathogenic mutations in mitochondrial DNA were found on whole exome sequencing.This patient recall historical hypothesis of secondary mitochondrial dysfunction in Lowe syndrome, that may be caused/intensified by some of disease symptoms.

Proximal renal tubular function in HIV-infected children on tenofovir disoproxil fumarate for treatment of HIV infection at two tertiary hospitals in Harare, Zimbabwe.

Renal abnormalities in HIV infected children may be due to the HIV infection or treatment among other factors. Tenofovir disoproxil fumarate (TDF) is associated with proximal renal tubular dysfunction, proteinuria and decrease in glomerular function. Studies in developed countries have shown variable prevalence of proximal renal tubular dysfunction in children on TDF. There are no known studies in developing countries, including Zimbabwe, documenting the proximal tubular function in HIV infected children on TDF. The aim of this study was to assess renal and proximal renal tubular function in HIV infected children receiving TDF and determine factors associated with proximal tubular dysfunction. A descriptive cross-sectional study was conducted in HIV infected patients below 18 years of age attending outpatient clinics at two tertiary hospitals in Harare, who received a TDF-containing antiretroviral regimen for at least six months. Dipstick protein and glucose, serum and urine phosphate and creatinine levels were measured. Fractional excretion of phosphate was calculated. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula. Tubular dysfunction was defined by at least two of the following characteristics: normoglycaemic glycosuria, hypophosphatemia and fractional excretion of phosphate > 18%. One hundred and ninety-eight children below 18 years of age were recruited over a period of six months. The prevalence of tubular dysfunction was 0.5%. Normoglycaemic glycosuria occurred in 1 (0.5%), fractional excretion of phosphate >18% in 4 (2%), and hypophosphatemia in 22 [11.1%] patients. Severe stunting was associated with increased risk of hypophosphatemia (OR 9.31 CI (1.18, 80.68) p = 0.03). Reduction in estimated glomerular filtration rate (eGFR) < 90ml/min/1.73m2 and proteinuria was evident in 35.9% and 32.8% of children, respectively. Concurrent TDF and HIV-1 protease inhibitor-based regimen was the only independent factor associated with reduction in GFR (OR 4.43 CI (1.32; 4.89) p = 0.016). Tubular dysfunction was uncommon in Zimbabwean children on a TDF-based ART regimen. Hypophosphatemia, proteinuria and reduction in eGFR were common. Reassessing renal function using more sensitive biomarkers is needed to examine the long-term tolerance of TDF.

Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: identification of candidate genes for the neurodevelopmental and eye manifestations

BackgroundLowe syndrome (LS) is caused by loss-of-function mutations in the X-linked gene OCRL, which codes for an inositol polyphosphate 5-phosphatase that plays a key role in endosome recycling, clathrin-coated pit formation, and actin polymerization. It is characterized by congenital cataracts, intellectual and developmental disability, and renal proximal tubular dysfunction. Patients are also at high risk for developing glaucoma and seizures. We recently developed induced pluripotent stem cell (iPSC) lines from three patients with LS who have hypomorphic variants affecting the 3′ end of the gene, and their neurotypical brothers to serve as controls.MethodsIn this study, we used RNA sequencing (RNA-seq) to obtain transcriptome profiles in LS and control neural progenitor cells (NPCs).ResultsIn a comparison of the patient and control NPCs (n = 3), we found 16 differentially expressed genes (DEGs) at the multiple test adjusted p value (padj) < 0.1, with nine at padj < 0.05. Using nominal p value < 0.05, 319 DEGs were detected. The relatively small number of DEGs could be due to the fact that OCRL is not a transcription factor per se, although it could have secondary effects on gene expression through several different mechanisms. Although the number of DEGs passing multiple test correction was small, those that were found are quite consistent with some of the known molecular effects of OCRL protein, and the clinical manifestations of LS. Furthermore, using gene set enrichment analysis (GSEA), we found that genes increased expression in the patient NPCs showed enrichments of several gene ontology (GO) terms (false discovery rate < 0.25): telencephalon development, pallium development, NPC proliferation, and cortex development, which are consistent with a condition characterized by intellectual disabilities and psychiatric manifestations. In addition, a significant enrichment among the nominal DEGs for genes implicated in autism spectrum disorder (ASD) was found (e.g., AFF2, DNER, DPP6, DPP10, RELN, CACNA1C), as well as several that are strong candidate genes for the development of eye problems found in LS, including glaucoma. The most notable example is EFEMP1, a well-known candidate gene for glaucoma and other eye pathologies.ConclusionOverall, the RNA-seq findings present several candidate genes that could help explain the underlying basis for the neurodevelopmental and eye problems seen in boys with LS.

Neutropenia associated with proximal renal tubular dysfunction and mild bilateral cataract

We report an 11-year-old girl admitted to nephrology section due to growth failure, neutropenia, renal glycosuria, and proteinuria and also hypophosphatemic rickets. She had a history of repeated hospitalization because of respiratory or gastrointestinal infections. Bone marrow aspiration revealed hyper-cellular bone marrow with mild dysplastic pattern. Eyes examination showed mild bilateral posterior cataract. X-ray of the wrist demonstrated a bone age of 3.5 ±6 months with evidence of rickets. We could not find a syndrome that can explain these associations.

Nocturnal enteral nutrition is therapeutic for growth failure in Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterised by impaired glucose liver homeostasis and proximal renal tubular dysfunction. It is caused by pathogenic variants in SLC2A2 coding for the glucose transporter GLUT2. Main clinical features include hepatomegaly, fasting hypoglycaemia, postprandial hyperglycaemia, Fanconi-type tubulopathy occasionally with rickets, and a severe growth disorder. While treatment for renal tubular dysfunction is well established, data regarding optimal nutritional therapy are scarce. Similarly, detailed clinical evaluation of treated FBS patients is lacking. These unmet needs were an incentive to conduct the present pilot study. We present clinical findings, laboratory parameters and molecular genetic data on 11 FBS patients with emphasis on clinical outcome under various nutritional interventions. At diagnosis, the patients' phenotypic severity could be classified into two categories: a first group with severe growth failure and rickets, and a second group with milder signs and symptoms. Three patients were diagnosed early and treated because of family history. All patients exhibited massive glucosuria at diagnosis and some in both groups had fasting hypoglycaemic episodes. Growth retardation improved drastically in all five patients treated by intensive nutritional intervention (nocturnal enteral nutrition) and uncooked cornstarch with final growth parameters in the normal range. The four severely affected patients who were treated with uncooked cornstarch alone did not catch up growth. All patients received electrolytes and l-carnitine supplementation to compensate for the tubulopathy. This is one of the largest series of FBS on therapeutic management with evidence that nocturnal enteral nutrition rescues growth failure.

Tenofovir nephrotoxicity among Asians living with HIV: review of the literature.

Tenofovir disoproxil fumarate (TDF), prodrug of tenofovir (TFV), is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection in resource-rich and resource-limited settings with proven efficacy and safety, and also for the treatment of hepatitis B infections. However, TDF can cause renal proximal tubular dysfunction and also reduces estimated glomerular filtration rate (eGFR) more than other NRTIs. To date, TDF-associated renal dysfunction is generally regarded as mild and tolerable. However, it is notable that low body weight is one of the risk factors for TFV nephrotoxicity and that Asians are generally of smaller body stature and can be susceptible to such nephrotoxicity, as shown in several cohort studies. Until tenofovir alafenamide (TAF), another prodrug of TFV with minimal renal toxicity, becomes widely accessible for people living with HIV and replaces TDF, it is warranted that physicians who prescribe TDF have a good understanding of TFV nephrotoxicity. This paper reviews recent literature on TFV nephrotoxicity among people living with HIV especially focusing on Asians who might be susceptible to TFV nephrotoxicity due to their lower body weight and discusses implications for clinical care and future directions.

Treatment of Human Immunodeficiency Virus Infection With Tenofovir Disoproxil Fumarate-Containing Antiretrovirals Maintains Low Bone Formation Rate, But Increases Osteoid Volume on Bone Histomorphometry.

Bone mineral density (BMD) loss is a known complication of human immunodeficiency virus (HIV) infection and its treatment, particularly with tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens. Although renal proximal tubular dysfunction and phosphaturia is common with TDF, it is unknown whether BMD loss results from inadequate mineralization. We evaluated change in BMD by dual-energy X-ray absorptiometry (DXA) and bone histomorphometry by tetracycline double-labeled transiliac crest biopsies in young men living with HIV before (n = 20) and 12 months after (n = 16) initiating TDF/lamivudine/efavirenz. We examined relationships between calciotropic hormones, urinary phosphate excretion, pro-inflammatory and pro-resorptive cytokines, and bone remodeling-related proteins with changes in BMD and histomorphometry. Mean age was 29.6 ± 5.5 years, with mean CD4 + T cell count of 473 ± 196 cells/mm3 . At baseline, decreased bone formation rate and increased mineralization lag time were identified in 16 (80%) and 12 (60%) patients, respectively. After 12 months, we detected a 2% to 3% decrease in lumbar spine and hip BMD by DXA. By histomorphometry, we observed no change in bone volume/total volume (BV/TV) and trabecular parameters, but rather, increases in cortical thickness, osteoid volume, and osteoblast and osteoclast surfaces. We did not observe significant worsening of renal phosphate excretion or mineralization parameters. Increases in PTH correlated with decreased BMD but not histomorphometric parameters. Overall, these data suggest abnormalities in bone formation and mineralization occur with HIV infection and are evident at early stages. With TDF-containing antiretroviral therapy (ART), there is an increase in bone remodeling, reflected by increased osteoblast and osteoclast surfaces, but a persistence in mineralization defect, resulting in increased osteoid volume. © 2019 American Society for Bone and Mineral Research.

The clinical and pathological features of adefovir dipivoxil-related renal impairment .

To investigate the clinicopathological features and outcomes of adefovir dipivoxil (ADV)-related renal impairment in Chinese patients. Clinical, pathological, and follow-up data from 15 patients with ADV-related renal impairment were studied. Proximal renal tubular dysfunction (PRTD) was defined by the presence of at least two of the following four abnormalities: hypophosphatemia, hypouricemia, nondiabetic glucosuria, and proteinuria. All patients were treated for 3 - 15 (mean 6.7) years with daily ADV of 10 mg. Renal impairment manifested as PRTD (12, 80%), elevated serum creatinine (12, 80%), and hematuria (2, 13.3%). Mild to moderate tubulointerstitial injury primarily affecting the proximal tubules by light microscopy, and enlarged, dysmorphic mitochondria with loss and disorientation of cristae by electron microscope were identified in all of our cases. Four patients had pathological evidence of IgA nephropathy. The phosphorus, serum uric acid, and creatinine levels were normalized after ADV cessation in 66.7% (8/12) of affected patients, 27.3% (3/11) of affected patients, and 25% (3/12) of affected patients, respectively; proteinuria was eliminated in 7 of 13 affected patients (53.8%); and glucosuria and hematuria both disappeared in all affected patients. These abnormalities had hardly any recovery, and even aggravated with new-onset glucosuria, new-onset hematuria in 3 patients who replaced ADV with tenofovir. Nephrotoxicity developed in patients undergoing long-term ADV treatment and was partially reversible after drug cessation. Tubulointerstitial lesions and heteromorphic mitochondria were the predominant pathological changes. Patients with ADV-induced renal impairment should replace ADV with other antiviral agents other than tenofovir. .