Proximal Renal Tubular Dysfunction Research Articles

Abstract 72: Redox-sensitive Transcriptional Regulation of Renal Dopamine D1 Receptor Function during Hypertension

Oxidative stress plays an important role in the development of hypertension. We and others have shown that renal dopamine D1 receptor (D1R), a major contributor to sodium homeostasis and BP regulation, is negatively regulated by oxidative stress. It is reported that antioxidants can reduce BP and redox-sensitive transcription factor Nrf2 could provide important clues for antihypertensive properties of antioxidants. Here in we investigated the signaling molecules responsible for redox-sensitive renal proximal tubular D1R dysfunction and how the induction of renal specific Nrf2, in response to antioxidants, will protect D1R function and reduce BP. Wild type (WT) and renal proximal tubular specific Nrf2 knockout (KO) mice were treated with 10 mM L-buthionine-sulfoximine (BSO, a pro-oxidant) without and with sulforaphane (S, a polyphenol antioxidant; 5 μM daily by gavage) for 5 wks. In WT mice, BSO treatment increased oxidative stress and BP (mm Hg, WT: 104 ± 3, WT-BSO: 125 ± 5), reduced renal tubular D1R expression and attenuated SKF38393 (a D1R agonist)-induced Na/K-ATPase inhibition and sodium excretion. BSO also activated transcription factors activator protein (AP) 1 and SP3. However, the onset and severity of hypertension (BP, Nrf2-KO: 101 ± 3, Nrf2-KO-BSO: 137 ± 4) as well as oxidative stress, activation of AP1 and SP3 and D1R dysfunction were more robust in BSO-treated Nrf2 KO compared to WT mice. More importantly, sulforaphane activated Nrf2, reduced oxidative stress, normalized AP1 and SP3 activation, rescued DIR function and lowered BP (WT-S: 97 ± 4, WT-BSO+S: 109 ± 6) in BSO-treated WT mice but failed to normalize renal D1R function or reduce BP (Nrf2-KO-S: 99 ± 3, Nrf2-KO-BSO+S: 131 ± 4) in Nrf2 KO mice. Further experiments in human proximal tubular cultures revealed that BSO via AP1 activated SP3 which in turn transcriptionally down-regulated D1R expression and sulforaphane, via Nrf2 activation, abolished BSO-induced AP1 and SP3 activation and protected D1R function. In conclusion, oxidative stress via AP1-SP3 pathway down-regulates D1R expression and function which leads to sodium retention and hypertension. Antioxidants, via Nrf2 activation, reduce oxidative stress and normalize AP1-SP3 signaling and D1R function which reduces BP.

Low-dose adefovir-induced hypophosphatemic osteomalacia on whole-body bone scintigraphy.

While adefovir dipivoxil (ADV) effectively suppresses the hepatitis B virus, it can cause proximal renal tubular dysfunction leading to phosphate wasting [1, 2]. The safety of low-dose ADV (a dose of 10 mg/day), which does not induce clinically significant nephrotoxicity, is well recognized, but a few cases of hypophosphatemic osteomalacia (HO) caused by low-dose ADV therapy have recently been reported [3–6]. Although HO induced by low-dose ADV therapy is rare, the presence of bone pain in patients treated with ADV should be monitored. Bone scintigraphy can be performed to confirm the occurrence of osteomalacia and to determine the disease extent. Bone scintigraphic and radiological image findings with a brief review of the literature are presented in this article. We report two cases of HO induced by low-dose ADV therapy that showed multifocal increased radiotracer uptakes in the bilateral bony ribs, spines, pelvic bones and lower extremities on whole-body bone scintigraphy (Figs. 1 and ​and2).2). Bone pain gradually improved after phosphate supplementation and by changing the antiviral agent. Fig. 1 A 44-year-old man presented with a 6-month history of diffuse musculoskeletal pain in the chest, back and both knees without antecedent trauma. The patient had a history of chronic hepatitis B infection and had received adefovir dipivoxil (ADV) (10 mg/day) ... Fig. 2 A 42-year-old man who had taken adefovir dipivoxil (ADV) (10 mg/day) for 7 years for treatment of chronic hepatitis B complained of a 2-year history of diffuse musculoskeletal pain in the anterior chest area with absence of antecedent ... Whole-body bone scintigraphy is a highly sensitive imaging tool and can show disease extent at once in the setting of the wide range of the clinical spectrum with nonspecific radiological findings [5]. Furthermore, frequent involvement of the lower extremities, as a result of maximum weight bearing, could be an additional scintigraphic clue for the diagnosis of HO [6, 7]. These cases could be helpful for both clinicians prescribing ADV and nuclear physicians to prevent delayed diagnosis and plan further appropriate treatment.

Acquired Proximal Renal Tubular Dysfunction in 9 Labrador Retrievers with Copper‐Associated Hepatitis (2006–2012)

Copper-associated hepatitis (CAH) has been well described in Labrador Retrievers. However, the association of CAH with proximal renal tubular dysfunction in this breed has not been characterized. To report clinical features, hepatic and renal histopathologic findings, tissue copper concentrations, and outcome of Labradors with CAH and proximal renal tubular disease. Nine Labrador Retrievers with renal glucosuria and biopsy-confirmed CAH. Clinical, clinicopathologic, and light microscopic findings were retrospectively reviewed. Rhodanine staining or atomic emission spectroscopy was performed on all hepatic samples and available renal tissue (4 dogs) to assess copper concentrations. Eight dogs had a history of polyuria and polydipsia, and all dogs had increased serum bilirubin concentrations. Five dogs had hyperchloremic metabolic acidosis. Three dogs with acidemia had paradoxical alkalinuria. All renal specimens had increased copper concentrations. Renal tubular vacuolization, degeneration, and regeneration were observed on light microscopy. Four dogs died within 10 days of diagnosis. One dog survived 2 months; 4 dogs survived more than 1 year. In long-term survivors, including 2 that did not undergo immediate copper chelation, resolution of renal tubular dysfunction occurred within weeks to months. Labrador Retrievers with CAH can develop clinical and laboratory evidence of renal tubular dysfunction in association with increased renal copper concentrations. Given the rarity of renal tubular disorders, detection of renal glucosuria and increased ALT activity in a Labrador Retriever is suggestive of CAH. Although renal tubular dysfunction may indicate advanced disease, successful long-term outcome is possible with a variety of therapies.

Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18‐2 mutations

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare primary immune disorder defined by mutations in the syntaxin binding protein 2 (STXBP2) alias MUNC18-2. Despite defective immunity and a hyper-inflammatory state, clinical findings such as neurological, gastrointestinal, and bleeding disorders are present in a significant number of patients and suggest an impaired expression and function of STXBP2 in cells other than cytotoxic lymphocytes. We investigated four patients with FHL5 suffering from severe enteropathy and one of whom also had renal tubular dysfunction despite successful hematopoietic stem cell transplantation (HSCT). Gastrointestinal and renal biopsy specimens were analyzed by immunohistochemistry and electron microscopy. Histopathology revealed an intracytoplasmatic accumulation of PAS-positive granules and an enlarged intracytoplasmatic CD10-positive band along the apical pole of enterocytes. Electron microscopy revealed short microvilli and granules filled with electro lucent material. In addition, we described mildly dilated renal tubules and electron micrographs displayed a higher number of cytoplasmic inclusions, electrodense lysosomal and electrolucent endosomal vesicles. Mutations in STXBP2 do not only affect cytotoxic T lymphocytes but also cause changes in the intestinal and renal epithelium resulting in severe, osmotic diarrhea and renal proximal tubular dysfunction. These defects persist after successful treatment of hemophagocytic lymphohistocytosis by HSCT. Clinical manifestations in FHL5 patients despite successful HSCT may therefore be related to defective membrane trafficking in the gut and kidney.

Incidence of renal toxicity in HIV-infected, antiretroviral-naïve patients starting tenofovir/emtricitabine associated with efavirenz, atazanavir/ritonavir, or lopinavir/ritonavir

We performed a retrospective cohort study of HIV-infected antiretroviral-naïve patients starting a first antiretroviral therapy with tenofovir/emtricitabine plus efavirenz (EFV), atazanavir/ritonavir (ATV/r), or lopinavir/ritonavir (LPV/r). The incidence of renal impairment or proximal tubular dysfunction was evaluated during a 12-month follow-up. Renal impairment was diagnosed by a reduced estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) formula, and tubular dysfunction was diagnosed when ≥ 2 among proteinuria, glucosuria, hypouricaemia, hypophosphataemia, and hypokalaemia, were identified. A total of 235 patients were enrolled: 82 taking EFV, 78 ATV/r, and 75 LPV/r. The mean decline in eGFR after the 12-month follow-up was significantly greater in subjects treated with ATV/r (-10.4 ml/min/1.73 m(2)) than in those receiving EFV (- 5.1; p = 0.002) or LPV/r (-4.8; p = 0.003). Similarly, a significantly higher incidence of proximal tubulopathy was observed among ATV/r-treated patients (14.1%) compared with patients receiving EFV (4.9%) or LPV/r (5.3%). In our retrospective study, naïve patients receiving tenofovir/emtricitabine and ATV/r for 12 months showed a significantly higher decline in eGFR and a significantly higher incidence of proximal tubulopathy than those receiving tenofovir/emtricitabine plus EFV or LPV/r, even though clinically evident renal toxicity associated with tenofovir-based treatment is a very uncommon event.

Clinical and pathological spectrums of aristolochic acid nephropathy

To study the clinical and pathological characteristics of aristolochic acid nephropathy (AAN). 86 patients with AAN during 2001 and 2009 in our department were recruited in this retrospective study. The clinical and pathological features were analyzed. There were 47 males and 39 females, aging from 12 to 69 years old. Abnormal urine analysis and gastro-intestinal diseases were two main underlying causes for patients taking aristolochic acid (AA) containing drugs. All patients suffered from renal function impairment. 19 patients (22.0%) presented with acute kidney injury (AKI), while 67 patients (78%) presented as chronic cases. Among them, 31 patients (36.0%) lacked symptoms, 30 patients (34.8%) were accompanied with hypertension, and 26 patients (30.2%) presented with gastrointestinal symptoms. Laboratory examination revealed elevated urine retinol-binding protein (RBP) (90.7%) and urine N-acetyl-β-glucosaminidase (NAG) (80.2%). Anemia and glucosuria accounted for 64.0% and 58.1%, respectively. Renal biopsy showed prominent tubular brush border ablation (84.2%) in acute cases, while obvious tubular basement membrane (TBM) thickening (81.4%) and interstitial fibrosis were present in chronic cases. During the follow- up, 11 (57.9%) acute cases gained renal function recovery. They had lower urine RBP level and lower incidence of hypokalemia than the non-recovery acute cases. In the chronic group, 27 patients (40.2%) progressed to endstage renal disease (ESRD), with 11 dialysis and 5 renal transplantation cases. AAN patients usually suffered from renal impairment with an associated history of taking AA containing drugs. Proximal renal tubular dysfunction and structure destroying would be the main positive findings in laboratory tests and renal biopsy. Urine RBP and hypokalemia might determine the outcome of acute AAN patients.

Renal tubular dysfunction during long‐term adefovir or tenofovir therapy in chronic hepatitis B

Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD). To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B. A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria. Among 51 patients treated for 1-10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0-3.0 mg/dL), creatinine (1.6-1.1 mg/dL), uric acid (2.7-3.8 mg/dL) and proteinuria. Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2-9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy.

Importance of assessment of microalbuminuria in β-thalassemia major patients

Introduction: β-thalassemia major is one of the most common hereditary hematologic disorders characterized by severely impaired β-globulin synthesis. Renal proximal tubular dysfunction may occur in children with β-thalassemia major without clinical manifestations of renal dysfunction or decrease in GFR. However, there is paucity of information about renal involvement in this disease and its early detection in patients with β-thalassemia major is rare. Aims and Objectives: The aim of the present study was to determine the levels of urinary microalbumin along with serum levels of urea, creatinine, uric acid, calcium and inorganic phosphate and to correlate the levels of urinary microalbumin with the above parameters in β-thalassemia major patients. Results: Serum urea, uric acid and phosphate increased ( P P P Conclusion: Our study emphasizes the need to include microalbuminuria levels into the routine follow up of these patients. Thereby, impedance of disease progress will improve the patients' quality of life.

Fanconi's Syndrome and Nephrogenic Diabetes Insipidus in an Adult Treated with Ifosfamide

Fanconi's syndrome is a serious condition characterized by type II proximal renal tubular dysfunction, with urinary loss of glucose, amino acids, phosphate, bicarbonate, and potassium. Ifosfamide-induced Fanconi's syndrome is reported in about 1.4-5% of children being treated for solid tumors, yet only a few cases have been reported in adults. We describe a 54-year-old man who came to the hospital with symptoms of neutropenic fever 4days after his fourth cycle of ifosfamide and doxorubicin treatment for recurrent sarcoma with metastases to the lung. During admission, he was noted to have severe renal tubular dysfunction; ifosfamide-induced nephrogenic diabetes insipidus and Fanconi's syndrome were suspected. He received supportive therapy that resulted in incomplete resolution of signs and symptoms. The patient was discharged after a 5-day hospital stay when his white blood cell count increased from 0.1-2.5×10(3) /mm(3) and his fever had resolved. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of diabetes insipidus and Fanconi's syndrome and his use of ifosfamide. This dual diagnosis of diabetes insipidus and Fanconi's syndrome in an adult makes this case unusual, as well as therapeutically challenging. We conducted a review of the existing literature regarding ifosfamide-induced Fanconi's syndrome and describe the proposed mechanisms and therapeutic options. This case suggests that patients treated with ifosfamide should be monitored closely for renal function to identify, and perhaps prevent, these rare adverse events. Preliminary animal models show promise for adding N-acetylcysteine to ifosfamide treatment, but more research is necessary before using this drug as a therapeutic option.

Fanconi-Bickel syndrome as an example of marked allelic heterogeneity

Renal tubular acidosis (RTA) encompasses many renal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap. Untreated patients usually complain of growth failure, osteoporosis, rickets, nephrolithiasis and eventually renal insufficiency. Fanconi-Bickel syndrome (FBS) is an example of proximal RTA due to a single gene disorder; it is caused by defects in the facilitative glucose transporter 2 gene that codes for the glucose transporter protein 2 expressed in hepatocytes, pancreatic β-cells, enterocytes and renal tubular cells. It is a rare inherited disorder of carbohydrate metabolism manifested by huge hepatomegaly [hence it is classified as glycogen storage disease (GSD) type XI; GSD XI], severe hypophosphatemic rickets and failure to thrive due to proximal renal tubular dysfunction leading to glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hypophosphatemia. The disorder has been reported from all parts of Europe, Turkey, Israel, Arabian countries, Japan and North America. Many mutant alleles have been described, its exact frequency is unknown and there is no single mutation found more frequently than the others. The presence of consanguinity in affected families suggests an autosomal recessive pattern of inheritance. New cases of FBS have been recently reported in the Middle and Far East in collaboration with specialized centers. Two novel mutations have been discovered in two unrelated Egyptian families. The first was two bases deletion, guanine and adenine, (c.253_254delGA) causing a frameshift mutation (p. Glu85fs) and the second is mutation in exon6 in splicing acceptor site with intron5 (c.776-1G>C or IVS5-1G>A). Moreover, a new different mutation was described in a 3 year old Indian boy.

Fanconi- Bickel Syndrome: Mutation in An Indian Patient

Fanconi -Bickel Syndrome (FBS) is described as an autosomal recessive Glycogen Storage Disorder type XI. The underlying enzyme defect is unknown. The gene GLUT2 maps to 3q26.1-q26.3; encodes a facultative glucose transporter gene. A 6-y-old girl presented with the characteristic facial gestalt, glucose and galactose intolerance, proximal renal tubular dysfunction, hepatomegaly, and altered liver function. To confirm the diagnosis, mutation analysis was performed. Patient showed homozygous mutation in exon 9 of GLUT2 gene 1093 C>T, the mutation causing transition from arginine to stop codon at position 365 and causing premature termination of protein. The mutation was found to be causative as previously described. To the best of authors' knowledge this is first Indian patient ever reported with a mutation. Genetic testing can be employed as a method of confirming diagnosis, especially where definitive mutation can be useful for prenatal diagnosis and prognostication.

OCRL controls trafficking through early endosomes via PtdIns4,5P2-dependent regulation of endosomal actin

Mutations in the phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P(2)) 5-phosphatase OCRL cause Lowe syndrome, which is characterised by congenital cataracts, central hypotonia, and renal proximal tubular dysfunction. Previous studies have shown that OCRL interacts with components of the endosomal machinery; however, its role in endocytosis, and thus the pathogenic mechanisms of Lowe syndrome, have remained elusive. Here, we show that via its 5-phosphatase activity, OCRL controls early endosome (EE) function. OCRL depletion impairs the recycling of multiple classes of receptors, including megalin (which mediates protein reabsorption in the kidney) that are retained in engorged EEs. These trafficking defects are caused by ectopic accumulation of PtdIns4,5P(2) in EEs, which in turn induces an N-WASP-dependent increase in endosomal F-actin. Our data provide a molecular explanation for renal proximal tubular dysfunction in Lowe syndrome and highlight that tight control of PtdIns4,5P(2) and F-actin at the EEs is essential for exporting cargoes that transit this compartment.

Fanconi–Bickel syndrome in a 3-year-old Indian boy with a novel mutation in the GLUT2 gene

Fanconi-Bickel syndrome is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction and impaired utilization of glucose and galactose. Most cases have been reported from Europe, Japan, Turkey and the Mediterranean belt. We report a 3-year-old boy from southern India who presented with doll-like facies, florid rickets, massive hepatomegaly, growth retardation, renomegaly and laboratory evidence of proximal renal tubular dysfunction. Liver biopsy demonstrated evidence of glycogenosis. Direct sequencing of genomic DNA confirmed a diagnosis of Fanconi-Bickel syndrome, revealing a G-to-A substitution at position -1 of the splicing acceptor site in intron 1 of the GLUT2 gene in a homozygous pattern (c.16-1G>A or IVS1-1G>A). This novel mutation has not been described in earlier studies. The child was treated with oral potassium citrate, oral phosphorus supplementation, and alpha-calcitriol, on which metabolic derangements were corrected.

A case of hypophosphatemic osteomalacia secondary to deferasirox therapy

Patients with β-thalassemia major require iron-chelation therapy to avoid the complication of iron overload. Until recently, deferoxamine (DFO) was the major iron chelator used in patients requiring chronic hypertransfusion therapy, but DFO required continuous subcutaneous therapy. The availability of deferasirox (Exjade®), an orally active iron chelator, over the past 4 years represented a necessary alternative for patients requiring chelation therapy. However, there have been increasing reports of proximal renal tubular dysfunction and Fanconi syndrome associated with deferasirox in the literature. We report a case of hypophosphataemic osteomalacia secondary to deferasirox therapy.

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.

Aminoglycoside-induced nephrotoxicity studied by proton magnetic resonance spectroscopy of urine

Acute kidney injury is a relatively common complication of aminoglycoside therapy that affects 10-20% of patients receiving antibiotics of this class. Although the vast majority of patients do recover, the presence of certain risk factors may alter the clinical presentation and result in permanent renal damage. Thus, aminoglycoside-induced nephrotoxicity is a major concern and early diagnosis is critical. The aim of the present study was to characterize the early stages of aminoglycoside-induced nephrotoxicity using proton nuclear magnetic resonance ((1)H NMR) spectroscopy of urine. We studied 19 previously healthy patients who were hospitalized in our clinic due to bacterial infections. Combined antibiotic treatment with amikacin (1 g once daily) and a beta-lactam antibiotic was instituted in all patients. Urine and blood samples were collected before and after 5 days of aminoglycoside treatment. (1)H NMR spectroscopic data showed increased amounts of alanine and lactic acid (+138 and +255% compared to baseline values, respectively) and decreased hippurate (-50%) after aminoglycoside treatment. In addition, fractional excretions of sodium, magnesium and calcium were significantly increased (+271, +295 and +60%, respectively). These findings indicate that aminoglycosides can affect nephron tubules through two unrelated mechanisms that produce a partial 'Fanconi-like syndrome' and a 'Bartter-like syndrome'. However, because none of the study participants developed renal failure, these alterations are probably reversible and should not be used as sensitive or specific indicators of impending renal insufficiency. Our study findings confirm that aminoglycosides can induce both proximal and distal renal tubular dysfunction. However, it remains unclear whether the early functional changes detected by (1)H NMR spectroscopy in patients treated with aminoglycosides are of prognostic value.

Early detection of renal damage caused by fumaric acid ester therapy by determination of urinary β2-microglobulin

Fumaric acid esters are considered efficacious and safe drugs for the treatment of psoriasis. Renal damage, caused either by acute renal injury or Fanconi syndrome, is a recognized side-effect of this therapy. To investigate whether the measurement of urinary excretion of β2-microglobulin, a marker of renal proximal tubular dysfunction, allows early detection of kidney damage before an increase in serum creatinine or significant proteinuria occurs. Urinary β2-microglobulin excretion was measured regularly in 23 patients undergoing fumaric acid ester therapy. Urinary β2-microglobulin remained normal in all 10 male patients. Three (23%) out of 13 female patients experienced an increase in urinary β2-microglobulin excretion. In two of these patients a sharp increase was observed in association with high doses. One further patient had moderately elevated levels on rather low doses of fumaric acid esters. After discontinuing treatment, urinary β2-microglobulin levels returned to normal within a few weeks. Determination of urinary β2-microglobulin possibly allows early detection of renal damage by fumaric acid esters. Female patients seem to be prone to this side-effect, especially when taking high doses.

Clinical monitoring and correlates of nephropathy in SIV-infected macaques during high-dose antiretroviral therapy

BackgroundIn many preclinical AIDS research studies, antiretroviral therapy (ART) is administered to experimentally simian immunodeficiency (SIV)-infected rhesus macaques for reduction of viral load to undetectable levels. Prolonged treatment of macaques with a high dose of PMPA (9-[2-(r)-(phosphonomethoxy) propyl] adenine or tenofovir; 30 mg/kg of body weight subcutaneously once daily) can result in proximal renal tubular dysfunction, a Fanconi-like syndrome characterized by glucosuria, aminoaciduria, hypophosphatemia, and bone pathology. In contrast, chronic administration of a low dose of PMPA (10 mg/kg subcutaneously once daily) starting at birth does not seem to be associated with any adverse health effects within 3 years of treatment. In contrast to PMPA, limited information on systemic toxicity in rhesus monkeys is available for FTC (5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; emtricitabine) and stavudine (d4T).ResultsIn this study, the clinical and biochemical correlates of tubular nephrosis in SIV-infected rhesus macaques associated with systemic administration of high-dose ART consisting of the three nucleoside analog inhibitors PMPA, FTC, and d4T were investigated. It was found that acute renal failure was uncommon (7.1% of treated animals) and that morphologic evidence of nephropathy, which persisted for more than 300 days following discontinuation of the drug cocktail, was more frequent (52.4% of treated animals). While parameters from single time points lacked predictive value, biochemical alterations in Blood Urea Nitrogen (BUN) and phosphorus were frequently identified longitudinally in the blood of ART-treated animals that developed evidence of nephropathy, and these longitudinal changes correlated with disease severity.ConclusionsRecommendations are proposed to limit the impact of drug-induced renal disease in future SIV macaque studies.

Two cases of Fanconi-Bickel syndrome: first report from China with novel mutations of SLC2A2 gene

Fanconi-Bickel syndrome (FBS) is a rare inherited disease caused by mutations in the glucose transporter 2 gene, SLC2A2. We reported the first two Chinese cases of FBS. Both cases presented typical clinical features of hepatomegaly, hypophosphatemic rickets, severely stunted growth, fasting hypoglycemia along with postprandial hyperglycemia, and proximal renal tubular dysfunction with disproportionately severe glucosuria. Genetic analysis of SLC2A2 gene revealed novel compound heterozygous mutations in both patients. The characteristics of being born as small for gestational age and apparent liver dysfunction in our cases have been seldom discussed in the literature. It seems FBS patients in general have lower birth weight than normal, but further data collection is still needed. Symptomatic treatments were effective, but the serum transaminase of patient 2 remained moderately increased, and he patient needed further follow-up. The present study will supplement the up-to-date clinical characteristic spectrum for FBS.

Hypophosphatemic Rickets: Presenting Features of Fanconi—Bickel Syndrome

Fanconi-Bickel Syndrome (FBS) is a rare variety of glycogen storage disease (GSD). Characterized by massive hepatomegaly due to glycogen accumulation, severe hypophosphatemic rickets, and marked growth retardation due to proximal renal tubular dysfunction. We report a young boy presented as hypophosphatemic rickets with hepatomegaly and subsequently diagnosed as FBS.