Proximal Renal Tubular Function Research Articles

Cadmium (Third Edition) (Chemicals and Contaminants).

Exposure to cadmium tends to be higher in Japan than in other countries due to the wide spreading of ore deposits and many mines throughout Japan. The proximal tubule of the kidney is recognized as the most susceptible site to be affected by cadmium exposure. Food Safety Commission of Japan (FSCJ) considered it appropriate to investigate studies of the effects of cadmium intake on renal proximal tubular function using urinary β2-microglobulin concentration of 1,000 μg/g creatinine as a criterion for the dysfunction. Based on these epidemiological studies, FSCJ established a tolerable weekly intake (TWI) of 7 µg/kg bw per week for cadmium. This value is derived from the results of actual dietary surveys and urinary β2-microglobulin concentrations in Japan, and not from the results of application of blood or urinary cadmium levels to theoretical models. Therefore, no uncertainty factor is required. The estimated dietary intake of cadmium in 2022 was 2.03 µg/kg bw per week, approximately 30% of the TWI of 7 µg/kg bw per week. Therefore, it is unlikely that dietary cadmium intake in the general Japanese population would cause adverse health effects.

Fabrication of Nephrotoxic Model by Kidney-on-a-Chip Implementing Renal Proximal Tubular Function In Vitro

Fabrication of Nephrotoxic Model by Kidney-on-a-Chip Implementing Renal Proximal Tubular Function In Vitro

Bisphenol A impairs renal function by reducing Na+/K+-ATPase and F-actin expression, kidney tubule formation in vitro and in vivo

The kidney proximal tubule is responsible for reabsorbing water and NaCl to maintain the homeostasis of the body fluids, electrolytes, and nutrients. Thus, abnormal functioning of the renal proximal tubule can lead to life-threatening imbalances. Bisphenol A (BPA) has been used for decades as a representative chemical in household plastic products, but studies on its effects on the kidney proximal tubule are insufficient. In this study, immunocytochemical and cytotoxicity tests were performed using two- and three-dimensional human renal proximal tubular epithelial cell (hRPTEC) cultures to investigate the impact of low-dose BPA (1–10 μM) exposure. BPA was found to interfere with straight tubule formation as observed by low filamentous actin formation and reduced Na+/K+-ATPase expression in the tubules of hRPTEC 3D cultures. Similar results were observed in rat pup kidneys following oral administration of 250 mg/kg BPA. Moreover, the expression of HO-1 and 8-OHdG, key markers for oxidative stress, was increased in vitro and in vivo following BPA administration, whereas that of OAT1 and OAT, important transporters of the renal proximal tubules, was not altered. Overall, no-observed-adverse-effect-level (NOAEL)-dose BPA exposure can decrease renal function by promoting abnormal tubular formation both in vitro and in vivo. Therefore, we propose that although it does not exhibit life-threatening toxicity, exposure to low levels of BPA can negatively affect homeostasis in the body by means of long-term deterioration of renal proximal tubular function in humans.

Early switching of tenofovir disoproxil fumarate (TDF) in HIV-infected patients with TDF-induced nephrotoxicity: a prospective study

Background: Tenofovir disoproxil fumarate (TDF) can induce proximal renal tubulopathy (PRT) and necessitate changes in treatment regimen. This prospective study aimed to compare tubular function recovery following early switching versus late switching of TDF in human immunodeficiency virus (HIV)-infected patients with TDF-induced PRT. Methods: For this prospective study, conducted during 2017–2019, we enrolled HIV-1-infected, virologically suppressed adults undergoing TDF-containing combination antiretroviral therapy. Patients were separated into a late-switching group (LSG) and an early-switching group (ESG). The LSG included patients having an estimated glomerular filtration rate (eGFR) decrease ≥25% from the pretreatment level or Fanconi syndrome. The ESG included patients having ≥2 of the following indicators of PRT: fractional excretion of phosphate (FEUP) ≥10%, low tubular maximum reabsorption of phosphate (TmP)/GFR, or uricosuria; fractional uric acid excretion ≥10%; urine protein–creatinine index (UPCI) ≥500 mg/g creatinine, normoglycemic glycosuria, or decrease in eGFR of 15%–24%. Recovery of proximal tubular function at 6 and 12 months after TDF discontinuation was assessed. Complete recovery was defined as normalization of all abnormal tubular markers. Results: Thirty-three HIV-infected patients were enrolled (70% male). Except for tubular function markers, baseline characteristics were not significantly different between the two groups. The proportion of patients having complete recovery was significantly higher in the ESG (p = 0.007, log-rank test). FEUP improved significantly in the ESG after TDF discontinuation; improvements of eGFR and UPCI were greater in the LSG. An eGFR change of 10% from baseline was the only independent predictor of failure to achieve complete recovery after switching. After median follow-up of 2.25 years post-trial, sustained recovery of eGFR within 5% of pre-TDF eGFR was achieved only in the ESG. Conclusions: Early-switching of TDF in HIV patients with PRT may allow complete recovery of proximal renal tubular function.

Drug-induced Fanconi syndrome in patients with kidney allograft transplantation

BackgroundPatients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical.MethodsThis retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis.ResultsThe onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A.ConclusionsFor the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

Changes in the renal function after acute mercuric chloride exposure in the rat are associated with renal vascular endothelial dysfunction and proximal tubule NHE3 inhibition

Mercury is an environmental pollutant and a threat to human health. Mercuric chloride (HgCl2)-induced acute renal failure has been described by several reports, but the mechanisms of renal dysfunction remain elusive. This study tested the hypothesis that HgCl2 directly impairs renal vascular reactivity. Additionally, due to the mercury toxicity on the proximal tubule, we investigated whether the HgCl2-induced natriuresis is accompanied by inhibition of Na+/H+ exchanger isoform-3 (NHE3). We found that 90-min HgCl2 infusion (6.5 μg/kg i.v.) remarkably increased urinary output, reduced GFR and renal blood flow, and increased vascular resistance in rats. “In vitro” experiments of HgCl2 infusion in isolated renal vascular bed demonstrated an elevation of perfusion pressure in a concentration- and time-dependent manner, associated with changes on the endothelium-dependent vasodilatation and the flow-pressure relationship. Moreover, by employing “in vivo” stationary microperfusion of the proximal tubule, we found that HgCl2 inhibits NHE3 activity and increases the phosphorylation of NHE3 at serine 552 in the renal cortex, in line with the HgCl2-induced diuresis. Changes in renal proximal tubular function induced by HgCl2 were parallel to increased urinary markers of proximal tubular injury. Besides, atomic spectrometry showed that mercury accumulated in the renal cortex. We conclude that acute HgCl2 exposure causes renal vasoconstriction that is associated with reduced endothelial vasodilator agonist- and flow-mediated responses and inhibition of NHE3-mediated sodium reabsorption. Thus, our data suggest that HgCl2-induced acute renal failure may be attributable at least in part by its direct effects on renal hemodynamics and NHE3 activity.

985. Impact of Age and Medical Comorbidities on Renal Outcomes in the DISCOVER Trial

BackgroundIn DISCOVER, emtricitabine/tenofovir alafenamide (F/TAF) was noninferior to F/tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) in men who have sex with men and transgender women, with a superior renal laboratory profile. The differential impact of F/TAF and F/TDF on renal parameters among older individuals and those with medical comorbidities is unknown.MethodsDISCOVER randomized participants 1:1 to daily blinded F/TAF or F/TDF. We examined renal outcomes at week 48 including estimated glomerular filtration rate (eGFR) by Cockcroft-Gault, β2 microglobulin (M):Creatinine (Cr) and retinol binding protein (RBP):Cr ratios (markers of proximal renal tubular function), and discontinuations due to investigator reported study drug-related renal adverse events (AEs).ResultsMedian age was 34 years (yrs)(range 18-76), with 12.5% vs 10.9% < 25yrs, 12.2% vs 14.4% ≥ 50yrs, and 1.1% vs 0.9% > 65yrs for F/TAF and F/TDF, respectively. The prevalence of medical comorbidities at baseline were; eGFR < 90mL/min= 9.1% vs 9.3%, diabetes= 2.9% vs 3.3%, and hypertension= 10.5 vs 11.1%, for F/TAF and F/TDF, respectively. eGFR changes by age category and medical comorbidity status are found in the Table. Forty participants had study drug-related renal AEs; 14 with F/TAF and 26 with F/TDF. Of these, 25% were > 50yrs, 20% had baseline eGFR < 90mL/min, 7.5% had history of diabetes, and 22.5% had history of hypertension. β2M:Cr and RBP:Cr changes were more favorable in participants receiving F/TAF, with greater magnitude of difference in older participants (data not shown).Table. ConclusionThe DISCOVER trial allows for a large single variable comparison of the two tenofovir prodrugs in the absence of underlying HIV infection and in the absence of third antiretroviral agents. F/TAF was associated with favorable changes in renal biomarkers regardless of age or medical comorbidity. Participants ≥50yrs or with comorbidities were proportionately more likely to develop study drug related renal AEs, but these were present in the minority of cases.Disclosures Eric Daar, MD, BMS (Consultant)Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator)Janssen (Consultant)Merck (Consultant, Grant/Research Support)Teva (Consultant)Theratechnology (Consultant)Viiv Healthcare (Consultant, Grant/Research Support) Jason Brunetta, MD, AbbVie (Consultant)Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau, Other Financial or Material Support, Conference attendance sponsorship)Janssen (Other Financial or Material Support, Conference attendance sponsorship)Merck (Consultant, Speaker’s Bureau, Other Financial or Material Support, Conference attendance sponsorship)Viiv Healthcare (Consultant, Speaker’s Bureau, Other Financial or Material Support, Conference attendance sponsorship) Eric Cua, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) David Asmuth, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Christoph C. Carter, MD, Gilead Sciences Inc. (Employee, Shareholder) Yongwu Shao, PhD, Gilead Sciences Inc. (Employee, Shareholder) Pamela Wong, MPH, Gilead Sciences Inc. (Employee, Shareholder) Ramin Ebrahimi, MSc, Gilead Sciences Inc. (Employee, Shareholder) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Diana M. Brainard, MD, Gilead Sciences (Employee) Amanda Clarke, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Conference attendance sponsorship)Viiv Healthcare (Consultant, Other Financial or Material Support, Conference travel sponsorship)

995. Safety and Efficacy of F/TAF and F/TDF for PrEP in DISCOVER Participants Taking F/TDF for PrEP at Baseline

BackgroundDISCOVER is an ongoing trial comparing emtricitabine plus tenofovir alafenamide (F/TAF) or tenofovir disoproxil fumarate (F/TDF) for HIV pre-exposure prophylaxis (PrEP). DISCOVER included some participants already taking F/TDF for PrEP at baseline (BL) creating a unique opportunity to study outcomes after switching from F/TDF to F/TAF.MethodsMen who have sex with men and transgender women at risk of HIV were randomized to receive blinded daily F/TAF or F/TDF and followed for at least 96 weeks; participants taking BL F/TDF for PrEP could enroll without a washout period. Laboratory assessments included estimated glomerular filtration rate (eGFR), markers of renal proximal tubular function (RBP and β2M to creatinine ratios), and fasting cholesterol levels; these were analyzed by 2-sided Wilcoxon rank sum test. Bone mineral density (BMD) was assessed in a subset of participants and analyzed by ANOVA.Results905 of 5387 (16.8%) participants were on BL F/TDF for PrEP for a median duration of 399 days; baseline characteristics are found in Table 1. There was one HIV infection among BL PrEP users, in a participant randomized to F/TDF who had intermittent low adherence. Participants on BL PrEP randomized to F/TAF had improvements in eGFR and markers of proximal tubular function compared to F/TDF. Median change in BMD was not statistically different for BL PrEP users assigned to F/TAF vs F/TDF, however de novo F/TAF participants had improved BMD profiles compared to F/TDF. BL PrEP users in the F/TAF arm had increases in LDL cholesterol (median +6mg/dL) compared to F/TDF, while changes in HDL and total:HDL ratio were similar. Lipid-modifying agent (LMA) initiation in BL PrEP users was more frequent in the F/TAF arm, while LMA initiation in de novo PrEP participants was similar between arms (Table 2).Table 1. Characteristics of DISCOVER participants Table 2. Efficacy and safety results ConclusionHIV incidence was low in participants taking BL PrEP. Participants who switched from F/TDF to F/TAF had improvements in renal biomarkers. There was no statistical difference in BMD among BL PrEP users, although numbers were small. The observed lipid changes in BL PrEP users are consistent with the LDL and HDL suppressive effect of TDF, and the small but higher rate of LMA initiation with F/TAF is likely related to withdrawal of this effect.Disclosures Thomas Campbell, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Amanda Clarke, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Conference attendance sponsorship)Viiv Healthcare (Consultant, Other Financial or Material Support, Conference travel sponsorship) Benoit Trottier, MD, AbbVie (Grant/Research Support, Other Financial or Material Support, Personal fees)Bristol-Myers Squibb (Grant/Research Support, Other Financial or Material Support, Personal fees)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Other Financial or Material Support, Personal fees)Janssen (Grant/Research Support, Other Financial or Material Support, Personal fees)Merck (Grant/Research Support, Other Financial or Material Support, Personal fees)Viiv Healthcare (Grant/Research Support, Other Financial or Material Support, Personal fees) Christoph C. Carter, MD, Gilead Sciences Inc. (Employee, Shareholder) Yongwu Shao, PhD, Gilead Sciences Inc. (Employee, Shareholder) Ramin Ebrahimi, MSc, Gilead Sciences Inc. (Employee, Shareholder) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Diana M. Brainard, MD, Gilead Sciences (Employee) Jay Gladstein, MD, Gilead Sciences Inc. (Scientific Research Study Investigator)

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.

Next generation sequencing as second-tier test in high-throughput newborn screening for nephropathic cystinosis

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder, which causes loss of renal proximal tubular function and progressive loss of glomerular function, finally leading to end stage renal failure at school age. In the course of the disease most patients will need kidney transplantation if treatment has not been started before clinical manifestation. With an effective treatment available, a newborn screening assay is highly demanded. Since newborns with cystinosis usually do not show symptoms within the first months of life and no biochemical markers are easily detectable, a DNA-based method seems to be an obvious tool for early diagnosis. Screening was performed using high-throughput nucleic acid extraction followed by 384-well qPCR and melting analysis for the three most frequent variants (57 kb deletion NC_000017.11:g.3600934_3658165del (GRCh38); c.18_21del GACT; c.926dupG) responsible for the defective lysosomal membrane protein cystinosin (CTNS). To increase sensitivity, all heterozygous samples identified in qPCR assay were verified and screened for additional variants by applying next generation sequencing. From January 2018 to July 2019 nearly 292,000 newborns were successfully screened. We identified two newborns with a homozygous 57 kb deletion and a second one with heterozygous 57 kb deletion and a G>C substitution at position c.-512 on the second allele. Cystinosis is an example for diseases caused by a limited number of high prevalence and a high number of low prevalence variants. We have shown that qPCR combined with NGS can be used as a high throughput, cost effective tool in newborn screening for such diseases.

Tenofovir Alafenamide Fumarate Induced Hypoglycemia in HIV Positive Patient with Insulin Dependent Diabetes

With the advances in highly active antiretroviral therapy, HIV is now considered a chronic disease. However, as the HIV population ages and have more co-morbidities, clinicians need to be increasingly aware about medication interactions. From our literature search, this is the first known case report of a patient switched from tenofovir disoproxil to tenofovir alafenamide and experienced improved renal proximal tubular function which we hypothesize led to improved insulin reuptake resulting in hypoglycemic episodes and subsequent need for insulin dose adjusting.

Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide.

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12weeks. This was a prospective single-arm open-label study of 75 CHB patients treated with TDF 300mg daily who were switched to TAF 25mg daily and followed for 24weeks. All patients had been treated with TDF for at least 12months and had HBV DNA <21IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P<0.01). There were significant decreases in urinary beta-2-microglobulin to creatinine and retinol-binding protein to creatinine ratios by week 12 (P<0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P<0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.

Phosphaturia in kidney stone formers: Still an enigma.

Calcium kidney stones are common worldwide. Most are idiopathic and composed of calcium oxalate. Calcium phosphate is present in around 80% and may initiate stone formation. Stone production is multifactorial with a polygenic genetic contribution. Phosphaturia is found frequently among stone formers but until recently received scant attention. This review examines possible mechanisms for the phosphaturia and its relevance to stone formation from a wide angle. There is a striking lack of clinical data. Phosphaturia is associated, but not correlated, with hypercalciuria, increased 1,25 dihydroxy-vitamin D [1,25 (OH)2D], and sometimes evidence of disturbances in proximal renal tubular function. Phosphate reabsorption in the proximal renal tubules requires tightly regulated interaction of many proteins. Paracellular flow through intercellular tight junctions is the major route of phosphate absorption from the intestine and can be reduced therapeutically in hyperphosphatemic patients. In monogenic defects stones develop when phosphaturia is associated with hypercalciuria, generally explained by increased 1,25 (OH)2D production in response to hypophosphatemia. Calcification does not occur in disorders with increased FGF23 when phosphaturia occurs in isolation and 1,25 (OH)2D is suppressed. Candidate gene studies have identified mutations in the phosphate transporters, but in few individuals. One genome-wide study identified a polymorphism of the phosphate transporter gene SLC34A4 associated with stones. Others did not find mutations obviously linked to phosphate reabsorption. Future genetic studies should have a wide trawl and should focus initially on groups of patients with clearly defined phenotypes. The global data should be pooled.

Sa1499 - Improvement of Bone Mineral Density and Markers of Proximal Renal Tubular Function in 12 Weeks in Chronic Hepatitis B Patients Switched from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide

Sa1499 - Improvement of Bone Mineral Density and Markers of Proximal Renal Tubular Function in 12 Weeks in Chronic Hepatitis B Patients Switched from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide

Brief Report: Long-Term (96-Week) Efficacy and Safety After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected, Virologically Suppressed Adults.

In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n = 333) vs. remain on tenofovir disoproxil fumarate (TDF; n = 330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies per milliliter [adjusted difference -0.5% (95% confidence interval: -5.3 to 4.4%)]. Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well-tolerated, and durable nucleotide reverse transcriptase inhibitor backbone.

Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate.

Although Fanconi syndrome is rare in patients with epilepsy treated with sodium valproate (VPA), the prevalence might be higher in children with severe motor and intellectual disabilities (SMID). VPA-induced Fanconi syndrome usually has a favorable outcome, but the long-term outcome of renal tubular dysfunction in SMID patients remains unknown. The aim of this study was therefore to investigate the long-term outcome of renal proximal dysfunction in SMID children with Fanconi syndrome caused by VPA. The records of six children with SMID and Fanconi syndrome caused by VPA were retrospectively reviewed to assess long-term proximal renal tubular function after discontinuation of VPA. All six patients had intractable epilepsy and required tube feeding. Proximal tubular dysfunction improved in almost all patients after VPA discontinuation, although abnormal uric acid reabsorption persisted in three patients. Five patients had hypocarnitinemia. After carnitine supplementation, one of these three patients with decreased ability to reabsorb uric acid had a normal serum level and improved fractional excretion of uric acid. Secondary carnitine deficiency may cause prolonged tubular dysfunction in some SMID patients with VPA-induced Fanconi syndrome. Fanconi syndrome caused by VPA is a usually reversible dysfunction of the proximal tubules, but can be permanent. Although not effective for all patients, carnitine is recommended for patients with VPA-induced Fanconi syndrome, especially children with SMID.

Induction of long noncoding RNA MALAT1 in hypoxic mice.

Long thought to be “junk DNA”, in recent years it has become clear that a substantial fraction of intergenic genomic DNA is actually transcribed, forming long noncoding RNA (lncRNA). Like mRNA, lncRNA can also be spliced, capped, and polyadenylated, affecting a multitude of biological processes. While the molecular mechanisms underlying the function of lncRNAs have just begun to be elucidated, the conditional regulation of lncRNAs remains largely unexplored. In genome-wide studies our group and others recently found hypoxic transcriptional induction of a subset of lncRNAs, whereof nuclear-enriched abundant/autosomal transcript 1 (NEAT1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appear to be the lncRNAs most ubiquitously and most strongly induced by hypoxia in cultured cells. Hypoxia-inducible factor (HIF)-2 rather than HIF-1 seems to be the preferred transcriptional activator of these lncRNAs. For the first time, we also found strong induction primarily of MALAT1 in organs of mice exposed to inspiratory hypoxia. Most abundant hypoxic levels of MALAT1 lncRNA were found in kidney and testis. In situ hybridization revealed that the hypoxic induction in the kidney was confined to proximal rather than distal tubular epithelial cells. Direct oxygen-dependent regulation of MALAT1 lncRNA was confirmed using isolated primary kidney epithelial cells. In summary, high expression levels and acute, profound hypoxic induction of MALAT1 suggest a hitherto unrecognized role of this lncRNA in renal proximal tubular function.

P99 Renal and bone safety of tenofovir alafenamide vs tenofovir disoproxil fumarate

<h3>Background</h3> Off-target renal and bone side effects may occur with tenofovir disoproxil fumarate (TDF) use. Compared with TDF, tenofovir alafenamide (TAF) results in significantly reduced plasma tenofovir (TFV) and may have less renal and bone toxicity. <h3>Methods</h3> Treatment naïve HIV-1+ adults were randomised 1:1 to a single tablet regimen of E/C/F/TAF or E/C/F/TDF once daily in two double blind studies. Assessments for all subjects included measures of glomerular and proximal renal tubular function, and bone mineral density (BMD). Four pre-specified secondary safety endpoints were tested: serum creatinine, treatment-emergent proteinuria, spine and hip BMD. Week 48 off-target side effects data are described. <h3>Results</h3> 1,733 subjects were randomised and treated. Plasma TFV was &gt;90% lower (mean AUC_tau 297 vs. 3,410 ng·hr/mL) in the E/C/F/TAF arm, compared to the E/C/F/TDF arm. Serum creatinine (mean change: +0.08 vs +0.11 mg/dL, p &lt; 0.001), quantified proteinuria (UPCR, median % change; -3 vs +20, p &lt; 0.001), and fractional excretion of phosphate (median % change; +0.9 vs +1.7), all favoured E/C/F/TAF. There were no cases of proximal tubulopathy in either arm. Mean% decrease in BMD was significantly less in the E/C/F/TAF arm for both lumbar spine (−1.30 vs −2.86, p &lt; 0.001) and total hip (−0.66 vs −2.95, p &lt; 0.001). <h3>Conclusions</h3> Through 48 weeks, subjects receiving E/C/F/TAF had significantly better outcomes related to renal and bone health than those treated with E/C/F/TDF;. These data demonstrate important safety benefits of TAF relative to TDF, especially given the ageing of the HIV population and the need for long-term treatment.

Tolerability of HIV integrase inhibitors

This review discusses the available safety data for three integrase strand transfer inhibitors (INSTIs)--raltegravir, elvitegravir and dolutegravir--derived from studies in both HIV-infected and HIV-uninfected cohorts. Phase 2 and 3 clinical trials show that all three INSTIs are well tolerated in treatment-naive and treatment-experienced patients with headache and gastrointestinal effects being the most commonly reported adverse events. Other nervous system (including neuropsychiatric) effects are often reported with INSTIs but are milder and less frequent than with efavirenz. Limited data suggest that effects upon lipid metabolism with raltegravir and dolutegravir are favourable compared with efavirenz and protease inhibitors, with more variable findings for elvitegravir because of coadministration with the boosting agent cobicistat. Cobicistat and dolutegravir have effects upon proximal renal tubular function causing mild-to-moderate creatinine elevation. Rare and severe events possibly related to INSTIs include systemic hypersensitivity reactions and rhabdomyolysis. INSTIs are an important recent addition to the antiretroviral armamentarium, with good short-term and medium-term safety. Long-term data from ongoing clinical studies are needed for a definitive assessment of their safety profile.

Current Status of Cadmium Exposure among Japanese, Especially Regarding the Safety Standard for Cadmium Concentration in Rice and Adverse Effects on Proximal Renal Tubular Function Observed in Farmers Exposed to Cadmium through Consumption of Self-Grown Rice

Because the staple food in Japan is rice, which absorbs cadmium (Cd) from the soil efficiently, rice is the main source of exposure to Cd in the Japanese population. In addition, there have been many Cd-contaminated farming areas in Japan. Therefore, a safety standard for the Cd concentration in rice was set as 0.4 ppm by the Japanese government. This safety standard has been followed for decades without any appropriate scientific or legal basis. However, recent epidemiological studies of female Japanese farmers exposed to Cd through self-grown rice, that is, a series of Japanese Multi-centered Environmental Toxicant Study (JMETS), showed evidence that the safety standard is appropriate. Therefore, general Japanese consumers are unlikely exposed to Cd excessively with the application of this safety standard, considering the trend of decreasing amount of rice consumed among the Japanese population. On the other hand, Japanese farmers were found to be at risk of Cd exposure through the consumption of self-grown rice with a high Cd concentration. Actually, the JMETS showed that female farmers at 70 years of age or older had a decreased proximal renal tubular function due to the high renal accumulation of Cd. On the basis of these findings, "medical examinations for Cd exposure" have recently been implemented for farmers residing in Cd-polluted areas in northern Japan. Because it has been estimated that such Cd-polluted areas are actually larger, it is necessary to implement medical examinations of more farmers there, particularly the elderly.