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- Executive summary of the consensus document on the management of renal disease in HIV-infected patients. [JOURNAL ARTICLE]
- Nefrologia 2014 Nov 17; 34(6):768-788.
The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in HIV-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glucosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indications for and evaluation and management of dialysis and renal transplantation are also addressed.
- Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes. [JOURNAL ARTICLE]
- Postgrad Med 2014 Oct; 126(6):33-48.
Most antihyperglycemic agents available for the treatment of type 2 diabetes mellitus (T2DM) have insulin-dependent mechanisms of action; that is, they either stimulate insulin production (sulfonylureas, glinides, incretin mimetics, dipeptidyl peptidase-4 inhibitors), improve insulin sensitivity (thiazolidinediones, biguanides), or directly augment endogenous insulin (basal and prandial insulins). As β-cell function deteriorates, combination therapy is usually needed to effectively control glycemia. Moreover, some antihyperglycemic agents are associated with adverse effects, such as weight gain and hypoglycemia. A novel approach for treating T2DM is to inhibit renal glucose reabsorption through inhibition of sodium glucose co-transporter 2 (SGLT2), which is responsible for the majority of glucose reabsorption in the renal proximal tubule. By reducing the renal capacity to reabsorb filtered glucose, SGLT2 inhibitors increase excretion of excess glucose in urine, thereby decreasing plasma glucose concentration. Thus, although glucosuria is often viewed as an indicator of systemic hyperglycemia, this perception needs to be modified in patients treated with SGLT2 inhibitors where glucosuria is an indicator of the desired treatment effect. Currently, 2 SGLT2 inhibitors, canagliflozin and dapagliflozin, are approved in the United States for the treatment of patients with T2DM; other SGLT2 inhibitors are in various stages of clinical development. Clinical studies in patients with T2DM on a variety of background diabetes treatments have demonstrated the efficacy of canagliflozin and dapagliflozin in improving glycemic control and reducing body weight and blood pressure. Canagliflozin and dapagliflozin are generally well tolerated, with a low risk of hypoglycemia when not used in combination with insulin and/or sulfonylurea. Higher incidences of genital mycotic infections and adverse events related to osmotic diuresis and volume depletion were observed with both agents; they were generally mild or moderate and infrequently led to study discontinuation. Based on current evidence, SGLT2 inhibitors provide an important new treatment option for patients with T2DM.
- Tenofovir-Related Nephropathies in HIV-Infected Patients. [JOURNAL ARTICLE]
- Curr Vasc Pharmacol 2014 Nov 20.
The number of human immunodeficiency virus (HIV)-infected patients has increased significantly, although the number of deaths due to HIV and acquired immunodeficiency syndrome (AIDS) has dramatically reduced. Highly active antiretroviral therapy (HAART) has increased survival but has also increased the risk of death caused by other diseases or by long-term side effects of these drugs.The aim of this study is to evaluate the nephrotoxicity of one of the most common anti-retroviral drugs, tenofovir disoproxil fumarate (TDF).We examined 27 patients with HIV infection (10 women). Patients have assumed TDF for a mean period of 8.03 months. Indexes of renal function and serum electrolytes were measured, and glomerular filtration rate was estimated (eGFR). Proteinuria, glycosuria, bicarbonaturia, and phosphaturia were assessed, and renal ultrasound examination was carried out.Acute kidney injury with glycosuria, bicarbonaturia, and phosphaturia was seen in 22 patients. Substantial recovery of renal function occurred in 19 patients.This study highlights that TDF nephrotoxicity is a widely frequent but reversible form of renal damage with preferentially proximal tubular dysfunction. We suggest that all patients at the time of HIV diagnosis should carry out a screening for kidney disease with eGFR assessment, proteinuria, and urine analysis.
- Switching from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor. [Journal Article]
- J Int AIDS Soc 2014; 17(4 Suppl 3):19824.
Cobicistat (COBI) is a pharmacoenhancer and one of the components of ECF/TDF (elvitegravir/cobicistat/emtricitabine/tenofovir DF), which is approved in treatment-naïve HIV patients with creatinine clearance (CrCl) ≥70 mL/min. Study 118 assessed the renal safety of COBI-containing regimens in HIV patients with mild to moderate renal impairment.Phase 3, open label study in HIV-1-infected patients with CrCl 50-89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted atazanavir (ATV) or darunavir (DRV). Patients switched RTV to COBI, while keeping the rest of their regimen unchanged. We present the 96-week (Wk) data.Seventy-three patients were enrolled. Mean age was 54 years; male 82%; white 77%; hypertension 38%; diabetes 18%; baseline proteinuria (≥trace) 51%; median CrCl 71 mL/min (range: 42-98). At Wk 96, 89% maintained virologic suppression (95% CI 77.4-95.8%). No emergent resistance developed. Reductions in CrCl (median [IQR]) were observed as early as Wk 2, after which they were nonprogressive through Wk 96 (Wk 48: -3.8 [-9-0.8]; Wk 96: -5.0 [-13.0-0.1]). Changes in CrCl by baseline CrCl (<70 vs ≥70) at Wk 96 were: -3.1 [-5.1-0.5] vs -7.6 [-15.2 to -3.6], respectively. Cystatin C-based eGFR remained stable through Wk 96 (median [IQR]: -2.8 [-7.4-8.9 mL/min/1.73 m(2)). Actual GFR assessment using CLiohexol (n=14) was unaffected over 24 Wks (median at baseline: 82.5, median changes from baseline at Wks 2, 4, and 24: 1.6, 7.0, -4.1 mL/min, respectively). Three renal discontinuations occurred (two worsening CrCl and one proteinuria/hematuria); none had proximal renal tubulopathy [PRT]. No patient had laboratory evidence of PRT (>1 confirmed renal laboratory abnormalities [increase in serum Cr≥0.4 mg/dL, ≥2-grade increase in proteinuria,≥1-grade increase in normoglycemic glycosuria or hypophosphatemia]).In HIV-infected patients with CrCl 50-89 mL/min, on ATV- or DRV-based regimen switching to COBI from RTV, demonstrated that COBI was well tolerated with no cases of PRT through 96 Wks. The renal safety profile of COBI in patients with mild to moderate renal impairment was consistent with the long-term data in patients without renal impairment (CrCl≥70 mL/min) from the phase 3 studies of COBI-containing regimens.
- Renal safety profile of STB in virologically suppressed subjects from two randomized phase 3b switch trials. [Journal Article]
- J Int AIDS Soc 2014; 17(4 Suppl 3):19807.
Cobicistat, a component of stribild (STB), is known to inhibit renal creatinine secretion. A detailed analysis of the renal safety profile of STB in two Phase 3b switch studies of virologically-suppressed individuals on stable therapy: STRATEGY(S)-PI (STB vs a RTV-boosted protease inhibitor [PI] with emtricitabine and tenofovir DF [FTC/TDF]); and STRATEGY(S)-NNRTI (STB versus a non-nucleoside reverse transcriptase inhibitor [NNRTI] with FTC/TDF) is herein described.Baseline eGFR ≥70 mL/min was an inclusion criterion. The renal safety profile of STB was examined by baseline eGFR through week 48 (i.e., changes in eGFR, renal tubular laboratory abnormalities, investigator-reported renal adverse events leading to discontinuation and unreported subclinical proximal renal tubulopathy [PRT]). Subclinical PRT was defined as a confirmed serum-creatinine increase ≥0.4 mg/dL and two or three markers of renal tubular dysfunction (hypophosphatemia, normoglycemic glycosuria, proteinuria) occurring at the same visit at least once and with no alternative etiologies.In S-PI, 433 subjects (STB 293; PI 140) and in S-NNRTI, 434 subjects (STB 291; NNRTI 143) were randomized and treated. Most (>85%) STB subjects had a baseline eGFR ≥90 mL/min. STB subjects with baseline eGFR <90 mL/min had smaller declines in eGFR compared to those with baseline eGFR ≥90 mL/min and similar occurrences of renal tubular laboratory abnormalities (Table 1). Rate of renal adverse events leading to study drug discontinuation were similar for the STB group (one PRT in a subject with baseline tubular laboratory abnormalities consistent with underlying PRT and one isolated increase in serum creatinine) and PI group (one isolated decrease in eGFR); none in the NNRTI group. The case of PRT improved after study drug discontinuation. There were no cases of unreported subclinical PRT in any group.In this virologically suppressed patient population, the renal safety of STB did not differ by baseline eGFR. The renal discontinuation rate was low in the STB group, similar to the RTV-boosted PI group, and consistent with published historical rates.
- Prevalence and European AIDS Clinical Society (EACS) criteria evaluation for proximal renal tubular dysfunction diagnosis in patients under antiretroviral therapy in routine setting. [Journal Article]
- J Int AIDS Soc 2014; 17(4 Suppl 3):19564.
Tenofovir (TDF) is an antiretroviral drug often used in combination regimen in HIV-positive patients. Adverse effects affecting kidneys consist in an increase or a new onset proteinuria, a decrease of glomerular filtration rate (GFR), and/or a proximal renal tubular dysfunction (PRTD) that rarely leads to Fanconi's syndrome. EACS guidelines propose to screen PRTD in patients with chronic renal insufficiency, with a sudden decrease of eGFR, with hypophosphataemia (if non-renal causes such as vitamin D deficiency are excluded) and with a new onset proteinuria. We aim to evaluate the prevalence of PRTD by comparing the group of patients under TDF to the group free of TDF, in our cohort of 300 patients. We also aim to evaluate the accuracy of EACS criteria for screening PRTD in routine settings and to assess the utility of urinary samples in PRTD diagnosis.During two consecutive years, we collected annually blood and urine samples at the same time in our outpatient clinic. We assessed kidney function, plasma levels and fractional excretion of phosphate, uric acid, potassium, plasma glucose and proteinuria. PRTD was defined by the presence of at least two out of the five following criteria: fractional excretion (FE) of phosphate >20% (or >10% when serum phosphate <0.8 mmol/L), non-diabetic glycosuria (positive urine glucose with plasma glucose <70 mg/dL), renal tubular acidosis (urinary pH >5.5 and serum bicarbonate <21 mmol/L), uric acid FE >10% or potassium FE >10%. After the first year, patients with TDF regimen who were diagnosed with PRTD were shifted to TDF-free regimen and included again in the study.For PRTD (first line), they are expressed in number of diagnoses/total number of patients in this group. The second line resumes the number of PRTD diagnose patients who should have been screened according to EACS criteria.PRTD screening according to EACS criteria is not sufficient to diagnose every case, especially minor PRTD, mainly because the prevalence is low and its diagnosis remains difficult in routine settings. We recommend performing a urine test including proteinuria every year for patients undergoing TDF treatment. The next step will be to follow PRTD patients to evaluate the time laps until full recovery after TDF shift.
- Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. [JOURNAL ARTICLE]
- Am J Physiol Renal Physiol 2014 Nov 5.:ajprenal.00555.2014.
Objective: Plasma uric acid (PUA) is associated with metabolic, cardiovascular and renal abnormalities in patients with type 2 diabetes, but is less well understood in type 1 diabetes (T1D). Our aim was to compare PUA levels and fractional UA excretion (FEUA) in patients with T1D vs. healthy controls (HC) during euglycemia and hyperglycemia. Methods: PUA, FEUA, blood pressure (BP), glomerular filtration rate (GFR-inulin) and effective renal plasma flow (ERPF - paraaminohippurate) were evaluated in patients with T1D (n=66) during clamped euglycemia (glucose 4-6 mmol/L) and hyperglycemia (9-11 mmol/L), and in HC (n=41) during euglycemia. To separate the effects of hyperglycemia vs. increased glycosuria, parameters were evaluated during clamped euglycemia in a subset of T1D patients before and after SGLT2 inhibition for 8 weeks. Results: PUA was lower in T1D vs. HC (228±62 µmol/L vs. 305±75 μmol/L, p<0.0001). In T1D, hyperglycemia further decreased PUA (228±62 μmol/L to 199±65 μmol/L, p<0.0001), which was accompanied by an increase in FEUA (7.3±3.8 to 11.6±6.7, p<0.0001). In T1D, PUA levels correlated positively with SBP (p=0.029) and negatively with ERPF (p=0.031) and GFR (p=0.028). After induction of glycosuria with SGLT2 inhibition while maintaining clamped euglycemia, PUA decreased (p<0.0001) and FEUA increased (p<0.0001). Conclusions: PUA is lower in T1D vs. HC, and positively correlates with SBP and negatively with GFR and ERPF in T1D. Glycosuria rather than hyperglycemia increases uricosuria in T1D. Future studies examining the effect of UA lowering therapies should account for the impact of ambient glycemia, which causes an important uricosuric effect.
- Inhibition of Kidney Proximal Tubular Glucose Reabsorption Does Not Prevent against Diabetic Nephropathy in Type 1 Diabetic eNOS Knockout Mice. [Journal Article]
- PLoS One 2014; 9(11):e108994.
Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect.We induced diabetes using a low dose streptozotocin protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice).Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.
- Hyperosmolar Hyperglycemic State: A Historic Review of the Clinical Presentation, Diagnosis, and Treatment. [REVIEW]
- Diabetes Care 2014 Nov; 37(11):3124-3131.
The hyperosmolar hyperglycemic state (HHS) is the most serious acute hyperglycemic emergency in patients with type 2 diabetes. von Frerichs and Dreschfeld described the first cases of HHS in the 1880s in patients with an "unusual diabetic coma" characterized by severe hyperglycemia and glycosuria in the absence of Kussmaul breathing, with a fruity breath odor or positive acetone test in the urine. Current diagnostic HHS criteria include a plasma glucose level >600 mg/dL and increased effective plasma osmolality >320 mOsm/kg in the absence of ketoacidosis. The incidence of HHS is estimated to be <1% of hospital admissions of patients with diabetes. The reported mortality is between 10 and 20%, which is about 10 times higher than the mortality rate in patients with diabetic ketoacidosis (DKA). Despite the severity of this condition, no prospective, randomized studies have determined best treatment strategies in patients with HHS, and its management has largely been extrapolated from studies of patients with DKA. There are many unresolved questions that need to be addressed in prospective clinical trials regarding the pathogenesis and treatment of pediatric and adult patients with HHS.
- Amyloid A amyloidosis with subcutaneous drug abuse. [Journal Article]
- J Renal Inj Prev 2014; 3(1):11-6.
Amyloid A (AA) amyloidosis is a systemic form of amyloidosis secondary to chronic infections and inflammatory disorders. An acute-phase protein produced by the liver, serum amyloid A (SAA) is the precursor of AA amyloid fibrils. AA amyloid deposition occurs predominantly in the kidneys, spleen, adrenal glands, liver and gastrointestinal tract. The manifestations of AA amyloidosis involving the kidneys include proteinuria, tubular dysfunction and progressive loss of renal function.We report a 47-year-old drug addict who developed AA amyloidosis as a result of recurrent suppurative skin infections secondary to subcutaneous drug injection. Elevated C-reactive protein concentrations attested to the presence of a chronic systemic inflammatory state. He suffered from the nephrotic syndrome and insidious loss of renal function. Isosthenuria and glycosuria were indicative of renal tubular dysfunction. Renal biopsy demonstrated AA amyloidosis involving the glomeruli, tubular basement membranes and blood vessel walls.Superimposed acute tubular necrosis due to concomitant endocarditis and cocaine use accelerated his renal disease. CASE presentation is followed by a brief discussion of clinical features, natural history and outcome of AA amyloidosis with a particular emphasis on AA amyloidosis as a complication of subcutaneous drug abuse.