Tenofovir-induced toxicity in renal proximal tubular epithelial cells: involvement of mitochondria.

OBJECTIVE: In-vivo studies suggest that mitochondria is involved in tenofovir (TFV)-induced renal toxicity, but the underlying mechanisms are still unclear. The aim of the present study was to assess the effects of TFV and its prodrug, TFV disoproxil fumarate, on mitochondrial function and cell survival/viability in a renal proximal tubular cell line. DESIGN AND METHODS: We evaluated parameters of cellular proliferation/survival (cell count, cell cycle, viability) and mitochondrial function (oxygen consumption, mitochondrial membrane potential, reactive oxygen species production) in NRK-52E cells. Intracellular TFV was measured by HPLC and expression of antioxidant genes was analysed by real-time PCR. RESULTS: Similar intracellular levels of TFV were reached with lower concentrations of the prodrug than of the drug, and correlated directly with a decrease in cell number. Both compounds inhibited proliferation and compromised mitochondrial function by decreasing mitochondrial membrane potential and increasing oxygen consumption and mitochondrial superoxide production. Altered oxidative status was confirmed by the overexpression of antioxidant genes. CONCLUSIONS: Intracellular accumulation of TFV induces mitochondrial toxicity in an in-vitro renal model and alters cell proliferation and viability. Our findings call for caution regarding the use of this nucleotide analogue reverse transcriptase inhibitor in patients with other risk factors that compromise mitochondrial function in the kidney.

Vascular calcification in patients with nondialysis CKD over 3 years.

BACKGROUND AND OBJECTIVES: Vascular calcification (VC) is common in CKD, but little is known about its prognostic effect on patients with nondialysis CKD. The prevalence of VC and its ability to predict death, time to hospitalization, and renal progression were assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Study of Mineral and Bone Disorders in CKD in Spain is a prospective, observational, 3-year follow-up study of 742 patients with nondialysis CKD stages 3-5 from 39 centers in Spain from April to May 2009. VC was assessed using Adragao (AS; x-ray pelvis and hands) and Kauppila (KS; x-ray lateral lumbar spine) scores from 572 and 568 patients, respectively. The primary end point was death. Secondary outcomes were hospital admissions and appearance of a combined renal end point (beginning of dialysis or drop >30% in eGFR). Factors related to VC were assessed by logistic regression analysis. Survival analysis was assessed by Cox proportional models. RESULTS: VC was present in 79% of patients and prominent in 47% (AS≥3 or KS>6). Age (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.02 to 1.07; P<0.001), phosphorous (OR, 1.68; 95% CI, 1.28 to 2.20; P<0.001), and diabetes (OR, 2.11; 95% CI, 1.32 to 3.35; P=0.002) were independently related to AS≥3. After a median follow-up of 35 months (interquartile range=17-36), there were 70 deaths (10%). After multivariate adjustment for age, smoking, diabetes, comorbidity, renal function, and level of phosphorous, AS≥3 but not KS>6 was independently associated with all-cause (hazard ratio [HR], 2.07; 95% CI, 1.07 to 4.01; P=0.03) and cardiovascular (HR, 3.46; 95% CI, 1.27 to 9.45; P=0.02) mortality as well as a shorter hospitalization event-free period (HR, 1.14; 95% CI, 1.06 to 1.22; P<0.001). VC did not predict renal progression. CONCLUSIONS: VC is highly prevalent in patients with CKD. VC assessment using AS independently predicts death and time to hospitalization. Therefore, it could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.

Consensus document on the management of renal disease in HIV-infected patients.

OBJECTIVE: To update the 2010 recommendations on the evaluation and management of renal disease in HIV-infected patients. METHODS: This document was approved by a panel of experts from the AIDS Working Group (GESIDA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Nephrology (S.E.N.), and the Spanish Society of Clinical Chemistry and Molecular Pathology (SEQC). The quality of evidence and the level of recommendation were evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: 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 advises on the optimal time for referral of a patient to the nephrologist and provides indications for renal biopsy. The indications for and evaluation and management of dialysis and renal transplantation are also addressed. CONCLUSIONS: Renal function should be monitored in all HIV-infected patients. The information provided in this document should enable clinicians to optimize the evaluation and management of HIV-infected patients with renal disease.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

[Executive summary of the recommendations on the evaluation and management of renal disease in human immunodeficiency virus-infected patients]. / Resumen ejecutivo del documento de consenso sobre el manejo de la patología renal en pacientes con infección por el virus de la inmunodeficiencia humana.

The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in human immunodeficiency virus (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 glycosuria. 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.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

Diabetic kidney disease: from physiology to therapeutics.

Diabetic kidney disease (DKD) defines the functional, structural and clinical abnormalities of the kidneys that are caused by diabetes. This complication has become the single most frequent cause of end-stage renal disease. The pathophysiology of DKD comprises the interaction of both genetic and environmental determinants that trigger a complex network of pathophysiological events, which leads to the damage of the glomerular filtration barrier, a highly specialized structure formed by the fenestrated endothelium, the glomerular basement membrane and the epithelial podocytes, that permits a highly selective ultrafiltration of the blood plasma. DKD evolves gradually over years through five progressive stages. Briefly they are: reversible glomerular hyperfiltration, normal glomerular filtration and normoalbuminuria, normal glomerular filtration and microalbuminuria, macroalbuminuria, and renal failure. Approximately 20-40% of diabetic patients develop microalbuminuria within 10-15 years of the diagnosis of diabetes, and about 80-90% of those with microalbuminuria progress to more advanced stages. Thus, after 15-20 years, macroalbuminuria occurs approximately in 20-40% of patients, and around half of them will present renal insufficiency within 5 years. The screening and early diagnosis of DKD is based on the measurement of urinary albumin excretion and the detection of microalbuminuria, the first clinical sign of DKD. The management of DKD is based on the general recommendations in the treatment of patients with diabetes, including optimal glycaemic and blood pressure control, adequate lipid management and abolishing smoking, in addition to the lowering of albuminuria.

Consensus document for the detection and management of chronic kidney disease.

Chronic kidney disease (CKD) is a major public health problem that, in its different stages, may affect up to 10% of the Spanish population and results in high morbidity and mortality, as well as high consumption of National Health System resources. Ten scientific societies involved in the management of kidney patients agreed to update the 2007 CKD consensus document. The current version is an abridged edition of the detailed general document, which can be consulted on the webpages of each signatory society. It includes the following aspects: CKD definition, epidemiology and risk factors and criteria on diagnosis, assessment and staging of CKD, albuminuria and glomerular filtration estimation. Progression factors and concept. Criteria for referral to Nephrology. Patient follow-up, attitudes and objectives by specialty. Prevention of nephrotoxicity. Detection of cardiovascular damage. Attitudes, lifestyle and treatment: management of high blood pressure, dyslipidaemia, hyperglycaemia, smoking, obesity, hyperuricaemia, anaemia and mineral and bone metabolism disorders. Coordinated follow-up by Primary Care – other specialties – Nephrology. Management of renal replacement therapy, haemodialysis, peritoneal dialysis and renal transplantation patients. Palliative treatment of terminal uraemia. We hope that this document will be very useful in the multidisciplinary management of CKD patients, in view of the updated recommendations.

Gender differences related to the presence of atrial fibrillation in older hypertensive patients.

AIM: To determine whether there are gender differences in the epidemiological profile of atrial fibrillation (AF) and to characterise the clinical, biochemical, and therapeutic factors associated with AF. METHODS: Each investigator (primary care physicians or physicians based in hospital units for hypertension treatment) recruited the first 3 patients with an age of ≥ 65 years and a clinical diagnosis of hypertension (ambulatory blood pressure monitoring and an electrocardiogram, were performed) on the first working day of the week for 5 wk and identified those individuals with atrial fibrillation. A binary logistic regression was performed, including all of the variables that were significant in the univariate analysis, to establish the variables that were associated with the presence of arrhythmia. RESULTS: A total of 1028 patients were included in the study, with a mean age of 72.8 ± 5.8 years. Of these patients, 47.3% were male, 9% were smokers, 27.6% were diabetics, 48.3% had dyslipidaemia, 10.9% had angina, and 6.5% had experienced a myocardial infarction. Regarding gender differences, the men exhibited a larger waist circumference, a lower body mass index, less obesity, and a more extensive history of diabetes, smoking, ischaemic heart disease, kidney failure, peripheral arterial disease and carotid disease than the women. There were no differences, however, in the prevalence of AF between the men and the women (11.5% vs 9.2%, respectively; P = no significant). Regarding treatment, the women received antiplatelet agents and diuretics less frequently, but there were no other differences in the use of antihypertensive and antithrombotic therapies. In the multivariate analysis, AF in the total study population was associated with age, alcohol consumption, the presence of heart disease, and decreased glomerular filtration. In the women, AF was associated with all of the factors included in the overall analysis, as well as the presence of left ventricle hypertrophy. In contrast, in the men, the only risk factors associated with AF were age, the presence of heart disease and alcohol consumption. CONCLUSION: In patients with hypertension over 65 years of age, there are relevant gender differences in the factors associated with AF.

Maintenance of target hemoglobin level in stable hemodialysis patients constitutes a theoretical task: a historical prospective study.

Maintenance of target hemoglobin (Hb) values in hemodialysis patients treated with erythropoiesis-stimulating agents (ESAs) remains difficult. We examined Hb variability in the clinical setting in hemodialysis patients. Hemodialysis patients treated with ESAs who maintained the recommended Hb range of 11-13 g per 100 ml over 3 months and were not admitted to hospital, did not require transfusion, and did not experience any major clinical event during this period were followed prospectively for 1 year. Anemia events, Hb variation events (any value out of +/-1.5 g per 100 ml of the median Hb level in the total follow-up period for the individual patient), risk factors for anemia, and Hb variation events were assessed. We studied 420 patients (63% males, mean age 61 years), 222 received short-acting erythropoietin (EPO) and 198 long-acting darbepoetin. A total of 4654 blood samples (mean 11.1 per patient-year) were analyzed. Only 3.8% of patients were maintained within the target Hb levels (11-13 g per 100 ml) during 1 year. Hb variation events occurred in 20.8% of laboratory values and anemia events in 14.7%, with a median time to the first event of 3 months. Treatment with short-acting EPO (vs long-acting darbepoetin), change of ESA dose in the previous visit, resistance index, and hospitalization were significant risk factors for both anemia events and Hb variation events. Our results show that Hb values are rarely maintained within the recommended guidelines even in more stable hemodialysis patients. Hb variability is frequently associated with clinical events or ESA dose changes. Long-acting darbepoetin achieved better Hb stability than short-acting EPO.