Is It Time for a Requiem for Creatine Supplementation-Induced Kidney Failure? A Narrative Review.

Creatine has become one of the most popular dietary supplements among a wide range of healthy and clinical populations. However, its potential adverse effects on kidney health are still a matter of concern. This is a narrative review of the effects of creatine supplementation on kidney function. Despite a few case reports and animal studies suggesting that creatine may impair kidney function, clinical trials with controlled designs do not support this claim. Creatine supplementation may increase serum creatinine (Crn) concentration for some individuals, but it does not necessarily indicate kidney dysfunction, as creatine is spontaneously converted into Crn. Based on studies assessing kidney function using reliable methods, creatine supplements have been shown to be safe for human consumption. Further studies with people who have pre-existing kidney disease remain necessary.

Tenofovir-induced renal and bone toxicity: report of two cases and literature review.

Tenofovir Disoproxil Fumarate (TDF) is one of the drugs in the initial first-line antiretroviral regimen for the treatment of hepatitis B and HIV infections. Despite its effectiveness and few adverse effects, it is related to renal and bone toxicity. We described two cases of HIV-positive middle-aged women who had been using TDF for two and four years (cases 1 and 2, respectively) and were admitted to the emergency room. Case 1 presented with metabolic ileum and diffuse bone pain while case 2 presented with bilateral coxo-femoral pain after a fall from standing height. Both cases had similar laboratory tests: hyperchloremic metabolic acidosis, hypophosphatemia, hypokalemia, hypouricemia and elevated plasma creatinine. In urinary exams, there was evidence of renal loss of electrolytes, justifying the serum alterations, in addition to glucosuria and proteinuria. The bone pain investigation identified bone fractures and reduced bone mineral density, together with increased levels of parathyroid hormone, alkaline phosphatase and vitamin D deficiency. These two cases illustrate the spectrum of adverse renal and bone effects associated with TDF use. TDF was discontinued and treatment was focused on correcting the electrolyte disturbances and acidosis, in addition to controlling the bone disease through vitamin D and calcium supplementation. The renal changes found in both cases characterized the Fanconi's syndrome, and occurred due to TDF toxicity to proximal tubule cells mitochondria. Bone toxicity occurred due to direct interference of TDF in bone homeostasis, in addition to vitamin D deficiency and phosphaturia resulting from tubulopathy. During the follow-up, both cases evolved with chronic kidney disease and in one of them, the Fanconi's syndrome did not revert. We emphasize the need to monitor markers of bone metabolism and glomerular and tubular functions in patients using TDF.

Tenofovir-induced renal and bone toxicity: report of two cases and literature review

ABSTRACT Tenofovir Disoproxil Fumarate (TDF) is one of the drugs in the initial first-line antiretroviral regimen for the treatment of hepatitis B and HIV infections. Despite its effectiveness and few adverse effects, it is related to renal and bone toxicity. We described two cases of HIV-positive middle-aged women who had been using TDF for two and four years (cases 1 and 2, respectively) and were admitted to the emergency room. Case 1 presented with metabolic ileum and diffuse bone pain while case 2 presented with bilateral coxo-femoral pain after a fall from standing height. Both cases had similar laboratory tests: hyperchloremic metabolic acidosis, hypophosphatemia, hypokalemia, hypouricemia and elevated plasma creatinine. In urinary exams, there was evidence of renal loss of electrolytes, justifying the serum alterations, in addition to glucosuria and proteinuria. The bone pain investigation identified bone fractures and reduced bone mineral density, together with increased levels of parathyroid hormone, alkaline phosphatase and vitamin D deficiency. These two cases illustrate the spectrum of adverse renal and bone effects associated with TDF use. TDF was discontinued and treatment was focused on correcting the electrolyte disturbances and acidosis, in addition to controlling the bone disease through vitamin D and calcium supplementation. The renal changes found in both cases characterized the Fanconi's syndrome, and occurred due to TDF toxicity to proximal tubule cells mitochondria. Bone toxicity occurred due to direct interference of TDF in bone homeostasis, in addition to vitamin D deficiency and phosphaturia resulting from tubulopathy. During the follow-up, both cases evolved with chronic kidney disease and in one of them, the Fanconi's syndrome did not revert. We emphasize the need to monitor markers of bone metabolism and glomerular and tubular functions in patients using TDF.

The role of urea-induced osmotic diuresis and hypernatremia in a critically ill patient: case report and literature review / O papel da diurese osmótica induzida por ureia na geração de hipernatremia no paciente crítico: relato de caso e revisão da literatura

Abstract Hypernatremia is a common electrolyte problem at the intensive care setting, with a prevalence that can reach up to 25%. It is associated with a longer hospital stay and is an independent risk factor for mortality. We report a case of hypernatremia of multifactorial origin in the intensive care setting, emphasizing the role of osmotic diuresis due to excessive urea generation, an underdiagnosed and a not well-known cause of hypernatremia. This scenario may occur in patients using high doses of corticosteroids, with gastrointestinal bleeding, under diets and hyperprotein supplements, and with hypercatabolism, especially during the recovery phase of renal injury. Through the present teaching case, we discuss a clinical approach to the diagnosis of urea-induced osmotic diuresis and hypernatremia, highlighting the utility of the electrolyte-free water clearance concept in understanding the development of hypernatremia.

Resumo A hipernatremia é um distúrbio eletrolítico comum no ambiente de terapia intensiva, com uma prevalência que pode chegar a 25%. Está associada a maior tempo de internação hospitalar e é um fator de risco independente para a mortalidade. Este relato ilustra um caso de hipernatremia de origem multifatorial no ambiente de terapia intensiva. Destacaremos o papel da diurese osmótica por geração excessiva de ureia, uma causa de hipernatremia pouco conhecida e subdiagnosticada. Este cenário pode estar presente em pacientes em uso de elevadas doses de corticoides, com sangramento gastrointestinal, em uso de dietas e suplementos hiperproteicos e estado de hipercatabolismo, especialmente durante a fase de recuperação de injúria renal. A seguir, discutiremos uma abordagem clínica para o diagnóstico da hipernatremia secundária à diurese osmótica induzida por ureia, destacando a importância do conceito de clearance de água livre de eletrólitos nesse contexto.

The role of urea-induced osmotic diuresis and hypernatremia in a critically ill patient: case report and literature review.

Hypernatremia is a common electrolyte problem at the intensive care setting, with a prevalence that can reach up to 25%. It is associated with a longer hospital stay and is an independent risk factor for mortality. We report a case of hypernatremia of multifactorial origin in the intensive care setting, emphasizing the role of osmotic diuresis due to excessive urea generation, an underdiagnosed and a not well-known cause of hypernatremia. This scenario may occur in patients using high doses of corticosteroids, with gastrointestinal bleeding, under diets and hyperprotein supplements, and with hypercatabolism, especially during the recovery phase of renal injury. Through the present teaching case, we discuss a clinical approach to the diagnosis of urea-induced osmotic diuresis and hypernatremia, highlighting the utility of the electrolyte-free water clearance concept in understanding the development of hypernatremia.

Vitamin D Deficiency in Chronic Kidney Disease: Recent Evidence and Controversies.

Vitamin D (VD) is a pro-hormone essential for life in higher animals. It is present in few types of foods and is produced endogenously in the skin by a photochemical reaction. The final step of VD activation occurs in the kidneys involving a second hydroxylation reaction to generate the biologically active metabolite 1,25(OH)2-VD. Extrarenal 1α-hydroxylation has also been described to have an important role in autocrine and paracrine signaling. Vitamin D deficiency (VDD) has been in the spotlight as a major public healthcare issue with an estimated prevalence of more than a billion people worldwide. Among individuals with chronic kidney disease (CKD), VDD prevalence has been reported to be as high as 80%. Classically, VD plays a pivotal role in calcium and phosphorus homeostasis. Nevertheless, there is a growing body of evidence supporting the importance of VD in many vital non-skeletal biological processes such as endothelial function, renin-angiotensin-aldosterone system modulation, redox balance and innate and adaptive immunity. In individuals with CKD, VDD has been associated with albuminuria, faster progression of kidney disease and increased all-cause mortality. Recent guidelines support VD supplementation in CKD based on extrapolation from cohorts conducted in the general population. In this review, we discuss new insights on the multifactorial pathophysiology of VDD in CKD as well as how it may negatively modulate different organs and systems. We also critically review the latest evidence and controversies of VD monitoring and supplementation in CKD patients.

Allopurinol attenuates acute kidney injury following Bothrops jararaca envenomation.

Snakebites have been recognized as a neglected public health problem in several tropical and subtropical countries. Bothrops snakebites frequently complicate with acute kidney injury (AKI) with relevant morbidity and mortality. To date, the only treatment available for Bothrops envenomation is the intravenous administration of antivenom despite its several limitations. Therefore, the study of novel therapies in Bothrops envenomation is compelling. The aim of this study was to evaluate the protective effect of Allopurinol (Allo) in an experimental model of Bothrops jararaca venom (BJ)-associated AKI. Five groups of Wistar rats were studied: Sham, Allo, BJ, BJ+Allo, BJ+ipAllo. BJ (0.25 mg/kg) was intravenously injected during 40'. Saline at same dose and infusion rate was administered to Sham and Allo groups. Allo and BJ+Allo groups received Allo (300 mg/L) in the drinking water 7 days prior to Saline or BJ infusion respectively. BJ+ipAllo rats received intraperitoneal Allo (25 mg/Kg) 40' after BJ infusion. BJ rats showed markedly reduced glomerular filtration rate (GFR, inulin clearance) associated with intense renal vasoconstriction, hemolysis, hemoglobinuria, reduced glutathione and increased systemic and renal markers of nitro-oxidative stress (Nitrotyrosine). Allo ameliorated GFR, renal blood flow (RBF), renal vascular resistance and arterial lactate levels. In addition, Allo was associated with increased serum glutathione as well as reduced levels of plasma and renal Nitrotyrosine. Our data show that Allo attenuated BJ-associated AKI, reduced oxidative stress, improved renal hemodynamics and organ perfusion. It might represent a novel adjuvant approach for Bothrops envenomation, a new use for an old and widely available drug.

Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor?

Vitamin D (VD) is a fat-soluble steroid essential for life in higher animals. It is technically a pro-hormone present in few food types and produced endogenously in the skin by a photochemical reaction. In recent decades, several studies have suggested that VD contributes to diverse processes extending far beyond mineral homeostasis. The machinery for VD production and its receptor have been reported in multiple tissues, where they have a pivotal role in modulating the immune system. Similarly, vitamin D deficiency (VDD) has been in the spotlight as a major global public healthcare burden. VDD is highly prevalent throughout different regions of the world, including tropical and subtropical countries. Moreover, VDD may affect host immunity leading to an increased incidence and severity of several infectious diseases. In this review, we discuss new insights on VD physiology as well as the relationship between VD status and various infectious diseases such as tuberculosis, respiratory tract infections, human immunodeficiency virus, fungal infections and sepsis. Finally, we critically review the latest evidence on VD monitoring and supplementation in the setting of infectious diseases.

Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women.

We aimed to investigate whether creatine supplementation affects the measured glomerular filtration rate in postmenopausal women (age, 58 ± 3 years). Subjects were randomly assigned to receive either creatine (20 g·day(-1) for 1 week and 5 g·day(-1) thereafter) or a placebo. Kidney function was assessed at baseline and after 12 weeks. [(51)Cr]EDTA clearance remained unchanged (CR-PRE: 86.16 ± 14.36 mL·min(-1) per 1.73 m(2), POST: 87.25 ± 17.60 mL·min(-1) per 1.73 m(2); PL-PRE: 85.15 ± 8.54 mL·min(-1) per 1.73 m(2), POST: 87.18 ± 9.64 mL·min(-1) per 1.73 m(2); p = 0.81). Thus, we concluded that creatine supplementation does not affect glomerular filtration rate in postmenopausal women.

Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial.

Creatine supplementation may have a therapeutic role in diabetes, but it is uncertain whether this supplement is safe for kidney function. The aim of this study was to investigate the effects of creatine supplementation on kidney function in type 2 diabetic patients. A randomized, double-blind, placebo-controlled trial was performed. The patients were randomly allocated to receive either creatine or placebo for 12 weeks. All the patients underwent exercise training throughout the trial. Subjects were assessed at baseline and after the intervention. Blood samples and 24-h urine samples were obtained for kidney function assessments. Additionally, (51)Cr-EDTA clearance was performed. To ensure the compliance with creatine intake, we also assessed muscle phosphorylcreatine content. The creatine group presented higher muscle phosphorylcreatine content when compared to placebo group (CR Pre 44 ± 10, Post 70 ± 18 mmol/kg/wt; PL Pre 52 ± 13, Post 46 ± 13 mmol/kg/wt; p = 0.03; estimated difference between means 23.6; 95% confidence interval 1.42-45.8). No significant differences were observed for (51)Cr-EDTA clearance (CR Pre 90.4 ± 16.9, Post 96.1 ± 15.0 mL/min/1.73 m(2); PL Pre 97.9 ± 21.6, Post 96.4 ± 26.8 mL/min/1.73 m(2); p = 0.58; estimated difference between means -0.3; 95% confidence interval -24.9 to 24.2). Creatinine clearance, serum and urinary urea, electrolytes, proteinuria, and albuminuria were unchanged. CR supplementation does not affect kidney function in type 2 diabetic patients, opening a window of opportunities to explore its promising therapeutic role in this population. ClinicalTrials.gov registration number: NCT00992043.

Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression.

Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial Mg2+ channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular defects has potential clinical implications.

Renal involvement in leptospirosis--new insights into pathophysiology and treatment.

Acute renal failure (ARF) is one of the most common complications of leptospirosis although the causal mechanisms are still unclear. Diverse mechanisms are implicated in leptospiral nephropathy and new data supports the role of peculiar ion transport defects. Besides antibiotic therapy, ARF management in leptospirosis requires dialytic therapy which is most efficient when started early. Dialysis is the standard supportive therapy even though recent evidence suggests clinical benefit from alternative treatments such as plasmapheresis and hemofiltration. Renal recovery is achieved soon after clinical improvement. The comprehension of the primary mechanisms of renal dysfunction will be helpful in the development of additional therapeutic tools for improving supportive therapy for leptospiral nephropathy. This review discusses new insights into mechanisms implicated in leptospiral ARF and recent advances in treatment.

Rosiglitazone-enriched diet did not protect liver ischemia-reperfusion injury in a rat model / Dieta enriquecida com rosiglitazona não protege a lesão de isquemia e reperfusão hepática em modelo experimental no rato

PURPOSE: To determine whether rosiglitazone-enriched diet offer protection in a classical model of liver ischemia-reperfusion injury in rats. METHODS: Two days before the experiment, rats were divided into 2 groups: Control Group (n=13) rats fed with standard diet; Rosi Group (n=13): rats fed with a powdered standard diet supplemented with rosiglitazone. The animals were submitted to liver ischemia-reperfusion by clamping the pedicle of median and left anterolateral lobes. After 1 hour of partial hepatic ischemia, the clamp was removed for reperfusion. After 2 or 24 hours (Control and Rosi Groups), blood was collected for enzymes and cytokines analysis. Ischemic and non-ischemic liver were collected for malondialdehyde analysis and histological assessment. Lungs were removed for tissue myeloperoxidase quantification. RESULTS: There were no statistical differences between groups for all analysed parameters. CONCLUSION: In this model, rosiglitazone-enriched diet did not protect liver against ischemia-reperfusion injury.

OBJETIVO: Determinar se a dieta enriquecida com rosiglitazona oferece proteção em um modelo clássico de lesão de isquemia e reperfusão hepática em ratos. MÉTODOS: Dois dias antes do experimento, os ratos foram divididos em 2 grupos: Grupo Controle (n=13): ratos alimentados com dieta padrão; Grupo Rosi (n=13): ratos alimentados com dieta em pó padrão enriquecida com rosiglitazona. Os animais foram submetidos à isquemia e reperfusão hepática por clampeamento do pedículo dos lobos médio e anterolateral esquerdo. Após 1 hora de isquemia, o clampe foi removido para a reperfusão. Após 2 ou 24 horas (Grupos Controle e Rosi), o sangue foi coletado para análise de enzimas e citocinas. Os fígados isquêmico e não isquêmico foram coletados para análise de malondialdeído e avaliação histológica. Pulmões foram removidos para quantificação da mieloperoxidase tecidual. RESULTADOS: Não houve diferenças estatísticas entre grupos em todos os parâmetros analisados. CONCLUSÃO: Nesse modelo, a dieta enriquecida com rosiglitazona não protegeu contra a lesão de isquemia e reperfusão hepática.

Rosiglitazone-enriched diet did not protect liver ischemia-reperfusion injury in a rat model.

PURPOSE: To determine whether rosiglitazone-enriched diet offer protection in a classical model of liver ischemia-reperfusion injury in rats. METHODS: Two days before the experiment, rats were divided into 2 groups: Control Group (n=13) rats fed with standard diet; Rosi Group (n=13): rats fed with a powdered standard diet supplemented with rosiglitazone. The animals were submitted to liver ischemia-reperfusion by clamping the pedicle of median and left anterolateral lobes. After 1 hour of partial hepatic ischemia, the clamp was removed for reperfusion. After 2 or 24 hours (Control and Rosi Groups), blood was collected for enzymes and cytokines analysis. Ischemic and non-ischemic liver were collected for malondialdehyde analysis and histological assessment. Lungs were removed for tissue myeloperoxidase quantification. RESULTS: There were no statistical differences between groups for all analysed parameters. CONCLUSION: In this model, rosiglitazone-enriched diet did not protect liver against ischemia-reperfusion injury.

Renal involvement in leptospirosis: new insights into pathophysiology and treatment: [review]

Acute renal failure (ARF) is one of the most common complications of leptospirosis although the causal mechanisms are still unclear. Diverse mechanisms are implicated in leptospiral nephropathy and new data supports the role of peculiar ion transport defects. Besides antibiotic therapy, ARF management in leptospirosis requires dialytic therapy which is most efficient when started early. Dialysis is the standard supportive therapy even though recent evidence suggests clinical benefit from alternative treatments such as plasmapheresis and hemofiltration. Renal recovery is achieved soon after clinical improvement. The comprehension of the primary mechanisms of renal dysfunction will be helpful in the development of additional therapeutic tools for improving supportive therapy for leptospiral nephropathy. This review discusses new insights into mechanisms implicated in leptospiral ARF and recent advances in treatment.

A suplementação de creatina prejudica a função renal? / Does creatine supplementation harm renal function?

Enquanto o consumo de creatina por atletas e praticantes de atividade física tem crescido vertiginosamente, os efeitos adversos desse suplemento continuam sendo alvos de calorosos debates científicos, sobretudo no que se refere à função renal. O objetivo dessa revisão é descrever as falhas metodológicas e lacunas na literatura, que contribuem para a divergência do tema. Relatos de caso sugerem que a creatina é um potencial agente nefrotóxico. Em contrapartida, estudos longitudinais, embora possuam diversas limitações, indicam o oposto. Pesquisas com humanos não demonstram efeitos deletérios da suplementação de creatina à função renal, porém a falta de controle experimental e o caráter retrospectivo da maioria delas comprometem as conclusões dos autores. Já os estudos experimentais com ratos empregam bons marcadores de função renal e possuem controle de variáveis satisfatório. Contudo, os resultados destes são contraditórios. Estudos futuros devem investigar os efeitos da suplementação de creatina em diversas patologias renais, assim como em idosos, diabéticos do tipo 2 e hipertensos, cuja propensão a nefropatia é bem descrita. Não há evidências de que a suplementação de creatina prejudique a função renal em sujeitos saudáveis, quando consumida na dosagem preconizada. Diante disso, questiona-se a legitimidade científica da proibição do comércio de creatina no Brasil.

While creatine consumption has been greatly increasing among athletes and physical activity practitioners, the adverse effects of this supplement remain scientifically controversial, especially concerning renal function. The aim of this review is to describe the methodological limitations and gaps in the literature which contribute to the topic’s divergence. Case reports suggest that creatine is a nephrotoxic agent. On the other hand, despite having several limitations, longitudinal studies have indicated the opposite. Research with humans does not demonstrate any deleterious effects as a consequence of creatine supplementation; however, the absence of experimental control as well as their retrospective characteristics compromise the authors’ conclusion. Experimental studies with animal models though, use both gold standard for renal function and have satisfactory variable control. However, the results remain controversial. Future studies should investigate the effects of creatine supplementation in several kidneys diseases as well as in the elderly, type 2 diabetis and hypertensive individuals, whose tendency to renal dysfunction is well-described. There is not evidence that creatine supplementation causes renal deterioration in healthy subjects when it is ingested in the recommended dosage. Thus, we have some concerns about the sale prohibition of creatine supplementation in Brazil.

Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial.

Creatine (CR) supplementation is commonly used by athletes. However, its effects on renal function remain controversial. The aim of this study was to evaluate the effects of creatine supplementation on renal function in healthy sedentary males (18-35 years old) submitted to exercise training. A randomized, double-blind, placebo-controlled trial was performed. Subjects (n = 18) were randomly allocated to receive treatment with either creatine (CR) ( approximately 10 g day(-1) over 3 months) or placebo (PL) (dextrose). All subjects undertook moderate intensity aerobic training, in three 40-min sessions per week, during 3 months. Serum creatinine, serum and urinary sodium and potassium were determined at baseline and at the end of the study. Cystatin C was assessed prior to training (PRE), after 4 (POST 4) and 12 weeks (POST 12). Cystatin C levels (mg L(-1)) (PRE CR: 0.82 +/- 0.09; PL: 0.88 +/- 0.07 vs. POST 12 CR: 0.71 +/- 0.06; PL: 0.75 +/- 0.09, P = 0.0001) were decreased over time, suggesting an increase in glomerular filtration rate. Serum creatinine decreased with training in PL but was unchanged with training in CR. No significant differences were observed within or between groups in other parameters investigated. The decrease in cystatin C indicates that high-dose creatine supplementation over 3 months does not provoke any renal dysfunction in healthy males undergoing aerobic training. In addition, the results suggest that moderate aerobic training per se may improve renal function.

Magnesium supplementation combined with N-acetylcysteine protects against postischemic acute renal failure.

Magnesium is a potent vasodilator whose effects have not been evaluated in renal ischemia. The antioxidant properties of N-acetylcysteine (NAC) partially protect animals from ischemic/reperfusion injury. This study was designed to evaluate magnesium supplementation, alone or combined with NAC, on ischemic acute renal failure. Rats were maintained on normal diets, supplemented or not with MgCl(2).6H(2)O (1% in drinking water) for 23 d, and some rats received NAC (440 mg/kg body wt) on days 20 to 23. On day 21, ischemia was induced by clamping both renal arteries for 30 min. Five groups were studied: Normal, ischemia, ischemia+magnesium, ischemia+NAC, and ischemia+magnesium+NAC. GFR (inulin clearance), renal blood flow (RBF), FEH(2)O, and FENa were determined. Serum magnesium was decreased in ischemia-only rats. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. However, NAC completely restored the tubular damage induced by ischemia/reperfusion. Semiquantitative immunoblotting showed that NAC prevented the decreased expression of Na-K-2Cl co-transporter and aquaporin 2 after renal ischemia/reperfusion. Untreated rats with acute renal failure demonstrated markedly decreased endothelial nitric oxide synthase expression. Significantly, treatment with NAC, magnesium, or both completely inhibited downregulation of endothelial nitric oxide synthase. The tubular necrosis scores were lower in rats that were treated with NAC alone or with the magnesium-NAC combination. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. The NAC protected tubules from ischemia, decreased infiltrating macrophages/lymphocytes, and had a mild protective effect on GFR. In ischemic/reperfusion injury, renal function benefits more from the magnesium-NAC combination than from magnesium alone.

Influence of age and vitamin E on post-ischemic acute renal failure.

The aging process causes progressive deterioration in kidney structure and function. Aberrant generation of reactive oxygen species has been implicated in both age-related and ischemia-related tissue injury. Vitamin E (VE), one of the most powerful and effective exogenous antioxidants, prevents lipid peroxidation and protects against the effects of oxidative stress. The objective of this study was to determine the influence of age and VE on post-ischemic acute renal failure (ARF). Young adult, middle-aged and aged male Wistar rats were maintained on three different 30-day diets: Normal, VE absent and VE supplemented. On day 30, urinary protein and serum cholesterol and VE were measured. On day 31, rats were subjected to 60' clamping of the left renal artery plus right nephrectomy. Inulin clearance (InCl) was performed 48 h after renal ischemia. Malondialdehyde (MDA) was measured in the cortex of normal and 48-h post-ischemic kidneys. Urinary protein and serum cholesterol were higher in aged rats than in other rats. With aging, InCl decreased progressively. Vitamin E deficiency aggravated ARF. In middle-aged and aged rats, VE supplementation protected against ARF. In the absence of VE, MDA increased with age. In conclusion, our data suggest that ARF becomes more severe with age and that ischemia/reperfusion injury is exacerbated when antioxidant-scavenging ability of the kidney is impaired by VE deficiency. Supplementation with VE is essential for protecting aging kidneys against ischemic ARF.

Vasodilator agents protect against indinavir nephrotoxicity.

Indinavir (IDV) is a protease inhibitor widely used in AIDS treatment. A sustained elevation of creatinine was identified in IDV-treated patients. We have previously demonstrated that IDV causes renal vasoconstriction in rats. The objective of this study was to investigate the mechanism of IDV-induced vasoconstriction and the effect that the vasodilator agents L-arginine (LA), nifedipine (NF), as well as magnesium supplementation (Mg), have on IDV-induced nephrotoxicity. Male Wistar rats were kept on fast overnight and given free access to water. IDV (80 mg/kg BW) and NF (3 mg/kg BW) were given by gavage for 15 days. LA (1.5%) and MgCl2 x 6H2O (1%) were added to drinking water. Six groups were studied: Control (n=6): normal rats treated with vehicle, a 0.05 M citric acid solution; IDV (n=7): IDV-treated rats; IDV+LA (n=6): IDV- and LA-treated rats; IDV+NF (n=7): IDV- and NF-treated rats; IDV+Mg (n=7): IDV- and MgCl2-treated rats; IDV+Mg+L-NAME (n=9): IDV- and MgCl2-treated rats, supplemented with L-NAME (2.5 mg/l in drinking water). Clearance studies and evaluations of urinary nitrite (NO2) excretion were performed on day 16. No changes in blood pressure were observed. NO2 excretion decreased in IDV-treated rats. LA and NF protected against IDV effects, improving GFR (IDV+LA, 1.95 +/- 0.10; IDV+NF, 1.94 +/- 0.07 vs IDV, 1.15 +/- 0.07 ml/min, P<0.001) and RBF (IDV+LA, 7.83 +/- 0.09; IDV+NF, 7.63 +/- 0.14 vs IDV, 6.17 +/- 0.25 ml/min, P<0.001). These results suggest that IDV-induced vasoconstriction is mediated by NO and Ca2+ channels. Magnesium also ameliorated GFR and RBF in IDV-treated rats (GFR IDV+Mg, 1.77 +/- 0.08 ml/min, P<0.001; RBF IDV+Mg, 7.35 +/- 0.158 ml/min, P<0.001). Magnesium protection is not NO-mediated since it was not blocked by L-NAME. In conclusion, LA, NF and Mg protect against IDV-induced nephrotoxicity in rats. This study may have potential clinical implications for prevention of IDV-induced nephrotoxicity.