Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs / Aspectos fisiopatológicos da nefropatia por anti-inflamatórios não esteroidais

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.

Resumo Os anti-inflamatórios não esteroidais (AINEs) são medicamentos comumente utilizados, associados à nefrotoxicidade, sobretudo quando utilizados cronicamente. Fatores como idade avançada e comorbidades, que por si só já levam à diminuição da taxa de filtração glomerular, aumentam o risco de nefrotoxicidade dos AINEs. O principal mecanismo de ação dos AINEs é a inibição da enzima ciclooxigenase (COX), interferindo na conversão do ácido araquidônico em prostaglandinas E2, prostaciclinas e tromboxanos. Nos rins, as prostaglandinas atuam como vasodilatadoras, aumentando a perfusão renal. Essa vasodilatação atua como uma contrarregulação de mecanismos, como a atuação do sistema renina-angiotensina-aldosterona e do sistema nervoso simpático, culminando com uma compensação para assegurar o fluxo adequado ao órgão. O uso de AINEs inibe esse mecanismo, podendo causar lesão renal aguda (LRA). Altas doses de AINEs têm sido implicadas como causas de LRA, especialmente em idosos. A principal forma de LRA por AINEs é a hemodinamicamente mediada. A segunda forma de apresentação da LRA induzida por AINES é a nefrite intersticial aguda, que pode se manifestar com proteinúria nefrótica. O uso de AINEs em longo prazo pode ocasionar doença renal crônica (DRC). Nos pacientes sem doenças renais, jovens e sem comorbidades, os AINEs não apresentam grandes malefícios. Entretanto, por seu efeito dose-dependente, deve-se ter grande cautela no uso crônico, por aumentar risco de desenvolver nefrotoxicidade.

Risks associated with sunitinib use and monitoring to improve patient outcomes

No abstract available.

Renal adverse effects of sunitinib and its clinical significance: a single-center experience in Korea

BACKGROUND/AIMS: Sunitinib is an oral multitargeted tyrosine kinase inhibitor used mainly for the treatment of metastatic renal cell carcinoma. The renal adverse effects (RAEs) of sunitinib have not been investigated. The aim of this study was to determine the incidence and risk factors of RAEs (proteinuria [PU] and renal insufficiency [RI]) and to investigate the relationship between PU and antitumor efficacy. METHODS: We performed a retrospective review of medical records of patients who had received sunitinib for more than 3 months. RESULTS: One hundred and fifty-five patients (mean age, 58.7 +/- 12.6 years) were enrolled, and the mean baseline creatinine level was 1.24 mg/dL. PU developed in 15 of 111 patients, and preexisting PU was aggravated in six of 111 patients. Only one patient developed typical nephrotic syndrome. Following discontinuation of sunitinib, PU was improved in 12 of 17 patients but persisted in five of 17 patients. RI occurred in 12 of 155 patients, and the maximum creatinine level was 3.31 mg/dL. RI improved in two of 12 patients but persisted in 10 of 12 patients. Risk factors for PU were hypertension, dyslipidemia, and chronic kidney disease. Older age was a risk factor for RI. The median progression-free survival was significantly better for patients who showed PU. CONCLUSIONS: The incidence of RAEs associated with sunitinib was lower than those of previous reports. The severity of RAEs was mild to moderate, and partially reversible after cessation of sunitinib. We suggest that blood pressure, urinalysis, and renal function in patients receiving sunitinib should be monitored closely.

Stepwise Treatment Using Corticosteroids Alone and in Combination with Cyclosporine in Korean Patients with Idiopathic Membranous Nephropathy

PURPOSE: We undertook an observational study to investigate the effects of immunosuppressive treatment on proteinuria and renal function in 179 Korean idiopathic membranous nephropathy patients with nephrotic syndrome. MATERIALS AND METHODS: The primary outcome was regarded as the first appearance of remission and the secondary outcomes as a decline in estimated glomerular filtration rate (eGFR) >50% or initiation of dialysis, and all-cause mortality. Seventy-two (40.2%) and 50 (27.9%) patients were treated with corticosteroids alone (C) and corticosteroids plus cyclosporine (C+C), respectively, whereas 57 (31.8%) did not receive immunosuppressants (NTx). Cyclosporine was added if there was no reduction in proteinuria of >50% from baseline by corticosteroids alone within 3 months. RESULTS: There were no differences in baseline renal function and the amount of proteinuria among the three groups. Overall, complete remission (CR) was achieved in 88 (72.1%) patients by immunosuppressants. In a multivariate analysis adjusted for covariates associated with adverse renal outcome, the probability of reaching CR was significantly higher in the C [hazard ratio (HR), 4.09; p<0.001] and C+C groups (HR, 2.57; p=0.003) than in the NTx group. Kaplan-Meier analysis revealed that 5-year CR rates of C, C+C, and NTx groups were 88.5%, 86.2%, and 56.7% (p<0.001). Ten-year event-free rates for the secondary endpoints in these three groups were 91.7%, 79.9%, and 57.2% (p=0.01). CONCLUSION: Immunosuppressive treatment was effective in inducing remission and preserving renal function in these patients. Therefore, stepwise treatment using corticosteroids alone and in combination with cyclosporine is warranted in these patients.

Análisis crítico de un artículo: La suspensión de inhibidores de la bomba de protones induciría síntomas de reflujo / Critically appraised article

Background & Aims: Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI). IfRAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications. Methods: A randomized, double-blind, placebo-controlled trial with 120 healthy volunteers was conducted. Participants were randomized to 12 weeks of placebo or 8 weeks of esomeprazole 40 mg/d followed by 4 weeks with placebo. The Gastrointestinal Symptom Rating Scale (GSRS) was filled out weekly. A score of >2 on 1 of the questions regarding heartburn, acid regurgitation, or dyspepsia was defined as a clinically relevant acid-related symptom. Results: There were no significant differences between groups in GSRS scores at baseline. GSRS scores for acid-related symptoms were significantly higher in the PPIgroup at week 10 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .023), week 11 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .009), and week 12 (1.3 ± 1.2 vs 1.0 ± 0.3; P = .001). Forty-four percent (26/59) of those randomized to PPI reported >1 relevant, acid-related symptom in weeks 9-12 compared with 15% (9/59; P < .001) in the placebo group. The proportion reporting dyspepsia, heartburn, or acid regurgitation in the PPIgroup was 13 of 59 (22%) at week 10,13 of59 (22%) at week 11, and 12 of 58 (21%) at week 12. Corresponding figures in the placebo group were 7% at week 10 (P = .034), 5% at week 11 (P = .013), and 2% at week 12 (P = .001). Conclusions: PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal. This study indicates unrecognized aspects of PPI withdrawal and supports the hypothesis that RAHS has clinical implications.

Influência da ciclosporina na evoluçäo da nefropatia induzida por adriamicina / Influence of ciclosporin on the evolution of nephropathy induced by adriamycin

Com o objetivo de avaliar a açäo da ciclosporina, na nefropatia induzida por adriamicina, foram realizados 2 protocolos. Protocolo I - No protocolo I, a nefropatia foi induzida com adriamicina (3.0 mg/kg de peso corporal) por via intravenosa, em uma única inoculaçäo, e tratada com ciclosporina A (10 mg/kg/dia, durante 5 dias por semana, por via intraperitoneal). O tratamento foi iniciado 2 semanas após a inoculaçäo de adriamicina e se estendeu até a 6a semana. Ao final do experimental (6 semanas), observou-se que os animais que receberam adriamicina, tratados com ciclosporina, quando comparados aos animais do grupo controle sadio, apresentaram: 1. Proteinúria intensa; 2. Aumento do tamanho renal; 3. Aumento da área glomerular; 4. Relaçäo área glomerular/área tubulointersticial mantida e 5. Discreta lesäo glomerular e tubulointersticial. Quando se compararam animais com nefropatia por adriamicina, tratados com ciclosporina, com aqueles näo tratados, observou-se: 1. Menor intensidade de proteinúria de 24 h; 2. Menor tamanho renal; 3. Menor área glomerular; näo havendo diferença quanto à: 1. Depuraçäo de creatinina endógena e 2. Intensidade da alteraçäo morfológica renal. Protocolo II - No protocolo II, a nefropatia foi induzida com 4.5 mg/kg de adriamicina, por via intravenosa, sendo a dose total dividida em duas inoculaçöes, com intervalo de 10 semanas entre elas; o tratamento com ciclosporina A (10 mg/kg/dia, durante 5 dias por semana, por via intraperitoneal) foi iniciado 16 semanas após a inoculaçäo de adriamicina e manteve-se até a semana 26. Na semana 27, os animais foram sacrificados. Ao final do experimento (semana 27), observou-se que os animais que receberam adriamicina quando comparados aos animais do grupo controle sadio apresentavam: 1. Proteinúria intensa; 2. Aumento do tamanho renal; 3. Relaçäo área glomerular/área tubulointersticial diminuída; 4. Aumento da quantidade de colágeno no parênquima renal; 5. Intensa lesäo glomerular e tubulointersticial e 6. Diminuiçäo intensa da depuraçäo de creatinina endógena. A comparaçäo entre os animais nefróticos tratados com ciclosporina com os animais nefróticos näo tratados mostrou näo haver diferenças entre ambos os grupos, ao se considerarem as variáveis estudadas no presente trabalho. A análise dos dados de ambos os protocolos permite A. Concluir: A ciclosporina, quando introduzida precocemente, diminui a intensidade da nefropatia induzida por adriamicina e...

Reduction of urine volume ameliorates adriamycin-induced nephropathy

1. Adriamycin, a commonly used antineoplastic antibiotic, induces glomerular lesions in rats, resulting in persistent proteinuria and glomerulosclerosis. 2. The effect of urine volume on the progression of adriamycin-induced nephropathy was studied in 70 male Wistar rats (180-200 g) observed for 30 weeks and separated into 4 groups: healthy control group (HCG, N = 10) inoculated i.v. with 1 ml of saline, and nephrotic groups inoculated iv with a single dose of adriamycin of 3 mg/kg body weight. The nephrotic rats were separated into 3 groups (N = 20): nephrotic control group (NCG) receiving only adriamycin; dehydrated nephrotic group (DNG) water deprived for 36 h within each 48-h period, and furosemide nephrotic group (FNG) treated with 12 mg/dl furosemide, and 0.9 g/dl NaCl in the drinking water. 3. The 30-week survival rates of the DNG (100 per cent ) and HCG (100 per cent ) were significantly higher than those of the NCG (85 per cent ) and FNG (55 per cent ). 4. The proteinuria observed in the HCG (range, 7.38 +/- 0.7 to 13.6 +/- 1.27 mg/24 h) was significantly lower than that observed for all the nephrotic groups throughout the experiment. The DNG presented significantly less proteinuria (range, 42.71 +/- 6.83 to 140.10 +/- 19.22 mg/24 h) than the NCG (range, 35.32 +/- 7.64 to 250.00 +/- 25.91 mg/24 h) from week 10 on. There was no significant difference between the mean 24-h proteinuria of the NCG (range, 35.32 +/- 7.64 to 250.00 +/- 25.91 mg/24 h) and the FNG (range, 35.82 +/- 7.91 to 221.54 +/- 26.74). 5. The mean frequency of damaged glomeruli was 0.3 per cent +/- 0.3 for HCG, 42 per cent +/- 6 per cent for CNG, 40.8 per cent +/- 8 per cent for DNG, and 47 per cent +/- 14 per cent for FNG. The median value of the tubulointerstitial lesion, evaluated by a semiquantitative method, was 0 in HCG, 10 in CNG, 8.5 in DNG and 9.5 in FNG (P < 0.05 for all groups compared to HCG). 6. The data indicate that reduction of urine volume has a protective effect on adriamycin-induced nephropathy

Nephrotoxicity of human Bence Jones protein in rats: proteinuria and enzymuria profile

The effect of intravenous administration of 80 mg purified human Bence Jones protein twice weekly for 5 weeks was investigated in male Wistar rats (N = 7; 2 months old). A state of immunological tolerance was demonstrated by the absence of a B-cell response (plaque-forming cells and hemagglutination titers) and by the absence of detectable antigen or antibody deposition in glomeruli, as indicated by light and electron microscopy. No rise in blood urea level was detected (33.9 +/- 4.3 vs 32.8 +/- 1.3 mg per cent ). There was an increase in proteinuria (5.3 +/- 0.9 vs 32.8 +/- 4.0 mg/day), mainly due to Bence Jones protein excretion (0 vs 29.2 +/- 5.2 mg/day), with a slight but significant increase in albuminuria (0.2 +/- 0.1 vs 1.0 +/- 0.2 mg/day). There was a significant increase of lysosomal N-acetyl-beta-D-glucosaminidase in the urine (6.1 +/- 1.3 vs 72.7 +/- 18.8 mU/mg in creatinine). Lysosomal accumulation of Bence Jones protein in proximal tubular cells was evidenced by immunoelectronmicroscopy with protein A-gold. These results clearly showed proximal tubular dysfunction induced by chronic Bence Jones protein administration, without interference of autologous immune response as demonstrated by immunological state of tolerance

Nefropatía atribuible a penicilamina en una paciente con enfermedad de Wilson / Nephropathy to D-penicillamine attributable on patients of Wilson's disease

Se presenta una mujer de 20 años de edad tratada con 2000 mg/día de DPA desde los 17 años por enfermedad de Wilson. Consultó en agosto de 1988: tenía artropatía, hematuria parda, fiebre, amenorrea, úlcera de lengua, pancitopenia, FAN y anti-DNA positivos, síndrome nefrótico y función renal alterada con antiestreptolisina O, hepatograma, coagulograma, completo y tensión arteriales normales. Al suspender DPA desaparecieron la artropatía, la úlcera de lengua y la fiebre y se negativizaron FAN y anti-DNA. En setiembre de 1988 tuvo fiebre y disnea con infiltrado parahiliar izquierdo algodonoso; se descartaron colagenopatías e infecciones, remitiendo en forma espontánea. La biopsia renal mostró alteraciones avanzadas de una glomerulonefritis necrotizante y proliferativa, moderada arteriolonefroesclerosis y ausencia de inmunodepósitos. Recibió pulsos de corticoides y ciclofosfamida sin beneficio. En los seis meses siguientes desapareció la hematuria, reapareció el período menstrual y redujo la proteinuria. Al reiniciar la DPA aumento la proteinuria, suspendiéndose la droga. En julio de 1989 la proteinuria era moderada y la creatinina normal. No se describe glomerulopatía asociada al Wilson; los síntomas y la serología de LES desaparecieron al suprimir la droga. El síndrome urinario, el síndrome pulmonar sin hemoptisis que coincidió con deterioro de la función renal al momento de la biopsia y el tipo de lesión, hallada en la paciente permitirían inscribir este cuadro entre las formas atípicas de púrpura pulmonar y nefritis, cuya incidencia fue estimada en menos del 0,5%en pacientes tratados con DPA por enfermedad de Wilson