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.

Daño renal agudo secundario a nefritis tubulointersticial aguda por uso de medicamentos. Caso clínico / Acute renal damage secondary to acute tubulointerstitial nephritis drug use. Case report

Resumen Introducción: La nefritis tubulointersticial aguda (NTIA) es infrecuente en la edad pediátrica. Se caracteriza por la infiltración del parénquima renal por células mononucleares y/o polinucleares con afectación secundaria de los túbulos sin lesión glomerular, y puede ser producida por infecciones, enfermedades inmunológicas, fármacos, o ser de origen idiopático. Objetivo: Describir un caso de NTIA secundario a antiinflamatorios no esteroidales (AINE) en un lactante, con énfasis en esta aso ciación para ser considerada por los pediatras. Caso clínico: Lactante de 10 meses, sin antecedentes previos, trasladada a nuestro hospital por daño renal agudo estadio 3, clasificación KDIGO 2012. Los tres días previos recibió tratamiento con amoxicilina e ibuprofeno por otitis media aguda. En la exploración física destacaba leve edema palpebral con presión arterial normal. En la orina presentaba proteinuria no nefrótica con componente tubular, microhematuria y leucocituria. La ecografía renal no mostraba alteraciones. Ante la sospecha de NTIA se cambió el antibiótico a cefotaxima intrave nosa y se suspendió el ibuprofeno realizándose manejo conservador del daño renal agudo. Presentó aumento de la creatinina (4.14 mg/dL) y eosinofilia, siendo el estudio inmunológico negativo. Se trató con metilprednisolona, con normalización de la función renal. Conclusión: La NTIA se puede producir por cualquier medicamento mediante una reacción inmunológica idiosincrásica. Entre los medicamentos responsables se identifican fármacos de uso frecuente en la edad pediátrica, como los AINEs, por lo que se necesita una alta sospecha diagnóstica por parte de los pediatras.

Abstract Introduction: Acute tubulointerstitial nephritis (ATIN) is a rare entity in the pediatric age. It is de fined by the infiltration of the renal parenchyma by mononuclear and/or polynuclear cells with se condary involvement of the tubules, without glomerular injury. It can be triggered by infections or immunological diseases, drugs like NSAIDs or be of idiopathic origin. Objective: To raise awareness among pediatricians about the prescription of NSAIDs, especially to patients of less than a year old, since they can provoke renal damage. Case report: A ten month old child, with no nephrological an tecedents of interest, was transferred to our hospital due to acute renal failure stage 3 KDIGO 2012. The three previous days received treatment with amoxicillin and ibuprofen for acute otitis media. Physical examination revealed mild eyelid edema with normal blood pressure. In the urine analysis, there were non-nephrotic proteinuria with tubular component, microhematuria and leukocyturia. Renal ultrasound showed no abnormalities. ATIN was suspected and so the antibiotic was changed to intravenous cefotaxime and ibuprofen was discontinued, opting for conservative management of acute renal damage. There was an increase in the number of creatinine up to 4.14 mg/dL and eosinophilia, with the immunological study being negative. Treatment with methylprednisolone was initiated, achieving normalization of renal function. Discussion: NTIA can be produced by any me dication through an idiosyncratic immune reaction. Among the responsible drugs, there are ones commonly used in the pediatric age, such as NSAIDs. Therefore, the pediatricians should pay special attention during prescriptions and have a high diagnostic suspicion of this disease.

Increased expression of p38 mitogen- activated protein kinase is related to the acute renal lesions induced by gentamicin

Mitogen-activated protein kinases (MAPK) may be involved in the pathogenesis of acute renal failure. This study investigated the expression of p-p38 MAPK and nuclear factor kappa B (NF-kappaB) in the renal cortex of rats treated with gentamicin. Twenty rats were injected with gentamicin, 40 mg/kg, im, twice a day for 9 days, 20 with gentamicin + pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor), 14 with 0.15 M NaCl, im, twice a day for 9 days, and 14 with 0.15 M NaCl , im, twice a day for 9 days and PDTC, 50 mg kg-1 day-1, ip, twice a day for 15 days. The animals were killed 5 and 30 days after the last of the injections and the kidneys were removed for histological, immunohistochemical and Western blot analysis and for nitrate determination. The results of the immunohistochemical study were evaluated by counting the p-p38 MAPK-positive cells per area of renal cortex measuring 0.05 mm². Creatinine was measured by the Jaffé method in blood samples collected 5 and 30 days after the end of the treatments. Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. In addition, animals killed 5 days after the end of gentamicin treatment presented acute tubular necrosis and increased nitrate levels in the renal cortex. Increased expression of p-p38 MAPK and NF-kappaB was also observed in the kidneys from these animals. The animals killed 30 days after gentamicin treatment showed residual areas of interstitial fibrosis in the renal cortex, although the expression of p-p38 MAPK in their kidneys did not differ from control. Treatment with PDTC reduced the functional and structural changes induced by gentamicin as well as the expression of p-p38 MAPK and NF-kappaB. The increased expression of p-p38 MAPK and NF-kappaB observed in these rats suggests that these signaling molecules may be involved in the pathogenesis of tubulointerstitial nephritis induced by gentamicin.

NSAIDs and kidney.

NSAIDs are commonly used drugs. Even with the advent of selective COX-2 inhibitors, nephrotoxicity still remains a concern. The adverse effects of NSAIDs are mediated via inhibition of prostaglandin synthesis from arachidonic acid by non-specific blocking of the enzyme cyclooxygenase leading to vasoconstriction and reversible mild renal impairment in volume contracted states. When unopposed, this may lead to acute tubular necrosis and acute renal failure. NSAIDs also produce interstitial nephritis with or without nephrotic syndrome secondary to minimal change disease. Although this presents as acute renal failure, it can progress in some cases to chronic renal failure. Papillary necrosis has been incriminated in the development of chronic renal failure secondary to NSAIDs. In patients on long term NSAIDs without acute or chronic renal failure, subclinical renal dysfunction such as reduced creatinine clearance and impaired urine concentrating ability has been shown to be present. Although this sub-clinical dysfunction is reversible on withdrawal of NSAIDs, some reports have suggested a persistent residual dysfunction. Even with a wide range of NSAIDs at our disposal, a renal safe NSAID is yet to be discovered.

Nefritis intersticial aguda y lamotrigina / Acute interstitial nephritis associated to lamotrigine use: report of one case

Acute interstitial nephritis is a mononuclear and sterile inflammation of the renal interstice caused by drugs, infections or immune phenomena. The clinical presentation is characterized by the triad of rash, fever and eosinophilia. We report a 32 years old man, in treatment with lamotrigine for depression, admitted to the hospital due to fever, abdominal pain, jaundice, cutaneus rash and malaise. Due to an oliguric renal failure of acute onset, a renal biopsy was done. The pathological study showed a granulomatous acute interstitial nephritis. He was started on hemodialysis and treated with cessation of the drug and corticosteroids, with complete recovery of the renal function (Rev Méd Chile 2004; 132: 742-6).

Acute renal failure due to acute tubulointerstitial nephritis.

Acute interstitial nephritis (AIN) should be ruled out in children with unexplained acute renal failure. We present a 4 1/2 year old girl who presented with oliguric acute renal failure preceded by a febrile illness. Renal histopathology revealed features of drug induced AIN. She recovered with dialysis, other supportive treatment and a course of steroids.

Riñón y medicamentos / Kidney and drugs

El riñón tiene un rol muy importante en la excreción de los medicamentos y de sus metabolitos, muchos de los cuales provocan alteraciones de la función renal o daño de sus diversas estructuras (glomérulos, túbulos, intersticio). las alteraciones producidas pueden ser agudos y reversibles o crónicas. Los medicamentos que tienen más efectos adversos sobre el riñón son los analgésicos (paracetamol) y antiinflamatorios, los medios de contraste yodados, los inhibidores de la enzima de conversión de la angiotensina, los aminoglicósidos (gentamicina), la ciclosporina y las sales de oro. La administración de estos medicamentos, potencialmente nefrotóxicos requiere de prudencia, especialmente en los ancianos y portadores de daños renales previos (diabéticos, hipertensos, etc.) y de controles seriados de orina y creatininemia

Risk factors between analgesic use and chronic nephropathy in Thailand.

Analgesic abuse is common in Thailand. Heavy use of analgesic may also increase risk of chronic nephropathy. However, the extent of this risk remains unclear. We carried out a case-control study in three referral hospitals. A total of 84 patients with newly diagnosed of chronic tubulointerstitial nephritis were enrolled as cases. Two control groups were randomly selected, 192 from hospitalized patients who had no renal disease and serum creatinine below 1.2 mg/dl and 166 from relatives of friends visiting the hospitals. Both cases and controls were interviewed by a standardized pre-coded questionnaire to obtain histories of analgesic use before diagnosis of renal disease. On multiple logistic regression analysis, patients whose estimated lifetime use of acetaminophen of 1,000 g or more had an increased risk of chronic nephropathy compared with non-users, the odds ratio (OR) was 5.9 (95% confidence interval (CI) 1.3-25.6, hospital controls) and OR = 5.8 (95% CI 1.04-31.9, visitor controls). Also, uses of aspirin showed a similar relationship. Patients who used aspirin 1,000 g or more per lifetime had higher risk of chronic nephropathy when compared to non-users, the odds ratio were 7.1 (95% CI 2.0-25.8, hospital controls) and 20.4 (95% CI 2.4-174.2) for visitor controls. These data indicate that analgesic abuse increased risk of chronic nephropathy in Thailand.

Nefrite intersticial induzida por drogas / Interstitial nephritis induced by drugs

Sao relatados quatro casos sugestivos de nefrite intersticial aguda relacionados ao uso de antibióticos, em pacientes internados na enfermaria de Clínica Médica do Hospital Universitário Lauro Wanderley, no período de abril de 1992 a janeiro de 1993. Os pacientes foram admitidos com quadro infeccioso grave, receberam antibióticos beta-lactâmicos, desenvolvendo, no curso do tratamento, síndrome de hipersensibilidade caracterizada por febre, exantema, eosinofilia e alteraçoes urinárias. Concomitantemente, foi realizada revisao da literatura a cerca do assunto, discutindo-se sua etiopatogenia e tratamento.

Sucesso terapêutico com uso de esteróide em um caso de nefrite intersticial aguda secundária à rifampicina / Therapeutic success with use of steroid in a case of acute interstitial nephritis secondary to rifampin

O uso de corticosteróides e/ou outras drogas imunossupressoras no tratamento de nefrite intersticial aguda (NIA) permanece controverso. Os autores relatam um caso de NIA, secundária ao uso de rifampicina, tratado com prednisona, no qual se obteve excelente resposta: paciente feminina com diagnóstico de tuberculose pulmonar, que se apresentava com funçäo renal normal, foi submetida a terapêutica tríplice (rifampicina e pirazinamida). No quadragésimo dia de tratamento, mostrou creatinina de 2,4mg/dl e BUN de 27mg/dl; após três dias, foi submetida a exames que mostraram: creatinina plasmática, 5,5mg/dl; nitrogênio uréico plasmático, 74mg/dl; sódio urinário, 78mEq/1; osmolalidade urinária, 416mOsm/Kg de H2O e fraçäo de excreçäo de sódio de 4,3%; exame do sedimento urinário com leucocitúria, hematúria e eosinofilúria; proteinúria de 24 horas de 900mg; ultra-som renal normal. A biopsia renal revelou tratar-se de NIA, sendo suspensa a rifampicina e, como a funçäo renal continuava a piorar, iniciou-se prednisona. Houve estabilizaçäo dos níveis de escórias nitrogenadas e queda a partir do quarto dia de tratamento, recebendo alta hospitalar com funçäo renal normal

O uso do lítio e sua açöes sobre o rim / Lithium use and its effects on the kdney

O carbonato de lítio é usado no tratamento das desordens maníaco-depressivas. Esta droga produz muitas manifestaçöes tóxicas renais, incluindo dificuldade de acidificar e de concentrar a urina, poliúria, insuficiência renal aguda e nefropatia tubulointersticial. A poliúria é a manifestaçäo mais freqüente. Ela se desenvolve em aproximadamente 10% dos pacientes que recebem doses amnutençöes de lítio. A dificuldade de concentrar a urina resistente a vasopressina é o principal mecanismo envolvido. Diuréticos tiazídicos têm sido utilizados no tratamento da poliúria. Mais recentemente, observou-se que o amiloride, diurético poupador de potássio que atua no túbulo coletor cortical, antagoniza o efeito inibitório do lítio no transporte de água induzido pela vasopressina. Assim, o amiloride pode ser mais específico para o tratamento da políuria ineduzida pelo lítio. O mais controverso problema é se o lítio induz nefrite intersticial crônica com conseqüente insuficiência renal irreversível. Os dados disponíveis até o momento näo suportam os achados iniciais, de que terapia a longo prazo com lítio posa levar a insuficiência renal severa. É importante, para reduzir o número de efeitos renais tóxicos, realizar monitorizaçäo clínica e laboratorial adequada

Paraquat poisoning with acute renal failure--a case report.

Paraquat poisoning is relatively rare and is associated with mortality varying from 35 to 50%. A patient who consumed paraquat developed features of non-oliguric acute renal failure and recovered following haemodialysis. Renal biopsy done during the early recovery phase showed features of acute tubulo-interstitial nephritis with no disruption of tubular basement membrane. On recovery the patient had no evidence of proximal renal tubular dysfunction.