Pathophysiological mechanisms underlying a rat model of triple whammy acute kidney injury


Simultaneous administration of certain antihypertensive (renin–angiotensin system inhibitors and diuretics) and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a renal toxicity syndrome known as “triple whammy” acute kidney injury (TW-AKI), yet poorly characterized at the pathophysiological level, as no specific experimental model exists on which to conduct preclinical research. Herein, we generated and characterized a rat model of TW-AKI (0.7 mg/kg/day trandolapril +400 mg/kg/day ibuprofen +20 mg/kg/day furosemide). Double treatments involving the NSAID caused a subclinical acute kidney injury, as they reduced glomerular filtration rate to a significant but not sufficient extent to increase Crpl concentration. Only the triple treatment generated an overt AKI with increased Crpl provided that animals were under partial water ingestion restriction. Histological examination revealed no evidence of tissue renal injury, and no proteinuria or makers of renal damage were detected in the urine. These findings, along with a normal fractional excretion of sodium and glucose, indicated that these drug combinations produce a prerenal type of AKI. In fact, blood pressure and renal blood flow were also reduced (most markedly following the triple combination), although renal dysfunction was more pronounced than expected for the corresponding pressure drop, supporting a key pathological role of the interference with renal autoregulation mechanisms. In summary, prerenal TW-AKI only occurs when volemia is challenged (i.e., by furosemide in partially water-deprived animals) under the effects of renin–angiotensin system inhibitors and NSAIDs. This model will facilitate further pathophysiological knowledge for a better diagnosis and clinical handling of this syndrome.

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Fig. 1: Triple whammy induces overt AKI, whereas double and single treatments do not.
Fig. 2: Triple whammy induces a prerenal AKI: histological analysis.
Fig. 3: Triple whammy induces a prerenal AKI: urinary biochemical evidence.
Fig. 4: Blood pressure reduction does not suffice to cause triple whammy AKI.
Fig. 5: Effect of triple whammy on renal blood flow.
Fig. 6: Critical effect of partial restriction of water ingestion for triple whammy (TW) AKI.
Fig. 7: Effect of autoregulation on the relationship between blood pressure and glomerular filtration rate.


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This study was supported by grants from the Government of Spain [Instituto de Salud Carlos III (PI14/01776, DT15S/00166, PI15/01055 and PI18/00996, PI19/00588 and Retic RD016/0009/0025, REDINREN), Ministerio de Economía y Competitividad (IPT-2012-0779-010000)], FEDER funds, the Canada 150 Research Chair program and the NSERC Discovery grant program.

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Correspondence to Francisco J. López-Hernández.

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Prieto-García, L., Vicente-Vicente, L., Blanco-Gozalo, V. et al. Pathophysiological mechanisms underlying a rat model of triple whammy acute kidney injury. Lab Invest (2020).

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