#1962 Development of triple-whammy induced pre-renal AKI is highly dependent on the hydration status
Authors: Diaz-Morales Noelia , Carniglia Giada , Baranda-Alonso Eva M , Düwel Annette , Martín-Fernández Nuria , Martinez Sandra M Sancho , Salgado Carlos Martinez , Lopez-Hernandez Francisco J 
Published: May 2024

Abstract

Background and Aims
The concomitant use of diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), and angiotensin system inhibitors is known as Triple Whammy (TW) and significantly increases the risk of acute kidney injury (AKI) due to a reduction in the glomerular filtration rate. Maintenance of hydration contributes to correct kidney perfusion, and effective renal haemodynamic regulation allows the kidneys to cope with everyday stressors and challenges, such as TW therapy. Interference with these adaptive mechanisms frequently occurs due to extrinsic (environmental conditions, lifestyle, drugs) or intrinsic (comorbidities, ageing) factors and may lead to dehydration, a negative body liquid balance with a high impact on health. Identifying modifiable risk factors that pose individuals at high risk of AKI following TW therapy is key for the search and prescription of preventive strategies in a personalized manner. The aim of this work was to study the role of hydration status on the renal effect of TW.

Method
Two-month-old male Wistar rats were divided into 3 experimental groups:
Blood and 24-hour urine samples were collected at basal state (B), two days after water deprivation (D0), and two days after TW therapy (D2). Body weight was monitored during the experiment.
Haematocrit was assessed from blood samples, and osmolality, concentration of creatinine (Jaffe reaction), and urea (Jung method) were determined in plasma. Urinary flow was recorded, and specific gravity, osmolality and creatinine concentration were measured in urine samples.

Results
Dehydration was observed after 48 h water deprivation, evidenced by a 12% weight loss and significant increases in haematocrit and plasma osmolality. As expected, during this dehydrated state rats excreted a very reduced volume of a highly concentrated urine with elevated levels of specific gravity and osmolality.
No changes in renal function were observed after 48 h water deprivation, nor after TW treatment in fully hydrated rats. Administration of TW triggered significant alterations of the renal function, indicative of AKI, only in rats previously deprived of water for 48 h. These alterations were markedly increased when dehydration was partially sustained during the TW treatment by a 60% water restriction.

Conclusion
TW-induced AKI in young Wistar rats is facilitated when the hydration status worsens. In this sense, assessing hydration and implementing (re)hydration strategies may help to reduce or prevent TW-induced AKI.
This study was supported by Project PI21/01226, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and a grant from the Conserjería de Educación, Junta de Castilla y León (IES160P20), Spain, co-funded by FEDER funds. Noelia Diaz-Morales is recipient of a Juan de la Cierva-Formación postdoctoral contract (FJC2020-043205-I) funded by MCIN/AEI/10.13039/501100011033 and European Union “NextGenerationEU/PRTR”.