#1408 Dehydration cannot substitute for any of the triple whammy drugs to cause acute kidney injury
Authors: Baranda-Alonso Eva M , Fuentes-Calvo Isabel , Diaz-Morales Noelia , Martinez Sandra M Sancho , Salgado Carlos Martinez , Lopez-Hernandez Francisco J 
Published: May 2024

Abstract

Background and Aims
Polymedication in patients with chronic diseases, such as hypertension, can lead to undesired drug interactions. The combination of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) with diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) can cause triple whammy (TW)-induced acute kidney injury (TW-AKI). Up to 9% of hypertensive patients used NSAIDs in combination with ACEIs / ARBs and diuretics. AKI has a mortality rate of 40% and TW increases the risk of AKI by 30% compared to the combination of only two drugs. In addition, TW-AKI is associated with other risk factors such as dehydration, which may exacerbate the injury. Consequently, the aim of our study was to determine whether dehydration combined with two of the TW drugs could induce AKI in an in vivo experimental model.

Method
Three months old male Spontaneously Hypertensive Rats (SHR) were divided into four experimental groups: control group (CT); TW group (TW), which received four days of double therapy with trandolapril and furosemide, followed by a triple therapy for two days with trandolapril, furosemide and ibuprofen; trandolapril and ibuprofen group (T+I), which received four days of trandolapril followed by two days of trandolapril and ibuprofen; furosemide and ibuprofen group (F+I), which received four days of furosemide followed by two days of furosemide and ibuprofen; and trandolapril and furosemide group (T+F), which received six days of trandolapril and furosemide. All groups were subjected to a 60-70% water restriction of basal intake (i.e. 15 mL/day) to generate mild dehydration. Blood and urine samples were collected at baseline (B), day 4 and day 6. Blood pressure was measured at baseline and day 4. Renal function was assessed by plasma creatinine, plasma urea and creatinine clearance, and hydration status was determined by plasma osmolarity and water balance (i.e. water intake minus urine flow).

Results
Under basal conditions, all rats were hypertensive. The combination of trandolapril and furosemide significantly reduced the mean blood pressure on day 4 (p = 0.0066), while trandolapril or furosemide alone did not achieve these decreases. After four days of water restriction to 15 mL/day, all groups showed mild dehydration with a decrease in water balance and an increase in plasma osmolarity by. Plasma creatinine and plasma urea values were only increased on day 6 in the TW group (p = 0.0009 and p = 0.02, respectively). Creatinine clearance was also clearly reduced in the TW group (p = 0.0004). F+I and T+F groups showed slight decreases in creatinine clearance at day 6, as well as slight increases in plasma urea. However, these changes were not as pronounced as those observed in the TW group.

Conclusion
In our in vivo model of TW-AKI, mild dehydration cannot replace any of the TW drugs, although it appears that combination of F+I and T+F in dehydrated rats slightly alter plasma urea and creatinine clearance values at day 6, suggesting that this condition maintained over time might lead to the development of AKI.

Funding
This research was funded by grants from Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación (PI21/01226 and PI21/00548 co-funded by the European Union; and RICORS2040, RD21/0005/0004, co-funded by the European Union—NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR)) and from Consejería de Educación, Junta de Castilla y León (IES160P20), 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 the European Union “NextGenerationEU/PRTR”. Eva M. Baranda-Alonso is recipient of a predoctoral fellowship from the Junta de Castilla y Leon (Spain) and the European Social Fund from the European Commission.