Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still mix up CKD with chronic kidney insufficiency or failure, For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus, health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is “solved” by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated aging and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality which is 10- o 100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients (AAKP) and the European Kidney Health Alliance (EKHA). Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true.

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BACKGROUND AND AIMS Frailty is a pre-morbid condition characterized by physiological decline and reduced physiological reserve leading to increased vulnerability to disease, especially common among older adults. Tissue and organ function is underpinned by effective haemodynamic regulation coping with everyday acute challenges and stressors. Impairment of the haemodynamic response may lead to tissue hypoperfusion and subsequent adverse events, such as acute kidney injury (AKI) and others. ‘Haemodynamic frailty’ defines a clinically silent condition characterized by a compromised haemodynamic reserve and impaired adaptive response to supervening circumstances (i.e. stressors such as drugs). Yet, frailty also offers a window of opportunity for disease prevention and health maintenance. Dehydration, hypertension and some drugs are important causes of haemodynamic frailty [1]. In this work, we aimed to develop a pre-clinical model of haemodynamic frailty, based on dehydration and hypertension, predisposing to AKI. METHOD Three-month old male spontaneously hypertensive (SHR) rats were divided into four groups: (1) Control (CT): rats with ad libitum access to drinking water, receiving saline solution (0.9% NaCl, i.p.). (2) Cisplatin (CDDP): rats with ad libitum access to drinking water, receiving a sub nephrotoxic dose of cisplatin (2.5 mg/kg, i.p.). (3) Water deprivation (WD): rats with no access to drinking water during 48 h, receiving saline solution (0.9% NaCl, i.p.). (4) Water deprivation + cisplatin (WD + CDDP): rats with no access to drinking water during the 48 h previous to the cisplatin administration (2.5 mg/kg, i.p.). The dose of cisplatin had proved to be sub-nephrotoxic for normal rats in our previous studies [2]. 24-hour urine and tail vein blood samples were collected at basal state (B), 2 days after water deprivation (D0), and 4 days after cisplatin administration (D4, day of maximum kidney damage). Urine samples were analysed for volume (urinary flow), specific gravity, osmolality, and proteinuria (Bradford method). Haematocrit was calculated from blood samples and plasma was used to determine osmolality, concentration of creatinine (Jaffe reaction) and urea (Jung method). RESULTS SHR rats with 48 hours of water deprivation showed a 10% weight loss, increases in haematocrit and plasma osmolality and a highly concentrated urine (with elevated levels of urine specific gravity and osmolality), which indicates a moderate to severe state of dehydration. No alterations in renal function were observed after water deprivation. Administration of cisplatin triggered significant increases in plasma creatinine, plasma urea and proteinuria, indicative of AKI, only in rats previously deprived of water for 48 h. All the parameters studied remained normal in cisplatin-treated rats without water restriction. Our results suggest that our experimental animal model, based on a combination of hypertension and dehydration, reproduces a state of haemodynamic frailty in which rats become predisposed to undergoing renal failure following exposure to stressors (e.g. a sub-nephrotoxic dose of cisplatin) that are harmless to haemodynamically competent rats. CONCLUSION To our knowledge, this is the first experimental model of haemodynamic frailty predisposing to AKI. This model will allow us to further study mechanisms and biomarkers useful for diagnosis and stratification of haemodynamic frailty in order to develop strategies to prevent undesired health outcomes, including renal damage.

BACKGROUND AND AIMS Hypertension has a high prevalence in adult population and represents an important cause of premature death worldwide. Its treatment often consists of the combination of several antihypertensive drugs, including angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) and diuretics. Hypertensive patients eventually receive analgesic treatments linked to other pathologies. The combination of antihypertensive treatments (ACEi/ARB and diuretics) with non-steroidal anti-inflammatory drugs (NSAIDs) may generate an acute kidney injury (AKI) due to a reduction in the glomerular filtration rate. According to different studies, the incidence of AKI following this triple therapy or Triple Whammy (TW) ranges from < 1% to up to 22%. This suggests that additional factors determine the renal impact of the TW. Because the incidence of TW-induced AKI is higher among older adults, and because the prevalence of dehydration is especially elevated among them, the aim of our study was to model in rats the influence of water restriction and ageing on the renal effect of the TW. METHOD Male Spontaneously Hypertensive Rats (SHR) of 3 and 7 months of age were divided in four experimental groups: control group (CT), control group with 60%–70% water restriction of basal intake (i.e. 15 mL/day) (CT-WR), TW group (TW), and TW group with 60%–70% water restriction of basal intake (i.e. 15 mL/day) (TW-WR). Both TW groups received antihypertensive treatment with Trandolapril in drinking water and Furosemide i.p. for 4 days, and then a triple therapy for 2 days with Trandolapril and Ibuprofen in drinking water and Furosemide i.p. Urine and blood samples were collected at basal state (B), after 4 days of the combined treatment of Trandolapril + Furosemide (day 4) and two days after adding ibuprofen treatment (day 6). Blood pressure was measured on B and day 4, and the kidneys were removed at the end of the experiment. We analyzed the hydration status (water balance), the renal function (plasma creatinine and urea determination) and renal histological alterations (hematoxylin–eosin staining). RESULTS Antihypertensive treatment decreased systolic blood pressure in the TW and TW-WR groups, and did not induce any effects in CT and CT-WR groups. Water balance was lower in CT-WR, TW and TW-WR groups than in CT group, which may indicate partial dehydration, being this balance negative in TW-WR group. No differences in creatinine and plasma urea levels were found on day 6 between 3- and 7-months-old rats in TW group. An experimental AKI was observed in rats treated with TW and water restriction, characterized by increased creatinine and plasma urea; this experimental AKI was more severe in 7-month-old rats. CT and CT-WR groups showed normal renal function. There were no histological alterations in any of the experimental groups. CONCLUSION Water restriction is an important risk factor in the development of AKI in TW therapy, and although age differences do not have a relevant effect on their own, the combination of age and water restriction increases the risk.

Background and Aims Renin-angiotensin system inhibitors, diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) is known as Triple Whammy (TW), a common combination used in hypertensive patients suffering from pain or inflammation; this combination of drugs can cause in some cases acute kidney injury (AKI). The renal outcome of the TW therapy seems to be influenced by additional factors, as the incidence of TW-induced AKI ranges from <1% to up to 22% depending on the study. The incidence of TW-AKI is higher among older adults, therefore age and other clinical conditions such as dehydration could be associated with TW-AKI. Furthermore, loss of functional nephrons in chronic kidney disease is a risk or predisposing factor for new AKI episodes. Consequently, the aim of our study was to analyse in vivo the influence of dehydration, age, renal mass reduction and hypertension (HTA) in TW therapy-induced AKI. Method Five experimental groups were subjected to TW therapy: (1) control group (3 months old Wistar rats); (2) dehydrated rats (3 months old Wistar rats with 60-70% water restriction); (3) aged rats (16 month old Wistar rats); (4) renal mass reduction (RMR) rats (3 months old Wistar rats with a 5/6 reduction of renal mass one month before the experiment); and (5) 3 months old spontaneously hypertensive rats). All rats received antihypertensive double therapy with Trandolapril in water and Furosemide i.p. for 4 days, and then a triple therapy for 2 days with Trandolapril and Ibuprofen in drinking water and Furosemide i.p. Blood and urine samples were collected at baseline (B), after 4 days of double therapy (day 4) and two days after triple therapy (day 6). Renal outcomes of the TW therapy were analysed by plasma creatinine, creatinine clearance, plasma urea and proteinuria. Results Risk factors such as dehydration or the loss of nephrons significantly increase plasma creatinine and urea and reduce creatinine clearance at day 6 compared to 3 months old Wistar rats without risk factors. Creatinine clearance is significantly reduced at day 4 in RMR and dehydration groups. Also, the RMR group shows at baseline and day 4 decreased creatinine clearance and increased plasma creatinine and urea than 3 months old Wistar rats. Proteinuria values are within normal ranges (< 10mg/day) in all experimental groups. Conclusion Renal mass reduction and dehydration are important risk factors in the development of AKI after TW therapy, while hypertension and age do not seem to influence renal outcomes. The knowledge of the specific conditions and the different factors that increase the risk of developing AKI in patients undergoing TW therapy will help us to stratify these patients based on their individual risk and to apply in each case the appropriate individualized treatment. This research was funded by grants from Instituto de Salud Carlos III (ISCIII) PI21/00548 and PI21/01226 co-funded by the European Union and Red de Investigación Renal RICORS2040 (Kidney Disease), RD21/0005/0004 co-funded by the European Union – NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR). 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.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”.

Background and Aims Renal frailty (RF) is a premorbid and, at least partly, modifiable condition arising from diminished renal functional reserve and defective adaptive response capacity predisposing to acute kidney injury (AKI). RF ensues from subclinical wear or distortion of the renal haemodynamic and tubular homeostatic responses that defend the renal excretory function from supervening circumstances (i.e., stressors such as drugs). In this work, we aimed to study the impact of RF generated by the combined effect of the hydration state, hypertension and ageing on the nephrotoxicity developed by a low dose of cisplatin in the rat. Method Young Wistar rats, young spontaneously hypertensive rats (SHR), and aged Wistar rats were used. Rats in each group were randomly subject to four experimental conditions: - Control: rats with ad libitum water intake, receiving vehicle (0.9% NaCl, i.p). - Cisplatin: rats with ad libitum water intake, treated with 2.5 mg/kg, i.p. cisplatin. - Water deprivation: rats deprived of water for 48 h, receiving vehicle (0.9% NaCl, i.p.). - Water deprivation + cisplatin: rats deprived of water for the 48 h prior to 2.5 mg/kg i.p. cisplatin administration. Tail vein blood and 24-hour urine samples were collected at basal time (B), after water deprivation (D0), and 4 days after cisplatin/vehicle administration (D4, day of maximum kidney damage). Haematocrit was measured and plasma osmolality, plasma creatinine (Jaffe reaction) and urea (Jung method) concentrations were determined. Urine samples were analysed for volume (urinary flow), osmolality, and proteinuria (Bradford method). Body fluid composition was measured by bioimpedance spectroscopy with an ImpediVETTM VetBIS1 device. Results All rats showed clear signs of dehydration after 48 hours of water deprivation: weight loss, increases in plasma osmolality and haematocrit (more pronouncedly in young Wistar and SHR than in aged animals), and reduced flow of a highly concentrated urine (i.e., with elevated osmolality). Bioimpedance analysis revealed a parallel loss of intracellular and extracellular water and net loss of total body water (explaining most of weight loss), with no changes in the liquid distribution between the intracellular and extracellular compartments. Dehydration was reverted after 4 days of rehydration in vehicle-treated rats, and no alteration of renal function was observed due to water deprivation. Administration of cisplatin in young, normohydrated Wistar rats showed minimal loss of renal function that was not worsened by water deprivation. Hypertensive rats showed completely normal renal function when cisplatin was administered under normohydration. Interestingly, however, dehydrated SHR did suffer a cisplatin-induced AKI (significant increases in plasma creatinine, plasma urea and proteinuria). In aged Wistar rats, cisplatin compromised renal function (as supported by increases in plasma creatinine and urea concentration), and this effect was significantly amplified by water deprivation. Conclusion This study suggests that dehydration in fully competent young rats is not in itself a significant risk factor for AKI, while the combination of dehydration and hypertension in young rats significantly increases the risk of AKI. Furthermore, ageing poses animals in a state of frailty that renders their kidneys unable to respond to stressors (such as a low dose of cisplatin). Frailty is boldly worsened in dehydrated aged animals. In perspective, models reproducing conditions of increased vulnerability to AKI provide useful tools to search for biomarkers pre-emptively predicting undesired health outcomes before exposure to stressors, and for developing preventing strategies. 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 Consejería 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”.