Integrated Care Model by the Village Health Volunteers to Prevent and Slow down Progression of Chronic Kidney Disease in a Rural Community, Thailand.

INTRODUCTION: Chronic kidney disease (CKD) is a major health problem in Thailand and health behaviors are central to its risk and progression. Because of the shortage of healthcare personnel, village health volunteers (VHVs) have been collaborating in the primary health care system. However, the contribution of VHVs to CKD reduction has not been evaluated yet. This study aimed to evaluate the efficacy of the VHV-integrated model in preventing and slowing down CKD and its risk factors. METHODS: The population-based cohort study was conducted in a rural community of Thailand between 2017 and 2019. Baseline clinical and behavioral characteristics including CKD, diabetes, hypertension, and other high-risk factors of the participants were collected. The integrated care model was initiated by the multidisciplinary care team that facilitated, empowered, and trained VHVs targeting risk factors of CKD, health literacy, and health promotion. Then the participants were educated and trained for lifestyle modification and were monitored continuously for 18 months by VHVs. Changes in the CKD risk factors, and kidney functions before and after the application of integrated care model were compared. RESULTS: A total of 831 subjects participated in the study with an average age of 57.5 years, and 69.5% were female. Among them, 222 participants (26.7%) were diagnosed as having CKD, the vast majority (95%) of which were in the early stages (G1-G3 and A1-A2). CKD risk factors such as high salt intake, smoking, alcohol consumption, self-NSAID (non-steroidal anti-inflammatory drugs) use were significantly decreased after application of the care model. Also, hemoglobin A1c was significantly reduced in diabetic patients, and blood pressure was controlled better than before in the hypertensive patients. Most importantly, a decline of estimated glomerular filtration rate of the CKD group was improved and lower than the non-CKD group. CONCLUSION: The integrated care model through VHV significantly attenuated the risk factors associated with CKD in the general and high-risk population and effectively slowed down the progression of CKD.

Improving Chronic Kidney Disease Risk Factor Screening Among Older Adults: A Quality Improvement Project.

Evidence-based screening tools and guidelines for chronic kidney disease (CKD) are inconsistently utilized in primary care. A quality improvement (QI) project evaluated the impact of a CKD education workshop for interprofessional clinical staff and the implementation of the Screening for Occult Renal Disease (SCORED) risk assessment tool to improve identification of patients at risk for CKD in a primary care clinic. Results of the SCORED risk assessment indicated 92% of patient participants were at high risk for CKD. Overall, the SCORED risk assessment reinforced CKD risk factor knowledge among health care professionals.

SGLT2 inhibitor dapagliflozin protects the kidney in a murine model of Balkan nephropathy.

Proximal tubular uptake of aristolochic acid (AA) forms aristolactam (AL)-DNA adducts, which cause a p53/p21-mediated DNA damage response and acute tubular injury. Recurrent AA exposure causes kidney function loss and fibrosis in humans (Balkan endemic nephropathy) and mice and is a model of (acute kidney injury) AKI to chronic kidney disease (CKD) transition. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. C57BL/6J mice (15-wk-old) were administered vehicle or AA every 3 days for 3 wk (10 and 3 mg/kg ip in females and males, respectively). Dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. All dapa effects were sex independent, including a robust glycosuria. Dapa lowered urinary kidney-injury molecule 1 (KIM-1) and albumin (both normalized to creatinine) after the last AA injection and kidney mRNA expression of early DNA damage response markers (p53 and p21) 3 wk later at the study end. Dapa also attenuated AA-induced increases in plasma creatinine as well as AA-induced up-regulation of renal pro-senescence, pro-inflammatory and pro-fibrotic genes, and kidney collagen staining. When assessed 1 day after a single AA injection, dapa pretreatment attenuated AL-DNA adduct formation by 10 and 20% in kidney and liver, respectively, associated with reduced p21 expression. Initiating dapa application after the last AA injection also improved kidney outcome but in a less robust manner. In conclusion, the first evidence is presented that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.NEW & NOTEWORTHY Recurrent exposure to aristolochic acid (AA) causes kidney function loss and fibrosis in mice and in humans, e.g., in the form of the endemic Balkan nephropathy. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. Here we provide the first evidence in a murine model that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.

Association between an Antioxidant-Rich Japanese Diet and Chronic Kidney Disease: The Ohasama Study.

AIMS: Although physiological effects of hydrophilic- (H-) and lipophilic- (L-) antioxidant capacities (AOCs) are suggested to differ, the association of an antioxidant-rich diet and chronic kidney disease (CKD) incidence has not been examined. We therefore explored the association between the H- or L-AOC of a whole Japanese diet and CKD risk in a general population. METHODS: A total of 922 individuals without CKD (69.2% women; mean age, 59.5 years old) from Ohasama Town, Japan, were examined. CKD incidence was defined as the presence of proteinuria and/or an estimated glomerular filtration rate (eGFR) of ＜60 ml/min/1.73 m2. Consumption of H-/L-AOC was determined based on the oxygen radical absorbance capacity in a specially developed Japanese food AOC database. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for new-onset CKD using a Cox proportional hazards model. RESULTS: During the median follow-up of 9.7 years, 137 CKD incidents were recorded. After adjusting for potential confounding variables, the highest quartile of L-AOC was significantly associated with a 51% reduced CKD risk among only women. An increased L-AOC intake was more effective in preventing eGFR reduction than in preventing proteinuria in women. These associations were not seen for H-AOC intake in both sexes and L-AOC intake in men. CONCLUSIONS: A high intake of lipophilic antioxidants may be associated with a reduced CKD risk. The balance between dietary antioxidant intake and pro-oxidants induced by unhealthy lifestyles may be crucial for preventing future kidney deterioration.

Coffee consumption and risk of kidney function decline in a Dutch population-based cohort.

BACKGROUND AND AIMS: Whether coffee consumption is associated with changes in estimated glomerular filtration rate (eGFR) is unknown. We investigated the relationship between coffee consumption and annual eGFR change in a large Dutch population-based study. METHODS AND RESULTS: This study was performed in 78,346 participants without chronic kidney disease (CKD) in the population-based Lifelines Cohort Study. Coffee consumption was assessed at baseline using food frequency questionnaires. Outcomes were annual eGFR change and a composite kidney outcome (defined as eGFR <60 mL/min per 1.73 m2 or >20 % eGFR decline). Multivariable linear and logistic regression analyses were used to evaluate the associations of coffee consumption (categories and cups/day) with kidney outcomes. Overall, 90 % of the participants drank coffee daily and 36 % drank >2-4 cups/day. Unadjusted mean ± SD annual eGFR change ranged from -2.86 ± 2.96 (for non-coffee drinkers) to -2.35 ± 2.62 (for participants consuming >6 cups/day) mL/min per 1.73 m2. During 3.6 ± 0.9 years follow-up, 11.1 % of participants reached the composite kidney outcome. As compared to non-coffee drinkers, higher coffee consumption was associated with less annual eGFR decline in multivariable models (ß [95 % CIs] ranged from 0.15 [0.07, 0.22] for >0-2 cups/day to 0.29 [0.20, 0.38] for >6 cups/day, P-trend <0.001). Consumption of one more cup of coffee per day was associated with a 3 % lower risk of the composite kidney outcome (OR [95%CI], 0.97 [0.96, 0.99]). The inverse association was more pronounced in a subgroup of individuals with diabetes. CONCLUSION: Coffee consumption was inversely associated with annual eGFR change and CKD risk in a large Dutch population-based cohort.

Letramento funcional em saúde em renais crônicos: um desafio na abordagem preventiva / Alfabetización funcional en salud en pacientes renales crónicos: un desafío en el enfoque preventivo / Functional health literacy in chronic kidney disease patients: a challenge in the preventive approach

Resumo Objetivo Identificar a prevalência de letramento funcional em saúde e analisar a associação entre os níveis de letramento funcional em saúde e as variáveis clínicas e sociodemográficas em pacientes renais crônicos não dialíticos. Métodos Estudo transversal realizado com 167 renais crônicos em acompanhamento no ambulatório de nefrologia de um município de grande porte do estado de Minas Gerais, Brasil. Para as entrevistas foram utilizados questionário sociodemográfico e clínico e a versão brasileira do Short Assessment of Health Literacy for Portuguese Speaking Adults - SAHLPA-18, para mensurar o letramento funcional em saúde. Realizado estatística descritiva para variáveis sociodemográficas e clínicas; testes de correlação e modelos de regressão lineares para associação com letramento funcional em saúde. Resultados A maior parte dos participantes era idosa com mediana de idade de 68 anos, 33,3% (56 pacientes) se encontravam no estágio 3B da doença renal crônica e 53,9% (90 pacientes) apresentaram letramento funcional em saúde inadequado. Não houve associação entre os níveis de letramento funcional em saúde e as variáveis clínicas. A maioria referiu não usar internet e o estágio mais avançado da doença renal crônica apresentou menores escores de letramento. Piores escores de letramento funcional em saúde também foi identificado naqueles com menor renda. Conclusão A maioria dos participantes apresentou letramento funcional em saúde inadequado. As variaveis clínicas não foram preditoras dos ecores de letramento. No entanto, escores mais baixos de letramento em saúde foram identificados naqueles em estágio mais avancado da doença renal, menor renda e menor uso da internet.

Resumen Objetivo Identificar la prevalencia de la alfabetización funcional en salud y analizar la asociación entre los niveles de alfabetización funcional en salud y las variables clínicas y sociodemográficas en pacientes renales crónicos no dializados. Métodos Estudio transversal realizado con 167 pacientes renales crónicos con seguimiento en consultorios externos de nefrología de un municipio de gran porte del estado de Minas Gerais, Brasil. Para las entrevistas se utilizó un cuestionario sociodemográfico y clínico y la versión brasileña del Short Assessment of Health Literacy for Portuguese Speaking Adults - SAHLPA-18, para medir la alfabetización funcional en salud. Se realizó estadística descriptiva para variables sociodemográficas y clínicas, pruebas de correlación y modelos de regresión lineales para asociación con alfabetización funcional en salud. Resultados La mayoría de los participantes eran personas mayores de 68 años de mediana de edad, el 33,3 % (56 pacientes) se encontraba en la etapa 3B de la enfermedad renal crónica y el 53,9 % (90 pacientes) presentó alfabetización funcional en salud inadecuada. No hubo asociación entre los niveles de alfabetización funcional en salud y las variables clínicas. La mayoría relató que no usaba internet y la etapa más avanzada de la enfermedad renal crónica presentó menor puntaje de alfabetización. Se identificaron peores puntajes de alfabetización funcional en salud en aquellos con menores ingresos. Conclusión La mayoría de los participantes presentó alfabetización funcional en salud inadecuada. Las variables clínicas no fueron predictoras de los puntajes de alfabetización. Sin embargo, se identificaron puntajes más bajos de alfabetización en salud en aquellos en etapa más avanzada de la enfermedad renal, con menores ingresos y menor uso de internet.

Abstract Objective To identify the prevalence of functional health literacy and analyze the association between functional health literacy levels and clinical and sociodemographic variables in non-dialysis chronic kidney disease patients. Methods This is a cross-sectional study carried out with 167 chronic kidney disease patients being monitored at the nephrology outpatient clinic of a large city in the state of Minas Gerais, Brazil. For the interviews, a sociodemographic and clinical questionnaire and the Brazilian version of the Short Assessment of Health Literacy for Portuguese Speaking Adults (SAHLPA-18) were used to measure functional health literacy. Descriptive statistics were performed for sociodemographic and clinical variables, and correlation tests and linear regression models for association with functional health literacy. Results Most participants were older adults with a median age of 68 years, 33.3% (56 patients) were in stage 3B of chronic kidney disease and 53.9% (90 patients) had inadequate functional health literacy. There was no association between functional health literacy levels and clinical variables. The majority reported not using the internet and the more advanced stage of chronic kidney disease had lower literacy scores. Worse functional health literacy scores were also identified in those with lower income. Conclusion Most participants had inadequate functional health literacy. Clinical variables were not predictors of literacy scores. However, lower health literacy scores were identified in those with more advanced stage kidney disease, lower income and less internet use.

Implications of Renal Disease in Patients Undergoing Structural Interventions.

Percutaneous structural interventions have a major impact on the morbidity, mortality, and quality of life of patients by providing a lower-risk alternative to cardiac surgery. However, renal disease has a significant impact on outcomes of these interventions. This review explores the incidence, outcomes, pathophysiology, and preventative measures of acute kidney injury and chronic kidney disease on transcatheter aortic valve replacement, transcatheter mitral valve repair, and percutaneous balloon mitral valvuloplasty. Given the expanding indications for percutaneous structural interventions, further research is needed to identify ideal patients with chronic kidney disease or end-stage renal disease who would benefit from intervention.

Physical activity and nutrition in chronic kidney disease.

PURPOSE OF REVIEW: Lifestyle intervention is considered a cornerstone in chronic kidney disease management and has been recommended in different international or regional clinical practice guidelines in chronic kidney disease. However, evidence was largely based on the general population. Here we summarized the latest evidence supporting lifestyle intervention in chronic kidney disease. RECENT FINDINGS: Both observational cohort studies as well as randomized controlled trials have demonstrated health benefits with more physical activity in chronic kidney disease. There are compelling observational data supporting different health and kidney benefits with a healthy dietary pattern rich in fruits and vegetables, whole grains, plant-based foods and low in salt, low in sugar, saturated fat, red meat and ultraprocessed foods, a plant-based diet or Mediterranean diet in chronic kidney disease population. Clinical and epidemiologic studies also showed that higher 24 h urine potassium excretion (as proxy of higher dietary potassium intake) may be associated with lower blood pressure, better kidney outcomes and lower mortality in chronic kidney disease population. Randomized controlled trials also suggested that salt substitutes improved blood pressure control, reduced all-cause death and cardiovascular event risk in the general population compared with regular salt. SUMMARY: Accumulating evidence supports the current recommendation of encouraging physical activity and promoting a healthy dietary pattern in chronic kidney disease patients. Whether potassium needs restriction in chronic kidney disease diet requires further review. The safety versus benefits of salt substitutes in patients with moderate and advanced chronic kidney disease warrants further investigation.

The relationship between diabetes-related knowledge and kidney disease knowledge, attitudes, and practices: a cross-sectional study.

BACKGROUND: Diabetes mellitus (DM) is one of the main noncommunicable diseases encountered in primary health care clinics. DM is considered one of the most common causes of chronic kidney disease (CKD). In this study, we aimed to assess the knowledge, attitudes, and practices (KAP) of patients with DM on the early detection and prevention of CKD, determine its relationship with other variables, and examine the relationship between KAP scores for the prevention and early detection of CKD and the Michigan Diabetic Knowledge Test. METHODS: We collected data from 2 Nablus primary healthcare centers using a questionnaire that contains three sections: sociodemographic section, questions related to DM, and CKD screening index, which is formed of three scales. We used the Michigan Diabetic Knowledge Test (MDKT) to assess the knowledge of diabetic patients. RESULTS: The study was carried out among 386 diabetic patients with a mean age of 57.62 ± 12.4 years (ranging from 28 to 90). The median (interquartile range) was 11 (8-14) for the knowledge scale, 56 (52-59) for the attitude scale, and 30 (26-33) for the practice scale. In the multiple linear regression, only patients under 55 years old (p = 0.012), with normal BMI (p = 0.030), high educational level (p < 0.001), high monthly income (p = 0.020), and MDKT test score (p = 0.007) were significantly associated with higher knowledge score. Furthermore, patients who were over or equal to 55 years old (p = 0.007), had a high monthly income (p = 0.016), used a single oral diabetic drug (p = 0.003), had a total number of medications less than 4 (p = 0.010), and had a high knowledge and MDKT test were significantly associated with a higher attitude score. Finally, a patient with normal BMI (p = 0.002), city residency (p = 0.034), high educational level (p = 0.003), less frequent tobacco use (p < 0.001), last HbA1c (p = 0.023) and greater knowledge, attitude, and MDKT score were significantly associated with better practices toward CKD prevention and early detection. CONCLUSION: Regarding KAP analysis, higher practice scores for the prevention and early detection of CKD were significantly associated with patients with normal BMI, being city residents, high educational level, less tobacco use, last HbA1c below 7, and higher knowledge, attitude, and MDKT score.

Clinically Relevant Mesenchymal Stem/Stromal Cell Sheet Transplantation Method for Kidney Disease.

Chronic kidney disease (CKD) is the irreversible loss of nephron function, leading to a build-up of toxins, prolonged inflammation, and ultimately fibrosis. Currently, no effective therapies exist to treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cell (MSC) transplantation is a promising strategy to treat kidney diseases, and multiple clinical trials are currently ongoing. We previously demonstrated that rat bone marrow-derived MSC (BMSC) sheets transplanted onto surgically decapsulated kidney exert therapeutic effects that suppressed renal fibrosis progression based on enhanced vascularization. However, there are clinical concerns about kidney decapsulation such as impaired glomerular filtration rate and Na+ ion and H2O excretion, leading to kidney dysfunction. Therefore, for transitioning from basic research to translational research using cell sheet therapy for kidney disease, it is essential to develop a new cell sheet transplantation strategy without kidney decapsulation. Significantly, we employed cell sheets engineered from clinical-grade human clonal BMSC (cBMSC) and transplanted these onto intact renal capsule to evaluate their therapeutic ability in the rat ischemia-reperfusion injury (IRI) model. Histological analysis 1-day postsurgery showed that cBMSC sheets engrafted well onto intact renal capsule. Interestingly, some grafted cBMSCs migrated into the renal parenchyma. At 1-3 days postsurgery (acute stage), grafted cBMSC sheets prevented tubular epithelial cell injury. At 28 days postsurgery (chronic phase), we observed that grafted cBMSC sheets suppressed renal fibrosis in the rat IRI model. Taken together, engineered cBMSC sheet transplantation onto intact renal capsule suppresses tubular epithelial cell injury and renal fibrosis, supporting further development as a possible clinically relevant strategy. Impact statement Chronic kidney disease (CKD) produces irreversible loss of nephron function, leading to toxemia, prolonged inflammation, and ultimately kidney fibrosis. Currently, no therapies exist to effectively treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cells (MSCs) are widely known to secret therapeutic paracrine factors, which is expected to provide a new effective therapy for unmet medical needs. However, unsatisfied MSC quality and administration methods to patients limit their therapeutic effects. In this study, we engineered clonal bone marrow-derived MSC sheets and established clinically relevant cell sheet transplantation strategy to treat renal fibrosis, which would improve MSC treatment for kidney disease.

The effect of the Kasuya CKD network on prevention of the progression of chronic kidney disease: successful collaboration of a public health service, primary care physicians and nephrologists-community based cohort study.

BACKGROUND: In 2012, we established a CKD network in collaboration with the public health service, primary care physicians, and nephrologists in the Kasuya area. The aim of this study was to clarify if our CKD network was effective in preventing CKD progression. METHODS: 1591 subjects, who had CKD in health checks in 2012 were included in this study. The slope of estimated glomerular filtration rate (eGFR) was compared before and after 2012. Parameters at the first health check visit before 2012, visit in 2012, and the last visit after 2012, were compared. Paired t test, analysis of variance for repeated measurements, and the Friedman test were used for the analysis. RESULTS: Mean age was 65 years. There were 781 men and 810 women. Mean eGFR was 59 ml/min/1.73 m2. The mean slope of eGFR before 2012 was -1.833 ml/min/1.73 m2/year and significantly reduced to - 0.297 after 2012. Low-density lipoprotein cholesterol showed a significant serial lowering. Uric acid was significantly elevated in 2012 compared to the first visit and had decreased by the last. The dipstick urinary protein significantly increased in 2012 compared to the first visit and decreased by the last. The number of current smokers showed a significant reduction over time. On the other hand, systolic blood pressure (SBP) and HbA1c significantly elevated at the last visit. CONCLUSION: The Kasuya CKD network may be effective in preventing CKD progression.

Irisin protects against obesity-related chronic kidney disease by regulating perirenal adipose tissue function in obese mice.

BACKGROUND: Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. METHODS: C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. RESULTS: Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor-nitric oxide axis. CONCLUSIONS: Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT-kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.

Perinatal Garlic Oil Supplementation Averts Rat Offspring Hypertension Programmed by Maternal Chronic Kidney Disease.

Garlic (Allium sativum) is a functional food, having hydrogen sulfide (H2S)-releasing capacity, which exhibits considerable effects on hypertension and gut microbiota. H2S is strongly associated with hypertension and chronic kidney disease (CKD). Maternal CKD leads to hypertension in adult rat progeny, which was linked to disruption of the gut microbiota. This study validated the benefits of perinatal garlic oil supplementation against offspring hypertension induced by maternal CKD via modulation of H2S signaling, nitric oxide (NO), and the gut microbiota. Before pregnancy, female rats received a 0.5% adenine diet for 3 weeks to develop an animal model to mimic human CKD. Garlic oil (100 mg/kg/day) or vehicle was administered to pregnant rats by oral gavage during gestation and lactation. Perinatal garlic oil supplementation protected against maternal CKD-induced hypertension in offspring at 12 weeks of age. The beneficial effects of garlic oil are associated with enhanced H2S signaling, increased NO bioavailability, and shifts in gut microbiota. Perinatal garlic oil supplementation reduces abundance of genera Variovorax, Nocardia, Sphingomonas, and Rhodococcus. Our findings provide insight into the role of early H2S-targeted intervention as a preventive strategy in hypertension for further translational research.

Oxidant- induced preconditioning: A pharmacologic approach for triggering renal 'self defense'.

Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given these facts, a multitude of experimental studies have addressed potential methods for inducing AKI prevention in high-risk patients. However, successful clinical translation of promising experimental data has remained elusive. Over the past decade, our laboratory has focused on developing a method for safely triggering AKI protection by inducing "kidney preconditioning" in mice by the intravenous administration of a combination of Fe sucrose (FeS) + tin protoporphyrin (SnPP). These agents induce mild, but short lived, 'oxidant stress' which synergistically activate a number of kidney 'self-defense' pathways (e.g., Nrf2, ferritin, IL-10). Within 18-24 h of Fe/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS/SnPP-mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called "organ cross talk" phenomenon. Given these promising experimental data, three phase 1b clinical trials were undertaken in healthy subjects and patients with stage 3 or 4 CKD. These studies demonstrated that FeS/SnPP were well tolerated and that they up-regulated the cytoprotective Nrf2, ferritin, and IL-10 pathways. Two subsequent phase 2 trials, conducted in patients undergoing 'on-pump' cardiovascular surgery or in patients hospitalized with COVID 19, confirmed FeS/SnPP safety. Furthermore, interim data analyses revealed statistically significant improvements in several clinical parameters. The goals of this review are to: (i) briefly discuss the historical background of renal "preconditioning"; (ii) present the experimental data that support the concept of FeS/SnPP- induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an 'oxidant preconditioning' strategy.

Exercise reduces the risk of chronic kidney disease in individuals with nonalcoholic fatty liver disease: A nationwide cohort study.

AIMS: Recent studies of individuals with nonalcoholic fatty liver disease (NAFLD) have indicated benefits of exercise in improving outcomes. We investigated whether exercise reduces the risk of chronic kidney disease (CKD) in individuals with NAFLD. METHODS: A total of 7275 participants from the Korea National Health and Nutrition Examination Survey (KNHANES) cohort, and 40,418 participants with NAFLD from the National Health Insurance Service (NHIS) cohort were included for the cross-sectional and longitudinal analyses, respectively. For the cross-sectional analysis, the primary outcome was prevalent CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. For the longitudinal analysis, the primary outcome was incident CKD, defined as the occurrence of eGFR <60 mL/min/1.73m2 or proteinuria (≥ trace) on two consecutive measurements during follow-up. RESULTS: In the KNHANES cohort, prevalent CKD was observed in 229 (6.1%), 48 (2.6%), and 36 (2.1%) participants in the 0, 1-2, and ≥ 3 exercise sessions/week groups, respectively. The likelihood of prevalent CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted OR 0.49; 95% CI, 0.33-0.71; P < 0.001). During a median follow-up of 5.0 years in the NHIS cohort, incident CKD occurred in 1,047 (9.7/1,000 person-years), 188 (7.3/1,000 person-years), and 478 (7.4/1,000 person-years) participants in the 0, 1-2, and ≥ 3 sessions/week groups, respectively. The risk of incident CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted HR 0.85; 95% CI, 0.76-0.95; P = 0.004). CONCLUSIONS: Exercise was significantly associated with a reduced risk of both prevalent and incident CKD in individuals with NAFLD.

Long-term consumption of a mediterranean diet or a low-fat diet on kidney function in coronary heart disease patients: The CORDIOPREV randomized controlled trial.

BACKGROUND & AIMS: Lifestyle and dietary habits influence kidney function, playing an important role in the prevention and development of chronic kidney disease (CKD). The effectiveness of the Mediterranean diet in preserving kidney function has been seen in primary prevention. However, no scientific evidence is currently available to determine which dietary pattern is more effective in the management of CKD in secondary cardiovascular disease prevention. Thus, our aim was to evaluate the efficacy of the long-term consumption of two healthy dietary patterns (a Mediterranean diet rich in extra-virgin olive oil (EVOO) compared to a low-fat diet rich in complex carbohydrates) in preserving kidney function in coronary heart disease (CHD) patients. METHODS: CHD patients (n = 1002) from the CORDIOPREV study were randomized to follow a Mediterranean diet (35% fat, 22% MUFA, <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, >55% carbohydrates). Kidney function was assessed by the determination of serum creatinine-based estimated glomerular filtration rate (eGFR) at baseline and after 5-years of dietary intervention. Patients were classified according to their type 2 diabetes (T2DM) status, using baseline eGFR (normal eGFR: ≥ 90 mL/min/1.73 m2; mildly-impaired eGFR: 60 to <90 mL/min/1.73 m2, severely-impaired eGFR: <60 mL/min/1.73 m2) to evaluate its influence on the progression of kidney function. Multiple linear regression analysis were performed to determine the contribution of different clinical and anthropometric parameters to changes in eGFR. RESULTS: Although eGFR declined after both dietary interventions compared to baseline (all p < 0.001), the Mediterranean diet produced a lower decline of eGFR compared to the low-fat diet in patients with T2DM (p = 0.040). This effect was also observed when the overall population was considered (p = 0.033). No significant differences were observed in eGFR between the two diets in non-T2DM patients. In addition, this differential effect of the Mediterranean diet was mainly observed in patients with mildly-impaired eGFR in which this diet slowed eGFR progression (p = 0.002). CONCLUSIONS: The long-term consumption of a Mediterranean diet rich in EVOO, when compared to a low-fat diet, may preserve kidney function, as shown by a reduced decline in eGFR in CHD patients with T2DM. Patients with mildly-impaired eGFR may benefit more from the beneficial effect of the consumption of the Mediterranean diet in preserving kidney function. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular disease prevention. CLINICAL TRIAL REGISTRATION: URL, http://www.cordioprev.es/index.php/en. Clinicaltrials.gov number, NCT00924937.

Pretherapeutic estimated glomerular filtration rate predicts development of chronic kidney disease in patients receiving PSMA-targeted radioligand therapy.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) may be associated with renal toxicity. We aimed to identify predictive parameters for the development of chronic kidney disease (CKD) in patients with metastatic castration resistant prostate cancer (mCRPC) undergoing RLT. METHODS: In 46 mCRPC patients scheduled for Lu-177-PSMA-RLT, pretherapeutic estimated glomerular filtration rate (eGFR [ml/min/1.73 m2 ]), Tc-99m-mercaptoacetyltriglycine (Tc-99m-MAG3) clearance and baseline Ga-68-PSMA-ligand positron emission tomography (PET)-derived renal cortical uptake and PSMA-tumor volume (TV) were determined. We tested the predictive capability of these parameters and clinical risk factors for the occurrence of CKD (defined as CTCAE vers. 5.0 grade 2 or higher) during follow-up. RESULTS: After 4 ± 3 cycles of RLT average eGFR declined from 76 ± 17 to 72 ± 20 ml/min/1.73 m2 (p = 0.003). Increased estimated renal radiation dose (eRRD) was significantly associated with renal functional decline (p = 0.008). During follow-up, 16/46 (30.4%) developed CKD grade 2 (no grade 3 or higher). In receiver operating characteristic (ROC) analysis, pretherapeutic eGFR was highly accurate in identifying the occurrence of CKD vs no CKD with an area under the curve (AUC) of 0.945 (p < 0.001; best threshold, 77 ml/min/1.73 m2 ), followed by Tc-99m-MAG3-derived tubular extraction rate (TER; AUC, 0.831, p < 0.001; best threshold, 200 ml/min/1.73 m2 ). Renal PET signal (p = 0.751) and PSMA-TV (p = 0.942), however, were not predictive. Kaplan-Meier analyses revealed adverse renal outcome for patients with lower eGFR (p = 0.001) and lower scintigraphy-derived TER (p = 0.009), with pretherapeutic eGFR emerging as the sole predictive parameter in multivariate analysis (p = 0.007). CONCLUSION: Serious adverse renal events are not a frequent phenomenon after PSMA-targeted RLT. However, in patients developing moderate CKD after RLT, pretherapeutic eGFR is an independent predictor for renal impairment during follow-up.

Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation.

BACKGROUND: Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI. METHODS: To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy. RESULTS: In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment. CONCLUSIONS: Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can inhibit liver fibrogenesis in animal models. We aimed to evaluate the impact of ACEI/ARB use on the risk of liver cancer and cirrhosis complications in patients with NAFLD. APPROACH AND RESULTS: We conducted a retrospective, territory-wide cohort study of adult patients with NAFLD diagnosed between January 2000 and December 2014 to allow for at least 5 years of follow-up. ACEI or ARB users were defined as patients who had received ACEI or ARB treatment for at least 6 months. The primary endpoint was liver-related events (LREs), defined as a composite endpoint of liver cancer and cirrhosis complications. We analyzed data from 12,327 NAFLD patients (mean age, 54.2 ± 14.7 years; 6163 men [50.0%]); 6805 received ACEIs, and 2877 received ARBs. After propensity score weighting, ACEI treatment was associated with a lower risk of LREs (weighted subdistribution hazard ratio [SHR], 0.48; 95% CI, 0.35-0.66; p < 0.001), liver cancer (weighted SHR, 0.46; 95% CI, 0.28-0.75; p = 0.002), and cirrhosis complications (weighted SHR, 0.42; 95% CI, 0.27-0.66; p < 0.001), but ARB was not. In subgroup analysis, ACEI treatment was associated with greater reduction in LREs in patients with chronic kidney diseases (CKDs) than those without (CKD-weighted SHR, 0.74; 95% CI, 0.52-0.96; p = 0.036; non-CKD-weighted SHR, 0.15; 95% CI, 0.07-0.33; p < 0.001). CONCLUSIONS: ACEI, rather than ARB, treatment is associated with a lower risk of LREs in NAFLD patients, especially among those with CKD.