CKD Progression Research Articles

Excess body weight, duration of insulin and antihypertensive therapy slow down the rate of progression of chronic kidney disease in type 2 diabetes

Objective: to study and clinically substantiate the relationship between overweight and the dynamics of CKD progression in patients with type 2 diabetes of different age groups using the diagnostic parameter Index of glomerular filtration rate reduction. Material and methods: a single-stage cross-sectional observational study of clinical indicators in a population sample of patients with type 2 diabetes of different age groups was performed, patterns of relationships, significance of differences in mean values and measures of influence (OR (95%CI)) were studied between the indicators of BMI, the stage of obesity and the presence of a diagnosis of obesity in the anamnesis and the original calculated diagnostic parameter, the Index of glomerular filtration rate reduction (RI_GFR), which allows to give an objective quantitative characteristic of the rate of progression of CKD. Results: significant correlations were established between RI_GFR and indicators of age, BMI, DM experience and duration of insulin therapy, a significant inverse relationship with BMI was noted only in the older group; when analyzing differences in the average values of clinical indicators in the groups of rapid and slow progression of CKD, divided by the threshold value of RI_GFR, significant factors affecting the rate of progression were determined CKD: DM experience, duration of insulin therapy, BMI; the logistic regression analysis determined the measure of the influence of the above factors on the dynamics of GFR reduction, confirmed its significance; when analyzing the factors of drug treatment in the elderly group, it was revealed that an integrated approach to the appointment of antihypertensive therapy (prescribing drugs of three or more groups) significantly reduces the risk of rapid progression of CKD. Conclusions: the most significant risk factors for the high rate of progression of CKD in patients with type 2 diabetes and overweight in the general sample and in patients of the older age group are the length of diabetes and duration of insulin therapy; the dynamics of GFR reduction in patients with type 2 diabetes of different age groups is interrelated with BMI, and in patients with overweight CKD progresses more slowly; an integrated approach to prescribing antihypertensive therapy (prescribing drugs of three or more groups) in elderly patients with type 2 diabetes significantly reduces the risk of rapid progression of CKD.

Smoking status, cadmium, and chronic kidney disease

Abstract Background Chronic kidney disease (CKD) affects 10% of the general population in Western countries. Currently, CKD cannot be cured and there are only few strategies to prevent the onset of CKD, to reverse early stages of CKD, and to prevent the progression of established CKD to end-stage kidney disease. Cigarette smoking is a preventable cause of CKD. Methods This narrative review analyses the cause–effect relationship between cigarette smoking and CKD and discusses the association of inhaled cadmium and smoking-induced kidney damage. Results Cigarette smoking places individuals at risk for incident CKD. It accelerates the progression (decline in glomerular filtration rate, aggravation of proteinuria) of CKD to end-stage kidney disease (ESKD), and is associated with shortened kidney transplant graft survival. These harmful effects on kidney function/structure are dependent on the dose and duration of cigarette smoking. Smoking abstinence decreases the higher risk for proteinuria and CKD progression. Inhaled cadmium may be the biologic link between cigarette smoking and kidney dysfunction. Recent studies indicate that accumulation of cadmium in the blood mediates progression of CKD and places smokers at higher risk for all-cause mortality. Conclusions Smoking cessation is an effective intervention to reduce the risk of onset and progression of CKD as well as to reduce smoking-attributable morbidity and mortality.

Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis

We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023. A total of 1944 subjects or individuals from 17 studies were included in our final analysis. The correlation coefficient (r) between sKlotho and calcium was [0.14, (0.02, 0.26)], and a moderate heterogeneity was observed (I2 = 66%, P < 0.05). The correlation coefficient (r) between Klotho and serum phosphate was [− 0.21, (− 0.37, − 0.04)], with apparent heterogeneity (I2 = 84%, P < 0.05). The correlation coefficient (r) between sKlotho and parathyroid hormone and vascular calcification was [− 0.23,(− 0.29, − 0.17); − 0.15, (− 0.23, − 0.08)], with no significant heterogeneity among the studies. (I2 = 40%, P < 0.05; I2 = 30%, P < 0.05). A significant correlation exists between low sKlotho levels and an increased risk of CKD–MBD in patients with CKD. According to the findings, sKlotho may play a role in alleviating CKD–MBD by lowering phosphorus and parathyroid hormone levels, regulating calcium levels, and suppressing vascular calcification. As analysis showed that sKlotho has an important impact on the pathogenesis and progression of CKD–MBD in CKD patients. Nonetheless, further comprehensive and high-quality studies are needed to validate our conclusions.

Association of Dietary Inflammatory Index with CKD progression and estimated glomerular filtration rate in the American CKD population: A cross-sectional study.

The number of CKD patients is on the rise worldwide, and diet has become an essential aspect influencing the treatment and prognosis of CKD. However, limited research has explored the association of the Dietary Inflammatory Index (DII) with CKD progression and the essential kidney function indicator, eGFR, in CKD patients. This study aimed to analyze the association between DII and CKD progression and eGFR in the US CKD population using data from the National Health and Nutrition Examination Survey (NHANES). This study utilized data obtained from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018, with a total sample size of 2,488 individuals. Study used multiple imputation, based on 5 replications and a chained equation approach method in the R MI procedure, to account for missing data. Weighted multiple logistic regression was used to analyze the relationship between DII and the risk of higher CKD stage and a weighted multiple regression analysis was used to assess the relationship between DII and eGFR. Weighted Generalized Additive Models and smoothed curve fitting were applied to detect potential non-linear relationships in this association. In all three models, it was found that DII was positively associated with the risk of higher CKD stage (P < 0.0001), and an increase in DII was associated with a decrease in eGFR (P < 0.0001). The trend across quartiles of DII remained statistically significant, revealing a gradual elevation in higher CKD stage risk and reduction in eGFR levels for the second, third, and fourth quartiles compared to the lowest quartile (P for trend < 0.0001). Upon adjusting for age, gender, race, education level, poverty income ratio (PIR), marital status, body mass index (BMI), metabolic equivalent (MET) score, drinking, smoking, history of hypertension, history of diabetes, cotinine, systolic blood pressure, diastolic blood pressure, total triglycerides, and total cholesterol, we found a positive correlation between DII and the risk of higher CKD stage (OR = 1.26, 95% CI: 1.14-1.40). Further investigation revealed that an increase in DII was associated with a decrease in eGFR (β = -1.29, 95% CI: -1.75, -0.83). Smooth curves illustrated a non-linear positive correlation between DII and CKD risk, while a non-linear negative correlation was observed between DII and eGFR. Our study results indicate that an increase in DII is associated with an increased risk of higher CKD stage and a decrease in eGFR in all three models. In the fully adjusted model, the risk of higher CKD stage increased by 26% and the eGFR decreased by 1.29 ml/min/1.73 m2 for each unit increase in DII. This finding suggests that in patients with CKD in the US, improved diet and lower DII values may help slow the decline in eGFR and delay the progression of CKD.

A Point‐of‐Care Sensing Platform for Multiplexed Detection of Chronic Kidney Disease Biomarkers Using Molecularly Imprinted Polymers

AbstractChronic kidney disease (CKD) is one of the most serious non‐communicable diseases affecting the population. In the early‐stages patients have no obvious symptoms, until it becomes life‐threatening leading end‐stage kidney failure. Therefore, it is important to early diagnose CKD to allow therapeutic interventions and progression monitoring. Here, a point‐of‐care (POC) sensing platform is reported for the simultaneous detection of three CKD biomarkers, namely creatinine, urea, and human serum albumin (HSA), using reduced graphene oxide/polydopamine‐molecularly imprinted polymer (rGO/PDA‐MIP) fabricated with novel surface‐molecularly imprinting technology. A multi‐channel electrochemical POC readout system with differential pulse voltammetry (DPV) function is developed, allowing the simultaneous detection of the three biomarkers, in combination with the surface‐MIP electrodes. This sensing platform achieves the record low limit‐of‐detection (LoD) at a femtomolar level for all three analytes, with wide detection ranges covering their physiological concentrations. Clinical validation is performed by measuring these analytes in serum and urine from healthy controls and patients with CKD. The average recovery rate is 81.8–119.1% compared to the results obtained from the hospital, while this platform is more cost‐effective, user‐friendly, and requires less sample‐to‐result time, showing the potential to be deployed in resource‐limited settings for the early diagnosis and tracking progression of CKD.

Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study

BackgroundChronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population compared to non-Indigenous populations. Despite the identification of numerous genetic loci associated with kidney disease through GWAS, the Indigenous population such as Tiwi remains severely underrepresented and the increased prevalence of CKD in this population may be due to unique disease-causing alleles/genes.MethodsWe used albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) to estimate the prevalence of kidney disease in the Tiwi population (N = 492) in comparison to the UK Biobank (UKBB) (N = 134,724) database. We then performed an exploratory factor analysis to identify correlations among 10 CKD-related phenotypes and identify new multi-phenotype factors. We subsequently conducted a genome-wide association study (GWAS) on all single and multiple phenotype factors using mixed linear regression models, adjusted for age, sex, population stratification, and genetic relatedness between individuals.ResultsBased on ACR, 20.3% of the population was at severely increased risk of CKD progression and showed elevated levels of ACR compared to the UKBB population independent of HbA1c. A GWAS of ACR revealed novel association loci in the genes MEG3 (chr14:100812018:T:A), RAB36 (rs11704318), and TIAM2 (rs9689640). Additionally, multiple phenotypes GWAS of ACR, eGFR, urine albumin, and serum creatinine identified a novel variant that mapped to the gene MEIS2 (chr15:37218869:A:G). Most of the identified variants were found to be either absent or rare in the UKBB population.ConclusionsOur study highlights the Tiwi population’s predisposition towards elevated ACR, and the collection of novel genetic variants associated with kidney function. These associations may prove valuable in the early diagnosis and treatment of renal disease in this underrepresented population. Additionally, further research is needed to comprehensively validate the functions of the identified variants/genes.

Kidney Outcomes with Sodium-Glucose Cotransporter-2 Inhibitor Initiation after AKI among Veterans with Diabetic Kidney Disease.

The effect of SGLT2i on kidney function after acute kidney injury (AKI) is unknown. The study population was drawn from a retrospective cohort of Veterans with diabetes mellitus type 2 (DM2) and proteinuria. The study exposure was time-varying use of SGLT2i after an index AKI hospitalization. The two study outcomes were time-to- 1) a sustained decrease in eGFR over at least three months to <60 mL/minute/1.73 m2 and ≥30% below a post-AKI-updated eGFR and 2) recurrent hospitalization with AKI. AKI was defined as a rise in serum creatinine concentration to ≥50% above a moving outpatient creatinine baseline. DM2 was defined by ≥2 billing codes related to DM2 prior to the index AKI; proteinuria was defined by the most recent albuminuria, proteinuria, or urinalysis test. Veterans were required to have a baseline eGFR and an eGFR 3-12 months after the index AKI hospitalization ≥30 mL/minute/1.73 m2. 10,036 Veterans met study inclusion criteria. 2,794 (28%) received a SGLT2i. 775 (8%) had CKD progression and 1,816 (18%) had recurrent AKI over a median follow-up of 1.8 and 1.7 years, respectively, which began one year after the index AKI hospitalization. SGLT2i use was associated with lower risk for CKD progression [adjusted hazard ratio (aHR) 0.72 (95% confidence interval (CI): 0.57-0.91)] and for recurrent AKI [aHR 0.75 (95% CI: 0.65-0.88)]. SGLT2i use was associated with a lower risk for CKD progression and for recurrent AKI among those with diabetic kidney disease and recent AKI.

Predicting CKD progression using time-series clustering and light gradient boosting machines

Predicting the transition of kidney function in chronic kidney disease is difficult as specific symptoms are lacking and often overlooked, and progress occurs due to complicating factors. In this study, we applied time-series cluster analysis and a light gradient boosting machine to predict the trajectories of kidney function in non-dialysis dependent chronic kidney disease patients with baseline estimated glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2. Based on 5-year changes in estimated GFR, participants were stratified into groups with similar trajectories by cluster analysis. Next, we applied the light gradient boosting machine algorithm and Shapley addictive explanation to develop a prediction model for clusters and identify important parameters for prediction. Data from 780 participants were available for analysis. Participants were classified into five classes (Class 1: n = 78, mean [± standard deviation] estimated GFR 100 ± 19.3 mL/min/1.73 m2; Class 2: n = 176, 76.0 ± 9.3 mL/min/1.73 m2; Class 3: n = 191, 59.8 ± 5.9 mL/min/1.73 m2; Class 4: n = 261, 52.7 ± 4.6 mL/min/1.73 m2; and Class 5: n = 74, 53.5 ± 12.0 mL/min/1.73 m2). Declines in estimated GFR were 8.9% in Class 1, 12.2% in Class 2, 4.9% in Class 3, 12.0% in Class 4, and 45.1% in Class 5 during the 5-year period. The accuracy of prediction was 0.675, and the top three most important Shapley addictive explanation values were 1.61 for baseline estimated GFR, 0.12 for hemoglobin, and 0.11 for body mass index. The estimated GFR transition of patients with preserved chronic kidney disease mostly depended on baseline estimated GFR, and the borderline for estimated GFR trajectory was nearly 50 mL/min/1.73 m2.

Association between urinary C4d levels and disease progression in IgA nephropathy.

C4d mesangial deposition, a hallmark of lectin pathway activation in immunoglobulin A nephropathy (IgAN), has been shown to be associated with risk of kidney failure. To date, the relationship between urinary C4d and renal outcome remain unelucidated. A total of 508 patients with biopsy-proven IgAN were enrolled in this study, whose baseline urine samples at the time of biopsy were collected and the levels of urinary C4d were quantified by enzyme-linked immunosorbent assay. The time-averaged C4d (TA-C4d) and the change in proteinuria were measured in sequential urine samples obtained from IgAN patients. The kidney progression event was defined as a 50% estimated glomerular filtration rate (eGFR) decline or end-stage kidney disease or death. After a median follow-up of 36 months, 70 (13.8%) of the participants reached the kidney progression event. Higher levels of urinary C4d/Ucr were found to be associated with decreased eGFR, massive proteinuria, lower serum albumin levels, hypertension, and severe Oxford E and T scores. Upon adjusting for traditional risk factors (including demographics, eGFR, proteinuria, hypertension, Oxford pathologic score and immunosuppressive therapy), elevated levels of urinary C4d/Ucr were independently associated with an increased risk of chronic kidney disease progression [adjusted hazard ratio (HR) per standard deviation increment of log-transformed C4d/Ucr: 1.46; 95% CI 1.04-2.06; P=.030]. In reference to the low C4d group, the risk of poor renal outcome increased for the high C4d group (adjusted HR 1.93; 95% CI 1.05-3.54; P=.033). Additionally, a low baseline C4d level was independently associated with a favorable proteinuria response to immunosuppressive therapy at 3 months (adjusted relative risk 2.20; 95% CI 1.04-4.63, P=.038). The urinary C4d, serving as a non-invasive biomarker, is associated with the progression of IgAN and holds the potential to predict proteinuria response in this disease.

Correlation between neutrophil to lymphocyte ratio and platelet to lymphocyte ratio with proteinuria in different stages of chronic kidney disease

Abstract Background Chronic kidney disease (CKD) is a progressive failure of renal function with ongoing systemic inflammation. Inflammatory markers such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and proteinuria were documented as independent predictors of CKD progression. Although proteinuria estimated by the protein to creatinine ratio (UPCR) is generally employed to screen the disease progression of CKD, the correlation of NLR and PLR with different stages of CKD is yet to be studied. Consequently, this study strived to find the stage-wise correlation between NLR and PLR with proteinuria in CKD patients. Methods Eighty-five CKD patients with proteinuria who visited the Nephrology Clinic at Teaching Hospital Jaffna, Sri Lanka, were randomly selected and categorized as stages II to IV based on the estimated glomerular filtration rate (e-GFR). Blood samples were collected and subjected to investigate patients’ NLR and PLR. Furthermore, urine protein and creatinine were measured and UPCR was calculated. Participants’ demographic, clinical, and laboratory data were obtained from patients’ clinical registry. Spearman’s rank correlation and receiver operative characteristic (ROC) curve analysis was done, and the p value &lt; 0.05 was considered statistically significant. Results Amongst the total participants, males were predominant (58.8%), with a mean age of 58.1. Severity analysis based on the e-GFR revealed that 17.64%, 18.82%, 29.41%, and 34.11% of CKD patients were in stages II, IIIA, IIIB, and IV, respectively. Stage-wise correlation and ROC curve analysis indicated that NLR and PLR were positively correlated with UPCR in stages IIIA, IIIB, and IV of CKD with more than 80% predictive sensitivity and specificity. Conclusion NLR and PLR can be used as novel predictive markers for monitoring the severity of CKD; however, further large-scale cohort studies of NLR and PLR with serial monitoring and multiple closely spaced measurements are recommended to develop these markers into clinically acceptable markers for CKD progression.

Mathematical expansion and clinical application of chronic kidney disease stage as vector field.

There are cases in which CKD progression is difficult to evaluate, because the changes in estimated glomerular filtration rate (eGFR) and proteinuria sometimes show opposite directions as CKD progresses. Indices and models that enable the easy and accurate risk prediction of end-stage-kidney disease (ESKD) are indispensable to CKD therapy. In this study, we investigated whether a CKD stage coordinate transformed into a vector field (CKD potential model) accurately predicts ESKD risk. Meta-analysis of large-scale cohort studies of CKD patients in PubMed was conducted to develop the model. The distance from CKD stage G2 A1 to a patient's data on eGFR and proteinuria was defined as r. We developed the CKD potential model on the basis of the data from the meta-analysis of three previous cohort studies: ESKD risk = exp(r). Then, the model was validated using data from a cohort study of CKD patients in Japan followed up for three years (n = 1,564). Moreover, the directional derivative of the model was developed as an index of CKD progression velocity. For ESKD prediction in three years, areas under the receiver operating characteristic curves (AUCs) were adjusted for baseline characteristics. Cox proportional hazards models with spline terms showed the exponential association between r and ESKD risk (p<0.0001). The CKD potential model more accurately predicted ESKD with an adjusted AUC of 0.81 (95% CI 0.76, 0.87) than eGFR (p<0.0001). Moreover, the directional derivative of the model showed a larger adjusted AUC for the prediction of ESKD than the percent eGFR change and eGFR slope (p<0.0001). Then, a chart of the transformed CKD stage was developed for implementation in clinical settings. This study indicated that the transformed CKD stage as a vector field enables the easy and accurate estimation of ESKD risk and CKD progression and suggested that vector analysis is a useful tool for clinical studies of CKD and its related diseases.

Impact of Thyroid Status on Incident Kidney Dysfunction and Chronic Kidney Disease Progression in a Nationally Representative Cohort

ObjectiveTo examine the relationship between thyroid status and incident kidney dysfunction/chronic kidney disease (CKD) progression. Patients and MethodsWe examined incident thyroid status, ascertained by serum thyrotropin (TSH) levels measured from January 1, 2007, through December 31, 2018, among 4,152,830 patients from the Optum Labs Data Warehouse, containing deidentified retrospective administrative claims data from a large national health insurance plan and electronic health record data from a nationwide network of provider groups. Associations of thyroid status, categorized as hypothyroidism, euthyroidism, or hyperthyroidism (TSH levels >5.0, 0.5-5.0, and <0.5 mIU/L, respectively), with the composite end point of incident kidney dysfunction in patients without baseline kidney dysfunction and CKD progression in those with baseline CKD were examined using Cox models. ResultsPatients with hypothyroidism and hyperthyroidism had higher risk of incident kidney dysfunction/CKD progression in expanded case-mix analyses (reference: euthyroidism): adjusted hazard ratios (aHRs) (95% CIs) were 1.37 (1.34 to 1.40) and 1.42 (1.39 to 1.45), respectively. Incrementally higher TSH levels in the upper reference range and TSH ranges for subclinical, mild overt, and overt hypothyroidism (≥3.0-5.0, >5.0-10.0, >10.0-20.0, and >20.0 mIU/L, respectively) were associated with increasingly higher risk of the composite end point (reference: TSH level, 0.5 to <3.0 mIU/L): aHRs (95% CIs) were 1.10 (1.09 to 1.11), 1.37 (1.34 to 1.40), 1.70 (1.59 to 1.83), and 1.70 (1.50 to 1.93), respectively. Incrementally lower TSH levels in the subclinical (<0.5 mIU/L) and overt (<0.1 mIU/L) hyperthyroid ranges were also associated with the composite end point: aHRs (95% CIs) were 1.44 (1.41 to 1.47) and 1.48 (1.39 to 1.59), respectively. ConclusionIn a national cohort, TSH levels in the upper reference range or higher (≥3.0 mIU/L) and below the reference range (<0.5 mIU/L) were associated with incident kidney dysfunction/CKD progression.

Comparação de fórmulas para cálculo da taxa de filtração glomerular estimada e seus limiares diagnósticos para doença renal crônica em pessoas idosas: um estudo transversal

Abstract Objective To evaluate and compare the CKD-EPI, BIS1 and MDRD formulas and diagnostic thresholds of 45 and 60 ml/min/1.73m2 in older patients. Method A cross-sectional, descriptive, analytical observational study was conducted. Patients aged ≥65 years treated at a referral outpatient clinic between January 2020 and June 2022, were assessed. Patients with only one creatinine level or with transient GFR abnormalities were excluded. Results The GFR estimates using the CKD-EPI formula were higher than both the BIS1 and MDRD formulas in patient groups aged 65-74 years and 75-84 years. In the group of patients aged 85-94 years, the CKD-EPI showed no difference when compared with the MDRD, yielding higher estimates only compared with the BIS1. Greater dispersion was found between the CKD-EPI and BIS1, showing less agreement between these formulas, as confirmed by the Kappa test (76.7%), while there was almost perfect agreement between the CKD-EPI and MDRD. Conclusion The BIS1 formula showed stronger correlation of the decrease in eGFR with advancing age, reflecting the physiological renal aging process and serving as a potentially useful tool for estimating GFR in older adults. The formula can help provide a more accurate diagnosis of CKD and aid planning of interventions to slow the progression of CKD and predict the risk of mortality from cardiovascular diseases.

Beneficial effects of physical exercise on the osteo-renal Klotho-FGF-23 axis in Chronic Kidney Disease: A systematic review with meta-analysis.

The aim of this study was to investigate the efficacy of physical exercise in chronic kidney disease, describing its impact on the Klotho-FGF23 axis. PubMed, Web of Science and Scopus databases, updated to January 2023, were searched. The present study employed mean difference and a 95% confidence interval (CI) to examine the efficacy of the intervention. Heterogeneity was assessed through inconsistency statistics (I2). Out of the 299 studies identified, a total of 4 randomized controlled trials (RCTs), comprising 272 participants, met the eligibility criteria. Compared with the control group, physical exercise significantly decreased the concentrations of FGF23 (MD: -102.07 Pg/mL, 95% CI: -176.23.47, -27.91 I2= 97%, p = 0.001), and a significantly increased the concentrations of Klotho protein: (MD: 158.82 Pg/mL, 95% CI: 123.33, -194.31, I2 = 0%, p = 0.001). The results of our study indicated that the exercise has a direct relationship with Klotho-FGF23 axis. We can conclude that physical exercise in patients with CKD produces beneficial effects on the pathophysiological components related to this disease, including cardiorespiratory fitness and vascular functions. As observed, both endurance and aerobic physical exercise increase Klotho production and decrease FGF23 levels. Evidence indicates that exercise attenuates the progression of CKD, improves uremic parameters and down-regulates inflammation-related markers.

DYNAMICS OF β2-MICROGLOBULIN CONTENT IN BLOOD AND URINE IN PATIENTS WITH KIDNEY DAMAGE WHO HAD CORONAVIRUS DISEASE

The purpose of the work – to study the content of beta-2-microglobulin in the bloodand urine of patients with kidney damage who suffered from coronavirus disease, and tointerpret the results.Material and methods. 95 patients with kidney damage who suffered from coronavirusdisease were examined. In all patients, the content of beta-2-microglobulin in blood andurine was examined by the immunoenzymatic method.The results. The most significant increase in the content of beta-2-microglobulin inboth blood and urine was noted in patients who contracted the coronavirus diseaseagainst the background of chronic kidney disease (CKD) of the III-IV stage, includingin patients undergoing hemodialysis. In patients with stage I-II CKD with pyelonephritisand glomerulonephritis, an increase in the level of beta-2-microglobulin only in theblood was observed. In CKD patients with type II diabetes, an increase in the content ofbeta-2-microglobulin in the blood and urine was noted even in the presence of CKD-II stage.Conclusions. The coronavirus disease has a negative effect on the course of chronickidney disease and accelerates its progression due to a significant acceleration of thedevelopment of renal (tubular) dysfunction. This is indicated by the increase in thecontent of beta-2-microglobulin in the blood and urine of patients who have suffered fromthe coronavirus disease. Patients with type II diabetes with kidney damage who haveexperienced coronavirus disease are a separate group at risk of rapid progression ofCKD. This method of monitoring the dynamics of beta-2-microglobulin content in bloodand urine can be used for early diagnosis of the progression of CKD in patients who havesuffered from the coronavirus disease.

Clinical value of serum MMP-3 in chronic kidney disease

BackgroundChronic kidney disease (CKD) is defined as the progressive deterioration of renal parenchyma and decline in renal unit function. In the early stages of CKD(G1 + G2), symptoms are usually not obvious and cannot be effectively recognized on the basis of available clinical markers. Progression to the middle and late stages of CKD results in severe kidney damage with multiple complications causing adverse outcomes, including death. Therefore, the early diagnosis and monitoring of CKD is critical. Matrix metalloproteinase-3 (MMP-3), an extracellular matrix–degrading enzyme, plays an important role in kidney diseases. However, the clinical significance of serum MMP-3 levels in CKD has rarely been reported. MethodsWe quantified the serum MMP-3 levels of 237 patients with CKD and 96 healthy individuals by using a highly sensitive time-resolved fluorescence immunoassay and analyzed differences in MMP-3 levels among the stages of CKD and the correlations of these changes with clinical indicators. ResultsThe serum MMP-3 concentrations of patients with CKD (171.76 ± 165.22 ng/mL) were significantly higher than those of healthy controls (34.05 ± 22.93 ng/mL; P < 0.0001). In CKD, serum MMP-3 levels were significantly correlated with estimated glomerular filtration rate (eGFR) (r = − 0.5804, P < 0.0001), serum creatinine (CREA) (r = 0.5823, P < 0.0001), blood urea nitrogen (BUN) (r = 0.6106, P < 0.0001), and protein-to-creatinine ratio (r = 0.4992, P < 0.0001). Randomized forest analysis finds CREA, BUN, and MMP-3 most significant influences on CKD disease severity. The critical value of MMP-3 concentration of 40.39 ng/mL combined with eGFR was effective in diagnosing positive patients in the early (G1 + G2) stage of CKD and showed a positivity rate of 73.45 %. Moreover, in the early stages of CKD, patients with CKD who had serum MMP-3 concentration > 100 ng/mL had more severe renal impairment and inflammation than those with CKD who have lower serum MMP-3 concentrations. ConclusionElevated serum MMP-3 levels are correlated with decreased kidney function in CKD progression, and patients with concomitant inflammation may express high levels of serum MMP-3. Serum MMP-3 may assist eGFR in improving the diagnosis of patients with early CKD.

The evolution of ideas about the diagnosis and treatment of various phenotypes of chronic heart failure in type 2 diabetes mellitus

Despite the successes achieved in diagnosis and treatment, HF, regardless of the phenotype, remains one of the significant problems in the health sector, due to the high incidence, frequency of hospitalization, disability and mortality. In turn, patients with both type 2 diabetes and prediabetes are a vulnerable group in terms of the development of CHF. CH-sFV therapy has been focused for several decades on the treatment of concomitant diseases such as type 2 diabetes, hypertension, coronary heart disease, obesity and, if necessary, initiation of diuretic therapy to improve the quality of life. However, to date, great progress has been made in the treatment of HF-sFV. All guidelines for the management of patients with HF, based on the results of large randomized trials, postulate that iNGLT2 types are the basic drugs for the treatment of patients with HF, regardless of PV. Algorithms of specialized medical care for patients with diabetes recommend the appointment of iNGLT type 2 in the presence or high risk of developing CHF and/or CKD, regardless of the HbA1c level, in patients with type 2 diabetes to reduce the risk of hospitalization for HF, cardiovascular events and reduce the risks of CKD progression.

Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex

BackgroundThe sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown.ObjectiveWe performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex.DesignProspective randomized placebo-controlled trial.ParticipantsA total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes.InterventionDapagliflozin 10 mg versus placebo once daily.Main MeasuresPrimary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality.Key ResultsMedian follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope.ConclusionsDapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit.Trial Registryclinicaltrials.govNIH Trial Registry NumberNCT03036150

Prostacyclin Mitigates Renal Fibrosis by Activating Fibroblast Prostaglandin I 2 Receptor.

Renal fibrosis is a common pathologic process of progressive CKD. We have provided strong evidence that PGI 2 is an important component in the kidney injury/repairing process by reducing fibrosis and protecting renal function from declining. In our study, administration of a PGI 2 analog or selective PTGIR agonist after the acute injury ameliorated renal fibrosis. Our findings provide new insights into the role of PGI 2 in kidney biology and suggest that targeting PGI 2 /PTGIR may be a potential therapeutic strategy for CKD. Prostanoids have been demonstrated to be important modulators to maintain tissue homeostasis in response to physiologic or pathophysiologic stress. Prostacyclin (PGI 2 ) is a member of prostanoids. While limited studies have shown that PGI 2 is involved in the tissue injury/repairing process, its role in renal fibrosis and CKD progression requires further investigation. Prostacyclin synthase ( Ptgis )-deficient mice, prostaglandin I 2 receptor ( Ptgir )-deficient mice, and an oral PGI 2 analog and selective PTGIR agonist were used to examine the role of PGI 2 in renal fibrosis in mouse models. We also analyzed the single-cell RNA-Seq data to examine the PTGIR -expressing cells in the kidneys of patients with CKD. Increased PTGIS expression has been observed in fibrotic kidneys in both humans and mice. Deletion of the PTGIS gene aggravated renal fibrosis and decline of renal function in murine models. A PGI 2 analog or PTGIR agonist that was administered after the acute injury ameliorated renal fibrosis. PTGIR, the PGI 2 receptor, deficiency blunted the protective effect of the PGI 2 analog. Fibroblasts and myofibroblasts were the major cell types expressing PTGIR in the kidneys of patients with CKD. Deletion of PTGIR in collagen-producing fibroblastic cells aggravated renal fibrosis. The protective effect of PGI 2 was associated with the inhibition of fibroblast activation through PTGIR-mediated signaling. PGI 2 is an important component in the kidney injury/repairing process by preventing the overactivation of fibroblasts during the repairing process and protecting the kidney from fibrosis and decline of renal function. Our findings suggest that PGI 2 /PTGIR is a potential therapeutic target for CKD.

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.