Mind the Gap in Kidney Care: Translating What We Know Into What We Do.

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay. DOI: 10.52547/ijkd.8216.

ROC curve analysis: a useful statistic multi-tool in the research of nephrology.

In the past decade, scientific research in the area of Nephrology has focused on evaluating the clinical utility and performance of various biomarkers for diagnosis, risk stratification and prognosis. Before implementing a biomarker in everyday clinical practice for screening a specific disease context, specific statistic measures are necessary to evaluate the diagnostic accuracy and performance of this biomarker. Receiver Operating Characteristic (ROC) Curve analysis is an important statistical method used to estimate the discriminatory performance of a novel diagnostic test, identify the optimal cut-off value for a test that maximizes sensitivity and specificity, and evaluate the predictive value of a certain biomarker or risk, prediction score. Herein, through practical examples, we aim to present a simple methodological approach to explain in detail the principles and applications of ROC curve analysis in the field of nephrology pertaining diagnosis and prognosis.

Mind the gap in kidney care: translating what we know into what we do.

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay.

Prescribing the dialysis dose and treatment frequency in home haemodialysis.

BACKGROUND: There is growing interest in home haemodialysis (HHD) performed with low-flow dialysate devices and variable treatment schedules. The target standard Kt/V (stdKt/V) should be 2.3 volumes/week, according to KDOQI guidelines (2015). The current formula for stdKt/V does not help prescribe the dialysis dose (eKt/V) and treatment frequency (TF). The aim of this study was to obtain a formula for stdKt/V that is able to define the minimum required values of eKt/V and TF to achieve the targeted stdKtV. METHODS: Thirty-eight prevalent patients on HHD were enrolled. A total of 231 clinical datasets were available for urea modelling using the Solute-Solver software (SS), recommended by KDOQI guidelines. A new formula (stdKt/V = a + b × Kru + c × eKt/V) was obtained from multivariable regression analysis of stdKt/V vs eKt/V and residual kidney urea clearance (Kru). The values of coefficients a, b and c depend on the treatment schedules and the day of the week of blood sampling for the kinetic study (labdayofwk) and then vary for each of their foreseen 62 combinations. For practical purposes, we used only seven combinations, assuming Monday as a labdayofwk for each of the most common schedules of the 7 days of the week. RESULTS: The stdKt/V values obtained with SS were compared with the paired ones obtained with the formula. The mean ± standard deviation stdKt/V values obtained with SS and the formula were 3.043 ± 0.530 and 2.990 ± 0.553, respectively, with 95% confidence interval +0.15 to -0.26. A 'prescription graph' was built using the formula to draw lines expressing the relationship between Kru and required eKt/V for each TF. Using this graph, TF could have been reduced from the delivered 5.8 ± 0.8 to 4.8 ± 0.8 weekly sessions. CONCLUSIONS: The new formula for stdKtV is reliable and can support clinicians to prescribe the dialysis dose and TF in patients undergoing HHD.

Diuretics or ultrafiltration in the treatment of acute decompensated heart failure: An updated systematic review and meta-analysis.

INTRODUCTION: Hospitalization for decompensated heart failure is a major public health issue. METHODS: We performed a meta-analysis to summarize and analyze if there is a benefit in using ultrafiltration over diuretics in terms of reducing mortality or hospital readmissions, primarily and identified 10 randomized controlled trials (RCTs) including 941 patients. RESULTS: Compared to diuretics, treatment with ultrafiltration was associated with a significant reduction in heart failure hospitalizations (risk ratio [RR]: 0.72; 95% confidence interval [CI]: 0.55-0.96, p = 0.02) and significant increase in weight and net fluid loss (mean difference [MD]: -1.55, CI: -2.36 to -0.74, p = 0.0002) and (MD: -2.10, CI: -3.32 to -0.89, p = 0.0007), respectively. There was no significant difference among treatments regarding the duration of hospitalization, the increase in serum creatinine levels, and mortality. CONCLUSION: Among patients with decompensated heart failure, compared to diuretics, ultrafiltration is associated with reduced rehospitalizations and increased weight/net fluid loss.

Differential effects of biocompatible peritoneal dialysis fluids on human mesothelial and endothelial cells in 2D and 3D phenotypes.

INTRODUCTION: Peritoneal dialysis (PD) is a life maintaining treatment in patients with end-stage renal disease. Its chronic application leads to peritoneal mesothelial layer denudation and fibrotic transformation along with vascular activation of inflammatory pathways. The impact of different PD fluids (PDF) on mesothelial and endothelial cell function and repair mechanisms are not comprehensively described. MATERIALS AND METHODS: Mesothelial (MeT-5A) and endothelial cells (EA.hy926) were cultured in 1:1 ratio with cell medium and different PDF (icodextrin-based, amino acid-based, and glucose-based). Cell adhesion, cell migration, and cell proliferation in 2D and spheroid formation and collagen gel contraction assays in 3D cell cultures were performed. RESULTS: Cell proliferation and cell-mediated gel contraction were both significantly decreased in all conditions. 3D spheroid formation was significantly reduced with icodextrin and amino acid PDF, but unchanged with glucose PDF. Adhesion was significantly increased by amino acid PDF in mesothelial cells and decreased by icodextrin and amino acid PDF in endothelial cells. Migration capacity was significantly decreased in mesothelial cells by all three PDF, while endothelial cells remained unaffected. CONCLUSIONS: In 3D phenotypes the effects of PDF are more uniform in both mesothelial and endothelial cells, mitigating spheroid formation and gel contraction. On the contrary, effects on 2D phenotypes are more uniform in the icodextrin and amino acid PDF as opposed to glucose ones and affect mesothelial cells more variably. 2D and 3D comparative assessments of PDF effects on the main peritoneal membrane cell barriers, the mesothelial and endothelial, could provide useful translational information for PD studies.

2-Deoxy-glucose ameliorates the peritoneal mesothelial and endothelial barrier function perturbation occurring due to Peritoneal Dialysis fluids exposure.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis.

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.

Shared decision making in patients with kidney failure.

'Elderly' is most commonly defined as an individual aged 65 years or older. However, this definition fails to account for the differences in genetics, lifestyle and overall health that contribute to significant heterogeneity among the elderly beyond chronological age. As the world population continues to age, the prevalence of chronic diseases, including chronic kidney disease (CKD), is increasing and CKD frequently progresses to kidney failure. Moreover, frailty represents a multidimensional clinical entity highly prevalent in this population, which needs to be adequately assessed to inform and support medical decisions. Selecting the optimal treatment pathway for the elderly and frail kidney failure population, be it hemodialysis, peritoneal dialysis, or conservative kidney management is complex, because of the presence of comorbidities associated with low survival rates and impaired quality of life. Management of these patients should involve a multidisciplinary approach including doctors from various specialties, nurses, psychologists, dieticians, and physiotherapists. Studies are mostly retrospective and observational, lacking adjustment for confounders or address selection and indication biases, making it difficult to use these data to guide treatment decisions. Throughout this review we discuss the difficulty of making a one-size-fits-all recommendation for the clinical needs of older patients with kidney failure. We advocate that a research agenda for optimization of the critical issues we present in this review be implemented. We recommend prospective studies that address these issues, and systematic reviews incorporating the complementary evidence of both observational and interventional studies. Furthermore, we strongly support a shared decision making process matching evidence with patient preferences to ensure that individualized choices are made regarding dialysis vs. conservative kidney management, dialysis modality, and optimal vascular access.

Immune responses of patients on maintenance hemodialysis after infection by SARS-CoV-2: a prospective observational cohort study.

BACKGROUND: Immune dysregulation in patients with acute COVID-19 under chronic hemodialysis (CHD) is fully not elucidated. The changes of mononuclear counts and mediators before and after HD and associations with final outcome were studied. METHOD: In this prospective study, hospitalized patients with moderate-to-severe COVID-19 under CHD and matched comparators under HD were analyzed for their absolute counts of lymphoid cells and circulating inflammatory mediators. Blood samples were collected before start and at the end of the first HD session; dialysate samples were also collected. RESULT: Fifty-nine patients with acute COVID-19 under CHD and 20 uninfected comparators under CHD were enrolled. Circulating concentrations of tumor necrosis factor-alpha (TNFα), interleukin (IL)-10, interferon-γ and platelet-derived growth factor-A were increased in patients. Concentrations of mediators did not differ before and after HD. Significant decreases of CD4-lymphocytes and CD19-lymphocytes were found in patients. The decrease of the expression of HLA-DR on CD14-monocytes was associated with unfavorable outcome (defined as WHO-CPS 6 or more by day 28); increased counts of CD19-lymphocytes were associated with better outcomes. CONCLUSION: Patients under CHD develop an inflammatory reaction to SARS-CoV-2 characterized by increase of inflammatory mediators, decrease of circulating T-lymphocytes and decrease of the expression of HLA-DR on CD14-monocytes.

Home-Based Exercise Training and Cardiac Autonomic Neuropathy in Kidney Transplant Recipients with Type-II Diabetes Mellitus.

This randomized clinical trial aimed to examine the effects of a 6-month home-based, combined exercise training program on Cardiac Autonomic Neuropathy (CAN) in kidney transplant recipients (KTRs) with diabetes. Twenty-five KTRs (19 men (76.0%), with a mean age of 54.4 ± 11.3 years old, CAN and type II Diabetes Mellitus (DM-II)), were randomly assigned into two groups: A (n1 = 13 KTRs), who underwent a home-based exercise training program for 6 months, and B (n2 = 12 KTRs), who were assessed at the end of the study. A cardiopulmonary exercise testing (CPET), sit-to-stand test in 30 s (30-s STS), isokinetic muscle strength dynamometry, and 24-h electrocardiographic monitoring were applied to all participants, both at the baseline and at the end of the clinical trial. At first, there were no statistically significant differences between groups. After 6 months, group A showed higher values in exercise time by 8.7% (p = 0.02), VO2peak by 7.3% (p < 0.05), 30-s STS by 12.0% (p < 0.05), upper limb strength by 46.1% (p < 0.05), and lower limb strength by 24.6% (p = 0.02), respectively, compared to the B group. Furthermore, inter-group changes at the end of the 6-month study indicated that group A statistically increased the standard deviation of R-R intervals (SDNN) by 30.3% (p = 0.01), root mean square of successive differences between normal heartbeats (rMSSD) by 32.0% (p = 0.03), number of pairs of successive NN (R-R) intervals that differ by more than 50 ms (pNN50) by 29.0% (p = 0.04), high frequency (HF (ms2)) by 21.6% (p < 0.05), HF (n.u.) by 48.5% (p = 0.01), and turbulence slope (TS) by 22.5% (p = 0.02), and decreased the low frequency (LF (ms2)) by 13.2% (p = 0.01), LF (n.u.) by 24.9% (p = 0.04), and LF/HF ratio by 24% (p = 0.01), compared to group B. Linear regression analysis after the 6-month study showed that there was a strong positive correlation between VO2peak and SDNN (r = 0.701, p < 0.05) in group A. Moreover, multiple regression analysis showed that KTRs' participation in the exercise program showed favorable modifications to sympathovagal balance and aerobic capacity, as measured with SDNN and VO2peak, respectively. To summarize, diabetic KTRs' cardiac autonomic function and functional capacity can be improved after a home-based long-term exercise training program.

Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells.

Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1ß and TGF-ß1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.

Measures of frequency and effect in clinical research.

The assessment of risk and effect size of a specific endpoint associated to the presence/absence of a certain exposure is a hallmark in clinical and epidemiological research. In fact, before recommending any treatment, it is mandatory to investigate the magnitude of the benefits and harms between the exposure under investigation (e.g. a given treatment) and a specific disease or event. To do this, clinicians and statisticians use absolute (risk differences, number needed to treat, likelihood to be helped or harmed) and relative (risk ratio, incidence rate ratio, hazard ratio and odds ratio) measures of effect. Herein, using a series of clinical examples, we aim to present a step by step methodologic approach of measures of effect in the area of nephrology and urology.