The "Cardiovascular-Kidney-Metabolic" era in CKD management: Integrated risk factor control and prognostic benefits.

Chronic kidney disease (CKD) is a major health and economic burden within Australia. Estimated glomerular filtration rate (eGFR) and albuminuria (Alb) are used to determine if a patient has CKD, but these routine clinical kidney function measurements are inadequate when predicting progressive CKD. This thesis addressed two themes: firstly, clinical CKD biobanking within Australia; and secondly, improving clinical and research outcomes for CKD patients by developing a prognostic clinical tool.Four aims were completed. i) To establish a clinical biobank, termed the CKD Biobank, within Queensland, Australia and develop this into a bioresource. 100 CKD patients, consisting of patients with diabetic nephropathy, vascular diseases, genetic kidney diseases, glomerulonephritis, and a range of other primary kidney diseases, were recruited. In approximately 80% of these patients, baseline bio-specimens were collected alongside clinical data.ii) To address the need for a better definition of progressive CKD and to identify a robust definition of progressive kidney function decline. A systematic review was conducted to identify definitions of progressive kidney function decline currently used in research. A range of definitions was identified and subsequently investigated within the CKD Queensland Registry. A ≥30% decline in eGFR from baseline was found to be robust in distinguishing between patients who experienced a progressive decline in kidney function and those who did not.iii) To use the CKD Queensland Registry and CKD Biobank to identify biomarkers of progressive CKD. Discovery-based and hypothesis-based approaches were used, within the CKD Queensland Registry and the CKD Biobank, respectively, to identify novel and emerging biomarkers of progressive CKD. Several biomarkers were identified that characterised the pathophysiological mechanisms of CKD, with varying capacity to distinguish between progressive and non-progressive CKD.iv) To develop a novel prognostic clinical tool, termed the “distinguishing risk of progressive CKD” (DROP CKD) tool, for differentiating between progressive and non-progressive CKD patients at baseline biomarker measurements. The DROP CKD tool was a predictive model calculated by linear discriminant analysis and constructed from biomarkers that differed between progressive and non-progressive CKD patients. A step-backwards approach was used for biomarker selection to maximise accuracy of the DROP CKD tool.Three hypotheses were investigated. i) A biobank, designed for a specific application that overcomes the ethics, governance, and quality control hurdles, will prove a valuable bioresource. The CKD Biobank has proved a useful bioresource, not only for this thesis, but for several other research projects. The CKD Biobank was utilised for investigating progressive CKD biomarkers and developing the DROP CKD tool for predicting progressive CKD. This Biobank was used, additionally, to supply bio-specimens from healthy controls for a discovery-based project to identify metabolites with prognostic capabilities in kidney cancer, and bio-specimens from diabetic nephropathy and glomerulonephritis CKD patients for research concerning presence of coagulation proteases in urine.ii) Progressive and non-progressive CKD will be characterised by biomarkers of kidney function, tissue injury, inflammation, oxidative stress, tissue repair, fibrosis, and comorbidities of CKD within the venous blood or urine of CKD patients. Compared to non-progressive patients, progressive patients of the CKD Queensland Registry and the CKD Biobank were characterised as having reduced kidney function, being anaemic, having an altered electrolyte-water balance, metabolic acidosis, dyslipidaemia, and as having mineral and bone disease. Progressive CKD patients of the CKD Biobank were further characterised by tissue injury, inflammation, and hypercoagulability while progressive CKD patients of the CKD Queensland Registry were only additionally characterised by eosinophilia.iii) A panel of the biomarkers, measured at baseline, will accurately predict progressive CKD. Biomarkers that were observed as differing between progressive and non-progressive CKD patients of the CKD Biobank were utilised to develop the DROP CKD tool. Through the step-backwards method, a biomarker panel consisting of eGFR, serum creatinine, cystatin-c, urea, tumour necrosis factor (TNF)-α, TNF Receptor-I, TNF Receptor-II, stem cell factor, tryptase, neutrophil gelatinase-associated lipocalin, tissue factor, bicarbonate, calculated osmolality, and haematocrit were observed as having an accuracy of 95.5% when predicting progressive CKD based on baseline biomarker expression. Moreover, the DROP CKD tool was more accurate than traditional kidney function measurements for determining progressive CKD.This thesis attempted to expand upon CKD biobanking capabilities and improve clinical and research outcomes for CKD patients by developing a novel prognostic clinical tool for predicting progression of CKD. Several avenues of research are still required to produce translatable results that will improve patient outcomes. Defining progressive CKD requires further investigation to identify a definition that robustly characterises a “progressive” decline in kidney function, accounting for the non-linear nature of eGFR decline and associating with meaningful clinical outcomes without underdiagnosing progression. Additional biomarker discovery is needed to identify novel biomarkers which can characterise progressive CKD. Finally, pre-existing and novel biomarkers need to be combined into a panel that can predict progressive CKD. This panel must be assayed in a minimally-invasive, efficient, manner, and communicate clinically-meaningful information to inform clinical management of CKD patients.

Nutrition interventions to address cardiovascular outcomes in chronic kidney disease

Guest editorial: hypertension and kidney disease

Ambulatory Blood Pressure in Chronic Kidney Disease: Ready for Prime Time?

Background: Chronic kidney disease (CKD) is a public health priority of increasing concern worldwide. Sleep apnea (SA) of moderate-to-severe degree has a 3–9% prevalence in women and 10–17% in men in the general population. Summary: In CKD patients, the prevalence of SA parallels the decline of the GFR being 27% in CKD patients with a GFR of >60 mL/min/1.73 m2 and 57% in patients with end-stage kidney disease (ESKD). In the early CKD stages, fluid overload is probably the sole risk factor for SA in this population. At more severe CKD stages, disturbed central and peripheral chemosensitivity and the accumulation of uremic toxins might contribute to SA. Still, there is no direct evidence supporting this hypothesis in human studies. Observational studies coherently show that SA is a risk factor for CKD incidence and CKD progression as well as for cardiovascular disease and death in this population. However, there is no randomized clinical trial testing continuous positive airway pressure or other interventions documenting that attenuation of SA may have a favorable effect on renal and cardiovascular outcomes in CKD and ESKD patients. However, most likely, the causal nature of the association between SA and cardiorenal outcomes remains unproven. Renal transplantation is the most effective treatment of SA in patients with ESKD, but this disturbance re-emerges on long-term observation in this population. However, after renal transplantation, SA does not seem to be a predictor of adverse health outcomes.

A Comparison of Aerobic Exercise and Resistance Training in Patients With and Without Chronic Kidney Disease

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD

Background and Aims Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is reported to be associated with higher risk of decline in kidney function. However, little evidence exists about the relationship between NT-proBNP and kidney function progression stratified by estimated glomerular filtration rate (eGFR) in chronic kidney disease (CKD) patients without heart failure. Therefore, we aim to investigate the association of NT-proBNP and CKD progression in different CKD stages for CKD patients without heart failure. Method A multicentric retrospective cohort study recruited 23860 patients diagnosed with CKD from China Renal Data System (CRDS) database. Eligible participants were classified into five groups according to eGFR. CKD progression was defined as a composite of an increase in serum creatinine ≥50% or a decrease in eGFR ≥40% from baseline or a need for kidney replacement therapy. A linear regression model evaluated the relationship between eGFR and NT-proBNP. Cox regression analysis assessed the association between NT-proBNP and CKD progression. We also performed restricted cubic spline (RCS) and threshold effect analysis to investigate non-linear relationships between NT-proBNP and CKD progression. Results In a linear regression model, NT-proBNP was negatively correlated with eGFR in CKD patients. Each decrease of 15 ml/min/1.73 m2 in eGFR was associated with 1.06-fold, 1.50-fold, 1.52-fold, 1.94-fold, 3.37-fold higher levels of log (NT-proBNP) in CKD patients with stage 1-2, 3a, 3b, 4 and 5 respectively. In the multivariable Cox hazard model, elevated NT-proBNP was associated with a greater risk of kidney function progression, particularly among CKD stage 3 patients (stage 3a: HR, 1.42, 95% CI, 1.32-1.53; stage 3b: HR, 1.43, 95% CI, 1.32-1.54), with P-interaction≤0.001. However, the correlation of NT-proBNP and CKD progression had no statistical significance among CKD patients with stages 4-5 after sensitivity analyses. RCS and two-segment Cox regression model showed reversed L-shaped non-linear relationships between NT-proBNP and CKD progression in CKD patients with stages 1-4, with the inflection point at 250 pg/mL, 750 pg/mL, 653 pg/mL, 526 pg/mL, but not in stage 5 (Figure). Conclusion NT-proBNP may be a reliable biomarker to predict CKD progression in stages 1-3 CKD (mainly for stage 3) without heart failure. This helps clinicians predict a decline in kidney function early and set the threshold for therapy. However, the predictive role of NT-proBNP in in advanced CKD patients is insignificant.

Too Many for Too Few: Finding Appropriate Nephrology Referrals for Patients With CKD That Optimize Outcomes

BackgroundThe creatinine-to-cystatin C ratio (Cr/CysC) is a promising surrogate marker for muscle mass. While associated with adverse outcomes in various diseases, its prognostic utility for cardiorenal risks in the Chinese non-dialysis chronic kidney disease (CKD) population remains inadequately explored. This study aimed to investigate the association between the Cr/CysC ratio and the risks of cardiovascular disease (CVD) and CKD progression in a large Chinese CKD cohort.MethodsWe conducted a retrospective cohort study of 16,031 non-dialysis CKD patients from the China Renal Data System (CRDS). Cox proportional hazards models were used to assess the relationship between the serum Cr/CysC ratio and the incidence of CVD and CKD progression over 28,189.68 person-years of follow-up.ResultsIn CKD patients, a higher serum Cr/CysC ratio was significantly associated with lower risks of both CVD events and CKD progression. Compared to the lowest quartile (Q1), patients in the highest quartile (Q4) had a 21% lower risk of CVD (HR: 0.79, 95% CI: 0.67–0.92) and a 49% lower risk of CKD progression (HR: 0.51, 95% CI: 0.46–0.58). When analyzed as a continuous variable, each unit increase in the log-transformed ratio was associated with a significantly reduced risk for both outcomes (p < 0.001).ConclusionA higher serum Cr/CysC ratio is independently associated with reduced risks of CVD and CKD progression in Chinese patients with non-dialysis CKD. This ratio may serves as a useful prognostic marker for risk stratification in this population.

How Does SPRINT (Systolic Blood Pressure Intervention Trial) Direct Hypertension Treatment Targets for CKD?

In recent decades, high income countries (HIC) have been exposed to huge human migratory flows. Consistent with this influx, there has been a dramatic increase in the number of chronic kidney disease (CKD) patients in the immigrant population. In Italy, comparisons between Italian and immigrant CKD patients are still lacking, thus we aimed to describe the baseline clinical characteristics and the main outcomes of CKD patients who immigrated to Italy and reside in the Emilia Romagna region. This is a retrospective cohort study based on CKD patients from the Prevenzione Insufficienza Renale Progressiva (PIRP) project, which included 963 (3.1%) immigrants among the 30,702 patients seen by nephrologists between April 1st, 2004 and June 30th, 2020. We sub-divided the immigrants into seven groups based on their area of origin, and compared their baseline characteristics, CKD progression and time to end-stage kidney disease (ESKD) to those of Italian CKD patients. At presentation, Italian subjects were on average older (73.1years) and had less preserved kidney function (eGFR 34.3ml/min), while South and East Asians had the highest proportion of diabetes and obesity (approximately 45% and 30%, respectively). At 4-year follow-up, about 20% of patients from South Asia, Eastern Europe and Arab Countries were diagnosed with ESKD, compared to only 11% of Italians and Latin Americans. We found important differences between Italian and immigrant CKD patients, as well as among immigrant subgroups. First clinical encounters with nephrologists revealed that immigrants had varied patterns of clinical presentation and of nephropathy. During follow-up, immigrants showed faster kidney function decline which led to a higher risk of disease evolution and progression towards ESKD.

Unleashing the Power of Renal Nutrition in Value-Based Models of Kidney Care Choices: Leveraging Dietitians’ Expertise and Medical Nutrition Therapy to Delay Dialysis Initiation

The gut–kidney connection in advanced chronic kidney disease

KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD