High Glycemic Variability as a Risk Factor for CKD Progression in Type 2 Diabetes with Mild-to-Moderate Kidney Dysfunction.

Primary Versus Secondary Prevention of Chronic Kidney Disease: The Case of Dietary Protein

Using GFR, Albuminuria, and Their Changes in Clinical Trials and Clinical Care

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.

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

PurposeThe effects of statins on renal outcomes have already been studied in patients with chronic kidney disease (CKD); however, data on the general population are limited. We evaluated the association between statin use and risk of CKD in community-dwelling older people in Shanghai, China.Patients and MethodsThis registry-based cohort study was conducted in four communities in four districts in Shanghai. Participants with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 in 2016 were eligible for the study, and new-onset CKD in 2017, 2018, and 2019 was recorded. Poisson generalized linear models were conducted to examine the relationships among statin therapy, dyslipidemia, and CKD; linear mixed-effects models were conducted to examine the relationships between statin therapy and changes in eGFR. All analyses were performed with both conventional adjustment and propensity score-matching methods.ResultsOf the study cohort of 2455 participants (41.1% men; average age, 68.06 years), 624 (25.4%) were treated with stains. Two propensity score-matched cohorts of 604 participants each were analyzed (statin users and nonusers). Statin use was significantly associated with a decreased risk of new-onset CKD with hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.73 (0.59 to 0.91) (p<0.01) in the unmatched cohort and 0.75 (0.59 to 0.97) (p=0.02) in the matched cohort. There were significant differences in the eGFR decline between statin users and nonusers from baseline to 3 years in the unmatched and matched cohorts (both p<0.05). In addition, both statin users and nonusers with dyslipidemia experienced more new-onset CKD (both p<0.05).ConclusionStatin use was significantly associated with a decreased risk of new-onset CKD and a slower decline in eGFR in community-dwelling older people. Meanwhile, dyslipidemia was a risk factor for CKD progression among both statin users and nonusers.

We assessed the prospective association between baseline serum uric acid (SUA) concentrations and consequent risk of chronic kidney disease (CKD) progression in type 2 diabetes patients. Longitudinal data from a Japanese diabetes registry including 3454 type 2 diabetes patients were obtained. To assess the independent correlations between SUA and rapid CKD progression [i.e., 30% reduction in estimated glomerular filtration rate (eGFR) over 2years], participants were divided into five groups based on SUA levels:<5.0,≥5.0-6.0,≥6.0-7.0,≥7.0-8.0, and≥8.0mg/dl. Cox proportional hazards model adjusted for potential confounders was used for analysis. After 2years, rapid CKD progression was recognized in 169 patients (4.89%) who showed longer duration of type 2 diabetes (15.5 vs. 13.5years, p=0.005); higher systolic blood pressure (142.0 vs. 138.3mmHg, p=0.016), SUA (6.15 vs. 5.32mg/dl, p<0.001), and urinary albumin-creatinine ratio (1127.4 vs. 184.7mg/gCr, p<0.001); and lower diastolic blood pressure (69.7 vs. 72.8mmHg, p=0.003). Multivariate ratios for rapid CKD progression were 1.19 (p=0.371), 1.02 (p=0.937), 1.18 (p=0.625), and 3.04 (p=0.004), respectively, for the first, third, fourth, and fifth serum UA range groups; a second group was used as a reference. Higher SUA levels, independent of possible confounders, were associated with rapid eGFR decline and CKD progression in type 2 diabetes patients. SUA may be a useful biomarker for predicting future risk of rapid diabetic CKD progression.

Risk-Based Triage for Nephrology Referrals: The Time is Now

IntroductionChronic hypoparathyroidism, treated with conventional therapy of oral calcium supplements and active vitamin D, may increase the risk of kidney complications. This study examined risks of development and progression of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) decline in patients with chronic hypoparathyroidism.MethodsA retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017 included patients with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism followed for up to 5 years. Main outcome measures were (1) development of CKD, defined as new diagnosis of CKD stage 3 and higher or ≥ 2 eGFR measurements < 60 ml/min/1.73 m2 ≥ 3 months apart, (2) progression of CKD, defined as increase in baseline CKD stage, (3) progression to end-stage kidney disease (ESKD), and (4) eGFR decline ≥ 30% from baseline. Time-to-event analyses included Kaplan-Meier analyses with log-rank tests, and both unadjusted and adjusted Cox proportional hazards models were used to compare outcomes between cohorts.ResultsThe study included 8097 adults with and 40,485 without chronic hypoparathyroidism. In Kaplan-Meier analyses, patients with chronic hypoparathyroidism had higher risk of developing CKD and CKD progression and higher rates of eGFR decline (all P < 0.001). In multivariable Cox models adjusted for baseline characteristics, hazard ratios (95% confidence intervals [CIs]) were 2.91 (2.61–3.25) for developing CKD, 1.58 (1.23–2.01) for CKD stage progression, 2.14 (1.51–3.04) for progression to ESKD, and 2.56 (1.62–4.03) for eGFR decline (all P < 0.001) among patients with chronic hypoparathyroidism compared with those without hypoparathyroidism.ConclusionPatients with chronic hypoparathyroidism have increased risk of development and progression of CKD and eGFR decline compared with those without hypoparathyroidism. Further studies are warranted to understand underlying mechanisms for the associations between chronic hypoparathyroidism and kidney disease.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01658-1.

Medical Nutrition Therapy for Patients with Non–Dialysis-Dependent Chronic Kidney Disease: Barriers and Solutions

We recently developed and validated a hierarchical composite endpoint (HCE) for chronic kidney disease (CKD) progression combining time-to-event kidney outcomes with the rate of estimated glomerular filtration rate (eGFR) decline (eGFR slope). The CKD progression HCE is an informative endpoint for clinical trials in rare kidney diseases, such as focal segmental glomerulosclerosis (FSGS), where event-driven trials are often infeasible. We applied a HCE for CKD progression to the subset of patients with FSGS from the DAPA-CKD trial, a randomized double-blind, placebo-controlled clinical trial, to assess the effects of the sodium glucose co-transporter 2 inhibitor dapagliflozin on CKD progression in 4304 participants. We compared treatment effects for the primary composite endpoint (sustained 50% eGFR decline, kidney failure, or death due to kidney or cardiovascular causes), eGFR slope, and CKD progression HCE. We also compared statistical power for these outcomes using a bootstrap sampling procedure to evaluate the impact on trial efficiency. Overall, 115 participants were included (mean age, 54 years; 68% male; median urinary albumin-to-creatinine ratio, 1283 mg/g; mean eGFR, 42 mL/min/1.73m2). The effect of dapagliflozin on the primary composite endpoint (hazard ratio 0.45 [95% confidence interval [CI]: 0.13, 1.49]) and total eGFR slope (0.9 mL/min/1.73m2 (95%CI: -0.6, 2.3) were consistent with the overall trial results but the 95% CI crossed unity. The win-odds for the CKD progression HCE suggested benefits for dapagliflozin and the 95%CI did not cross unity (win-odds: 1.52 [95%CI: 1.01, 2.28]). Power calculations suggested that for a given sample size, statistical power was higher for the CKD progression HCE compared with the primary composite endpoint or eGFR slope. Our findings suggest that a CKD progression HCE, which integrates established CKD endpoints and eGFR slope, provides a sensitive and efficient measure to assess treatment effects in patients with FSGS. Validation of the HCE in prospective clinical trials will support its implementation.

Does Inflammation Fuel the Fire in CKD?

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

CKD Progression Prediction in a Diverse US Population: A Machine-Learning Model

HMOX1 and Acute Kidney Injury in Sickle Cell Anemia

Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood. We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to <22mmol/L (metabolic acidosis) or 22 to <30mmol/L (normal serum bicarbonate). Primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate over time. Cox proportional hazards models evaluated time to first occurrence of kidney stones during a median 3.2-year follow-up. A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post-index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0%vs 9.5%, P<.0001). Both lower baseline serum bicarbonate [hazard ratio (HR) 1.047; 95% confidence interval (CI) 1.036-1.057] and decreasing serum bicarbonate over time (HR 1.034; 95% CI 1.026-1.043) were associated with increased risk of kidney stone development. Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation.