Estimated Glomerular Filtration Rate Decline Is a Better Risk Factor for Outcomes of Systemic Disease-Related Nephropathy than for Outcomes of Primary Renal Diseases

<div><p>Background</p><p>Currently, the contribution of kidney function decline in renal and patient outcomes is unclear. There are few data on the associations of different etiologies of estimated glomerular filtration rate (eGFR) decline with outcomes in multidisciplinary care. The purpose of this investigation was to establish whether eGFR decline in patients with disease is an important risk factor for developing end-stage renal disease (ESRD) and death.</p><p>Methods</p><p>From December 1, 2001 to December 31, 2011, 5097 adults with chronic kidney disease (CKD) received biochemical tests, physical examinations, a pathological examination, and a comprehensive questionnaire. We used linear regression models and multivariate Cox proportional hazards model to examine the outcome of eGFR decline in renal diseases with different etiologies.</p><p>Results</p><p>Mean age was 68.1±16.1 (standard deviation, SD) years, and 63.3% patients were male. In the studied cohort, 58.2% of the patients had systemic disease-related nephropathy (SDRN), 29.4% had primary renal diseases (PRDs), and 12.4% had other etiologies. The eGFR decline in SDRN had a significant association with dialysis in the Cox proportional hazards model [crude hazard ratio (HR) = 1.07, 95% confidence interval (CI), 1.04 to 1.10; adjusted HR 1.05, 95% CI, 1.02 to 1.08]. Diabetic nephropathy (DN) had the most severe eGFR decline in CKD stages 3, 4, and 5, and all contributed to the initiation of dialysis and death regardless of whether DN with or without eGFR decline was considered to be the cause. Although hypertensive nephropathy (HN) was related to significant acceleration of eGFR decline, it did not lead to poor outcome. There were still discrepancies between eGFR decline and outcomes in PRDs, hypertensive nephropathy, and lupus nephritis.</p><p>Conclusions</p><p>eGFR decline and CKD staging provide an informative guide for physicians to make proper clinical judgments in the treatment of CKD, especially SDRN. Poor control of the underlying systemic disease will thus lead to more rapid progression of SDRN.</p></div

Association of eGFR decline with outcomes during study period by different disease etiologies.

<p>Model 1 is crude. Model 2 is adjusted for age, gender, eGFR decline, proteinuria, ACEI/ARB, and antilipemic agents.</p><p>Several disease types categorized as SDRN (e.g., multiple myeloma) that could potentially be successfully treated were excluded. In addition, PRDs (e.g., Crescentic GN or RPGN, obstructive nephropathy, acute rejection in kidney transplant recipients, and pyelonephritis) with extreme values were excluded in the preliminary analysis.</p><p>HR, hazard ratio; C.I., confidence interval.</p><p>Significant codes: *, <0.05; **, <0.01; ***, <0.001.</p

eGFR decline in primary renal diseases; IgAN, IgA nephropathy; MGN, membranous glomerulonephritis; FSGS, focal and segmental glomerulosclerosis; MCD, minimal change disease; MPGN, membranoproliferative glomerulonephritis; Other renal paren., other renal parenchymal disease; Crescentic GN& RPGN, crescentic glomerulonephritis and rapidly progressive glomerulonephritis (Significant codes: *, <0.05 means the eGFR decline is a significant value during this time interval under lineal regression model).

<p>eGFR decline in primary renal diseases; IgAN, IgA nephropathy; MGN, membranous glomerulonephritis; FSGS, focal and segmental glomerulosclerosis; MCD, minimal change disease; MPGN, membranoproliferative glomerulonephritis; Other renal paren., other renal parenchymal disease; Crescentic GN& RPGN, crescentic glomerulonephritis and rapidly progressive glomerulonephritis (Significant codes: *, <0.05 means the eGFR decline is a significant value during this time interval under lineal regression model).</p

Association of eGFR decline with dialysis and death in CKD stages 3∼5 cohort using univariate and multivariate cox proportional hazards analysis.

<p>Model 1 is crude. Model 2 is further adjusted for age, gender, proteinuria, ACEI/ARB, antilipemic agents, diseases with a relatively large subgroup of patients (diabetic nephropathy, hypertensive nephropathy, IgA nephropathy, and membranous nephropathy).</p><p>HR, hazard ratio; C.I., confidence interval</p><p>Significant codes: *, <0.05; **, <0.01; ***, <0.001.</p

Participants’ characteristics by different initial CKD stages.

<p>Note: Data for categorical variables are given as percentage; data for continuous variables are given as mean ± standard deviation or median (interquartile range).</p>†<p>The normal BMI value: male is 19.2–23.7 kg/m² and female is 18.3–22.7 kg/m² (Department of Health, Executive Yuan, Taiwan, R.O.C.). [Spindle 2009 health education advocacy plan survey summary report - The definition of body mass index in adults in Taiwan. February 2009 36(1) 23–26].</p>a<p>For trend; ^bBy one-way ANOVA test; ^cBy Chi-square test; ^dBy Kruskal-Wallis test.</p><p>Abbreviations: BMI, body mass index; MDRD, Modification of Diet in Renal Disease equation; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration formula; PCR, urine protein to urine creatinine ratio; eGFR, estimated glomerular filtration rate; NA, non-available; ACEI & ARB, angiotensin-converting enzyme inhibitors & angiotensin II receptor blockers; OAD, oral antidiabetics; ESA, erythropoiesis-stimulating agent.</p>††<p>CKD-EPI formula, references:</p><p>1. Delanaye, P, Mariat, C. (2013) The applicability of eGFR equations to different populations. Nat. Rev. Nephrol 9: 513–522.</p><p>2. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, et al. (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612.</p><p>3. Matsushita K, Mahmoodi BK, Woodward M, Emberson JR, Jafar TH, et al. (2012) Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA. 307: 1941–1951.</p

Diagnosed etiologies by different initial CKD stages.

a<p>By Chi-square test.</p>††<p>Other systemic disease-related nephropathy included amyloidosis, scleroderma, multiple myeloma, gouty nephropathy, liver cirrhosis, heart failure, eclampsia, metabolic diseases causing renal failure, and other systemic disease causing renal failure.</p><p>*Other renal parenchyma disease of the primary renal diseases including chronic pyelonephritis, unrecovered acute renal failure, chronic glomerulonephritis, post-infectious glomerulonephritis, chronic interstitial nephritis, rejection of kidney allograft.</p><p>^**Other etiology included obstructive nephropathy, urinary tract diseases, renal vascular diseases, hereditary diseases, other causes of renal failure, and renal failure with unknown causes.</p

eGFR decline in systemic disease-related nephropathy (Significant codes: *, <0.05 means the eGFR decline is a significant value during this time interval under lineal regression model).

<p>eGFR decline in systemic disease-related nephropathy (Significant codes: *, <0.05 means the eGFR decline is a significant value during this time interval under lineal regression model).</p

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p