Deterioration Of Kidney Function In Patients Research Articles

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR >1.1 g/g), and urinary protein excretion (% with urinary protein excretion >1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p < 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.

Febuxostat provides renoprotection in patients with hyperuricemia or gout: a systematic review and meta-analysis of randomized controlled trials.

It is unknown whether febuxostat can delay the progression of kidney dysfunction and reduce kidney endpoint events. The aim was to evaluate the renoprotective effect of febuxostat in patients with hyperuricemia or gout by performing a meta-analysis of randomized controlled trials (RCTs). MEDLINE, Web of science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Randomized Controlled Trials were searched. The main outcomes included kidney events (serum creatinine doubling or progression to end-stage kidney disease or dialysis). The secondary outcomes were the rate of change in the estimated glomerular filtration rate (eGFR) and changes in the urine protein or urine albumin to creatinine ratio from baseline to the end of follow-up. We used random-effects models to calculate the pooled risk estimates and 95% CIs. A total of 16 RCTs were included in the meta-analysis. In comparison with the control group, the patients who received febuxostat showed a reduced risk of kidney events (RR = 0.56, 95% CI 0.37-0.84, p = 0.006) and a slower decline in eGFR (WMD = 0.90 mL/min/1.73 m2, 95% CI 0.31-1.48, p = 0.003). The pooled results also revealed that febuxostat use reduced the urine albumin to creatinine ratio (SMD = -0.21, 95% CI -0.41 to -0.01, p = 0.042). Febuxostat use is associated with a reduced risk of kidney events and a slow decline in eGFR. In addition, the urine albumin to creatinine ratio decreased in febuxostat users. Accordingly, it is an effective drug for delaying the progression of kidney function deterioration in patients with gout.Systematic review registration: PROSPERO CRD42021272591.

Effect of Tyrosine Kinase Inhibitor Therapy on Estimated Glomerular Filtration Rate in Patients with Chronic Myeloid Leukemia

IntroductionThe advent of tyrosine kinase inhibitors (TKIs) was revolutionary in the management of chronic myeloid leukemia (CML). Although TKIs were generally considered to be safe, they can be associated with renal injury. We evaluated the effect of TKIs on renal functions in a cohort of patients with long-term follow-up. Material and MethodsWe retrospectively examined patients with chronic phase CML treated with TKIs. We analyzed the estimated glomerular filtration rate (eGFR) of patients from the initiation of TKI to the last follow-up. eGFR values of CML patients were compared to those of patients with stage 1 or 2 chronic kidney disease (CKD). ResultsA total of 195 patients with CML and 138 patients with CKD were examined. eGFR decline was 1.556 ml/min/1.73m2/year for patients with CML (P = .221). Patients receiving second-generation TKIs (2GTKI) were estimated to have 0.583 ml/min/1.73m2 higher eGFR value than that of the imatinib group, but it was not significant (P = .871). eGFR of patients who had used bosutinib had a downward trend. Duration of TKI therapy, age, and hypertension were found to be significant factors in eGFR decline for CML patients. Lower baseline GFR was associated with an increased risk of CKD development. ConclusionImatinib could result in a decline in eGFR which was clinically similar to early-stage CKD patients. We did not observe significant kidney function deterioration in patients receiving 2GTKIs including dasatinib and nilotinib. We recommend close renal function monitoring in patients receiving imatinib, especially for elderly patients with lower baseline eGFR and hypertension.

Perirenal Fat and Kidney Function Deterioration in Patients With Acute Decompensated Heart Failure.

The thick perirenal fat pad can induce high intracapsular pressure and cause compression of the renal vasculature and resultant congestive nephropathy. The current study investigated the association of perirenal fat thickness with kidney dysfunction in patients with acute decompensated heart failure (ADHF). Data from 266 patients hospitalized with ADHF were analyzed. Patients were divided into two groups according to the glomerular filtration rate (GFR) at admission (preserved kidney function [GFR ≥60 mL/min/1.73 m2] and reduced kidney function [GFR <60 mL/min/1.73 m2] groups). Right and left posterior perirenal fat thicknesses were measured using computed tomography, and their average values were calculated. Associated factors with reduced kidney function was assessed by logistic regression model, presenting with odds ratio (OR) and confidence interval (CI). Increasing age (OR, 1.08; 95% CI, 1.04-1.12; p<0.001), diabetes mellitus (OR, 2.46; 95% CI, 1.18-5.12; p<0.017), increased log N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR, 1.82; 95% CI, 1.32-2.52; p<0.001), and increased average perirenal fat thickness (OR, 1.11; 95% CI, 1.06-1.16; p<0.001) were independently associated with reduced kidney function. In the subgroup analyses, patients over 70 years old, the ratio of mitral-to-mitral annular velocity >15, elevated log NT-proBNP had a significantly higher association with increased perirenal fat thickness with reduced kidney function. Thick perirenal fat pads were independently associated with kidney function deterioration in patients hospitalized with ADHF.

Associations between urinary cysteine-rich protein 61 excretion and kidney function decline in outpatients with chronic kidney disease: a prospective cohort study in Taiwan

ObjectivesTo examine whether urinary excretion of cysteine-rich protein 61 (Cyr61), an acknowledged proinflammatory factor in kidney pathologies, increases in chronic kidney disease (CKD) and is associated with subsequent rapid kidney...

Early Chronic Kidney Disease Care Programme delays kidney function deterioration in patients with stage I–IIIa chronic kidney disease: an observational cohort study in Taiwan

ObjectivesTo investigate the effect of the Early Chronic Kidney Disease (CKD) Care Programme on CKD progression in patients with CKD stage I–IIIa.DesignObservational cohort study.SettingTaipei Medical University Research Database from three...

Urinary Melamine Levels and Progression of CKD.

CKD is a global public health problem. Some cross-sectional studies have associated environmental melamine exposure with kidney diseases, but evidence is limited. We conducted this prospective cohort study to enroll patients with eGFR≥30 ml/min per 1.73 m2 in 2006-2010. Urinary corrected melamine levels (ratio of urinary melamine to urinary creatinine) were measured by liquid chromatography/tandem mass spectrometry at enrollment. Kidney outcomes included doubling of serum creatinine levels, eGFR decline >3 ml/min per 1.73 m2 per year, and 30% decline in eGFR in the first 2 years. Subjects were followed until targeted kidney outcomes, cancer, death, last contact, or the end of observation in December 2016. In a total of 293 subjects, the median urinary corrected melamine level was 0.97 (interquartile range, 0.43-2.08) μg/mmol. Over a median follow-up period of 7.0 years, serum creatinine levels doubled in 80 subjects (27%). Subjects in the highest tertile of urinary melamine level 12.70 μg/mmol) had a 2.30 (95% confidence interval, 1.25 to 4.23; P<0.01) hazard risk for doubling of serum creatinine compared with those in the lowest tertile (0.02-0.58 μg/mmol). Similar significant dose-response results were found in eGFR decline >3 ml/min per 1.73 m2 per year and 30% decline in eGFR in the first 2 years. Urinary melamine level is significantly associated with kidney function deterioration in patients with early-stage CKD.

Urate-lowering agents for asymptomatic hyperuricemia in stage 3 - 4 chronic kidney disease: Controversial role of kidney function.

Because the serum uric acid level increases as the glomerular filtration rate (GFR) decreases, hyperuricemia is associated with chronic kidney disease (CKD). Although hyperuricemia is a risk factor for CKD progression, the causal role of uric acid remains controversial in patients with CKD and asymptomatic hyperuricemia. This study included 588 patients with stage 3–4 CKD and asymptomatic hyperuricemia. Using propensity score matching, 165 pairs treated and untreated with pharmacologic urate-lowering therapy were matched. Kaplan-Meier curves were constructed to determine the effect of urate-lowering agents on kidney survival. The prognostic value for kidney survival was ascertained using Cox regression analysis. The GFR changes over time between the patients treated and untreated with urate-lowering agents were assessed using a linear mixed model analysis. The mean age of the matched patients was 63.2 ± 12.7 years, and 52 (15.8%) patients had diabetic nephropathy. The mean estimated GFR (eGFR) and serum uric acid level were 36.7 mL/min/1.73 m2 and 7.8 mg/dL, respectively. During a mean follow-up period of 41.9 months, 87 developed end-stage kidney disease (ESKD). The incidence rates of ESKD were comparable between the patients treated and untreated with urate-lowering agents. The Kaplan-Meier analysis indicated that kidney survival was also comparable between them. In the multivariate analysis, heart failure and low eGFR were the significant prognostic factors for kidney survival. However, pharmacologic urate-lowering therapy was not predictive of kidney survival. The overall GFR decline rate was also comparable between the groups (P = 0.13). The efficacy of pharmacologic urate-lowering therapy in delaying CKD progression remains controversial. Therefore, further randomized controlled trials are needed to confirm its efficacy in attenuating kidney function deterioration in patients with stage 3–4 CKD.

Urinary excretion of liver-type fatty acid-binding protein as a marker of progressive kidney function deterioration in patients with chronic glomerulonephritis

BackgroundTo evaluate the value of basal urinary L-FABP (uL-FABP) excretion as a prognostic indicator of the progression of kidney function impairment in patients with chronic glomerulonephritis (CGN). MethodsOne hundred twenty-three patients with newly diagnosed, biopsy-proven primary CGN were included. In all patients, and in 28 healthy subjects, uL-FABP was measured using an ELISA. Risk factors of the progression of kidney function were evaluated. The patients were in follow-up for at least 5years. ResultsuL-FABP in the patients with CGN (76.58±17.3μg/g.cr) was greater than in the healthy subjects. A significant positive correlation between uL-FABP and proteinuria (R=0.501, P<0.01), serum creatinine (R=0.601, P<0.01) were found. Kaplan–Meier analysis revealed that uL-FABP >76.58μg/g.cr predicts progression of renal function. The cut off values for L-FABP at 119.8μg/g.cr was found to be more sensitive, area under the curve (AUC) was 0.95. ConclusionUrinary L-FABP may be a useful clinical biomarker for monitoring chronic glomerular disease. Urinary L-FABP can help predict the progression of chronic glomerular disease.

Urinary excretion of soluble tumour necrosis factor receptor 1 as a marker of increased risk of progressive kidney function deterioration in patients with primary chronic glomerulonephritis

The effects of tumor necrosis factor α (TNF α), a potent proinflammatory cytokine, in the kidneys are mediated by two membrane receptors (TNFR), TNFR1 and TNFR2. The expression of both TNF and TNFRs increases in several kidney diseases and is associated with the shedding of the receptors out of the cell membranes. In an experimental model of glomerulonephritis (GN), elevated concentrations of TNFRs in serum and TNFRs excretion in urine were demonstrated. The aim of this study was evaluation of urinary excretion of TNFR1 and its relationship with the clinical markers of kidney injury in patients with GN. The value of basal urinary TNFR1 excretion as a prognostic indicator of the progression of kidney function impairment was also assessed. Fifty-five patients with newly diagnosed, biopsy-proven primary GN were included in the study. In all patients, and in 20 healthy subjects, UTNFR1 was measured using an ELISA . In the patients, risk factors of the progression of impairment of kidney function (reduced eCcr, nephrotic syndrome, hypertension and intensity of morphological lesions in the kidneys) were evaluated. The appropriate treatment was then introduced and the patients were in follow-up for 4 years. The progression of kidney function impairment was defined as a reduction of eCcr > 5 mL/min/1.73 m2 /year during follow-up. The association of basal TNFR1 excretion with the progression was evaluated. Urinary excretion of TNFR1 in the patients with GN (4039.2 ± 3801.5 pg/mgCr) was greater than in the healthy subjects (1358.9 ± 927.8 pg/mgCr, P < 0,00002). A significant negative correlation between TNFR1 excretion and eCcr (Sr=0.464, P < 0.01) and a positive correlation between TNFR1 excretion and proteinuria (Sr = 0,463, P < 0.01) were found. In 13 patients, a marked reduction of eCcr was observed during follow-up. Logistic regression analysis revealed that TNFR1 excretion > 3863.3 pg/mgCr predicts progression of renal function impairment along with advanced interstitial fibrosis in the kidney biopsy specimens at presentation. Markedly elevated urinary TNFR1 excretion may be considered as a good marker of an activated TNFα-pathway in patients with newly diagnosed GN and as a potentially modifiable risk factor of progressive kidney function impairment.

Prescription des statines en cas d’insuffisance rénale: Efficacité, tolérance et maniement chez le patient insuffisant rénal et chez le patient transplanté rénal

Chronic kidney disease (CKD) is extremely common in adults, although often undiagnosed and thus untreated. Cardiovascular disease is the leading cause of death among patients with CKD and reducing its risk in this population is an important priority. Dyslipidemia is almost always present when proteinuria is above 3 gr/24 hours. Roughly two thirds of all patients with end-stage renal failure and kidney transplants suffer from dyslipidemia and should receive lipid-lowering therapy, as suggested by recent Afssaps (French drug agency) and NKF-K/DOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines. We reviewed recent studies on efficacy, tolerability and prescription recommendations of statins in CKD and renal transplant patients.We searched Medline, the international medical database, to conduct a systematic review of the literature on the efficacy and tolerability of statins in CKD and renal transplant patients and on specific recommendations for dosage adjustments in this population.The efficacy of statins in decreasing total cholesterol and LDL-cholesterol levels in dialysis and renal transplant patients is similar to that in the general population. On the other hand, large-scale randomized clinical trials among CKD (4D) and renal transplant (ALERT) patients do not demonstrate that statins significantly decrease rates of cardiovascular disease. They have a beneficial effect on proteinuria and lower the rate of kidney function deterioration in patients with dyslipidemia. Early introduction of a statin in transplant patients did not lead to improved kidney function or prevent loss of the graft. Although most statins are not excreted by the kidneys, the dosage of some must be adapted in CKD patients because of pharmacokinetic modifications induced by renal impairment.Statins at appropriately adapted doses have the same efficacy in CKD patients as in subjects with normal kidney function, and tolerance is not a problem. Their effectiveness in cardiovascular prevention in this population has not been demonstrated to date. Results about statin-induced kidney protection are encouraging but further and more specific studies are needed.