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1.
Lancet ; 402(10417): 2077-2090, 2023 12 02.
Article in English | MEDLINE | ID: mdl-37931634

ABSTRACT

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. FUNDING: Travere Therapeutics.


Subject(s)
Glomerulonephritis, IGA , Kidney Failure, Chronic , Female , Humans , Male , Angiotensin Receptor Antagonists/adverse effects , Double-Blind Method , Glomerulonephritis, IGA/drug therapy , Irbesartan/adverse effects , Proteinuria/drug therapy , Treatment Outcome , Adult
2.
Circ Cardiovasc Qual Outcomes ; 15(10): e008995, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36193750

ABSTRACT

BACKGROUND: Patients with chronic kidney disease (CKD) on dialysis (CKD G5D) have worse cardiovascular outcomes than patients with advanced nondialysis CKD (CKD G4-5: estimated glomerular filtration rate <30 mL/[min·1.73m2]). Our objective was to evaluate the relationship between achievement of cardiovascular guideline-directed medical therapy (GDMT) goals and clinical outcomes for CKD G5D versus CKD G4-5. METHODS: This was a subgroup analysis of ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) participants with CKD G4-5 or CKD G5D and moderate-to-severe myocardial ischemia on stress testing. Exposures included dialysis requirement at randomization and GDMT goal achievement during follow-up. The composite outcome was all-cause mortality or nonfatal myocardial infarction. Individual GDMT goal (smoking cessation, systolic blood pressure <140 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, statin use, aspirin use) trajectory was modeled. Percentage point difference was estimated for each GDMT goal at 24 months between CKD G5D and CKD G4-5, and for association with key predictors. Probability of survival free from all-cause mortality or nonfatal myocardial infarction by GDMT goal achieved was assessed for CKD G5D versus CKD G4-5. RESULTS: A total of 415 CKD G5D and 362 CKD G4-5 participants were randomized. Participants with CKD G5D were less likely to receive statin (-6.9% [95% CI, -10.3% to -3.7%]) and aspirin therapy (-3.0% [95% CI, -5.6% to -0.6%]), with no difference in other GDMT goal attainment. Cumulative exposure to GDMT achieved during follow-up was associated with reduction in all-cause mortality or nonfatal myocardial infarction (hazard ratio, 0.88 [95% CI, 0.87-0.90]; per each GDMT goal attained over 60 days), irrespective of dialysis status. CONCLUSIONS: CKD G5D participants received statin or aspirin therapy less often. Cumulative exposure to GDMT goals achieved was associated with lower incidence of all-cause mortality or nonfatal myocardial infarction in participants with advanced CKD and chronic coronary disease, regardless of dialysis status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01985360.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Myocardial Infarction , Renal Insufficiency, Chronic , Humans , Renal Dialysis/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/therapy , Myocardial Infarction/epidemiology , Cholesterol, LDL , Aspirin/adverse effects
3.
World J Diabetes ; 12(10): 1765-1777, 2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34754377

ABSTRACT

BACKGROUND: The genetic backgrounds of diabetic kidney disease (DKD) and end-stage kidney disease (ESKD) have not been fully elucidated. AIM: To examine the individual and cumulative effects of single-nucleotide polymorphisms (SNPs) previously associated with DKD on the risk for ESKD of diabetic etiology and to determine if any associations observed were specific for DKD. METHODS: Fourteen SNPs were genotyped in hemodialyzed 136 patients with diabetic ESKD (DKD group) and 121 patients with non-diabetic ESKD (NDKD group). Patients were also re-classified on the basis of the primary cause of chronic kidney disease (CKD). The distribution of alleles was compared between diabetic and non-diabetic groups as well as between different sub-phenotypes. The weighted multilocus genetic risk score (GRS) was calculated to estimate the cumulative risk conferred by all SNPs. The GRS distribution was then compared between the DKD and NDKD groups as well as in the groups according to the primary cause of CKD. RESULTS: One SNP (rs841853; SLC2A1) showed a nominal association with DKD (P = 0.048; P > 0.05 after Bonferroni correction). The GRS was higher in the DKD group (0.615 ± 0.260) than in the NDKD group (0.590 ± 0.253), but the difference was not significant (P = 0.46). The analysis of associations between GRS and individual factors did not show any significant correlation. However, the GRS was significantly higher in patients with glomerular disease than in those with tubulointerstitial disease (P = 0.014) and in those with a combined group (tubulointerstitial, vascular, and cystic and congenital disease) (P = 0.018). CONCLUSION: Our results suggest that selected SNPs that were previously associated with DKD may not be specific for DKD and may confer risk for CKD of different etiology, particularly those affecting renal glomeruli.

4.
Sci Rep ; 11(1): 14706, 2021 07 19.
Article in English | MEDLINE | ID: mdl-34282182

ABSTRACT

Diagnosis of pheochromocytomas and paragangliomas in patients receiving hemodialysis is troublesome. The aim of the study was to establish optimal conditions for blood sampling for mass spectrometric measurements of normetanephrine, metanephrine and 3-methoxytyramine in patients on hemodialysis and specific reference intervals for plasma metanephrines under the most optimal sampling conditions. Blood was sampled before and near the end of dialysis, including different sampling sites in 170 patients on hemodialysis. Plasma normetanephrine concentrations were lower (P < 0.0001) and metanephrine concentrations higher (P < 0.0001) in shunt than in venous blood, with no differences for 3-methoxytyramine. Normetanephrine, metanephrine and 3-methoxytyramine concentrations in shunt and venous blood were lower (P < 0.0001) near the end than before hemodialysis. Upper cut-offs for normetanephrine were 34% lower when the blood was drawn from the shunt and near the end of hemodialysis compared to blood drawn before hemodialysis. This study establishes optimal sampling conditions using blood from the dialysis shunt near the end of hemodialysis with optimal reference intervals for plasma metanephrines for the diagnosis of pheochromocytomas/paragangliomas among patients on hemodialysis.


Subject(s)
Blood Specimen Collection , Metanephrine/blood , Renal Dialysis , Adrenal Gland Neoplasms/blood , Adrenal Gland Neoplasms/diagnosis , Aged , Aged, 80 and over , Blood Chemical Analysis/methods , Blood Chemical Analysis/standards , Blood Specimen Collection/methods , Blood Specimen Collection/standards , Calibration , Dopamine/analogs & derivatives , Dopamine/analysis , Dopamine/blood , Female , Humans , Male , Metanephrine/analysis , Middle Aged , Paraganglioma/blood , Paraganglioma/diagnosis , Pheochromocytoma/blood , Pheochromocytoma/diagnosis , Poland , Pre-Analytical Phase/methods , Pre-Analytical Phase/standards , Reference Values , Tandem Mass Spectrometry/methods , Tandem Mass Spectrometry/standards
5.
Bone ; 133: 115188, 2020 04.
Article in English | MEDLINE | ID: mdl-31843681

ABSTRACT

PURPOSE: The usefulness of FRAX in predicting major bone fractures in patients with end-stage kidney disease on maintenance hemodialysis treatment has been confirmed in previous studies. For meaningful clinical use, the prognostic and intervention FRAX thresholds need to be established. METHODS: The primary aim of our study was to calculate the optimal cut-off point of FRAX for the best prediction of an increased bone fracture risk in dialysis patients and additionally, to propose its intervention threshold, indicating the need for antifracture pharmacological treatment. The study included 718 hemodialysis patients, who were followed up for two years. Thirty low-energy major bone fractures were diagnosed during the study period. We used the Polish version of FRAX (without the DXA examination) and some particular variables of the FRAX calculator. The optimal cut-off point for prediction of an increased major bone fracture risk was based on the analysis of the sensitivity and specificity curves of FRAX. RESULTS: The analysis revealed FRAX >5% (sensitivity of 70.0%, specificity of 69.8%) as the prognostic threshold for major bone fractures. Its sensitivity for bone fracture prediction was significantly higher, but specificity lower than those of FRAX ≥10%, used in general Polish population. The reason for this can be an underestimation of bone fracture risk with FRAX in dialysis patients. CONCLUSIONS: We conclude that the FRAX prognostic threshold for identification of an increased risk of major bone fractures in hemodialysis patients is >5%. We propose to use this specific value of FRAX as an intervention threshold for pharmacological antifracture treatment in hemodialysis patients.


Subject(s)
Fractures, Bone , Osteoporotic Fractures , Bone Density , Humans , Prognosis , Prospective Studies , Renal Dialysis/adverse effects , Risk Assessment , Risk Factors
7.
BMC Nephrol ; 17(1): 194, 2016 11 25.
Article in English | MEDLINE | ID: mdl-27884116

ABSTRACT

BACKGROUND: Longer life expectancy is associated with an increasing prevalence of kidney disease. Aging itself may cause renal damage, but the spectrum of kidney disorders that affect elderly patients is diverse. Few studies, mostly form US, Asia and West Europe found differences in the prevalence of some types of kidney diseases between elderly and younger patients based on renal biopsy findings, with varied proportion between glomerulopathies and arterionephrosclerosis as a dominant injury found. Here, for the first time in Eastern Europe we analyzed native kidney biopsy findings and their relationship to clinical characteristics at the time of biopsy in elderly individuals (aged ≥65) in comparison to younger adults (aged 18-64). METHODS: Biopsy and clinical data from 352 patients aged ≥65 were retrospectively identified, analyzed and compared with a control group of 2214 individuals aged 18-64. All kidney biopsies studied were examined at Medical University of Warsaw in years 2009-14. RESULTS: In elderly patients the leading indication for biopsy was nephrotic range proteinuria without hematuria (34.2%) and the most prevalent pathologic diagnoses were: membranous glomerulonephritis (MGN) (18.2%), focal segmental glomerulosclerosis (FSGS) (17.3%) amyloidosis (13.9%) and pauci immune glomerulonephritis (12.8%). Hypertension and age-related lesions very rarely were found an exclusive or dominant finding in a kidney biopsy (1.7%) and a cause of proteinuria (1.1%) in elderly individuals. There were 18.2% diabetics among elderly individuals, and as much as 75% of them had no morphologic signs of diabetic kidney disease in the renal biopsy. Amyloidosis, MGN, pauci immune GN, crescentic GN and light and/or heavy chain deposition disease (LCDD/HCDD) were more frequent whereas IgA nephropathy (IgAN), lupus nephritis (LN) and thin basement membrane disease (TBMD) were less common among elderly than in younger patients. CONCLUSIONS: Proteinuria, a dominating manifestation in elderly patients subjected to kidney biopsy was most commonly related to glomerulopathies. The relatively high prevalence of potentially curative kidney diseases in elderly individuals implicates the importance of renal biopsy in these patients.


Subject(s)
Kidney Diseases/epidemiology , Kidney Diseases/pathology , Adult , Age Factors , Aged , Aged, 80 and over , Biopsy , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Poland/epidemiology , Retrospective Studies
8.
Cent European J Urol ; 68(3): 376-82, 2015.
Article in English | MEDLINE | ID: mdl-26568885

ABSTRACT

Urological consultation is an important step in the procedure of a patient's preparation before placing him/her on a waiting list for a renal transplant. Urological work-up aims to diagnose, treat, and optimize any preexisting urological disease. In the present paper we present the review of the literature together with the authors' conclusions based on literature and their experience. There is not enough data in current literature and urology manuals on the adequate sequence of the urological management with patients qualified for renal transplant and the literature needs an update. This study presents the crucial steps of the qualification and emphasizes the urge for a more standardized urological approach in patients qualified for a kidney transplantation.

9.
Nephrology (Carlton) ; 19(5): 266-74, 2014 May.
Article in English | MEDLINE | ID: mdl-24506498

ABSTRACT

AIM: While darbepoetin alfa (DA) can be administered once monthly (QM) to maintain haemoglobin (Hb) concentrations in anaemic patients with chronic kidney disease not on dialysis (CKD-ND), the QM use of DA for anaemia correction has not been previously investigated. METHODS: In this randomized, double-blind, non-inferiority, active-controlled study, adult subjects with CKD-ND, Hb levels <10 g/dL, and not treated with an erythropoiesis-stimulating agent were randomized 1:1 to receive DA every 2 weeks (Q2W) or QM for 33 weeks with initial doses of 0.75 µg/kg Q2W or 1.5 µg/kg QM. Subjects were treated to target Hb levels of 10-12 g/dL and ≥1 g/dL increase from baseline. The primary end-point was Hb change between baseline and the evaluation period (weeks 29-33), with a non-inferiority margin of -0.5 g/dL. RESULTS: Three hundred and fifty-five subjects received ≥1 dose of DA. Mean (95% confidence interval [CI]) change in Hb between baseline and the evaluation period was 2.16 (1.98-2.33) g/dL for the Q2W group and 1.97 (1.80-2.14) g/dL for the QM group, the mean (95% CI) difference in Hb change being -0.19 (-0.43 to 0.05) g/dL. Most subjects (97.9% Q2W; 98.1% QM) achieved a Hb level ≥10.0 g/dL and ≥1.0 g/dL increase in Hb from baseline. Mean DA (SD) weekly equivalent doses over the evaluation period were 0.20 (0.23) and 0.27 (0.31) µg/kg per week for the Q2W and QM groups, respectively. Safety profiles were similar between groups. CONCLUSION: In subjects with CKD-ND, QM dosing was non-inferior to Q2W dosing for anaemia correction and had a similar safety profile.


Subject(s)
Anemia/drug therapy , Erythropoietin/analogs & derivatives , Hematinics/administration & dosage , Renal Insufficiency, Chronic/complications , Adult , Aged , Aged, 80 and over , Anemia/blood , Anemia/diagnosis , Anemia/etiology , Australia , Biomarkers/blood , Darbepoetin alfa , Double-Blind Method , Drug Administration Schedule , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Europe , Female , Hematinics/adverse effects , Hemoglobins/metabolism , Humans , Male , Mexico , Middle Aged , Renal Insufficiency, Chronic/diagnosis , Time Factors , Treatment Outcome , Up-Regulation , Young Adult
10.
Brain Res ; 1432: 7-14, 2012 Jan 13.
Article in English | MEDLINE | ID: mdl-22137655

ABSTRACT

Insulin modulates N-methyl-d-aspartate (NMDA) receptors in the CNS and potentiates recombinant NMDA receptor currents in Xenopus oocytes. We have previously found that insulin's potentiation of NMDA receptor currents in oocytes occurs in a subunit specific manner and via phosphorylation of specific C-terminal sites by protein tyrosine kinases (PTKs) and C-type protein kinases (PKCs). Insulin-mediated current potentiation of receptors containing the NR2A subunit occurs solely through the activation of PKCs. Activation of phosphoinositide 3-kinase (PI 3-kinase) is known to trigger many insulin-stimulated signaling pathways, and we show here that it lies at a critical step in the insulin-mediated potentiation of NMDA receptor currents. Incubation with the PI 3-kinase inhibitor wortmannin eliminates insulin potentiation of NMDA receptor currents in the oocytes. Atypical isoforms of PKC are known to be activated downstream in the insulin signaling pathway via activation of PI 3-kinase. We demonstrate that the atypical isoform PKC zeta (PKCζ) has a role in insulin-stimulated current potentiation of NR2A-containing NMDA receptors using an isoform-specific pseudosubstrate inhibitor of PKCζ.


Subject(s)
Insulin/physiology , Oocytes/physiology , Phosphatidylinositol 3-Kinases/physiology , Protein Kinase C/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Androstadienes/pharmacology , Animals , Enzyme Inhibitors/pharmacology , Female , Oocytes/drug effects , Oocytes/enzymology , Phosphoinositide-3 Kinase Inhibitors , Signal Transduction/drug effects , Signal Transduction/physiology , Substrate Specificity/drug effects , Substrate Specificity/physiology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Wortmannin , Xenopus laevis
14.
Pol Arch Med Wewn ; 112 Spec No: 125-38, 2004 Oct.
Article in Polish | MEDLINE | ID: mdl-15669209

ABSTRACT

In Europe, 20% of the populations is over 65 years of age. About 5% of the older adults have heart failure. Heart failure (HF) in the elderly is an increasing public health problem, leading cause of hospitalization in older patients and a major cause of morbidity and mortality. Prognosis has improved only slightly during the past decade. Typically, heart failure occurs when ventricles do not fill (diastolic heart failure - DHF) or empty blood (systolic heart failure - SHF) properly. Transthoracic echocardiography is the key investigation to confirm the underlying structural and functional abnormalities of the heart. Patients with heart failure due to left ventricular systolic dysfunction should be treated with a diuretic, an angiotensin converting enzyme inhibitor, and a beta-blocker (unless contraindicated). Several epidemiologic studies have recently shown that more than 50% of older patients who present with symptoms of HF have DHF. While numerous large trials have established specific therapies for SHF, such trials are lacking for DHF. The finding of similar key pathophysiologic abnormalities in DHF and SHF suggests the possibility that therapies that have been successful for SHF may have a role in therapy for DHF. A recent survey showed that despite physicians' awareness of the benefits of beta-blocker therapy, only minority of patients with heart failure are treated with beta-blocker or combination of ACE inhibitors and beta-blocker.


Subject(s)
Aging/pathology , Health Status , Heart Failure , Ventricular Dysfunction, Left , Adrenergic beta-Antagonists/therapeutic use , Age Factors , Aged , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cardiotonic Agents/therapeutic use , Controlled Clinical Trials as Topic , Diuretics/therapeutic use , Echocardiography/standards , Europe , Heart Failure/diagnosis , Heart Failure/drug therapy , Heart Failure/physiopathology , Humans , Research Design , Risk Factors , Vasodilator Agents/therapeutic use , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/physiopathology
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