Incremental dialysis for preserving residual kidney function-Does one size fit all when initiating dialysis?

While many patients have substantial residual kidney function (RKF) when initiating hemodialysis (HD), most patients with end stage renal disease in the United States are initiated on 3-times per week conventional HD regimen, with little regard to RKF or patient preference. RKF is associated with many benefits including survival, volume control, solute clearance, and reduced inflammation. Several strategies have been recommended to preserve RKF after HD initiation, including an incremental approach to HD initiation. Incremental HD prescriptions are personalized to achieve adequate volume control and solute clearance with consideration to a patient's endogenous renal function. This allows the initial use of less frequent and/or shorter HD treatment sessions. Regular measurement of RKF is important because HD frequency needs to be increased as RKF inevitably declines. We narratively review the results of 12 observational cohort studies of twice-weekly compared to thrice-weekly HD. Incremental HD is associated with several benefits including preservation of RKF as well as extending the event-free life of arteriovenous fistulas and grafts. Patient survival and quality of life, however, has been variably associated with incremental HD. Serious risks must also be considered, including increased hospitalization and mortality perhaps related to fluid and electrolyte shifts after a long interdialytic interval. On the basis of the above literature review, and our clinical experience, we suggest patient characteristics which may predict favorable outcomes with an incremental approach to HD. These include substantial RKF, adequate volume control, lack of significant anemia/electrolyte imbalance, satisfactory health-related quality of life, low comorbid disease burden, and good nutritional status without evidence of hypercatabolism. Clinicians should engage patients in on-going conversations to prepare for incremental HD initiation and to ensure a smooth transition to thrice-weekly HD when needed

The search for new pathogenesis of cardiorenal syndrome: the effect of local Schumann resonance on the occurrence of episodes of kidney disease and myocardial infarction

Background. The pandemic of noncommunicable chronic diseases and the high prevalence of combined damage to the cardiovascular system and kidneys determine the relevance of continuing scientific research to solve these medical problems. Therefore, the aim of this study was to compare the influence of the Earth’s electromagnetic field on the occurrence of episodes of kidney disease and myocardial infarction in order to search for new pathogenetic components of cardiorenal syndrome and deepen fundamental knowledge. According to the Lithuanian magnetometer GCI003, a number of stu­dies in 2014–2018 found that changes in the Earth’s electromagnetic field may play an important role in the pathogenesis of cardiovascular diseases as well as their incidence. Since the functioning of the cardiovascular system and kidneys are closely connected through the metabolic processes of the cardiorenal metabolic axis, this study tested the hypothesis that changes in the Earth’s electromagnetic field may also affect the pathogenesis of kidney disease as the changes of local magnetic field have been shown to influence the functioning of the cardiovascular system. Materials and methods. This was a search retrospective study on the relationship between the influence of local Schumann resonances and the occurrence of hospitalizations in 1340 patients with kidney disease. It also examined the relationship between local Schumann resonances and heart attacks in patients admitted to the University Hospital of the Lithuanian University of Health Sciences (703 patients). Mean power of local magnetic field fluctuations in Lithuania was measured in pT2 s2 in five different frequency ranges, which overlaps the Schumann resonance and electroencephalogram’s frequency ranges: SDelta (0–3.5 Hz), STheta (3.5–7 Hz), SAlpha (7–15 Hz), SBeta (15–32 Hz), SGamma (32–66 Hz). The data of hospitalizations to the Nephrology Department of University Hospital and the dynamics of Schumann resonances were analyzed from January 1, 2021 to December 31, 2021. The data of hospitalizations for myocardial infarction to the Cardiology Department of University Hospital and the dynamics of Schumann resonances were studied from January 1, 2016 to December 31, 2016. Results. It was found that changes in the strength of the Earth’s local magnetic field in 2016 and 2021 were comparable and corresponded to the characteristic annual dynamics of the Earth’s local electromagnetic fields. This made it possible to conduct a comparative analysis of annual correlation graphs and establish general trends in the dynamics of indicators and graphical similarities. It confirmed the pre­sence of a general dependence of reactions to the external electromagnetic field of the Earth in female and male patients both with nephrological pathology and myocardial infarction. In nephrological patients of both sexes, all correlation coefficients in all ranges of Schumann resonances were positive. The only negative correlation coefficient P5 (SGamma) [32; 65] Hz (r = –0.069; p = 0.313) was in the female group. This fact as well as the presence of a significant dynamics of the correlation coefficient P5 (SGamma) [32; 65] Hz (r = 0.009; p = 0.475) in the male group indicate that higher magnetic field strength in this frequency range may be associated with a reduced incidence of kidney disease. We obtained data that a higher magnetic field intensity in the gamma range from 32 to 65 Hz as a pathogenetic component can contribute to the destabilization of the cardiovascular system, but at the same time it is associated with a positive effect on the state of nephrological pathology. Based on this, we can tentatively assume the opposite direction of the Earth’s electromagnetic field influence on the pathogenetic mechanisms of renal and cardiovascular diseases. This is clearly demonstrated by comparing the correlation coefficients between the incidence of kidney disease and the occurrence of myocardial infarction in men and women. The Earth’s stronger magnetic field in the gamma range contributes to an increase in the incidence of myocardial infarction, which is confirmed by the large number of patients during this period. Under these same conditions, a decrease in the incidence of kidney disease has been detected. This opposite direction is observed in both sexes. But in women the reaction is stronger, which is confirmed by a larger difference in correlation coefficients. Conclusions. 1. Changes in the Earth’s electromagnetic field are related to the functional state of the cardiovascular system and the condition of the kidneys. 2. It can be assumed that the effect of the Earth’s electromagnetic field on the pathogenetic mechanisms of kidney disease is in the opposite direction of that on the cardiovascular one. 3. Reliable gender differences in correlations between the influence of changes in the local Schumann resonance on the functional state of the cardiovascular system and kidneys were not found. 4. The connection of the Earth’s local geomagnetic field with kidney function may be another new unexplored pathogenetic mechanism in cardiorenal syndrome and noncommunicable chronic diseases

Пошук нового патогенезу кардіоренального синдрому: зв'язок 2 локального резонансу Шумана з виникненням 3 епізодів захворювання нирок та інфаркту міокарда

Abstract: The aim of study was to compare the influence of the Earth's electromagnetic field on the 18 occurrence of episodes of kidney disease and myocardial infarction in order to search for new path-19 ogenetic components of cardiorenal syndrome and deepen fundamental knowledge. The results of 20 a retrospective study on the relationship between the influence of local Schumann resonances and 21 the occurrence hospitalizations of 1340 patients with kidney disease and a study examining the re-22 lationship between local Schumann resonances and the occurrence of heart attacks admitted to the 23 University Hospital of the Lithuanian University of Health Sciences (703 patients) concluded that: 24 1. Changes in the Earth's electromagnetic field related the functional state of the cardiovascular sys-25 tem and the condition of the kidneys. 2. It can be assumed that the connection of the Earth’s electro-26 magnetic field on the pathogenetic mechanisms of kidney pathology is in the opposite direction. 3. 27 Reliable gender differences in correlations between the influence of changes in the local Schumann 28 resonance on the functional state of the cardiovascular system and kidneys were not established. 4. 29 The connection of the Earth's local geomagnetic field on kidney function may be another new unex-30 plored pathogenetic mechanism in cardiorenal syndrome and Chronic Noncommunicable diseases.Метою дослідження було порівняти вплив електромагнітного поля Землі на виникнення епізодів захворювання нирок та інфаркту міокарда з метою пошуку нових шляхогенетичних компонентів кардіоренального синдрому та поглиблення фундаментальних знань. Результати 20 ретроспективного дослідження зв’язку між впливом місцевих резонансів Шумана та 21 виникненням госпіталізацій 1340 пацієнтів із захворюваннями нирок та дослідження повторного 22 зв’язку між місцевими резонансами Шумана та виникненням серцевих нападів у лікарні 23 Університетська лікарня Литовського університету наук про здоров’я (703 пацієнти) дійшли висновку, що: 24 1. Зміни в електромагнітному полі Землі пов’язані з функціональним станом серцево-судинної системи 25 та станом нирок. 2. Можна припустити, що вплив електромагнітного поля Землі на патогенетичні механізми патології нирок є протилежним. 3. 27 Достовірних гендерних відмінностей кореляційних зв’язків між впливом змін локального резонансу Шумана 28 на функціональний стан серцево-судинної системи та нирок не встановлено. 4. 29 Зв’язок локального геомагнітного поля Землі з функцією нирок може бути ще одним новим невивченим патогенетичним механізмом при кардіоренальному синдромі та хронічних неінфекційних захворюваннях..Целью исследования было сравнение влияния электромагнитного поля Земли на возникновение 18 эпизодов заболеваний почек и инфаркта миокарда с целью поиска новых генетических компонентов пути-19 кардиоренального синдрома и углубления фундаментальных знаний. Результаты 20 ретроспективного исследования связи между влиянием локальных резонансов Шумана и 21 частотой госпитализаций 1340 пациентов с заболеваниями почек и исследования, изучающего связь между локальными резонансами Шумана и частотой сердечных приступов, поступивших в 23 Университетская больница Литовского университета наук о здоровье (703 пациента) пришла к выводу, что: 24 1. Изменения электромагнитного поля Земли связаны с функциональным состоянием сердечно-сосудистой системы-25 и состоянием почек. 2. Можно предположить, что связь магнитного поля Электро-26 Земли с патогенетическими механизмами патологии почек имеет обратную направленность. 3. 27 Достоверных гендерных различий в корреляциях влияния изменений локального Шумановского 28 резонанса на функциональное состояние сердечно-сосудистой системы и почек не установлено. 4. 29 Связь местного геомагнитного поля Земли с функцией почек может быть еще одним новым исследованным в ходе исследования 30 патогенетическим механизмом кардиоренального синдрома и хронических неинфекционных заболеваний

Is incremental hemodialysis ready to return on the scene? From empiricism to kinetic modelling

Most people who make the transition to maintenance dialysis therapy are treated with a fixed dose thrice-weekly hemodialysis regimen without considering their residual kidney function (RKF). The RKF provides effective and naturally continuous clearance of both small and middle molecules, plays a major role in metabolic homeostasis, nutritional status, and cardiovascular health, and aids in fluid management. The RKF is associated with better patient survival and greater health-related quality of life, although these effects may be confounded by patient comorbidities. Preservation of the RKF requires a careful approach, including regular monitoring, avoidance of nephrotoxins, gentle control of blood pressure to avoid intradialytic hypotension, and an individualized dialysis prescription including the consideration of incremental hemodialysis. There is currently no standardized method for applying incremental hemodialysis in practice. Infrequent (once- to twice-weekly) hemodialysis regimens are often used arbitrarily, without knowing which patients would benefit the most from them or how to escalate the dialysis dose as RKF declines over time. The recently heightened interest in incremental hemodialysis has been hindered by the current limitations of the urea kinetic models (UKM) which tend to overestimate the dialysis dose required in the presence of substantial RKF. This is due to an erroneous extrapolation of the equivalence between renal urea clearance (Kru) and dialyser urea clearance (Kd), correctly assumed by the UKM, to the clinical domain. In this context, each ml/min of Kd clears the urea from the blood just as 1 ml/min of Kru does. By no means should such kinetic equivalence imply that 1 ml/min of Kd is clinically equivalent to 1 ml/min of urea clearance provided by the native kidneys. A recent paper by Casino and Basile suggested a variable target model (VTM) as opposed to the fixed model, because the VTM gives more clinical weight to the RKF and allows less frequent hemodialysis treatments at lower RKF. The potentially important clinical and financial implications of incremental hemodialysis render it highly promising and warrant randomized controlled trials

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein–creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein–creatinine ratio was statistically significantly greater in the sparsentan group (–49·8%) than the irbesartan group (–15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51–0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

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

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