Global access and quality of conservative kidney management.

BACKGROUND: Conservative kidney management (CKM) describes supportive care for people living with kidney failure who choose not to receive or are unable to access kidney replacement therapy (KRT). This study captured the global availability of CKM services and funding. METHODS: Data came from the International Society of Nephrology Global Kidney Health survey conducted between June and September 2022. Availability of CKM, infrastructure, guidelines, medications and training were evaluated. RESULTS: CKM was available in some form in 61% of the 165 responding countries. CKM chosen through shared decision-making was available in 53%. Choice-restricted CKM-for those unable to access KRT-was available in 39%. Infrastructure to provide CKM chosen through shared decision-making was associated with national income level, reported as being "generally available" in most healthcare settings for 71% of high-income countries, 50% of upper-middle-income countries, 33% of lower-middle-income countries and 42% of low-income countries. For choice-restricted CKM, these figures were 29%, 50%, 67% and 58%, respectively. Essential medications for pain and palliative care were available in just over half of the countries, highly dependent upon income setting. Training for caregivers in symptom management in CKM was available in approximately a third of countries. CONCLUSIONS: Most countries report some capacity for CKM. However, there is considerable variability in terms of how CKM is defined, as well as what and how much care is provided. Poor access to CKM perpetuates unmet palliative care needs, and must be addressed, particularly in low-resource settings where death from untreated kidney failure is common.

Experiences of social isolation and loneliness in chronic kidney disease: a secondary qualitative analysis.

BACKGROUND: Many patients with chronic kidney disease (CKD) experience loneliness and social isolation, which are associated with a higher risk of mortality, morbidity, and poor mental health. We aimed to describe the perspectives of patients with CKD and their caregivers on loneliness and social isolation, to inform strategies to increase social participation. METHODS: A secondary analysis of qualitative data from the Standardized Outcomes in Nephrology (SONG) initiative dataset (36 focus groups, three Delphi surveys and seven consensus workshops) was conducted. We extracted and thematically analyzed data from patients with CKD, including those receiving hemodialysis or peritoneal dialysis and those with a kidney transplant, as well as their caregivers, on the perspectives and experiences of loneliness and social isolation. RESULTS: Collectively the studies included 1261 patients and caregivers from 25 countries. Six themes were identified: restricted by the burdens of disease and treatment (withdrawing from social activities due to fatigue, consumed by the dialysis regimen, tethered to treatment, travel restrictions); external vulnerability (infection risk, anxiety of dining out); diminishing societal role (grieving loss of opportunities, social consequences of inability to work); fending for oneself in healthcare (no one to relate to, lost in uncertainty, unmet psychosocial needs); undermining self-esteem (unable to engage in activities which previously defined self, shame and self-consciousness about appearance, hindering confidence for intimate relationships); and feeling ostracized (disconnected by family and friends, fear of stigma and being misunderstood, guilt of burdening others). CONCLUSIONS: For patients with CKD and their caregivers, social participation is substantially impaired by the burden of CKD and its treatment, and fear of risks to health such as infection. This undermines patient and caregiver mental health, particularly self-esteem and sense of belonging. Additional interventions are needed to improve social connections among people with CKD and their caregivers.

A global overview of health system financing and available infrastructure and oversight for kidney care.

BACKGROUND: Governance, health financing, and service delivery are critical elements of health systems for provision of robust and sustainable chronic disease care. We leveraged the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to evaluate oversight and financing for kidney care worldwide. METHODS: A survey was administered to stakeholders from countries affiliated with the ISN from July to September 2022. We evaluated funding models utilized for reimbursement of medications, services for the management of chronic kidney disease, and provision of kidney replacement therapy (KRT). We also assessed oversight structures for the delivery of kidney care. RESULTS: Overall, 167 of the 192 countries and territories contacted responded to the survey, representing 97.4% of the global population. High-income countries tended to use public funding to reimburse all categories of kidney care in comparison with low-income countries (LICs) and lower-middle income countries (LMICs). In countries where public funding for KRT was available, 78% provided universal health coverage. The proportion of countries that used public funding to fully reimburse care varied for non-dialysis chronic kidney disease (27%), dialysis for acute kidney injury (either hemodialysis or peritoneal dialysis) (44%), chronic hemodialysis (45%), chronic peritoneal dialysis (42%), and kidney transplant medications (36%). Oversight for kidney care was provided at a national level in 63% of countries, and at a state/provincial level in 28% of countries. CONCLUSION: This study demonstrated significant gaps in universal care coverage, and in oversight and financing structures for kidney care, particularly in in LICs and LMICs.

Worldwide organization and structures for kidney transplantation services.

BACKGROUND: Kidney transplantation (KT) is the preferred modality of kidney replacement therapy with better patient outcomes and quality of life compared with dialytic therapies. This study aims to evaluate the epidemiology, accessibility and availability of KT services in countries and regions around the world. METHODS: This study relied on data from an international survey of relevant stakeholders (clinicians, policymakers and patient advocates) from countries affiliated with the International Society of Nephrology that was conducted from July to September 2022. Survey questions related to the availability, access, donor type and cost of KT. RESULTS: In total, 167 countries responded to the survey. KT services were available in 70% of all countries, including 86% of high-income countries, but only 21% of low-income countries. In 80% of countries, access to KT was greater in adults than in children. The median global prevalence of KT was 279.0 [interquartile range (IQR) 58.0-492.0] per million people (pmp) and the median global incidence was 12.2 (IQR 3.0-27.8) pmp. Pre-emptive KT remained exclusive to high- and upper-middle-income countries, and living donor KT was the only available modality for KT in low-income countries. The median cost of the first year of KT was $26 903 USD and varied 1000-fold between the most and least expensive countries. CONCLUSION: The availability, access and affordability of KT services, especially in low-income countries, remain limited. There is an exigent need to identify strategies to ensure equitable access to KT services for people with kidney failure worldwide, especially in the low-income countries.

Global data monitoring systems and early identification for kidney diseases.

BACKGROUND: Data monitoring and surveillance systems are the cornerstone for governance and regulation, planning, and policy development for chronic disease care. Our study aims to evaluate health systems capacity for data monitoring and surveillance for kidney care. METHODS: We leveraged data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA), an international survey of stakeholders (clinicians, policymakers and patient advocates) from 167 countries conducted between July and September 2022. ISN-GKHA contains data on availability and types of kidney registries, the spectrum of their coverage, as well as data on national policies for kidney disease identification. RESULTS: Overall, 167 countries responded to the survey, representing 97.4% of the global population. Information systems in forms of registries for dialysis care were available in 63% (n = 102/162) of countries, followed by kidney transplant registries (58%; n = 94/162), and registries for non-dialysis chronic kidney disease (19%; n = 31/162) and acute kidney injury (9%; n = 14/162). Participation in dialysis registries was mandatory in 57% (n = 58) of countries; however, in more than half of countries in Africa (58%; n = 7), Eastern and Central Europe (67%; n = 10), and South Asia (100%; n = 2), participation was voluntary. The least-reported performance measures in dialysis registries were hospitalization (36%; n = 37) and quality of life (24%; n = 24). CONCLUSIONS: The variability of health information systems and early identification systems for kidney disease across countries and world regions warrants a global framework for prioritizing the development of these systems.

A global assessment of kidney care workforce.

BACKGROUND: An adequate workforce is needed to guarantee optimal kidney care. We used the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to provide an assessment of the global kidney care workforce. METHODS: We conducted a multinational cross-sectional survey to evaluate the global capacity of kidney care and assessed data on the number of adult and paediatric nephrologists, the number of trainees in nephrology and shortages of various cadres of the workforce for kidney care. Data are presented according to the ISN region and World Bank income categories. RESULTS: Overall, stakeholders from 167 countries responded to the survey. The median global prevalence of nephrologists was 11.75 per million population (pmp) (interquartile range [IQR] 1.78-24.76). Four regions had median nephrologist prevalences below the global median: Africa (1.12 pmp), South Asia (1.81 pmp), Oceania and Southeast Asia (3.18 pmp) and newly independent states and Russia (9.78 pmp). The overall prevalence of paediatric nephrologists was 0.69 pmp (IQR 0.03-1.78), while overall nephrology trainee prevalence was 1.15 pmp (IQR 0.18-3.81), with significant variations across both regions and World Bank income groups. More than half of the countries reported shortages of transplant surgeons (65%), nephrologists (64%), vascular access coordinators (59%), dialysis nurses (58%) and interventional radiologists (54%), with severe shortages reported in low- and lower-middle-income countries. CONCLUSIONS: There are significant limitations in the available kidney care workforce in large parts of the world. To ensure the delivery of optimal kidney care worldwide, it is essential to develop national and international strategies and training capacity to address workforce shortages.

Global structures, practices, and tools for provision of chronic peritoneal dialysis.

BACKGROUND: Worldwide, the uptake of peritoneal dialysis (PD) compared with hemodialysis remains limited. This study assessed organizational structures, availability, accessibility, affordability and quality of PD worldwide. METHODS: This cross-sectional study relied on data from kidney registries as well as survey data from stakeholders (clinicians, policymakers and advocates for people living with kidney disease) from countries affiliated with the International Society of Nephrology (ISN) from July to September 2022. RESULTS: Overall, 167 countries participated in the survey. PD was available in 79% of countries with a median global prevalence of 21.0 [interquartile range (IQR) 1.5-62.4] per million population (pmp). High-income countries (HICs) had an 80-fold higher prevalence of PD than low-income countries (LICs) (56.2 pmp vs 0.7 pmp). In 53% of countries, adults had greater PD access than children. Only 29% of countries used public funding (and free) reimbursement for PD with Oceania and South East Asia (6%), Africa (10%) and South Asia (14%) having the lowest proportions of countries in this category. Overall, the annual median cost of PD was US$18 959.2 (IQR US$10 891.4-US$31 013.8) with full private out-of-pocket payment in 4% of countries and the highest median cost in LICs (US$30 064.4) compared with other country income levels (e.g. HICs US$27 206.0). CONCLUSIONS: Ongoing large gaps and variability in the availability, access and affordability of PD across countries and world regions were observed. Of note, there is significant inequity in access to PD by children and for people in LICs.

Global structures, practices, and tools for provision of hemodialysis.

BACKGROUND: Hemodialysis (HD) is the most commonly utilized modality for kidney replacement therapy worldwide. This study assesses the organizational structures, availability, accessibility, affordability and quality of HD care worldwide. METHODS: This cross-sectional study relied on desk research data as well as survey data from stakeholders (clinicians, policymakers and patient advocates) from countries affiliated with the International Society of Nephrology from July to September 2022. RESULTS: Overall, 167 countries or jurisdictions participated in the survey. In-center HD was available in 98% of countries with a median global prevalence of 322.7 [interquartile range (IQR) 76.3-648.8] per million population (pmp), ranging from 12.2 (IQR 3.9-103.0) pmp in Africa to 1575 (IQR 282.2-2106.8) pmp in North and East Asia. Overall, home HD was available in 30% of countries, mostly in countries of Western Europe (82%). In 74% of countries, more than half of people with kidney failure were able to access HD. HD centers increased with increasing country income levels from 0.31 pmp in low-income countries to 9.31 pmp in high-income countries. Overall, the annual cost of in-center HD was US$19 380.3 (IQR 11 817.6-38 005.4), and was highest in North America and the Caribbean (US$39 825.9) and lowest in South Asia (US$4310.2). In 19% of countries, HD services could not be accessed by children. CONCLUSIONS: This study shows significant variations that have remained consistent over the years in availability, access and affordability of HD across countries with severe limitations in lower-resourced countries.

Dialysis Outcomes Across Countries and Regions: A Global Perspective From the International Society of Nephrology Global Kidney Health Atlas Study.

Introduction: Kidney failure treated with hemodialysis (HD), or peritoneal dialysis (PD) is a major global health problem that is associated with increased risks of death and hospitalization. This study aimed to compare the incidence and causes of death and hospitalization during the first year of HD or PD among countries. Methods: The third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) was conducted between June and September 2022. For this analysis, data were obtained from the cross-sectional survey of key stakeholders from ISN-affiliated countries. Results: A total of 167 countries participated in the survey (response rate 87.4%). In 48% and 58% of countries, 1% to 10% of people treated with HD and PD died within the first year, respectively, with cardiovascular disease being the main cause. Access-related infections or treatment withdrawal owing to cost were important causes of death in low-income countries (LICs). In most countries, <30% and <20% of patients with HD and PD, respectively, required hospitalization during the first year. A greater proportion of patients with HD and PD in LICs were hospitalized in the first year than those in high-income countries (HICs). Access-related infection and cardiovascular disease were the commonest causes of hospitalization among patients with HD, whereas PD-related infection was the commonest cause in patients with PD. Conclusion: There is significant heterogeneity in the incidence and causes of death and hospitalization in patients with kidney failure treated with dialysis. These findings highlight opportunities to improve care, especially in LICs where infectious and social factors are strong contributors to adverse outcomes.

Long-term effect of increasing water intake on repeated self-assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease.

Background: The aim of this study was to determine the long-term effect of increasing water intake in patients with autosomal dominant polycystic kidney disease (ADPKD) on longitudinal changes in health-related quality of life (HRQoL) in the setting of a clinical trial. Methods: Self-completed HRQoL (using the KDQoL-SF, v.1.3 questionnaire) was assessed annually in participants of a 3-year randomized controlled clinical trial (n = 187), allocated (1:1) either to increase water intake to reduce urine osmolality to ≤270 mosmol/kg (implemented by dietetic coaching, self-monitoring tools, text messaging) or continue usual water intake. Results: Overall, 96% and 81.8% of participants (n = 187) completed the questionnaire at the baseline and final study visits, respectively. At baseline, the physical component summary score (PCS) and mental component summary score (MCS) were similar in the two groups (P > 0.05) and the five dimensions with the lowest scores in both groups were: energy and fatigue; general and overall health; sleep; emotional well-being; and pain. Within each group, there were no longitudinal changes over time. At the final visit, the PCS was higher in the increased water intake group (51.3 ± 7.6, mean ± standard deviation) compared to the usual water intake group 48.8 ± 9.3; P = 0.037) whereas the MCS was numerically similar. The improvement in the PCS was due to higher sub-scale values for physical functioning and pain (both P < 0.05). By multivariate analysis, only baseline PCS and height-corrected total kidney volume were associated with the final PCS (P < 0.05). Conclusion: HRQoL scores remained stable over a 3 year period, and were not adversely affected by the intervention to increase water intake. Future studies should evaluate the clinical significance of the higher PCS in the increased water intake group.

Drug repurposing for glomerular diseases: an underutilized resource.

Drug repurposing in glomerular disease can deliver opportunities for steroid-free regimens, enable personalized multi-target options for resistant or relapsing disease and enhance treatment options for understudied populations (for example, children) and in resource-limited settings. Identification of drug-repurposing candidates can be data driven, which utilizes existing data on disease pathobiology, drug features and clinical outcomes, or experimental, which involves high-throughput drug screens. Information from databases of approved drugs, clinical trials and PubMed registries suggests that at least 96 drugs on the market cover 49 targets with immunosuppressive potential that could be candidates for drug repurposing in glomerular disease. Furthermore, evidence to support drug repurposing is available for 191 immune drug target-glomerular disease pairs. Non-immunological drug repurposing includes strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis. Recommended strategies to expand drug-repurposing capacity in glomerular disease include enriching drug databases with glomeruli-specific information, enhancing the accessibility of primary clinical trial data, biomarker discovery to improve participant selection into clinical trials and improve surrogate outcomes and initiatives to reduce patent, regulatory and organizational hurdles.

The randomized controlled trial (NAVKIDS2) of a patient navigator program created for children with chronic kidney disease.

Patient navigators enable adult patients to circumnavigate complex health systems, improving access to health care and outcomes. Here, we aimed to evaluate the effects of a patient navigation program in children with chronic kidney disease (CKD). In this multi-center, randomized controlled trial, we randomly assigned children (aged 0-16 years) with CKD stages 1-5 (including children on dialysis or with kidney transplants), from low socioeconomic status backgrounds, and/or residing in remote areas, to receive patient navigation at randomization (immediate) or at six months (waitlist). The primary outcome was self-rated health (SRH) of participating children at six months, using intention to treat analysis. Secondary outcomes included caregivers' SRH and satisfaction with health care, children's quality of life, hospitalizations, and missed school days. Repeated measures of the primary outcome from baseline to six months were analyzed using cumulative logit mixed effects models. Semi-structured interviews were thematically evaluated. Of 398 screened children, 162 were randomized (80 immediate and 82 waitlist); mean age (standard deviation) of 8.8 (4.8) years with 64.8% male. SRH was not significantly different between the immediate and wait-listed groups at six months. There were also no differences across all secondary outcomes between the two groups. Caregivers' perspectives were reflected in seven themes: easing mental strain, facilitating care coordination, strengthening capacity to provide care, reinforcing care collaborations, alleviating family tensions, inability to build rapport and unnecessary support. Thus, in children with CKD, self-rated health may not improve in response to a navigator program, but caregivers gained skills related to providing and accessing care.

PAR2 activation on human tubular epithelial cells engages converging signaling pathways to induce an inflammatory and fibrotic milieu.

Key features of chronic kidney disease (CKD) include tubulointerstitial inflammation and fibrosis. Protease activated receptor-2 (PAR2), a G-protein coupled receptor (GPCR) expressed by the kidney proximal tubular cells, induces potent proinflammatory responses in these cells. The hypothesis tested here was that PAR2 signalling can contribute to both inflammation and fibrosis in the kidney by transactivating known disease associated pathways. Using a primary cell culture model of human kidney tubular epithelial cells (HTEC), PAR2 activation induced a concentration dependent, PAR2 antagonist sensitive, secretion of TNF, CSF2, MMP-9, PAI-1 and CTGF. Transcription factors activated by the PAR2 agonist 2F, including NFκB, AP1 and Smad2, were critical for production of these cytokines. A TGF-ß receptor-1 (TGF-ßRI) kinase inhibitor, SB431542, and an EGFR kinase inhibitor, AG1478, ameliorated 2F induced secretion of TNF, CSF2, MMP-9, and PAI-1. Whilst an EGFR blocking antibody, cetuximab, blocked PAR2 induced EGFR and ERK phosphorylation, a TGF-ßRII blocking antibody failed to influence PAR2 induced secretion of PAI-1. Notably simultaneous activation of TGF-ßRII (TGF-ß1) and PAR2 (2F) synergistically enhanced secretion of TNF (2.2-fold), CSF2 (4.4-fold), MMP-9 (15-fold), and PAI-1 (2.5-fold). In summary PAR2 activates critical inflammatory and fibrotic signalling pathways in human kidney tubular epithelial cells. Biased antagonists of PAR2 should be explored as a potential therapy for CKD.

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

The C. elegans Myc-family of transcription factors coordinate a dynamic adaptive response to dietary restriction.

Dietary restriction (DR), the process of decreasing overall food consumption over an extended period of time, has been shown to increase longevity across evolutionarily diverse species and delay the onset of age-associated diseases in humans. In Caenorhabditis elegans, the Myc-family transcription factors (TFs) MXL-2 (Mlx) and MML-1 (MondoA/ChREBP), which function as obligate heterodimers, and PHA-4 (orthologous to FOXA) are both necessary for the full physiological benefits of DR. However, the adaptive transcriptional response to DR and the role of MML-1::MXL-2 and PHA-4 remains elusive. We identified the transcriptional signature of C. elegans DR, using the eat-2 genetic model, and demonstrate broad changes in metabolic gene expression in eat-2 DR animals, which requires both mxl-2 and pha-4. While the requirement for these factors in DR gene expression overlaps, we found many of the DR genes exhibit an opposing change in relative gene expression in eat-2;mxl-2 animals compared to wild-type, which was not observed in eat-2 animals with pha-4 loss. Surprisingly, we discovered more than 2000 genes synthetically dysregulated in eat-2;mxl-2, out of which the promoters of down-regulated genes were substantially enriched for PQM-1 and ELT-1/3 GATA TF binding motifs. We further show functional deficiencies of the mxl-2 loss in DR outside of lifespan, as eat-2;mxl-2 animals exhibit substantially smaller brood sizes and lay a proportion of dead eggs, indicating that MML-1::MXL-2 has a role in maintaining the balance between resource allocation to the soma and to reproduction under conditions of chronic food scarcity. While eat-2 animals do not show a significantly different metabolic rate compared to wild-type, we also find that loss of mxl-2 in DR does not affect the rate of oxygen consumption in young animals. The gene expression signature of eat-2 mutant animals is consistent with optimization of energy utilization and resource allocation, rather than induction of canonical gene expression changes associated with acute metabolic stress, such as induction of autophagy after TORC1 inhibition. Consistently, eat-2 animals are not substantially resistant to stress, providing further support to the idea that chronic DR may benefit healthspan and lifespan through efficient use of limited resources rather than broad upregulation of stress responses, and also indicates that MML-1::MXL-2 and PHA-4 may have distinct roles in promotion of benefits in response to different pro-longevity stimuli.

Metformin for preventing the progression of chronic kidney disease.

BACKGROUND: Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression. OBJECTIVES: To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure. AUTHORS' CONCLUSIONS: This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.

Peritoneal dialysis versus haemodialysis for people commencing dialysis.

BACKGROUND: Peritoneal dialysis (PD) and haemodialysis (HD) are two possible modalities for people with kidney failure commencing dialysis. Only a few randomised controlled trials (RCTs) have evaluated PD versus HD. The benefits and harms of the two modalities remain uncertain. This review includes both RCTs and non-randomised studies of interventions (NRSIs). OBJECTIVES: To evaluate the benefits and harms of PD, compared to HD, in people with kidney failure initiating dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies from 2000 to June 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. MEDLINE and EMBASE were searched for NRSIs from 2000 until 28 March 2023. SELECTION CRITERIA: RCTs and NRSIs evaluating PD compared to HD in people initiating dialysis were eligible. DATA COLLECTION AND ANALYSIS: Two investigators independently assessed if the studies were eligible and then extracted data. Risk of bias was assessed using standard Cochrane methods, and relevant outcomes were extracted for each report. The primary outcome was residual kidney function (RKF). Secondary outcomes included all-cause, cardiovascular and infection-related death, infection, cardiovascular disease, hospitalisation, technique survival, life participation and fatigue. MAIN RESULTS: A total of 153 reports of 84 studies (2 RCTs, 82 NRSIs) were included. Studies varied widely in design (small single-centre studies to international registry analyses) and in the included populations (broad inclusion criteria versus restricted to more specific participants). Additionally, treatment delivery (e.g. automated versus continuous ambulatory PD, HD with catheter versus arteriovenous fistula or graft, in-centre versus home HD) and duration of follow-up varied widely. The two included RCTs were deemed to be at high risk of bias in terms of blinding participants and personnel and blinding outcome assessment for outcomes pertaining to quality of life. However, most other criteria were assessed as low risk of bias for both studies. Although the risk of bias (Newcastle-Ottawa Scale) was generally low for most NRSIs, studies were at risk of selection bias and residual confounding due to the constraints of the observational study design. In children, there may be little or no difference between HD and PD on all-cause death (6 studies, 5752 participants: RR 0.81, 95% CI 0.62 to 1.07; I2 = 28%; low certainty) and cardiovascular death (3 studies, 7073 participants: RR 1.23, 95% CI 0.58 to 2.59; I2 = 29%; low certainty), and was unclear for infection-related death (4 studies, 7451 participants: RR 0.98, 95% CI 0.39 to 2.46; I2 = 56%; very low certainty). In adults, compared with HD, PD had an uncertain effect on RKF (mL/min/1.73 m2) at six months (2 studies, 146 participants: MD 0.90, 95% CI 0.23 to 3.60; I2 = 82%; very low certainty), 12 months (3 studies, 606 participants: MD 1.21, 95% CI -0.01 to 2.43; I2 = 81%; very low certainty) and 24 months (3 studies, 334 participants: MD 0.71, 95% CI -0.02 to 1.48; I2 = 72%; very low certainty). PD had uncertain effects on residual urine volume at 12 months (3 studies, 253 participants: MD 344.10 mL/day, 95% CI 168.70 to 519.49; I2 = 69%; very low certainty). PD may reduce the risk of RKF loss (3 studies, 2834 participants: RR 0.55, 95% CI 0.44 to 0.68; I2 = 17%; low certainty). Compared with HD, PD had uncertain effects on all-cause death (42 studies, 700,093 participants: RR 0.87, 95% CI 0.77 to 0.98; I2 = 99%; very low certainty). In an analysis restricted to RCTs, PD may reduce the risk of all-cause death (2 studies, 1120 participants: RR 0.53, 95% CI 0.32 to 0.86; I2 = 0%; moderate certainty). PD had uncertain effects on both cardiovascular (21 studies, 68,492 participants: RR 0.96, 95% CI 0.78 to 1.19; I2 = 92%) and infection-related death (17 studies, 116,333 participants: RR 0.90, 95% CI 0.57 to 1.42; I2 = 98%) (both very low certainty). Compared with HD, PD had uncertain effects on the number of patients experiencing bacteraemia/bloodstream infection (2 studies, 2582 participants: RR 0.34, 95% CI 0.10 to 1.18; I2 = 68%) and the number of patients experiencing infection episodes (3 studies, 277 participants: RR 1.23, 95% CI 0.93 to 1.62; I2 = 20%) (both very low certainty). PD may reduce the number of bacteraemia/bloodstream infection episodes (2 studies, 2637 participants: RR 0.44, 95% CI 0.27 to 0.71; I2 = 24%; low certainty). Compared with HD; It is uncertain whether PD reduces the risk of acute myocardial infarction (4 studies, 110,850 participants: RR 0.90, 95% CI 0.74 to 1.10; I2 = 55%), coronary artery disease (3 studies, 5826 participants: RR 0.95, 95% CI 0.46 to 1.97; I2 = 62%); ischaemic heart disease (2 studies, 58,374 participants: RR 0.86, 95% CI 0.57 to 1.28; I2 = 95%), congestive heart failure (3 studies, 49,511 participants: RR 1.10, 95% CI 0.54 to 2.21; I2 = 89%) and stroke (4 studies, 102,542 participants: RR 0.94, 95% CI 0.90 to 0.99; I2 = 0%) because of low to very low certainty evidence. Compared with HD, PD had uncertain effects on the number of patients experiencing hospitalisation (4 studies, 3282 participants: RR 0.90, 95% CI 0.62 to 1.30; I2 = 97%) and all-cause hospitalisation events (4 studies, 42,582 participants: RR 1.02, 95% CI 0.81 to 1.29; I2 = 91%) (very low certainty). None of the included studies reported specifically on life participation or fatigue. However, two studies evaluated employment. Compared with HD, PD had uncertain effects on employment at one year (2 studies, 593 participants: RR 0.83, 95% CI 0.20 to 3.43; I2 = 97%; very low certainty). AUTHORS' CONCLUSIONS: The comparative effectiveness of PD and HD on the preservation of RKF, all-cause and cause-specific death risk, the incidence of bacteraemia, other vascular complications (e.g. stroke, cardiovascular events) and patient-reported outcomes (e.g. life participation and fatigue) are uncertain, based on data obtained mostly from NRSIs, as only two RCTs were included.