HomeArticleWeekly Nephrology Journal Review — 9 December 2025

Weekly Nephrology Journal Review — 9 December 2025

Prepared by: Kidney-Hub team

1) Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN — NEJM (Fakhouri et al., 2025)

Link: https://www.nejm.org/doi/abs/10.1056/NEJMoa2501510

summary
This phase-3, randomized, double-blind, placebo-controlled VALIANT trial enrolled adolescents and adults with biopsy-proven C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative GN (IC-MPGN), including native and post-transplant cases. The intervention arm received subcutaneous pegcetacoplan (a C3/C3b inhibitor) on a fixed regimen versus placebo for the 26-week double-blind phase, after which all participants entered an open-label extension. The primary endpoint was change in proteinuria (UPCR) at week 26; pegcetacoplan produced a large and clinically meaningful reduction in proteinuria (geometric mean ~68% reduction vs placebo) and a higher proportion meeting composite renal responses. Secondary and extension-phase data showed maintenance of proteinuria reductions to 52 weeks and histologic decreases in glomerular C3 staining in many biopsied patients. eGFR was stabilized overall in the treated group compared with placebo during follow-up; subgroup analyses suggested consistent benefit across age groups and in both native and recurrent disease. Safety signals included increased infection risk consistent with complement inhibition strategies; vaccination and infection prophylaxis were emphasized. No clear signal of excess allograft rejection or loss was reported in the transplant subgroup during the reported follow-up, though longer observation is needed. The trial constitutes the strongest randomized evidence to date that upstream C3 inhibition can alter proteinuric disease activity and glomerular complement deposition in C3G/IC-MPGN. Key uncertainties remain about durability beyond one year, long-term infection risk and vaccine strategy, cost and access, and whether hard endpoints (ESKD, transplantation) will be delayed. This is a potential paradigm shift toward targeted complement therapy in diseases historically managed with non-specific immunosuppression.

TL;DR (3 bullets)

  • Pegcetacoplan produced ~68% reduction in proteinuria at week 26 vs placebo and sustained reductions at 52 weeks.
  • Histologic reduction of glomerular C3 deposits observed in many treated patients.
  • Infection risk consistent with complement inhibition — vaccination/prophylaxis required.

Clinical takeaways (3)

  1. For patients with progressive C3G or recurrent IC-MPGN post-transplant, pegcetacoplan may become the first disease-modifying targeted therapy if adopted/regulatory-approved.
  2. Implement vaccination strategies and infection surveillance for any patient started on complement inhibitors.
  3. Discuss long-term data uncertainty (ESKD delay, cost, lifelong therapy) during shared decision-making.

2) Microvascular Inflammation of Kidney Allografts and Antibody-Mediated Rejection — NEJM (Sablik et al., 2025)

Link: https://www.nejm.org/doi/abs/10.1056/NEJMoa2408835

summary :
This large multicenter clinicopathologic cohort analyzed kidney-allograft biopsies across many centers and correlated microvascular inflammation (MVI) patterns with donor-specific antibody (DSA) profiles and graft outcomes. The investigators defined distinct MVI phenotypes (for example, dominant glomerular vs peritubular capillary patterns, acute vs chronic microangiopathy features) and quantified their associations with DSA strength and isotype. Certain MVI signatures—particularly those with severe capillary inflammation and high-titer complement-fixing DSA—were associated with markedly higher risk of graft failure versus milder MVI patterns. Importantly, response to standard antibody-directed therapies varied by MVI subtype; some phenotypes were relatively refractory to conventional plasmapheresis/IVIG/rituximab approaches. The authors propose incorporating MVI phenotype into routine biopsy reporting to stratify rejection risk and personalize post-biopsy management. They also show how MVI subtype classification could refine inclusion and stratification in clinical trials of anti-antibody therapies. Practical implications include prioritizing high-risk patients for aggressive or novel desensitization protocols, and adjusting surveillance intensity based on phenotype rather than treating all MVI as homogeneous. Limitations noted include observational design and potential center-level differences in biopsy thresholds and treatment algorithms. Overall, the paper advances precision transplant nephrology by linking histologic phenotype with immunologic profiling and outcomes.

TL;DR (3 bullets)

  • MVI in allografts is heterogeneous—distinct phenotypes have different prognoses.
  • High-severity MVI with strong DSAs predicts higher graft failure risk.
  • Treatment response differs by phenotype; biopsy reports should specify MVI subtype.

Clinical takeaways (3)

  1. Request explicit MVI-subtype notation in pathology reports to guide tailored therapy.
  2. High-risk MVI may warrant early escalation to antibody-targeted or trial therapies.
  3. Use MVI phenotyping to prioritize surveillance and consider enrollment in phenotype-stratified trials.

3) Chronic Kidney Disease — Seminar, The Lancet (Herrington et al., Nov 25, 2025)

Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01942-7/fulltext

summary :
This Lancet seminar synthesizes contemporary CKD science and policy: global epidemiology, pathophysiology, diagnostics, therapeutics and health-system responses. It documents that CKD prevalence is rising worldwide due to aging, diabetes, hypertension and metabolic risk factors; the burden is markedly uneven, with resource-limited regions facing under-diagnosis and limited treatment capacity. The pathophysiology section integrates new understanding of tubular stress, maladaptive repair, inflammation and microvascular dysfunction in CKD progression beyond glomerular injury alone. Diagnostics recommendations emphasize combined eGFR and albuminuria measures for risk stratification and advocate targeted population screening in high-risk groups. Therapeutic chapters reaffirm SGLT2 inhibitors as cornerstone therapy across many etiologies, summarize mineral metabolism and blood-pressure strategies, and review emerging agents (non-steroidal mineralocorticoid receptor antagonists, novel anti-inflammatories, metabolic therapies). The seminar calls for system-level interventions—primary-care integration, task-sharing, earlier KRT planning based on risk thresholds (e.g., 2-year KRT risk) and equity-focused policies to close access gaps. It highlights research priorities: affordable diagnostics, implementation science in LMICs, and trials for new agents. The authors argue that population health approaches plus therapeutic advances can materially reduce CKD burden if coupled with political will and resourcing. Limitations are typical for seminars—breadth over exhaustive meta-analysis—but the piece is a practical synthesis for clinicians and policymakers.

TL;DR (3 bullets)

  • CKD burden rising globally; early detection and treatment are key.
  • SGLT2 inhibitors and multifactorial risk-reduction are central to modern CKD care.
  • Policy/system changes are required for equitable CKD control.

Clinical takeaways (3)

  1. Prioritize eGFR+albuminuria testing in high-risk primary-care populations.
  2. Maximize use of SGLT2 inhibitors where indicated and optimize BP/RAAS control.
  3. Use risk thresholds to start timely KRT counseling and access planning.

4) Kidney Parameters with Tirzepatide in Obesity (SURMOUNT pooled analysis / JASN reports, 2025)

Link: https://journals.lww.com/jasn/fulltext/2025/11000/kidney_parameters_with_tirzepatide_in_obesity_with.12.aspx (and PubMed summary https://pubmed.ncbi.nlm.nih.gov/40512543/)

summary :
Investigators performed a pooled, post-hoc analysis of the SURMOUNT phase-3 obesity trials to evaluate renal parameters (UACR and eGFR) in participants treated with tirzepatide (dual GIP/GLP-1 receptor agonist). The cohort included adults with overweight/obesity with or without type-2 diabetes and monitored kidney markers through 72 weeks. Tirzepatide induced marked and sustained weight loss and was associated with reductions in urine albumin-to-creatinine ratio versus placebo that persisted through week 72. eGFR trajectories remained broadly stable compared with placebo over follow-up; no signal of accelerated kidney decline emerged in the observation window. Subgroup analyses suggested albuminuria reductions occurred even in non-diabetic participants, implying mechanisms beyond glycemic control—likely weight-loss, hemodynamic effects, or metabolic improvements. These findings are hypothesis-generating rather than definitive renal outcome evidence, because the trials were not designed or powered for hard renal endpoints (ESKD, sustained eGFR decline). Safety profiles were consistent with known GLP-1/GIP class effects; renal adverse events were uncommon. The authors conclude that tirzepatide shows promise as a metabolic therapy that could have ancillary kidney benefits; dedicated renal-outcome trials are needed before widening nephrology indications. Practical considerations include cardiometabolic collaboration and monitoring of BP/volume when initiating GLP-based agents in CKD patients.

TL;DR (3 bullets)

  • Tirzepatide reduced albuminuria through 72 weeks in SURMOUNT pooled analysis.
  • eGFR remained stable; supportive but not definitive renal outcome evidence.
  • Benefits observed even in non-diabetic participants — suggests weight/metabolic mechanisms.

Clinical takeaways (3)

  1. Discuss metabolic therapy and potential kidney benefits with obese CKD patients in multidisciplinary care.
  2. Monitor albuminuria and kidney function when initiating tirzepatide; interpret improvements as promising but preliminary.
  3. Await renal-specific randomized trials before routine nephrology endorsement for primary kidney protection.

5) Perceptions About Influenza and COVID-19 Vaccines Among People With CKD — AJKD (Zou et al., 2025)

Link: https://www.ajkd.org/article/S0272-6386(25)01018-2/fulltext (PubMed: https://pubmed.ncbi.nlm.nih.gov/40972704/)

summary :
This cross-sectional survey nested within the CRIC cohort evaluated attitudes toward influenza and COVID-19 vaccines among adults with CKD. About 278 respondents were included; roughly 17% reported hesitancy toward each vaccine. Hesitancy correlated strongly with beliefs about vaccine harms, low perceived personal benefit, and misinformation. Conversely, higher trust in health-care providers and receipt of clear, culturally tailored information were associated with vaccine acceptance. The study also explored demographic and socioeconomic correlates of hesitancy—identifying subgroups where outreach may be especially needed. Authors recommend embedding vaccine counseling into routine nephrology visits and using trusted clinician voices and tailored educational materials to address concerns. Clinics that offer on-site vaccination could reduce logistical barriers and improve uptake, and documentation of counseling may help quality programs. Limitations include self-selection and cohort characteristics that may limit generalizability, but findings echo broader literature on vaccine hesitancy in high-risk patients. Public-health implications are clear: improving vaccine uptake in CKD populations could reduce morbidity and health-system burden from respiratory infections.

TL;DR (3 bullets)

  • ~17% of surveyed CKD patients expressed hesitancy toward influenza and COVID-19 vaccines.
  • Hesitancy driven by safety concerns and low perceived benefit; provider trust mitigates hesitancy.
  • Clinic-based counseling and on-site vaccination recommended.

Clinical takeaways (3)

  1. Make vaccine counseling a standard item in CKD visits; use trusted clinician messaging.
  2. Provide culturally appropriate materials and consider on-site vaccination to reduce barriers.
  3. Document counseling and follow up on hesitancy to measure improvement.

6) Machine-Learning Models to Predict Major Cardiac Events and Death for People with Kidney Failure Undergoing Non-Cardiac Surgery — AJKD (Pabla et al., 2025)

Link: https://www.ajkd.org/article/S0272-6386(25)00706-0/fulltext (PubMed: https://pubmed.ncbi.nlm.nih.gov/40967556/)

summary :
This study developed simplified machine-learning (ML) risk models to predict 30-day major cardiac events and mortality after non-cardiac surgery specifically in patients with kidney failure (dialysis-dependent). Using large provincial cohorts from Canada (Alberta and Manitoba), investigators trained models on routinely available preoperative variables—demographics, dialysis vintage, comorbidities, basic labs, functional status and surgery type. The ML models outperformed conventional surgical risk calculators in discrimination and calibration in both derivation and external validation cohorts, demonstrating improved individualized risk estimates for this high-risk, historically underrepresented population. The authors emphasize the models’ potential use in preoperative clinics for shared decision-making, optimization (timing dialysis, medications, cardiology input), and informed consent discussions. They stress limitations: the models are retrospective, need broader external validation across different health systems and ethnic groups, and should be implemented as decision-support (not replacement for clinical judgment). The paper also addresses explainability and integration considerations, suggesting user-friendly interfaces and prospective impact studies before routine deployment. Overall, this represents an important step toward personalized perioperative risk stratification in dialysis patients.

TL;DR (3 bullets)

  • ML models tailored to dialysis patients improved perioperative cardiac/mortality risk prediction vs standard tools.
  • Validated in two Canadian cohorts; broader validation needed.
  • Intended as decision-support to personalize counseling and optimization.

Clinical takeaways (3)

  1. Consider piloting validated ML risk tools in preoperative clinics that manage dialysis patients.
  2. Use outputs to guide perioperative optimization (dialysis timing, cardiology consults).
  3. Maintain shared decision-making and prospectively evaluate outcomes after implementation.

7) Global, Regional, and National Prevalence of Kidney Failure Requiring Replacement Therapy, 1990–2022 — Lancet Global Health / GBD collaborators (Rafferty et al., 2025)

Link: https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(25)00198-6/fulltext

summary:
This GBD-style modeling study provides updated estimates of prevalence and geographical distribution of kidney failure requiring replacement therapy (KFRT) from 1990 to 2022, integrating epidemiologic, demographic and health-system capacity data. The analysis documents a global rise in absolute numbers of people requiring KRT, with pronounced regional heterogeneity: high-income regions show higher reported prevalence (reflecting capacity and survival), while many LMICs have lower reported prevalence due to limited access despite high underlying need. The study quantifies unmet need and highlights how health-system capacity, transplant rates and screening practices shape observed KFRT prevalence. Policy-relevant outputs include country-level estimates to inform dialysis and transplant capacity planning, workforce development, and financing strategies. The study underscores prevention and early CKD detection as the most cost-effective long-term approach to blunt rising KFRT demand. Limitations include data gaps in some regions and modeling assumptions, but transparency and scenario analyses help interpret uncertainty. These estimates are useful for ministries of health, NGOs and global funders prioritizing kidney-care investments.

TL;DR (3 bullets)

  • KFRT burden increased 1990–2022 with large geographic disparities.
  • Many LMICs have unmet KRT needs owing to limited capacity.
  • Prevention and early detection remain highest-value policy levers.

Clinical takeaways (3)

  1. Use country/regional estimates to advocate for KRT capacity and workforce planning.
  2. Strengthen CKD prevention and early detection programs to reduce future KRT demand.
  3. Support equitable transplant programs and donation systems where feasible.

8) ISN Launches Kidney International Case Reports (KICR) — ISN News Release (Dec 2025)

Link: https://www.theisn.org/blog/2025/12/01/the-isn-launches-kidney-international-case-reports-shaping-clinical-practice-in-global-kidney-care-through-real-world-insights/

summary :
The International Society of Nephrology announced a new open-access, peer-reviewed journal—Kidney International Case Reports (KICR)—designed to publish high-quality case reports, short clinical communications and practice-oriented reviews from across global nephrology. KICR aims to give clinicians and trainees a rapid, accessible venue for real-world observations: rare disease phenotypes, unusual therapeutic responses, procedural complications, region-specific clinical challenges and instructive transplant cases. The editorial leadership combines international representation to encourage submissions from LMICs and under-represented regions; the open-access format widens readership and educational reach. The journal will likely accelerate dissemination of clinically relevant case learning, generate hypotheses for larger studies, and support capacity building by sharing practical solutions from resource-limited settings. KICR can become a teaching resource for rounds and CPD and may complement traditional research journals by translating bedside observations into broader lessons. Submission guidelines are available on the ISN site and the inaugural issues are expected to appear shortly.

TL;DR (3 bullets)

  • ISN launched KICR: an open-access case-report journal for global nephrology.
  • Focus on practical, real-world clinical lessons from diverse settings.
  • Good venue for trainees and clinicians to publish instructive cases.

Clinical takeaways (3)

  1. Consider submitting rare or instructive cases, especially those from under-reported regions.
  2. Use KICR case reports as teaching material for trainees and multidisciplinary rounds.
  3. Monitor KICR for early signals that might inform larger studies or guideline updates.

9) Natural Killer Cells in Kidney Disease — Nature Reviews Nephrology (Review, Dec 2025)

Link: https://www.nature.com/nrneph/articles?year=2025

summary :
This authoritative review synthesizes the growing literature on natural killer (NK) cells’ roles across kidney physiology and pathology—acute kidney injury, chronic inflammation and transplant rejection. NK cells contribute to normal immune surveillance but can become drivers of tissue injury through direct cytotoxicity and cytokine production when activated by stress ligands or altered self. In AKI models, NK cells have been implicated in early tubular injury and amplification of inflammatory cascades; in CKD, persistently activated NK populations may maintain low-grade inflammation and fibrogenesis. In transplantation, NK cells participate in antibody-independent graft injury and chronic allograft dysfunction, suggesting innate immunity is a complementary target to adaptive immunity. The review discusses molecular targets (activating/inhibitory receptors like NKG2D), biomarkers to identify NK-driven disease, and emerging strategies to modulate NK activity (receptor blockade, cellular modulation). Authors caution about immune redundancy and infection risks with innate-immunity suppression, and they call for precise phenotyping and translational trials. The review positions NK cells as an actionable frontier for novel interventions and recommends biomarker development to select patients for early trials.

TL;DR (3 bullets)

  • NK cells are important actors in AKI, CKD progression and transplant injury.
  • Targeting NK pathways is a promising translational approach, but safety and selection biomarkers are needed.
  • Calls for translational and clinical trials with precise phenotyping.

Clinical takeaways (3)

  1. Expect trials targeting innate-immune (NK) pathways in the coming years; watch for biomarker guidance.
  2. Consider NK-related mechanisms when encountering unexplained inflammatory progression or refractory rejection.
  3. Collaborate with translational groups to collect biosamples and phenotype patients for future NK-targeted trials.

10) Preeclampsia and Offspring Kidney Health: Phenotypic Precision & Familial Controls — Kidney International (Perspective, Dec 2025)

Link: https://www.kidney-international.org/current

summary:
This perspective argues that studies linking maternal preeclampsia to offspring kidney disease must use refined phenotyping and familial control designs to avoid confounding and over-interpretation. Preeclampsia is heterogeneous—early vs late onset, severity, presence of fetal growth restriction and maternal comorbidities—each phenotype may carry different long-term risks for offspring. Shared genetic and environmental factors within families can bias cohort studies that lack sibling or familial controls. The authors recommend sibling-comparison designs, incorporation of genetic/epigenetic data, and careful specification of maternal phenotype (blood-pressure patterns, proteinuria severity, placental pathology) in future cohorts. Long-term, serial follow-up of offspring (BP, albuminuria, eGFR) is necessary because kidney outcomes often emerge decades after birth. For clinicians, the message is pragmatic: use targeted screening for offspring with high-risk maternal phenotypes or family histories rather than blanket surveillance. For researchers and policymakers, confirming causality would motivate perinatal interventions as a CKD prevention strategy, but robust methods are required first.

TL;DR (3 bullets)

  • Preeclampsia phenotypes and familial confounders complicate offspring-CKD research.
  • Sibling/familial designs and deep phenotyping recommended to infer causality.
  • Clinical screening should be targeted, not universal, until stronger causal data exist.

Clinical takeaways (3)

  1. Ask about maternal preeclampsia when taking histories—triage offspring with additional risk factors for screening.
  2. Avoid over-labelling offspring at high lifetime risk based solely on maternal preeclampsia without other risk markers.
  3. Encourage or participate in well-designed prospective cohorts with familial controls to clarify causality.
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