Michele Freerk Eisenga

Background: Anemia is highly prevalent in patients with kidney failure receiving peritoneal dialysis (PD). Oral iron supplementation is frequently prescribed, but adherence may be limited by pill burden and gastrointestinal adverse effects. Emerging evidence suggests that less frequent oral iron dosing may enhance iron absorption by reducing hepcidin-mediated inhibition, yet data in PD patients are lacking. We evaluated iron utilization and compared the effectiveness of different oral iron regimens in PD patients. Methods: This retrospective cohort study (2007-2025) included adults (≥18 years) receiving peritoneal dialysis at the Dialysis Center Groningen who were treated with oral ferrous fumarate for ≥3 months. Patients receiving intravenous iron, other iron formulations, non-standard dosing regimens, or with active gastrointestinal bleeding were excluded. Ferrous fumarate regimens included 200 mg once daily (OD), twice daily (BID), three times daily (TID), or three times weekly (TIW). Patients not receiving oral iron were evaluated for treatment eligibility. Primary outcomes were 6-month changes in hemoglobin, ferritin, and transferrin saturation. Regimen-specific trajectories were analyzed using linear mixed-effects models. Sensitivity analyses adjusted for age, sex, erythropoiesis-stimulating agent dose, and inflammation, and were restricted to incident iron users on PD. Results: Of the 140 patients screened, 85 patients were included (median age 61 years; 57.6% male). TIW dosing resulted in hemoglobin trajectories comparable to OD dosing (P = 0.30), with similar ferritin and transferrin saturation trajectories. In contrast, BID dosing was associated with a steeper hemoglobin increase (0.013 g/dL/day; P = 0.001) than OD dosing. Sensitivity analyses yielded similar results. Among patients not receiving iron therapy, 30% (n= 9/30) met contemporaneous guideline criteria for treatment. Conclusion: In this 18-year retrospective study of 85 PD patients, TIW and OD oral iron supplementation produced comparable hematologic outcomes, suggesting that less frequent dosing may represent an effective strategy to reduce treatment burden without compromising efficacy. Twice-daily dosing was associated with faster hemoglobin increases, likely reflecting greater cumulative iron exposure. Iron therapy was underutilized in a substantial proportion of eligible patients. Although limited by the modest sample size, these findings highlight the need for expert consensus to address evidence gaps and guide anemia management in PD.

Background: Kidney transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) may be at higher risk of venous thromboembolism than non-ADPKD recipients. Methods: We conducted an observational study of adult kidney transplant recipients at a single center, the University Medical Center Groningen (UMCG; n=1179, 393 with ADPKD), and replicated key analyses in the multicenter Swiss Transplant Cohort Study (STCS; n=4415, 710 with ADPKD). The primary endpoint was time to first venous thromboembolism after transplantation or death related to venous thromboembolism (identified through medical record review), analyzed using Kaplan–Meier estimates and Cox regression. Data were pooled for subgroup analyses and to assess determinants of post-transplant venous thromboembolism risk. Results: Venous thromboembolism occurred more often in ADPKD than non-ADPKD kidney transplant recipients (log-rank p=0.04 and p<0.001 for UMCG and STCS, respectively). The 10-year cumulative venous thromboembolism incidence was 13.5% [95% CI: 9.4, 17.5], versus 9.6% [95% CI: 7.0, 12.1] in ADPKD versus non-ADPKD recipients in UMCG, and 21.0% [95% CI: 17.0, 24.7] versus 15.1% [95% CI: 13.5, 16.6] in STCS. Median [Q1, Q3] time to venous thromboembolism were similar across cohorts (UMCG: 1.7 [0.4, 4.9], STCS: 1.4 [0.2, 4.8] years). Venous thromboembolism risk was highest in the early (<2 years) post-transplant period. After adjustment for venous thromboembolism risk factors, ADPKD remained independently associated with post-transplant venous thromboembolism in both cohorts (UMCG HR 1.80 [95% CI: 1.21, 2.69]; STCS HR 1.39 [95% CI: 1.13, 1.72]). The association between ADPKD and risk of venous thromboembolism was more pronounced in males. Hemoglobin levels after kidney transplantation were approximately 7.0 ± 0.8% higher in ADPKD recipients, particularly in males, with corresponding higher risks of erythrocytosis during follow-up. Incorporating longitudinal hemoglobin as a time-varying covariate attenuated the association between ADPKD and venous thromboembolism, suggesting that the association was at least partially driven by higher hemoglobin levels. Conclusions: Kidney transplant recipients were at high risk for venous thromboembolism, and those with ADPKD are at an even higher risk.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD) provides an update of the 2012 version. Its scope includes anemia diagnosis and use of iron therapy, erythropoiesis-stimulating agents (ESAs), hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), and red blood cell (RBC) transfusions to treat anemia in CKD. An international work group of patient partners, health care professionals, researchers, and clinicians defined the guideline scope. An independent evidence review team conducted systematic reviews through October 2024 and graded the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The final guideline incorporated feedback from a public review involving registered stakeholders in late 2024. This synopsis focuses on the 8 graded recommendations. Key points include the use of transferrin saturation and ferritin thresholds to guide iron therapy, with intravenous iron preferred over oral iron in people receiving hemodialysis; addressing correctable causes of anemia before use of an ESA or a HIF-PHI; using an ESA rather than a HIF-PHI as first-line treatment; individualized hemoglobin (Hb) thresholds for ESA initiation based on patient characteristics, symptoms, and values; and an upper Hb target of below 11.5 g/dL (<115 g/L) during ESA maintenance therapy. The guideline also includes 49 practice points representing expert consensus where robust evidence was limited or systematic review could not be conducted.

To the Editor: Long-term kidney allograft survival remains a major clinical challenge. Nearly half of deceased-donor transplants fail within a decade, and identifying modifiable risk factors is therefore a priority. 1 Environmental heavy metals such as cadmium (Cd), lead (Pb), and arsenic (As) are established nephrotoxins that promote oxidative stress, tubular injury, and progression of chronic kidney disease. 2 Kidney transplant recipients (KTRs) are particularly susceptible because of reduced renal clearance, comorbidities, and immunosuppressive therapy. Previous work by our group demonstrated that each of these metals independently predicts graft failure. 3,4 However, real-world exposure involves mixtures rather than single agents, and no prior study has evaluated their combined impact on long-term graft outcomes. We addressed this gap using advanced mixture modeling in a large prospective cohort.We analyzed 668 outpatient KTRs from the TransplantLines Food and Nutrition Biobank and Cohort Study. Plasma Cd, Pb, and As were quantified by inductively coupled plasma mass spectrometry.A composite mixture index was derived using quantile-based g-computation (Q-gcomp), which jointly estimates the effect of increasing all metals by one quantile while weighting each metal's contribution. 5 The primary outcome was death-censored graft failure. Bayesian Kernel Machine Regression (BKMR) was applied to capture non-linear and interactive effects, multivariable linear regression identified clinical determinants of the mixture index, and prespecified subgroup analyses were stratified by baseline estimated glomerular filtration rate (eGFR) and proteinuria.The median age was 54.7 years (IQR 44.8 to 62.9), 58% of participants were male, and median eGFR was 38.7 mL/min/1.73 m², assessed at a median of 5.3 years post-transplant. Plasma metal concentrations rose significantly across mixture-index tertiles, while inter-metal Spearman correlations between metals were generally weak (all r < 0.4), with distinct concentration distributions across KTRs (Figure 1A), supporting their treatment as distinct yet co-occurring exposures. Higher tertiles were accompanied by lower eGFR (47.4 to 31.3 mL/min/1.73 m², P < 0.001), greater proteinuria, lower transferrin saturation (TSAT), hemoglobin, and iron, and higher high-sensitivity C-reactive protein (hs-CRP) and uric acid, suggesting clustering of metal burden with kidney injury, anemia, and inflammation.During a median follow-up of 5.3 (IQR 4.5-6.0) years, 80 graft failure events occurred. In Q-gcomp analysis, a simultaneous one-tertile increase in all three metals was associated with a 73% higher risk of graft failure (HR 1.73, 95% CI 1.08 to 2.78, P = 0.023,Figure 1C). Cd contributed 50.3% of the overall mixture effect, As 44.0%, and only 5.7%, identifying Cd and As being the dominant nephrotoxic drivers in this population. For comparison, individual metal associations with graft failure are presented in Supplementary Results (Figure S1), which showed consistent patterns with Cd and As independently associated with increased risk. BKMR analysis confirmed a dose-dependent increase in risk above the 50th exposure percentile and revealed a synergistic interaction in which the nephrotoxic effect of Cd was amplified at higher As concentrations (Figure S2). Multivariable regression further identified higher eGFR (β = -0.260, P < 0.001), longer transplant duration, and higher TSAT as inverse correlates of mixture burden, whereas higher fish intake was a positive correlate, pointing to clinically actionable determinants of systemic exposure.A key observation was the strong variation in metal-associated graft failure risk according to baseline kidney function. Among KTRs with severe renal impairment (eGFR below 30 mL/min/1.73 m² or proteinuria of at least 0.5 g/24h), those in the highest quartile of metal exposure had nearly a fivefold increased risk of graft failure compared with the lowest quartile (RR 4.89, 95% CI 1.25 to 19.12, and RR 4.87, 95% CI 2.10 to 11.30, respectively, Figure 1B). In contrast, the risk difference was much smaller and only borderline significant among recipients with preserved eGFR (RR 1.74, 95% CI 0.96 to 3.16) or lowgrade proteinuria (RR 2.79, 95% CI 1.35 to 5.77). This gradient likely reflects impaired metal clearance and increased tissue accumulation in damaged kidneys, compounded by elevated oxidative stress and inflammation that sensitize the kidney to metal toxicity. 6,7 These findings support incorporating baseline kidney function into risk assessment strategies for KTRs and identify a high-risk subgroup that may benefit most from targeted intervention.From an environmental perspective, our findings align with concerns that current regulations, which typically evaluate metals individually, may underestimate risks from combined exposures.Epidemiological data from CKD-endemic regions such as Nicaragua and Sri Lanka show that agricultural workers chronically exposed to mixed metals develop kidney injury even at low levels. 8 Our results extend these observations to a vulnerable transplant population in a high-income setting, indicating that the burden of mixed exposure is not confined to occupationally or geographically high-risk groups, and underscoring the need for safety standards that explicitly address metal mixtures.The inverse association between TSAT and the mixture index suggests a protective effect of adequate iron status, as iron and cadmium compete for shared transporters such as DMT1 and ZIP proteins, affecting both intestinal absorption and tissue retention. 9 This finding is consistent with our previous report of an inverse relationship between TSAT and cadmium levels in KTRs and underscores the bidirectional interplay between iron metabolism and metal toxicity in this population. 9 The positive association with fish intake likely reflects dietary exposure to bioaccumulated environmental...

Background: Iron is essential for cellular function and cancer growth. While iron imbalance has been implicated in cancer development, epidemiological evidence remains inconsistent. Erythropoietin (EPO) may influence tumour progression. We aimed to investigate the associations between iron status, EPO levels, and cancer incidence in the general population. Method: Data were obtained from 6109 participants (mean age 52 ± 12 years; 49% male) in the Prevention of Renal and Vascular End‐stage Disease (PREVEND) cohort. Iron biomarkers, including ferritin, transferrin saturation, soluble transferrin receptor (sTfR), hepcidin and EPO levels, were measured at baseline. Results: Over a median 18.5 year follow‐up, 1090 participants developed cancer. Multivariable Cox regression revealed that higher EPO (HR 1.26; 95% CI 1.07–1.47; p = 0.005) was associated with increased overall cancer risk, while elevated hepcidin levels were associated with a lower risk (HR 0.88; 95% CI 0.80–0.96; p = 0.006). Higher sTfR (HR 1.35; 95% CI 1.01–1.80; p = 0.043) was suggestive for an increased risk of overall cancer. After excluding early diagnoses, the increased risk associated with higher EPO levels and decreased risk associated with higher hepcidin levels remained significant. Lower transferrin saturation was associated with increased haematological cancer risk, while higher hepcidin was associated with reduced gastrointestinal cancer risk, especially in women and those with BMI < 25 kg/m ² . In non‐smokers, higher sTfR and EPO were associated with increased overall and kidney cancer. Conclusion: These findings underscore the putative roles of iron metabolism and EPO in cancer, with consistently decreased risks associated with elevated hepcidin levels, particularly among women and individuals with lower BMI.

The 2026 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anemia in Chronic Kidney Disease represents a substantial update, coming more than a decade since the previous KDIGO guideline on the topic. This time lapse was necessary in order to accumulate new scientific evidence that was meaningful for an updated guideline. The new guideline now includes updated recommendations and practice points for anaemia management, incorporating recent evidence on intravenous iron therapies and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). This European Renal Best Practice commentary critically evaluates and comments on relevant and newer recommendations and practice points, focusing on key aspects from a European perspective. The new guideline emphasizes the need for a comprehensive evaluation of the patient at the time of diagnosis, to identify additional causes of anaemia other than erythropoietin insufficiency. Coherently, the timing and the type of treatment should be individualized. Moreover, it introduces more proactive thresholds for intravenous iron supplementation, especially for haemodialysis patients. Erythropoiesis-stimulating agents are recommended as the preferred first-line therapy due to persisting concerns regarding cardiovascular safety and methodological limitations of available HIF-PHI trials. The commentary includes considerations on special aspects not considered by the new KDIGO guideline, such as pregnancy, gender-specific considerations, and interactions with sodium-glucose cotransporter 2 inhibitors or inflammation. The commentary also highlights regional regulatory differences between European and US drug approvals for HIF-PHIs. While supporting most recommendations, European nephrologists should consider local contexts, regulatory approvals and emerging evidence when implementing these guidelines in clinical practice.

Anemia and iron deficiency (ID) are common and significant complications in kidney transplant recipients (KTRs) that can affect their health-related quality of life (HRQoL) and outcomes. Current anemia guidelines equate the post-transplant situation with the anemia associated with CKD in non-transplanted persons, not acknowledging relevant differences ranging from pathophysiology to clinical manifestation. Nephrologists caring for these patients tend to pay less attention to post-transplant anemia (PTA) and ID. than in non-transplanted persons with CKD. In this narrative review we summarize the available evidence about PTA and ID and their specifics in KTRs, including associations with patient and graft survival and poorer HRQoL. The prevalence of anemia is higher in KTRs than in non-transplanted patients with CKD for a given level of GFR due to kidney transplant (KT)-specific pathophysiological factors. ID should be detected and corrected in KTRs using oral or intravenous iron. Some IV iron formulations are associated with an increased risk of hypophosphatemia a typical complication in KTRs. Current guidelines suggest the same Hb targets for ESA therapy in transplanted and non-transplanted patients, despite that a higher hemoglobin target has been associated with a slower eGFR decline in KT. There is insufficient data to recommend the widespread use of HIF prolyl-hydroxylase inhibitors in PTA. Red blood cell transfusions should be avoided to minimize alosensitization. We call for increased awareness and targeted trials on anemia and ID in KTRs, accounting for the diverse and specific profiles of these patients.

The TransplantLines Biobank and Cohort Study (NCT03272841) is an ongoing prospective study conducted at the University Medical Centre Groningen, The Netherlands. TransplantLines aims to identify risk factors and biomarkers associated with health problems following solid organ transplantation and donation. Additionally, the study seeks to develop new interventions to reduce symptom burden and improve long-term outcomes, including health-related quality of life, cardiovascular complications, graft failure, and mortality. It includes recipients of (combined) heart, liver, lung, kidney, pancreas, and small bowel transplants, as well as living liver and kidney donors, and deceased (multi-)organ donors. The biobank contains a wide range of biomaterials including whole blood, serum, EDTA-plasma, buffy coat, 24-h urine samples, faeces, hair, nails, and tissues. Data collection includes physical and cognitive assessments, extensive laboratory analysis, metagenomic sequencing, and questionnaires. TransplantLines, initiated in 2015, consists of 5143 participants as of October 2024, among 2312 (45%) females. The mean age was 50 (± 16) years at transplantation, 55 (± 11) years at living donation and 56 (± 15) years at deceased donation. Both cross-sectional and longitudinal biomaterials and data are included. For recipients, longitudinal biomaterials and data were collected at: pre-transplantation, at transplantation, and at 3, 6, 12, 24, and 60 months post-transplantation. For living donors, data were collected at pre-donation, donation, 3 months post-donation, and/or 5 or 10 years post-donation.

Key Points: Kidney transplant recipients have higher urinary iron levels than controls and urinary iron levels are increased with oral iron supplementation. Urinary iron levels are associated with worse kidney function, increased tubular damage markers, and a higher mortality risk during follow-up. Further studies are warranted to provide insight into the potential tubulotoxic effect of urinary iron. Background: Increased urinary iron can result from ( 1 ) increased delivery of iron to the kidneys, ( 2 ) increased glomerular passage of iron, and/or ( 3 ) decreased tubular reuptake. Currently, the relevance of urinary iron levels is unknown. We investigated urinary iron with different pathways and clinical outcomes in kidney transplant recipient (KTRs). Methods: We measured urinary iron in samples from the prospective TransplantLines Food and Nutrition Biobank and Cohort study (NCT02811835). Multivariable linear and Cox regression models were applied. Results: We included 693 stable KTRs (age 53±13 years, 43% female, eGFR 52±20 ml/min per 1.73 m ² ). Higher urinary iron was associated with lower eGFR and higher kidney damage markers, including albuminuria, 24-hour urinary liver-type fatty acid-binding protein excretion, urinary endothelial growth factor to creatinine ratio, and plasma neutrophil-gelatinase–associated lipocalin (all P < 0.001). By contrast, urinary iron was not associated with systemic iron status but was increased with oral iron supplementation. During a follow-up of 5.3 years, 83 KTRs experienced graft failure and 150 died. Prospectively, higher urinary iron was associated with graft failure, but the association was decreased after adjustment for proteinuria. By contrast, urinary iron was independently associated with increased mortality risk (hazard ratio per doubling, 1.29; 95% confidence interval, 1.08 to 1.56). Conclusions: Higher urinary iron levels are associated with worse kidney function, more proteinuria, increased tubular damage markers and higher mortality. Oral iron supplementation seems to be an important determinant of urinary iron levels. These findings raise the possibility that urinary iron acts as a tubulotoxic agent, and mechanistic studies are warranted.