Sex and the Risk of Atheromatous and Non-Atheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study.

RATIONALE & OBJECTIVE: Sex differences in cardiovascular disease (CVD) are well-established, but whether chronic kidney disease (CKD) modifies these risk differences, and whether they differ between atheromatous (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France. EXPOSURE: Sex. OUTCOMES: Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic stroke, and arrhythmias). ANALYTICAL APPROACH: Multivariable cause-specific Cox proportional hazards models. RESULTS: 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m2) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m2. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied. LIMITATIONS: Cardiovascular biomarkers and sex hormones were not assessed. CONCLUSION: This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.

Haemoglobin trajectories in chronic kidney disease and risk of major adverse cardiovascular events.

BACKGROUND: The trajectories of haemoglobin in patients with chronic kidney disease (CKD) have been poorly described. In such patients, we aimed to identify typical haemoglobin trajectory profiles and estimate their risks of major adverse cardiovascular events (MACE). METHODS: We used 5-year longitudinal data from the CKD-REIN cohort patients with moderate to severe CKD enrolled from 40 nationally representative nephrology clinics in France. A joint latent class model was used to estimate, in different classes of haemoglobin trajectory, the competing risks of (i) MACE + defined as the first event among cardiovascular death, non-fatal myocardial infarction, stroke or hospitalization for acute heart failure, (ii) initiation of kidney replacement therapy (KRT) and (iii) non-cardiovascular death. RESULTS: During the follow-up, we gathered 33 874 haemoglobin measurements from 3011 subjects (median, 10 per patient). We identified five distinct haemoglobin trajectory profiles. The predominant profile (n = 1885, 62.6%) showed an overall stable trajectory and low risks of events. The four other profiles had nonlinear declining trajectories: early strong decline (n = 257, 8.5%), late strong decline (n = 75, 2.5%), early moderate decline (n = 356, 11.8%) and late moderate decline (n = 438, 14.6%). The four profiles had different risks of MACE, while the risks of KRT and non-cardiovascular death consistently increased from the haemoglobin decline. CONCLUSION: In this study, we observed that two-thirds of patients had a stable haemoglobin trajectory and low risks of adverse events. The other third had a nonlinear trajectory declining at different rates, with increased risks of events. Better attention should be paid to dynamic changes of haemoglobin in CKD.

Vascular calcification in chronic kidney disease: contribution of ferroptosis?

Vascular calcification associated with chronic kidney disease (CKD) is an active, regulated process. Apoptosis of vascular smooth muscle cells has long been known to play a major role in its pathogenesis, with apoptotic bodies derived from these cells acting as nucleating structures for calcium crystal formation and deposition. Ye et al. now show in experimental models in vitro and in vivo that ferroptosis can also contribute to the development of vascular calcification in CKD.

Parathyroid hormone oxidation in chronic kidney disease: clinical relevance?

In chronic kidney disease, parathyroid hormone (PTH), like all proteins, can undergo post-translational modifications, including oxidation. This can lead to structural and functional changes of the hormone. It has been hypothesized that currently used PTH measurement methods do not adequately reflect PTH-related bone and cardiovascular abnormalities in chronic kidney disease owing to the presence of oxidized, biologically inactive PTH in the circulation. Ursem et al. now report a strong correlation between serum non-oxidized and total PTH, and comparable associations with histomorphometric and circulating bone turnover markers, pleading against this hypothesis.

Role of proteinuria in the anemia of chronic kidney disease.

The most important contributors to the anemia of patients with chronic kidney disease are insufficient erythropoietin production and erythropoietin hyporesponsiveness, decreased red blood cell half-life, iron deficiency, and inflammation. However, in contrast to the role of kidney failure, that of proteinuria and nephrotic syndrome is less clear. Bissinger et al. now provide evidence in mouse models and patients with chronic kidney disease that heavy proteinuria alters erythrocyte metabolism and increases erythrocyte death.

Decreased monocyte calcium sensing receptor expression in patients with chronic kidney disease is associated with impaired monocyte ability to reduce vascular calcification.

In chronic kidney disease (CKD), calcium-sensing receptor (CaSR) expression and function have been extensively studied in parathyroid tissue and vascular tissues. To examine whether similar changes occurred in other tissues, we measured total and surface CaSR expression in monocytes of patients with various stages of CKD and healthy volunteers respectively in cross-sectional studies. We further explored in vitro the impact of uremic serum on CaSR expression in monocytes (U937 and THP-1 cell lines), and whether human peripheral blood mononuclear cells or U937 and THP-1 monocytes might modify vascular calcium deposition in rat carotid arteries in vitro. CKD was associated with a decrease in peripheral blood mononuclear cell CaSR expression both in total and at the monocyte surface alone (43% and 34%, respectively in CKD stages 4-5). This decrease was associated with a reduction in the ability of monocytes to inhibit vascular calcification in vitro. Pretreatment with the calcimimetic NPSR568 of peripheral blood mononuclear cells isolated from patients with CKD significantly improved monocyte capacity to reduce carotid calcification in vitro. The fewer peripheral blood mononuclear cells expressing cell surface CaSR, the more calcimimetic treatment enhanced the decrease of carotid calcium content. Thus, we demonstrate that monocyte CaSR expression is decreased in patients with CKD and provide in vitro evidence for a potential role of this decrease in the promotion of vascular calcification. Hence, targeting this alteration or following monocyte CaSR expression as an accessible marker might represent a promising therapeutic strategy in CKD-associated arterial calcification.

Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.

In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research.

The problem with transferrin saturation as an indicator of iron 'sufficiency' in chronic kidney disease.

After a brief review of physiological iron metabolism, we describe diagnostic tests for iron status and iron deficiency anemia in patients without chronic kidney disease (CKD) or inflammation. Thereafter we review the dysregulation of iron metabolism in CKD. Specific emphasis is placed on the role of the 'inflammatory' state that develops with the progression of CKD. It invokes changes in iron metabolism that are the exact opposite of those occurring during pure iron deficiency. As a result, transferrin saturation (TSAT) becomes a poorer index of iron availability to the bone marrow and serum ferritin no longer represents iron that can be used during erythropoiesis. We argue that serum iron may provide more information to guide iron therapy than TSAT. In other words, the emphasis on TSAT is misplaced. With the development of a number of hypoxia-inducible factor prolyl hydroxylase inhibitors, which restore iron metabolism toward the 'physiologic state', the iron indices indicating sufficient iron availability to avoid functional iron deficiency during therapy of CKD-associated anemia are likely to change. We summarize these changes in the section 'A peek into things to come!', citing the available data.

Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate-matched patients with CKD-preliminary results.

BACKGROUND: Although kidney transplantation prolongs survival relative to dialysis, it is associated with a higher death rate than in the general population. The objective of the present study was to assess and compare the risk of mortality and frequency of non-lethal cardiovascular (CV) events in kidney transplant recipients (KTRs) beyond 1 year after successful transplantation versus patients with chronic kidney disease (CKD) using propensity score-matched analysis of estimated glomerular filtration rate (eGFR) and other parameters. METHODS: After propensity score matching, we studied 340 KTRs from the French Données Informatisées et Validées en Transplantation cohort and 605 non-transplant patients with CKD (CKDps) from the French Chronic Kidney Disease-Renal Epidemiology and Information Network cohort. The mean ± standard deviation eGFR was 42 ± 13 and 41 ± 12 mL/min/ 1.73 m2, respectively (P = 0.649). Descriptive data were completed by a survival analysis with Cox regression models. RESULTS: After a median follow-up period of 2.8 years (KTRs 2.0 years, CKDp 2.9 years), 71 deaths were recorded (31 and 40 in the KTR and CKD groups, respectively). Univariate analysis showed that KTRs had a significantly greater risk of mortality than CKDps. In multivariable analysis, KTRs were found to have a 2.7-fold greater risk of mortality [hazard ratio 2.7 (95% confidence interval 1.6-4.7); P = 0.005]. There was no between-group difference concerning the risk of CV events (P = 0.448). CV death rates in KTRs (29.0%) approximated those of CKDps (22.5%), whereas death rates due to infections were higher in KTRs (19.4% versus 10.0%). CONCLUSION: Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.

Relative prognostic impact of nutrition, anaemia, bone metabolism and cardiovascular comorbidities in elderly haemodialysis patients.

BACKGROUND: The prognostic impact of nutrition and chronic kidney disease (CKD) complications has already been described in elderly haemodialysis patients but their relative weights on risk of death remain uncertain. Using structural equation models (SEMs), we aimed to model a single variable for nutrition, each CKD complication and cardiovascular comorbidities to compare their relative impact on elderly haemodialysis patients' survival. METHODS: This prospective study recruited 3165 incident haemodialysis patients ≥75 years of age from 178 French dialysis units. Using SEMs, the following variables were computed: nutritional status, anaemia, mineral and bone disorder and cardiovascular comorbidities. Systolic blood pressure was also used in the analysis. Survival analyses used Poisson models. RESULTS: The population average age was 81.9 years (median follow-up 1.51 years, 35.5% deaths). All variables were significantly associated with mortality by univariate analysis. Nutritional status was the variable most strongly associated with mortality in the multivariate analysis, with a negative prognostic impact of low nutritional markers {incidence rate ratio [IRR] 1.42 per 1 standard deviation [SD] decrement [95% confidence interval (CI) 1.32-1.53]}. The 'cardiovascular comorbidities' variable was the second variable associated with mortality [IRR 1.19 per 1 SD increment (95% CI 1.11-1.27)]. A trend towards low intact parathyroid hormone and high serum calcium and low values of systolic blood pressure were also associated with poor survival. The variable 'anaemia' was not associated with survival. CONCLUSIONS: These findings should help physicians prioritize care in elderly haemodialysis patients with CKD complications, with special focus on nutritional status.

Incidence, predictors and therapeutic consequences of hypocalcemia in patients treated with cinacalcet in the EVOLVE trial.

The calcimimetic cinacalcet is used to treat secondary hyperparathyroidism in patients receiving dialysis, and asymptomatic hypocalcemia is often observed following its initiation. Here we investigated the incidence, predictors and therapeutic consequences of hypocalcemia by a post hoc analysis of the randomized, double-blind, placebo-controlled EValuation Of Cinacalcet Hydrochloride Therapy to Lower CardioVascular Events (EVOLVE) trial. Hypocalcemia was classified as mild (total serum calcium 8.0-8.39 mg/dL), moderate (7.5-7.99 mg/dL) or severe (under 7.5 mg/dL). At least one episode of hypocalcemia developed within 16 weeks after the first administered dose among 58.3% of 1938 patients randomized to cinacalcet versus 14.9% of 1923 patients randomized to placebo. Hypocalcemia in the cinacalcet group was severe in 18.4% of the patients versus 4.4% in the placebo group. Severe hypocalcemia following administration of cinacalcet was associated with higher baseline plasma parathyroid hormone, lower corrected total serum calcium, higher serum alkaline phosphatase, geographic region (patients from Latin America and Russia had a higher risk relative to the United States) and higher body mass index. The median cinacalcet dose immediately prior to the first hypocalcemic episode was 54-58 mg/day and similar in the three hypocalcemia categories. In the majority of patients, hypocalcemia resolved spontaneously within 14 days without modification of background therapy. Among patients who received an intervention, the most common was an increase in the active vitamin D sterol dose. Thus, the occurrence of hypocalcemia is frequent following initiation of cinacalcet and the likelihood of developing hypocalcemia was related to the severity of secondary hyperparathyroidism. Hypocalcemia was generally asymptomatic and self-limited.