Marie Metzger

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Large Artery Stiffening and Remodeling Are Independently Associated With All-Cause Mortality and Cardiovascular Events in Chronic Kidney Disease

Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiovascular events. Subclinical damage to large arteries, such as increased arterial stiffness and outward remodeling, is a classical hallmark of patients with chronic kidney disease. Whether large artery stiffness and remodeling influence the occurrence of cardiovascular events and the mortality of patients with chronic kidney disease (stages 2–5) is still debated. This prospective study included 439 patients with chronic kidney disease (mean age, 59.8±14.5 years) with a mean measured glomerular filtration rate of 37 mL/min per 1.73 m2. Baseline aortic stiffness was estimated through carotid-femoral pulse wave velocity measurements; carotid stiffness, diameter, and intima-media thickness were measured with a high-resolution echotracking system. For the overall group of patients, the 5-year estimated survival and cumulative incidence of cardiovascular events were 87% and 16%, respectively. In regression analyses adjusted on classical cardiovascular and renal risk factors, aortic stiffness remained significantly associated with all-cause mortality (for 1 SD, Cox model–derived relative risk [95% CI], 1.48 [1.09–2.02]) and with fatal and nonfatal cardiovascular events (for 1 SD, Fine and Gray competing risks model–derived relative risk [95% CI], 1.35 [1.05–1.75]). Net reclassification improvement index was significant (29.0% [2.3–42.0%]). Carotid internal diameter was also independently associated with all-cause mortality. This study shows that increased aortic stiffness and carotid internal diameter are independent predictors of mortality in patients with stages 2 to 5 chronic kidney disease and that aortic stiffness improves the prediction of the risk.

Epidemiology and prognostic significance of chronic kidney disease in the elderly--the Three-City prospective cohort study.

BACKGROUND Little is known about normal kidney function level and the prognostic significance of low estimated glomerular filtration rate (eGFR) in the elderly. METHODS We determined age and sex distribution of eGFR with both the Modification of Diet in Renal Disease (MDRD) study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 8705 community-dwelling elderly aged ≥ 65 years and studied its relation to 6-year mortality. In a subsample of 1298 subjects examined at 4 years, we assessed annual eGFR decline and clinically relevant markers including microalbuminuria (3-30 mg/mmol creatinine) with diabetes, proteinuria ≥ 50 mg/mmol, haemoglobin <11 g/L or resistant hypertension despite three drugs. RESULTS Median (interquartile range) MDRD eGFR was 78 (68-89) mL/min/1.73 m(2) in men and 74 (65-83) in women; there were 79 (68-87) and 77 (67-85) for CKD-EPI eGFR, respectively. Prevalence of MDRD eGFR <60 mL/min/1.73 m(2) was 13.7% and of CKD-EPI eGFR was 12.9%. After adjustment for several confounders, only those with an eGFR <45 mL/min/1.73 m(2) had significantly higher all-cause and cardiovascular mortality than those with an eGFR of 75-89 mL/min/1.73 m(2) whatever the equation. In the subsample men and women with an MDRD eGFR of 45-59 mL/min/1.73 m(2), 15 and 13% had at least one clinical marker and 15 and 3% had microalbuminuria without diabetes, respectively; these percentages were 41 and 21% and 23 and 10% in men and women with eGFR <45, respectively. Mean MDRD eGFR decline rate was steeper in men than in women, 1.75 versus 1.41 mL/min/1.73 m(2)/year. CONCLUSIONS Moderately decreased eGFR is more often associated with clinical markers in men than in women. In both sexes, eGFR <45 mL/min/1.73 m(2) is related to poor outcomes. The CKD-EPI and the MDRD equations provide very similar prevalence and long-term risk estimates in this elderly population.

Association of Kidney Function, Vitamin D Deficiency, and Circulating Markers of Mineral and Bone Disorders in CKD

BACKGROUND Vitamin D (25 hydroxyvitamin D [25(OH)D]) deficiency is common in patients with chronic kidney disease (CKD). Neither the relation of this deficiency to the decrease in glomerular filtration rate (GFR) nor the effects on CKD mineral and bone disorders (MBD) are clearly established. STUDY DESIGN Cross-sectional analysis of baseline data from a prospective cohort, the NephroTest Study. SETTING & PARTICIPANTS 1,026 adult patients with all-stage CKD not on dialysis therapy or receiving vitamin D supplementation. PREDICTORS For part 1, measured GFR (mGFR) using (51)Cr-EDTA renal clearance; for part 2, 25(OH)D deficiency at <15 ng/mL. OUTCOMES & MEASUREMENTS For part 1, 25(OH)D deficiency and several circulating MBD markers; for part 2, circulating MBD markers. RESULTS For part 1, the prevalence of 25(OH)D deficiency was associated inversely with mGFR, ranging from 28%-51% for mGFR ≥60-<15 mL/min/1.73 m(2). It was higher in patients of African origin; those with obesity, diabetes, hypertension, macroalbuminuria, and hypoalbuminemia; and during winter. After adjusting for these factors, ORs for 25(OH)D deficiency increased from 1.4 (95% CI, 0.9-2.3) to 1.4 (95% CI, 0.9-2.1), 1.7 (95% CI, 1.1-2.7), and 1.9 (95% CI, 1.1-3.6) as mGFR decreased from 45-59 to 30-44, 15-29, and <15 (reference, ≥60) mL/min/1.73 m(2) (P for trend = 0.02). For part 2, 25(OH)D deficiency was associated with higher age-, sex-, and mGFR-adjusted ORs of ionized calcium level <1.10 mmol/L (2.6; 95% CI, 1.2-5.9), 1,25 dihydroxyvitamin D concentration <16.7 pg/mL (1.8; 95% CI, 1.3-2.4), hyperparathyroidism (1.8; 95% CI, 1.3-2.4), and serum C-terminal cross-linked collagen type I telopeptides concentration >1,000 pg/mL (1.6; 95% CI, 1.0-2.6). It was not associated with hyperphosphatemia (phosphate >1.38 mmol/L). LIMITATIONS Cross-sectional analysis of the data prevents causal inferences. CONCLUSIONS 25(OH)D deficiency is related independently to impaired mGFR. Both mGFR decrease and 25(OH)D deficiency are associated with abnormal levels of circulating MBD biomarkers.

Urinary ammonia and long-term outcomes in chronic kidney disease

Recent studies suggest that alkalinizing treatments improve the course of chronic kidney disease (CKD), even in patients without overt metabolic acidosis. Here, we tested whether a decreased ability in excreting urinary acid rather than overt metabolic acidosis may be deleterious to the course of CKD. We studied the associations between baseline venous total CO2 concentration or urinary ammonia excretion and long-term CKD outcomes in 1065 patients of the NephroTest cohort with CKD stages 1-4. All patients had measured glomerular filtration rate (mGFR) by (51)Cr-EDTA renal clearance. Median mGFR at baseline was 37.6 ml/min per 1.73 m(2). Urinary ammonia excretion decreased with GFR, whereas net endogenous acid production did not. After a median follow-up of 4.3 years, 201 patients reached end-stage renal disease (ESRD) and 114 died before ESRD. Twenty-six percent of the patients had mGFR decline rate greater than 10% per year. Compared with patients in the highest tertile of urinary ammonia excretion, those in the lowest tertile had a significantly increased hazard ratio for ESRD, 1.82 (95% CI, 1.06-3.13), and a higher odds ratio of fast mGFR decline, 1.84 (0.98-3.48), independent of mGFR and other confounders. Patients in the lowest tertile of venous total CO2 had significantly increased risk of fast mGFR decline but not of ESRD. None of these biomarkers was associated with mortality. Thus, these results suggest that the inability to excrete the daily acid load is deleterious to renal outcomes.

Timing and Determinants of Erythropoietin Deficiency in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Anemia in patients with CKD is highly related to impaired erythropoietin (EPO) response, the timing and determinants of which remain unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study measured EPO levels and studied their relation to GFR measured by 51Cr-EDTA renal clearance (mGFR) in 336 all-stage CKD patients not receiving any erythropoiesis-stimulating agent. RESULTS In patients with anemia defined by World Health Organization criteria (hemoglobin [Hb] <13 g/dl in men and 12 g/dl in women), EPO response to Hb level varied by mGFR level. EPO and Hb levels were negatively correlated (r=-0.22, P=0.04) when mGFR was >30 ml/min per 1.73 m(2), whereas they were not correlated when mGFR was <30 (r=0.09, P=0.3; P for interaction=0.01). In patients with anemia, the ratio of observed EPO to the level predicted by the equation for their Hb level decreased from 0.72 (interquartile range, 0.57-0.95) for mGFR ≥60 ml/min per 1.73 m(2) to 0.36 (interquartile range, 0.16-0.69) for mGFR <15. Obesity, diabetes with nephropathy other than diabetic glomerulopathy, absolute iron deficiency, and high C-reactive protein concentrations were associated with increased EPO levels, independent of Hb and mGFR. CONCLUSIONS Anemia in CKD is marked by an early relative EPO deficiency, but several factors besides Hb may persistently stimulate EPO synthesis. Although EPO deficiency is likely the main determinant of anemia in patients with advanced CKD, the presence of anemia in those with mGFR >30 ml/min per 1.73 m(2) calls for other explanatory factors.

Does kin recognition and sib-mating avoidance limit the risk of genetic incompatibility in a parasitic wasp?

Background When some combinations of maternal and paternal alleles have a detrimental effect on offspring fitness, females should be able to choose mates on the basis of their genetic compatibility. In numerous Hymenoptera, the sex of an individual depends of the allelic combination at a specific locus (single-locus Complementary Sex Determination), and in most of these species individuals that are homozygous at this sexual locus develop into diploid males with zero fitness. Methods and Findings In this paper, we tested the hypothesis of genetic incompatibility avoidance by investigating sib-mating avoidance in the solitary wasp parasitoid, Venturia canescens. In the context of mate choice we show, for the first time in a non-social hymenopteran species, that females can avoid mating with their brothers through kin recognition. In “no-choice” tests, the probability a female will mate with an unrelated male is twice as high as the chance of her mating with her brothers. In contrast, in choice tests in small test arenas, no kin discrimination effect was observed. Further experiments with male extracts demonstrate that chemical cues emanating from related males influence the acceptance rate of unrelated males. Conclusions Our results are compatible with the genetic incompatibility hypothesis. They suggest that the female wasps recognize sibs on the basis of a chemical signature carried or emitted by males possibly using a “self-referent phenotype matching” mechanism.

The Relation of Hepcidin to Iron Disorders, Inflammation and Hemoglobin in Chronic Kidney Disease

The metabolism of hepcidin is profoundly modified in chronic kidney disease (CKD). We investigated its relation to iron disorders, inflammation and hemoglobin (Hb) level in 199 non-dialyzed, non-transplanted patients with CKD stages 1–5. All had their glomerular filtration rate measured by 51Cr-EDTA renal clearance (mGFR), as well as measurements of iron markers including hepcidin and of erythropoietin (EPO). Hepcidin varied from 0.2 to 193 ng/mL. The median increased from 23.3 ng/mL [8.8–28.7] to 36.1 ng/mL [14.1–92.3] when mGFR decreased from ≥60 to <15 mL/min/1.73 m2 (p = 0.02). Patients with absolute iron deficiency (transferrin saturation (TSAT) <20% and ferritin <40 ng/mL) had the lowest hepcidin levels (5.0 ng/mL [0.7–11.7]), and those with a normal iron profile (TSAT ≥20% and ferritin ≥40), the highest (34.5 ng/mL [23.7–51.6]). In multivariate analysis, absolute iron deficiency was associated with lower hepcidin values, and inflammation combined with a normal or functional iron profile with higher values, independent of other determinants of hepcidin concentration, including EPO, mGFR, and albuminemia. The hepcidin level, although it rose overall when mGFR declined, collapsed in patients with absolute iron deficiency. There was a significant interaction with iron status in the association between Hb and hepcidin. Except in absolute iron deficiency, hepcidin’s negative association with Hb level indicates that it is not down-regulated in CKD anemia.

Does constrained oviposition influence offspring sex ratio in the solitary parasitoid wasp Venturia canescens

Abstract 1. In haplodiploid organisms, virgin or sperm‐depleted females can reproduce but are constrained to produce only male progeny. According to Godfray’s constrained model, when p, the proportion of females constrained to produce only male progeny, is not null in a panmictic population, unconstrained females should bias their sex allocation towards females to compensate for the excess of males. These unconstrained females should be able to adjust the sex ratio in response to local variation of p.

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria≥300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2α, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease.