Jack F.M. Wetzels

Cardiovascular and noncardiovascular mortality among patients starting dialysis

CONTEXT Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiovascular mortality risk only or whether noncardiovascular mortality is equally increased. DESIGN, SETTING, AND PATIENTS Using data from between January 1, 1994, and January 1, 2007, age-stratified mortality in a European cohort of adults starting dialysis and receiving follow-up for a mean of 1.8 (SD, 1.1) years (European Renal Association-European Dialysis and Transplant Association [ERA-EDTA] Registry [N = 123,407]) was compared with the European general population (Eurostat). MAIN OUTCOME MEASURES Cause of death was recorded by ERA-EDTA codes in patients and matching International Statistical Classification of Diseases, 10th Revision codes in the general population. Standardized cardiovascular and noncardiovascular mortality rates, their ratio, difference, and relative excess of cardiovascular over noncardiovascular mortality were calculated. RESULTS Overall all-cause mortality rates in patients and the general population were 192 per 1000 person-years (95% confidence interval [CI], 190-193) and 12.055 per 1000 person-years (95% CI, 12.05-12.06), respectively. Cause of death was known for 90% of the patients and 99% of the general population. In patients, 16,654 deaths (39%) were cardiovascular and 21,654 (51%) were noncardiovascular. In the general population, 7,041,747 deaths (40%) were cardiovascular and 10,183,322 (58%) were noncardiovascular. Cardiovascular and noncardiovascular mortality rates in patients were respectively 38.1 per 1000 person-years (95% CI, 37.2-39.0) and 50.1 per 1000 person-years (95% CI, 48.9-51.2) higher than in the general population. On a relative scale, standardized cardiovascular and noncardiovascular mortality were respectively 8.8 (95% CI, 8.6-9.0) and 8.1 (95% CI, 7.9-8.3) times higher than in the general population. The ratio of these rates, ie, relative excess of cardiovascular over noncardiovascular mortality in patients starting dialysis compared with the general population, was 1.09 (95% CI, 1.06-1.12). Relative excess in a sensitivity analysis in which unknown/missing causes of death were regarded either as noncardiovascular or cardiovascular varied between 0.90 (95% CI, 0.88-0.93) and 1.39 (95% CI, 1.35-1.43). CONCLUSION Patients starting dialysis have a generally increased risk of death that is not specifically caused by excess cardiovascular mortality.

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.

Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.

BACKGROUND Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population. METHODS We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method). RESULTS In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2). CONCLUSIONS An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.

Anti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.

BACKGROUND AND OBJECTIVES Circulating autoantibodies against the M-type phospholipase A(2) receptor (anti-PLA(2)R) were recently identified in the majority of patients in the United States with idiopathic membranous nephropathy (iMN). The objectives of this study were to assess the prevalence of anti-PLA(2)R in a separate, European cohort of iMN patients and to correlate the presence of anti-PLA(2)R with clinical parameters reflective of disease activity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Anti-PLA(2)R levels were blindly assessed by a Western blot immunoassay in 54 serum samples from 18 patients with iMN collected in various stages of clinical disease. Anti-PLA(2)R levels were correlated with other clinical parameters. RESULTS 77.8% of iMN patients in our cohort had antibodies reactive with human PLA(2)R. The antibody levels in these patients correlated strongly with both clinical status and proteinuria (r = 0.73, P < 0.01). CONCLUSIONS The role of PLA(2)R as a major antigen in iMN was confirmed in an independent, European patient cohort, and levels of circulating anti-PLA(2)R revealed a strong correlation with clinical disease activity. We propose that detection and measurement of these autoantibodies may provide a tool for monitoring of disease activity and treatment efficacy.

Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells

Cellular lesions form in Bowmans space in both crescentic glomerulonephritis and collapsing glomerulopathy. The pathomechanism and origin of the proliferating cells in these lesions are unknown. In this study, we examined proliferating cells by lineage tracing of either podocytes or parietal epithelial cells (PECs) in the nephrotoxic nephritis model of inflammatory crescentic glomerulonephritis. In addition, we traced the fate of genetically labeled PECs in the Thy-1.1 transgenic mouse model of collapsing glomerulopathy. In both models, cellular bridges composed of PECs were observed between Bowmans capsule and the glomerular tuft. Genetically labeled PECs also populated larger, more advanced cellular lesions. In these lesions, we detected de novo expression of CD44 in activated PECs. In contrast, we rarely identified genetically labeled podocytes within the cellular lesions of crescentic glomerulonephritis. In conclusion, PECs constitute the majority of cells that compose early extracapillary proliferative lesions in both crescentic glomerulonephritis and collapsing glomerulopathy, suggesting similar pathomechanisms in both diseases.

Serum hepcidin: reference ranges and biochemical correlates in the general population.

To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well-phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1 nM vs 8.5 nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8 nM). Serum hepcidin was strongly associated with serum ferritin in men and women: β-coefficient of log-transformed variables (95% confidence interval): 0.78 (0.74-0.82) and 0.83 (0.78-0.88), respectively. Additional significant, though less strong, associations were observed for C-reactive protein and total iron binding capacity in men and for total iron binding capacity, alanine aminotransferase, and glomerular filtration rate in women. Our study provides age- and sex-specific reference ranges of serum hepcidin concentration and indicates ferritin as the primary correlate of serum hepcidin concentration.

Immunochemical and Mass-Spectrometry–Based Serum Hepcidin Assays for Iron Metabolism Disorders

BACKGROUND Hepcidin is an iron-regulatory peptide hormone that consists of 3 isoforms: bioactive hepcidin-25, and inactive hepcidin-22 and hepcidin-20. Hepcidin is instrumental in the diagnosis and monitoring of iron metabolism disorders, but reliable methods for its quantification in serum are sparse, as is knowledge of their relative analytical strengths and clinical utility. METHODS We developed a competitive (c)-ELISA and an immunocapture TOF mass-spectrometry (IC-TOF-MS) assay. Exploiting these 2 methods and our previously described weak cation exchange (WCX)-TOF-MS assay, we measured serum hepcidin concentrations in 186 patients with various disorders of iron metabolism and in 23 healthy controls. RESULTS We found that (a) the relative differences in median hepcidin concentrations in various diseases to be similar, although the absolute concentrations measured with c-ELISA and WCX-TOF-MS differed; (b) hepcidin isoforms contributed to differences in hepcidin concentrations between methods, which were most prominent in patients with chronic kidney disease; and (c) hepcidin concentrations measured by both the c-ELISA and IC-TOF-MS correlated with ferritin concentrations <60 μg/L, and were suitable for distinguishing between iron deficiency anemia (IDA) and the combination of IDA and anemia of chronic disease. CONCLUSIONS c-ELISA is the method of choice for the large-scale quantification of serum hepcidin concentrations, because of its low limit of detection, low cost, and high-throughput. Because of its specificity for bioactive hepcidin-25, WCX-TOF-MS can be regarded as a valuable special-purpose assay for disorders with variable concentrations of hepcidin isoforms, such as chronic kidney disease.

Macroalbuminuria Is a Better Risk Marker than Low Estimated GFR to Identify Individuals at Risk for Accelerated GFR Loss in Population Screening

Macroalbuminuria, erythrocyturia, and impaired renal function are strong predictors of poor renal outcome in patients with known renal disease. However, the yield of mass screening for these variables to identify individuals who are at risk for GFR loss is yet unknown in a Western population. With the use of data from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort study, the cardiovascular and renal prognosis was investigated in patients with classical renal risk markers: Macroalbuminuria (> or =300 mg albumin/24 h urine), erythrocyturia (> or =250 erythrocytes/L, without leukocyturia), and impaired renal function (both 24-h creatinine clearance and Modification of Diet in Renal Disease clearance below the fifth percentile of age- and gender-matched control subjects). The 8592 patients who were included in this study were followed for a 4-yr period. We identified 134 patients with macroalbuminuria, 128 with erythrocyturia, and 103 with impaired renal function. There was only a little overlap among the three groups. The prevalence of macroalbuminuria, erythrocyturia, and impaired renal function was calculated to be in the general population 0.6, 1.3, and 0.9%, respectively. In all three groups, fewer than 30% of patients were known to have this laboratory abnormality before screening. The incidence of cardiovascular disease was high in the macroalbuminuria group (e.g., the age- and gender-adjusted hazard ratio for mortality as a result of cardiovascular disease is 2.6 [1.1 to 6.0]) and for the impaired renal function group (3.4 [1.5 to 8.0]). After a mean follow-up of 4.2 yr, the macroalbuminuria group showed a -7.2 ml/min per 1.73 m2 estimated GFR (eGFR) loss, compared with -2.3 ml/min per 1.73 m2 in the control group (difference P < 0.001), whereas the rate of eGFR loss in the impaired renal function group (-0.2 ml/min per 1.73 m2; P = 0.18) and the erythrocyturia group (-2.6 ml/min per 1.73 m2) was not different from the control group. Macroalbuminuria and impaired renal function both predict a worse prognosis with respect to cardiovascular morbidity and mortality. However, macroalbuminuria is a better risk marker than low eGFR or erythrocyturia to identify in population screening of individuals who are at risk for accelerated GFR loss.

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.

Antiphospholipase A2 Receptor Antibody Titer and Subclass in Idiopathic Membranous Nephropathy

The phospholipase A(2) receptor (PLA(2)R) is the major target antigen in idiopathic membranous nephropathy. The technique for measuring antibodies against PLA(2)R and the relationship between antibody titer and clinical characteristics are not well established. Here, we measured anti-PLA(2)R (aPLA(2)R) antibody titer and subclass in a well defined cohort of 117 Caucasian patients with idiopathic membranous nephropathy and nephrotic-range proteinuria using both indirect immunofluorescence testing (IIFT) and ELISA. We assessed agreement between tests and correlated antibody titer with clinical baseline parameters and outcome. In this cohort, aPLA(2)R antibodies were positive in 74% and 72% of patients using IIFT and ELISA, respectively. Concordance between both tests was excellent (94% agreement, κ=0.85). Among 82 aPLA(2)R-positive patients, antibody titer significantly correlated with baseline proteinuria (P=0.02). Spontaneous remissions occurred significantly less frequently among patients with high antibody titers (38% versus 4% in the lowest and highest tertiles, respectively; P<0.01). IgG4 was the dominant subclass in the majority of patients. Titers of IgG4, but not IgG1 or IgG3, significantly correlated with the occurrence of spontaneous remission (P=0.03). In summary, these data show high agreement between IIFT and ELISA assessments of aPLA(2)R antibody titer and highlight the pathogenetic role of these antibodies, especially the IgG4 subclass, given the observed relationships between aPLA(2)R titer, baseline proteinuria, and outcome.