natriuretic-peptide--c-type and Renal-Insufficiency--Chronic

Paracrine actions of CNP and rapid degradation at source severely limit study of CNP's many roles in vivo. However provided sensitive and validated assays are used, there is increasing evidence that low concentrations of bioactive CNP in plasma, and the readily detectable concentrations of the bio-inactive processed product of proCNP (aminoterminal proCNP), can be used to advance understanding of the hormone's role in pathophysiology. Provided renal function is normal, concordant changes in both CNP and NTproCNP reflect change in tissue production of proCNP whereas change in CNP alone results from altered rates of bioactive CNP degradation and are reflected in the ratio of NTproCNP to CNP. As already shown in juveniles, where plasma concentration of CNP products are higher and are associated with concurrent endochondral bone growth, measurements of plasma CNP products in mature adults have potential to clarify organ response to stress and injury. Excepting the role of CNP in fetal-maternal welfare, this review examines evidence linking plasma CNP products with function of a wide range of tissues in adults, including the impact of extraneous factors such as nutrients, hormone therapy and exercise.

Topics: Animals; Biomarkers; Bone Development; Cardiovascular Diseases; Fibrosis; Humans; Natriuretic Peptide, C-Type; Renal Insufficiency, Chronic

Renal osteodystrophy (ROD) is highly prevalent in chronic kidney disease (CKD). Because most patients with ROD are asymptomatic in the early stage and bone biopsy remains not a routine procedure in many clinical settings; therefore, several biochemical parameters may help to identify the existence of ROD. C-type natriuretic peptide (CNP) is considered as a positive regulator of bone formation. Both urinary excretion and renal expression of CNP are markedly up-regulated in the early stages of CKD, whereas they are still progressively declined accompanied by CKD progression, which invites speculation that the progressive decline of CNP may contribute, in part, to the pathogenesis of ROD. In addition, fibroblast growth factor (FGF)-23 is a bone-derived endocrine regulator of phosphate homeostasis. The elevation of serum FGF-23 has been recognized as a common feature in CKD to maintain normophosphatemia at the expense of declining 1,25-dihydroxyvitamin D values. Since the effects of CNP and FGF-23 on bone formation appear to oppose each other, it is reasonable to propose a direct interaction of their signaling pathways during the progression of ROD. CNP and FGF-23 act through a close or reciprocal pathway and are in agreement with recent studies demonstrating a down-regulatory role of the mitogen-activated protein kinase activity by CNP. The specific node may act at the level of RAF-1 through the activation of cyclic guanosine monophosphate-dependent protein kinases II.

Topics: Bone Remodeling; Chronic Kidney Disease-Mineral and Bone Disorder; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Mitogen-Activated Protein Kinase Kinases; Natriuretic Peptide, C-Type; Proto-Oncogene Proteins c-raf; Renal Insufficiency, Chronic; Signal Transduction; Vitamin D

Chronic renal inflammation and fibrosis are common sequelae in diabetes mellitus (DM) and are major causes of premature mortality. Although upregulation of. ProCNP products in urine were characterized with HPLC and a range of antisera directed to specific epitopes of amino-terminal proCNP (NTproCNP). The 5-kDa intact peptide was quantified in spot urine samples from healthy adults and 202 participants with DM selected to provide a broad range of renal function.. The predominant products of proCNP in urine were consistent with the 2-kDa fragment (proCNP 3-20) and a smaller peak of intact (5-kDa) fragment (proCNP 1-50, NTproCNP). No peaks consistent with bioactive forms (proCNP 82-103, 50-103) were identified. The urine NTproCNP to creatinine ratio (NCR) was more reproducible than the albumin to creatinine ratio (ACR) and strongly associated with the presence of chronic kidney disease. In models predicting independence, among 10 variables associated with renal function in DM, including plasma NTproCNP, only 3 (sex, ACR, and plasma creatinine) contributed to NCR.. Characterization of the products of proCNP in urine confirmed the presence of NTproCNP. In spot random urine from study participants with DM, NCR is inversely associated with estimated glomerular filtration rate. In contrast to ACR, NCR reflects nonvascular factors that likely include renal inflammation and fibrosis.

Topics: Adult; Aged; Albuminuria; Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Creatinine; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Natriuretic Peptide, C-Type; Renal Insufficiency, Chronic

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family and have been implicated to be involved in maintaining vascular homeostasis and acting as a cardiac chronotropic agent in experimental studies. However, clinical evidence of its participation in cardiovascular regulation is lacking, especially in patients with chronic kidney disease (CKD). We aimed to explore the association of circulating CNP with cardiovascular alterations in CKD.. Seventy-six subjects with CKD were recruited. Plasma CNP-22, the bioactive form of CNP in the circulation, was measured by an enzyme immunoassay. The patients also underwent several cardiovascular evaluations including measurement of blood pressure, endothelial function, heart rate variability (HRV) and pulse wave velocity.. Mean (±standard deviation) age of the patients were 59.9 (±14.9) years and 56.6% were male. Average plasma CNP level was 790.8 ± 309.1 pg/ml. Plasma CNP level was not increased as estimated glomerular filtration rate declined. There was no significant difference of CNP between patients with or without endothelial dysfunction (with vs. without endothelial dysfunction: 844.6 ± 365.5 pg/ml vs. 738.3 ± 231.8 pg/ml, p = 0.14). Plasma CNP showed no association with blood pressure or pulse wave velocity, but was negatively associated with time-domain HRV parameters (SDNN, RMSSD, Triangular Index). The association of CNP with HRV persisted after adjustment for potential covariates.. Our data highlights a possible link between circulating CNP and autonomic dysfunction in CKD patients. Further studies are warranted to explore the mechanisms underlying this association, as well as evaluate the ability of circulating CNP in predicting adverse cardiovascular event in CKD patients.

Topics: Aged; Biomarkers; Cross-Sectional Studies; Female; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, C-Type; Pulse Wave Analysis; Renal Insufficiency, Chronic

We aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy.. A systematic data integration approach was used to select biomarkers representing different disease pathways. Twenty-eight biomarkers were measured in 82 patients seen at an outpatient diabetes center in The Netherlands. Median follow-up was 4.0 years. We compared the cross-validated explained variation (R2) of two models to predict eGFR decline, one including only established risk markers, the other adding a novel panel of biomarkers. Least absolute shrinkage and selection operator (LASSO) was used for model estimation. The C-index was calculated to assess improvement in prediction of accelerated eGFR decline defined as <-3.0 mL/min/1.73m2/year.. Patients' average age was 63.5 years and baseline eGFR was 77.9 mL/min/1.73m2. The average rate of eGFR decline was -2.0 ± 4.7 mL/min/1.73m2/year. When modeled on top of established risk markers, the biomarker panel including matrix metallopeptidases, tyrosine kinase, podocin, CTGF, TNF-receptor-1, sclerostin, CCL2, YKL-40, and NT-proCNP improved the explained variability of eGFR decline (R2 increase from 37.7% to 54.6%; p=0.018) and improved prediction of accelerated eGFR decline (C-index increase from 0.835 to 0.896; p=0.008).. A novel panel of biomarkers representing different pathways of renal disease progression including inflammation, fibrosis, angiogenesis, and endothelial function improved prediction of eGFR decline on top of established risk markers in type 2 diabetes. These results need to be confirmed in a large prospective cohort.

Topics: Adaptor Proteins, Signal Transducing; Adipokines; Adult; Aged; Biomarkers; Bone Morphogenetic Proteins; Chemokine CCL2; Chitinase-3-Like Protein 1; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Fibrosis; Genetic Markers; Glomerular Filtration Rate; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Lectins; Male; Matrix Metalloproteinases, Secreted; Membrane Proteins; Middle Aged; Natriuretic Peptide, C-Type; Outpatients; Prognosis; Prospective Studies; Protein-Tyrosine Kinases; Receptors, Tumor Necrosis Factor, Type I; Renal Insufficiency, Chronic; Risk Factors