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PubMed2007

Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment.

Standard treatment in chronic kidney disease (CKD) patients includes an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. CKD is often characterized by sympathetic hyperactivity. This study investigates the prevalence of sympathetic hyperactivity (quantified by assessment of muscle sympathetic nerve activity [MSNA]) in a sizable group of patients with CKD and assessed whether chronic angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker normalizes increased MSNA. In 74 CKD patients (creatinine clearance 54+/-31 mL/min), MSNA, blood pressure, and plasma renin activity were measured in the absence of antihypertensive drugs except for diuretics. In a subgroup of 31 patients, another set of measurements was obtained after > or =6 weeks of enalapril (10 mg PO), losartan (100 mg PO), or eprosartan (600 mg PO). Patients as compared with control subjects (n=82) had higher mean arterial pressure (113+/-13 versus 89+/-7 mm Hg), MSNA (31+/-13 versus 19+/-7 bursts per minute), and log plasma renin activity (2.67+/-036 versus 2.40+/-0.32 fmol/L per second; all P<0.001). During angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy (n=31), mean arterial pressure (115+/-11 to 100+/-9 mm Hg) and MSNA (33+/-11 to 25+/-9 bursts per minute) decreased (both P<0.01) but were still higher than in control subjects (both P<0.01). Multiple regression analysis identified age and plasma renin activity as predictive for MSNA. In conclusion, sympathetic hyperactivity occurs in a substantial proportion of hypertensive CKD patients. Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment reduces but does not normalize MSNA.

Adult↗
PubMed2024

The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-&#x3b2;1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Animals↗
PubMed2005

Integrating clinical nutrition practice guidelines in chronic kidney disease.

Chronic kidney disease (CKD) is a permanent, progressive loss of kidney function characterized by a decline in glomerular filtration rate (GFR). Early identification of CKD risk factors provides an opportunity to prevent or delay the progression of kidney disease and decrease morbidity and mortality. There is increasing evidence to suggest that the adverse outcomes of CKD can be delayed or prevented by early detection and treatment. Current literature suggests that a low-protein, low-phosphorus diet may retard the progression of kidney disease. Other modifiable risk factors affecting CKD include proteinuria, hypertension, hyperglycemia, dyslipidemia, bone disease, anemia, and obesity. This discussion will review the current clinical nutrition guidelines for managing adult patients with CKD.

Humans↗
PubMed2006

Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan: NIPPON DATA90.

BACKGROUND: Chronic kidney disease (CKD) has been identified as a risk factor for cardiovascular disease (CVD). METHODS AND RESULTS: The risk of cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. Participants (mean age, 52.4 years) free of previous CVD were followed up for 10 years. Glomerular filtration rate (GFR) was estimated using the abbreviated equation developed at the Cleveland Clinic laboratory for the Modification of Diet in Renal Disease study. Of the 7,316 participants, 6.7% had CKD with a GFR<60 at baseline. Even after adjustment for other risk factors, the presence of CKD conferred an increased risk of cardiovascular death with a hazard ratio of 1.20 (95% confidence interval, 0.82-1.76). Furthermore, a negative, graded correlation between GFR and risk of cardiovascular death was observed: 1.09 (0.72-1.64) for a 60 or=90). The proportion of excess cardiovascular death due to CKD was 1.3%. CONCLUSION: CKD was an independent risk factor for cardiovascular death in a community-dwelling Japanese population.

Adult↗
PubMed2026

Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) occurs in 20-50% of the people living with Type 2 diabetes (T2D) and is the leading cause of kidney failure worldwide. The cause of CKD is not fully understood, and few interventions prevent CKD in individuals living with diabetes. Here, we use large-scale proteomics data to identify circulating proteins that mediate the relationship between T2D and kidney disorders. METHODS AND FINDINGS: First, we used two-sample mendelian randomization (MR) and identified 71 circulating proteins whose levels were altered by genetic predisposition to T2D based on circulating proteomic GWAS from deCODE with 35,559 individuals and T2D GWAS with 80,154 cases. Then, we used cis-genetic variants to proxy the causal effect of some of these T2D-influenced circulating proteins and found that, collectively, five proteins (INHBC, GNPTG, LPO, AGRN, and CTSD) affected three kidney traits (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR] and CKD risk) based on GWAS with up to 1,004,040 participants. Notably, we found that higher levels of circulating INHBC protein were estimated to lead to a lower eGFR and higher BUN based on MR analyses. We then replicated this MR analysis with proteomic GWAS from four additional cohorts, namely, UKB-PPP, Fenland, ARIC, and EPIC-Norfolk. We observed a consistent direction of effect across all four proteomic GWAS datasets, supporting the robustness of our results against platform and cohort variation. In observational analyses, increased circulating INHBC levels were associated with increased hazard for kidney disease diagnosis in 37,854 UK Biobank participants. We estimated that circulating INHBC levels mediate 1.3% (95% confidence interval [0.85%, 1.9%]) of the association between T2D and kidney disease diagnosis. There are important limitations in this study. Firstly, although we observed limited evidence for violations to the MR assumptions, some are untestable. Secondly, our study was not based on individuals with diabetic kidney diseases, but rather independent population-based studies assessing diabetes and kidney function separately. Therefore, additional functional analyses in disease specific cohort are needed. CONCLUSIONS: Collectively, these findings suggest that T2D influences the risk of CKD, in part, through increased circulating INHBC levels.

Humans↗
PubMed2004

Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease.

The performance of the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault (CG) equations as compared with measured (125)I-iothalamate GFR (iGFR) was analyzed in patients with chronic kidney disease (CKD) and in potential kidney donors. All outpatients (n = 1285) who underwent an iGFR between 1996 and 2003 were considered for analysis. Of these, 828 patients had CKD and 457 were potential kidney donors. Special emphasis was put on the calibration of the serum creatinine measurements. In CKD patients with GFR <60 ml/min per 1.73 m(2), the MDRD equation performed better than the CG formula with respect to bias (-0.5 versus 3.5 ml/min per 1.73 m(2), respectively) and accuracy within 30% (71 versus 60%, respectively) and 50% (89 versus 77%, respectively). Similar results are reported for 249 CKD patients with diabetes. In the kidney donor group, the MDRD equation significantly underestimated the measured GFR when compared with the CG formula, with a bias of -9.0 versus 1.9 ml/min per 1.73 m(2), respectively (P < 0.01), and both the MDRD and CG equations overestimated the strength of the association of GFR with measured serum creatinine. The present data add further validation of the MDRD equation in outpatients with moderate to advanced kidney disease as well as in those with diabetic nephropathy but suggest that its use is problematic in healthy individuals. This study also emphasizes the complexity of laboratory calibration of serum creatinine measurements, a determining factor when estimating GFR in both healthy individuals and CKD patients with preserved GFR.

Adult↗
PubMed2005

Effects of anemia and left ventricular hypertrophy on cardiovascular disease in patients with chronic kidney disease.

Left ventricular hypertrophy (LVH) and anemia are highly prevalent in moderate chronic kidney disease (CKD). Because anemia may potentiate the adverse effects of LVH on cardiovascular outcomes, the effect of both anemia and LVH on outcomes in CKD was examined. Data from four community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were calibrated indirectly across studies, and GFR was estimated using the Modification of Diet in Renal Disease equation. CKD was defined as GFR between 15 and 60 ml/min per 1.73 m(2). LVH was based on electrocardiogram criteria. Anemia was defined as hematocrit <36% in women and 39% in men. The primary outcome was a composite of myocardial infarction, stroke, and death; a secondary cardiac outcome included only myocardial infarction and fatal coronary heart disease. Among 2423 patients with CKD, 96% had electrocardiogram and anemia data. Median follow-up was 102 mo. In adjusted analysis, LVH was associated with increased risk for composite and cardiac outcomes (hazard ratio [HR], 1.67 [95% confidence interval (CI), 1.34 to 2.07] and 1.62 [95% CI, 1.18 to 2.24], respectively), whereas anemia was associated with increased risk for the only composite outcome (HR, 1.51 [95% CI, 1.27 to 1.81]). The combination of anemia and LVH was associated with an increased risk for both study outcomes compared with individuals with neither risk factor (HR, 4.15 [95% CI, 2.62 to 6.56] and 3.92 [95% CI, 2.05 to 7.48]; P = 0.02 and 0.01 for interaction term, respectively). The combination of anemia and LVH in CKD identifies a high-risk population.

Aged↗
PubMed2004

Serum phosphate levels and mortality risk among people with chronic kidney disease.

Elevated serum phosphate levels have been linked with vascular calcification and mortality among dialysis patients. The relationship between phosphate and mortality has not been explored among patients with chronic kidney disease (CKD). A retrospective cohort study was conducted from eight Veterans Affairs' Medical Centers located in the Pacific Northwest. CKD was defined by two continuously abnormal outpatient serum creatinine measurements at least 6 mo apart between 1999 and 2002. Patients who received chronic dialysis, those with a present or previous renal transplant, and those without a recent phosphate measurement were excluded. The primary end point was all-cause mortality. Secondary end points were acute myocardial infarction and the combined end point of myocardial infarction plus death. A total of 95,619 veterans with at least one primary care or internal medicine clinic contact from a Northwest VA facility and two or more outpatient measurements of serum creatinine, at least 6 mo apart, between January 1, 1999, and December 31, 2002, were identified. From this eligible population, 7021 patients met our definition of CKD. After exclusions, 6730 CKD patients were available for analysis, and 3490 had a serum phosphate measurement during the previous 18 mo. After adjustment, serum phosphate levels >3.5 mg/dl were associated with a significantly increased risk for death. Mortality risk increased linearly with each subsequent 0.5-mg/dl increase in serum phosphate levels. Elevated serum phosphate levels were independently associated with increased mortality risk among this population of patients with CKD.

Age Distribution↗
PubMed2005

Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation.

Increased intima-media thickness of the carotid arteries (cIMT) has been found in young adults with childhood-onset chronic kidney disease (CKD). The disease stage at which these patients first develop abnormalities of arterial texture is unknown. The objective of this study was to determine the onset and character of arterial changes in children aged 10 to 20 yr with different stages of CKD and to identify risk factors for early arteriopathy. High-resolution ultrasonography was conducted of common cIMT and femoral superficial artery IMT. Fifty-five children with stages 2 to 4 CKD (GFR 51 +/- 31 ml/min per 1.73 m2), 37 on dialysis, and 34 after renal transplantation (Rtx; GFR 73 +/- 31 ml/min per 1.73 m2) were studied. Control subjects were 270 healthy children, matched for age and gender. Compared with control subjects, cIMT, femoral superficial artery IMT (both as absolute values and as SD score of median of normal value), wall cross-sectional area, and lumen cross-sectional area of carotid artery were significantly increased in all patient groups and most markedly abnormal in dialysis patients. cIMT in CKD and Rtx patients was significantly lower in comparison with dialysis patients. cIMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged mean calcitriol dose. The cumulative phosphate binder intake, time-averaged Ca x P product, and young age were independent predictors of an increased cIMT. In children with CKD, thickening of IMT occurs early in the course of disease and is most marked in dialyzed patients. The changes may be partly reversible after Rtx.

Adolescent↗
PubMed2005

Low hemoglobin, chronic kidney disease, and risk for coronary heart disease-related death: the Blue Mountains Eye Study.

A recent report found that chronic kidney disease (CKD) increased the risk for coronary heart disease (CHD) events in people with anemia but not in those without anemia. This study aimed to verify these findings in the Blue Mountains Eye Study cohort, a prospective Australian population-based study of 3654 residents aged 49 to 97 yr. Fasting blood samples were obtained at baseline and confirmed CHD-related deaths over 9 yr with the Australian National Death Index. "Low hemoglobin" was defined as levels in the lowest quintile of the cohort. Body surface area-adjusted GFR was estimated using a variety of methods (Cockcroft-Gault, abbreviated Modification of Diet in Renal Disease, and Bjornsson equations). People with CKD (GFR <60 ml/min per 1.73 m2 as estimated using the Cockcroft-Gault equation) and low hemoglobin (mean 13.2 g/dl; range 7.6 to 14.6 g/dl) had an increased risk for CHD-related death (multivariable-adjusted hazard risk ratio 1.49; 95% confidence interval 1.08 to 2.06) compared with people with CKD but in higher hemoglobin quintiles. This effect was not evident in people without CKD. The interaction between GFR and hemoglobin was significant (P = 0.05) when GFR was estimated using either the Cockcroft-Gault or Bjornsson equations or when serum creatinine instead of GFR was used in the analyses but not when GFR was estimated using the abbreviated Modification of Diet in Renal Disease equation. In conclusion, this study found that low hemoglobin, even within the normal range, together with CKD increased the risk for CHD-related death.

Aged↗
PubMed2006

Risks for end-stage renal disease, cardiovascular events, and death in Hispanic versus non-Hispanic white adults with chronic kidney disease.

Rates of ESRD are rising faster in Hispanic than non-Hispanic white individuals, but reasons for this are unclear. Whether rates of cardiovascular events and mortality differ among Hispanic and non-Hispanic white patients with chronic kidney disease (CKD) also is not well understood. Therefore, this study examined the associations between Hispanic ethnicity and risks for ESRD, cardiovascular events, and death in patients with CKD. A total of 39,550 patients with stages 3 to 4 CKD from Kaiser Permanente of Northern California were included. Hispanic ethnicity was obtained from self-report supplemented by surname matching. GFR was estimated from the abbreviated Modification of Diet in Renal Disease equation, and clinical outcomes, patient characteristics, and longitudinal medication use were ascertained from health plan databases and state mortality files. After adjustment for sociodemographic characteristics, Hispanic ethnicity was associated with an increased risk for ESRD (hazard ratio [HR] 1.93; 95% confidence interval [CI] 1.72 to 2.17) when compared with non-Hispanic white patients, which was attenuated after controlling for diabetes and insulin use (HR 1.50; 95% CI 1.33 to 1.69). After further adjustment for potential confounders, Hispanic ethnicity remained independently associated with an increased risk for ESRD (HR 1.33; 95% CI 1.17 to 1.52) as well as a lower risk for cardiovascular events (HR 0.82; 95% CI 0.76 to 0.88) and death (HR 0.72; 95% CI 0.66 to 0.79). Among a large cohort of patients with CKD, Hispanic ethnicity was associated with lower rates of death and cardiovascular events and a higher rate of progression to ESRD. The higher prevalence of diabetes among Hispanic patients only partially explained the increased risk for ESRD. Further studies are required to elucidate the cause(s) of ethnic disparities in CKD-associated outcomes.

Aged↗
PubMed2006

Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcription-PCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD.

Adenoviridae↗
PubMed2006

Chronic kidney disease in long-term survivors of hematopoietic cell transplantation: epidemiology, pathogenesis, and treatment.

High-dose myeloablative hematopoietic cell transplantation is becoming an increasingly common treatment modality for a variety of diseases. Patient survival may be limited by substantial treatment-related toxicities, including chronic kidney disease (CKD). Although the majority of CKD after transplantation is idiopathic, thrombotic microangiopathic syndromes and nephrotic syndrome have been described. Epidemiology, pathogenesis, and potential treatment options for the various clinical syndromes that are associated with CKD in hematopoietic cell transplantation patients is reviewed. As the indications for and the numbers of transplants that are performed worldwide increases, so will the burden of CKD. The nephrologists and oncologists will have to work together to identify patients who are at risk for CKD early to prevent its development and progression to end-stage kidney disease.

Graft vs Host Disease↗
PubMed2006

Cardiovascular disease in early stages of chronic kidney disease in a Chinese population.

Cardiovascular disease (CVD) is one of the most serious complications of kidney disease, yet studies of CVD in early stage of chronic kidney disease (CKD) in Asian patients are very limited. Therefore, this study determined the prevalence and the spectrum of CVD in individuals with early-stage CKD and compared them with data of individuals without CKD. Compared with individuals with estimated GFR (eGFR) >90 ml/min per 1.73 m2, the prevalence of myocardial infarction, stroke, and total CVD of individuals with eGFR 60 to 89 ml/min per 1.73 m2 was increased by 91.4, 71.7, and 67.6%, respectively. For individuals with eGFR 30 to 59 ml/min per 1.73 m2, the percentage was 105.2, 289.1, and 200.7%, respectively. For each eGFR category, stroke was more prevalent than myocardial infarction. Compared with individuals with eGFR >90 ml/min per 1.73 m2, participants with eGFR 60 to 89 and 30 to 59 ml/min per 1.73 m2 tended to have more cardiovascular risk factors, and there were strong unadjusted and adjusted associations between CVD with different stages of eGFR (eGFR >90 ml/min per 1.73 m2 as reference). This is the first report on the prevalence and the spectrum of CVD in early stages of CKD in a community-based Chinese population. The spectrum of CVD in this Chinese population is different from reports of Western countries. Individuals with subtle decreased renal function seem much more likely to have multiple cardiovascular risk factors and have higher prevalence of CVD than those without CKD.

Adult↗
PubMed2006

Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy.

A model of chronic kidney disease (CKD)-induced vascular calcification (VC) that complicates the metabolic syndrome was produced. In this model, the metabolic syndrome is characterized by severe atherosclerotic plaque formation, hypertension, type 2 diabetes, obesity, and hypercholesterolemia, and CKD stimulates calcification of the neointima and tunica media of the aorta. The CKD in this model is associated the adynamic bone disorder form of renal osteodystrophy. The VC of the model is associated with hyperphosphatemia, and control of the serum phosphorus both in this animal model and in humans has been preventive in the development of VC. This article reports studies that demonstrate reduction of established VC by the addition of sevelamer carbonate to the diets of this murine metabolic syndrome model with CKD. Sevelamer, besides normalizing the serum phosphorus, surprisingly, reversed the CKD-induced trabecular osteopenia. Sevelamer therapy increased osteoblast surfaces in the metaphyseal trabeculae of the tibia and femur. It also increased osteoid surfaces and, importantly, bone formation rates. In addition, sevelamer was found to be effective in decreasing serum cholesterol levels. These results suggest that sevelamer may have important actions in decreasing diabetic and uremic vasculopathy and that sevelamer carbonate may be capable of increasing bone formation rates that are suppressed by diabetic nephropathy.

Animals↗
PubMedDate not supplied

Resource use and patient care associated with chronic kidney disease in a managed care setting.

OBJECTIVE: To describe the resource utilization and care of chronic kidney disease (CKD) patients in a managed care plan. METHODS: This was a retrospective claims analysis of a nationwide managed care medical and pharmacy database from September 1, 1998, to July 31, 2001. Twenty-seven health plans in 19 states distributed across the Northeast, Southeast, Midwest, and Southwest United States were represented in this analysis. CKD patients were identified using ICD-9 CM, CPT-4, and HCPCS codes indicative of dialysis. Patients continuously enrolled for at least 6 months before and 3 months after an initial dialysis event were included in the study. Health care charges and associated clinical information were assessed during 3 time periods: predialysis was from the sixth through the second month before initial dialysis, peridialysis was 30 days before and 30 days after initial dialysis, and postdialysis was the second and third month after initial dialysis. The main outcome measures were total health care charges, primary diagnoses, and diagnosis- related groups (DRGs). RESULTS: The per-patient-per-month charges were 4,265 dollars in the predialysis period (average for 5 months), 35,292 dollars in the peridialysis period (average for 2 months), and 15,399 dollars in the postdialysis period (average for 2 months). The most common primary diagnosis categories during all time periods were chronic renal failure and congestive heart failure. Similarly, the most common DRGs were related to renal and heart failure. A total of 38.2% of patients did not have an initial nephrologist visit until the first dialysis event. Treatments with nutritional supplements and medications such as angiotensin-converting enzyme inhibitors and erythropoietin were found to be suboptimal. CONCLUSION: CKD patients generate significant medical charges during the predialysis period and after initiation of dialysis. Further investigations are warranted to assess the impact of active management of CKD patients on CKD-related health care expenditures in kidney disease.

Adolescent↗
PubMed2006

An extended terminal half-life for darbepoetin alfa: results from a single-dose pharmacokinetic study in patients with chronic kidney disease not receiving dialysis.

BACKGROUND AND OBJECTIVE: Anaemia is a major and persistent manifestation of chronic kidney disease (CKD) caused by the deficient production of erythropoietin in the kidneys, the prevalence of which is proportional to the deterioration in kidney function. Darbepoetin alfa, an erythropoiesis-stimulating protein, exhibits a lower clearance and longer terminal half-life in serum than recombinant human erythropoietin, thereby allowing for a reduced dosing frequency. A recent study in patients with CKD, using a 4-week sampling period, suggested that the terminal half-life of darbepoetin alfa in serum is longer than that reported in previous studies, which were based on a 1-week sampling period. This study was conducted to characterise the pharmacokinetic profile of a single subcutaneous dose of darbepoetin alfa 1 microg/kg in patients with CKD, using a sampling duration of 4 weeks, which was hypothesised to allow better characterisation of the terminal half-life in serum. METHODS: Twenty patients with CKD not on dialysis, with a calculated glomerular filtration rate of 20-60 mL/min and who had not been treated with erythropoietic agents in the previous 12 weeks, were enrolled into this single-dose, open-label study. Patients received a single subcutaneous dose of darbepoetin alfa (Aranesp) 1 microg/kg on day 1, and blood samples were collected for pharmacokinetic analyses predose, 6 and 12 hours postdose and up to 28 days postdose. Seroreactivity sampling and further safety laboratory tests (clinical chemistry and urinalysis) were also performed. Patients were assessed for adverse events at each study visit. The primary endpoint was characterisation of the terminal half-life following a single subcutaneous dose of darbepoetin alfa 1 microg/kg. RESULTS: The mean terminal half-life in serum of darbepoetin alfa was determined to be 69.6 hours. Peak serum concentrations were reached in a median time of 36 hours postdose, and a mean apparent clearance of 3.51 mL/h/kg was comparable to that observed previously in this patient population. CONCLUSION: Based on an extended sampling schedule of 4 weeks, the terminal half-life of darbepoetin alfa was approximately 70 hours. This is longer than the 48.8 hours reported previously in patients with CKD on dialysis. These data suggest that the pharmacokinetic properties of darbepoetin alfa make this erythropoietic agent well suited to an extended dosing regimen.

Adult↗
PubMed2026

Integrating machine learning and GWAS for variant prioritization in the INCIPE cohort highlights ABC transporter genes in chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is a major public health challenge, affecting approximately 674 million people worldwide and representing one of the fastest-growing causes of mortality. Since CKD is frequently asymptomatic in its early stages, the identification of novel genetic biomarkers may improve early detection and risk stratification. Genome-Wide Association Studies (GWAS) have identified numerous genetic loci associated with CKD and related traits; however, their performance is often limited in small and imbalanced cohorts, where reduced statistical power increases both false-positive and false-negative findings. Machine learning (ML) approaches can complement conventional GWAS by prioritizing biologically relevant genetic signals from high-dimensional genomic data. METHODS: In this study, we implemented a nested ensemble (NCBC) model composed of an undersampler and a CatBoostClassifier (CBC) to prioritize candidate genetic variants associated with CKD in the INCIPE cohort. Prioritized variants were functionally annotated and evaluated through enrichment analyses, GTEx gene expression profiling, and protein-protein interaction network analyses. Genes identified by the CKDGen Consortium were analysed as an external reference set and used to validate the biological relevance of the prioritized results. RESULTS: The NCBC model outperformed conventional ML classifiers, achieving a ROC AUC score of 87.77%, compared to 50%-53% for the other evaluated models. Among the prioritized genes, 56.25% showed protein-protein interactions with genes previously reported by the CKDGen Consortium, whereas only 1.9% of randomly generated gene sets showed interactions. DISCUSSION: Our study demonstrates that the NCBC model improves the prioritization of biologically plausible candidate variants in a small and imbalanced CKD cohort. Functional analyses suggested ABC transporter-related genes, including ABCA13, ABCA4, and ABCC4 genes, as promising candidate for future validation, with ABCA4 showing substantial expression in kidney tissues. Overall, these findings support the integration of ML with GWAS to prioritize candidate genes and investigate the genetic architecture of complex diseases.

SNP prioritization↗