Showing papers in "Journal of The American Society of Nephrology in 2006"
TL;DR: The modified MDRD equations that were based on the Chinese patients with CKD offered significant advantages in different CKD stages and could be applied in clinical practice, at least in Chinese patientswith CKD.
Abstract: The Modification of Diet in Renal Disease (MDRD) equations provide a rapid method of assessing GFR in patients with chronic kidney disease (CKD). However, previous research indicated that modification of these equations is necessary for application in Chinese patients with CKD. The objective of this study was to modify MDRD equations on the basis of the data from the Chinese CKD population and compare the diagnostic performance of the modified MDRD equations with that of the original MDRD equations across CKD stages in a multicenter, cross-sectional study of GFR estimation from plasma creatinine, demographic data, and clinical characteristics. A total of 684 adult patients with CKD, from nine geographic regions of China were selected. A random sample of 454 of these patients were included in the training sample set, and the remaining 230 patients were included in the testing sample set. With the use of the dual plasma sampling 99m Tc-DTPA plasma clearance method as a reference for GFR measurement, the original MDRD equations were modified by two methods: First, by adding a racial factor for Chinese in the original MDRD equations, and, second, by applying multiple linear regression to the training sample and modifying the coefficient that is associated with each variable in the original MDRD equations and then validating in the testing sample and comparing it with the original MDRD equations. All modified MDRD equations showed significant performance improvement in bias, precision, and accuracy compared with the original MDRD equations, and the percentage of estimated GFR that did not deviate >30% from the reference GFR was >75%. The modified MDRD equations that were based on the Chinese patients with CKD offered significant advantages in different CKD stages and could be applied in clinical practice, at least in Chinese patients with CKD.
1,506 citations
TL;DR: This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality and determines which interventions best offset this risk remains a health priority.
Abstract: Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non–dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for
1,476 citations
TL;DR: It is shown that gadodiamide plays a causative role in nephrogenic systemic fibrosis, and seven patients became severely disabled, and one died 21 mo after exposure.
Abstract: Nephrogenic systemic fibrosis is a new, rare disease of unknown cause that affects patients with renal failure. Single cases led to the suspicion of a causative role of gadodiamide that is used for magnetic resonance imaging. This study therefore reviewed all of the authors' confirmed cases of nephrogenic systemic fibrosis (n = 13) with respect to clinical characteristics, gadodiamide exposure, and subsequent clinical course. It was found that all had been exposed to gadodiamide before the development of nephrogenic systemic fibrosis. The delay from exposure to first sign of the disease was 2 to 75 d (median 25 d). Odds ratio for acquiring the disease when gadodiamide exposed was 32.5 (95% confidence interval 1.9 to 549.2; P < 0.0001). Seven (54%) patients became severely disabled, and one died 21 mo after exposure. No other exposure/event than gadodiamide that was common to more than a minority of the patients could be identified. These findings indicate that gadodiamide plays a causative role in nephrogenic systemic fibrosis.
1,284 citations
TL;DR: All intracellular proteins and many extracellular proteins are continually “turning over;” i.e. they are being hydrolyzed to their constituent amino acids and replaced by new synthesis.
Abstract: All intracellular proteins and many extracellular proteins are continually “turning over;” i.e. , they are being hydrolyzed to their constituent amino acids and replaced by new synthesis. Although the continual destruction of cell proteins might seem wasteful, this process serves several
1,132 citations
TL;DR: Acute renal failure (ARF), classically defined as an abrupt decrease in kidney function that leads to accumulation of nitrogenous wastes such as blood urea nitrogen and creatinine, is a common clinical problem with increasing incidence, serious consequences, unsatisfactory therapeutic options, and
Abstract: Acute renal failure (ARF), classically defined as an abrupt decrease in kidney function that leads to accumulation of nitrogenous wastes such as blood urea nitrogen and creatinine, is a common clinical problem with increasing incidence, serious consequences, unsatisfactory therapeutic options, and
923 citations
TL;DR: Evidence indicating that proteinuria may accelerate kidney disease progression to end-stage renal failure is reviewed, and proximal tubular cell receptors for uptake of plasma proteins that are under investigation may provide activation signals on excess tubular protein handling.
Abstract: The possibility that proteinuria may accelerate kidney disease progression to end-stage renal failure has received support from the results of increasing numbers of experimental and clinical studies. Evidence indicating that this process occurs through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis, is reviewed. Macrophages are prominent in the interstitial inflammatory infiltrate. This cell type mediates progression of renal injury to the extent that macrophage numbers in renal biopsy predict renal survival in patients with chronic renal disease. Chemoattractants and adhesive molecules for inflammatory cells are upregulated by excess ultrafiltered protein load of proximal tubular cells via activation of NF-kappaB-dependent and NF-kappaB-independent pathways. This mechanism is a potential target for therapeutic approaches, as shown by beneficial effects of manipulations with inhibitory molecules of NF-kappaB activation or of chemokine receptors in experimental studies. Targeting complement synthesis or activation in proximal tubule might offer novel therapeutic opportunities. Finally, proximal tubular cell receptors for uptake of plasma proteins that are under investigation may provide activation signals on excess tubular protein handling.
711 citations
TL;DR: The incidence rate of ARF in Medicare beneficiaries has been increasing and those of older age, male gender, and black race are more likely to have ARF, which is a major contributor to morbidity and mortality in hospitalized patients.
Abstract: This study's objective was to determine the incidence and mortality of acute renal failure (ARF) in Medicare beneficiaries. Data were from hospitalized Medicare beneficiaries (5,403,015 discharges) between 1992 and 2001 from the 5% sample of Medicare claims. For 1992 to 2001, the overall incidence rate of ARF was 23.8 cases per 1000 discharges, with rates increasing by approximately 11% per year. Older age, male gender, and black race were strongly associated (P < 0.0001) with ARF. The overall in-hospital death rate was 4.6% in discharges without ARF, 15.2% in discharges with ARF coded as the principal diagnosis, and 32.6% in discharges with ARF as a secondary diagnosis. In-hospital death rates were 32.9% in discharges with ARF that required renal dialysis and 27.5% in those with ARF that did not require dialysis. Death within 90 d after hospital admission was 13.1% in discharges without ARF, 34.5% in discharges with ARF coded as the principal diagnosis, and 48.6% in discharges with ARF as a secondary diagnosis. Discharges with ARF were more (P < 0.0001) likely to have intensive care and other acute organ dysfunction than those without ARF. For discharges both with and without ARF, rates for death within 90 d after hospital admission showed a declining trend. In conclusion, the incidence rate of ARF in Medicare beneficiaries has been increasing. Those of older age, male gender, and black race are more likely to have ARF. These data show ARF to be a major contributor to morbidity and mortality in hospitalized patients.
706 citations
TL;DR: CKD prevalence in Norway was similar to that in the United States, suggesting that lower progression to ESRD rather than a smaller pool of individuals at risk accounts for the lower incidence of E SRD in Norway.
Abstract: ESRD incidence is much lower in Europe compared with the United States. This study investigated whether this reflects a difference in the prevalence of earlier stages of chronic kidney disease (CKD) or other mechanisms. CKD prevalence in Norway was estimated from the population-based Health Survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997 (participation rate 70.4%). Data were analyzed using the same methods as two US National Health and Nutrition Examination Surveys in 1988 through 1994 (n = 15,488) and 1999 through 2000 (n = 4101). The primary analysis used gender-specific cutoffs in estimating persistent albuminuria for CKD stages 1 and 2. ESRD rates and other relevant data were extracted from national registries. Total CKD prevalence in Norway was 10.2% (SE 0.5): CKD stage 1 (GFR >90 ml/min per 1.73 m2 and albuminuria), 2.7% (SE 0.3); stage 2 (GFR 60 to 89 ml/min per 1.73 m2 and albuminuria), 3.2% (SE 0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m2), 4.2% (SE 0.1); and stage 4 (GFR 15 to 29 ml/min per 1.73 m2), 0.2% (SE 0.01). This closely approximates reported US CKD prevalence (11.0% in 1988 through 1994 and 11.7% in 1999 through 2000). The relative risk for progression from CKD stages 3 or 4 to ESRD in US white patients compared with Norwegian patients was 2.5. This was only modestly modified by adjustment for age, gender, and diabetes. Age and GFR at start of dialysis were similar, hypertension and cardiovascular mortality in the populations were comparable, but US white patients were referred later to a nephrologist and had higher prevalence of obesity and diabetes. In conclusion, CKD prevalence in Norway was similar to that in the United States, suggesting that lower progression to ESRD rather than a smaller pool of individuals at risk accounts for the lower incidence of ESRD in Norway.
694 citations
TL;DR: This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.
Abstract: Regenerative medicine represents a critical clinical goal for patients with ESRD, but the identification of renal adult multipotent progenitor cells has remained elusive. It is demonstrated that in human adult kidneys, a subset of parietal epithelial cells (PEC) in the Bowman’s capsule exhibit coexpression of the stem cell markers CD24 and CD133 and of the stem cell–specific transcription factors Oct-4 and BmI-1, in the absence of lineage-specific markers. This CD24 + CD133 + PEC population, which could be purified from cultured capsulated glomeruli, revealed self-renewal potential and a high cloning efficiency. Under appropriate culture conditions, individual clones of CD24 + CD133 + PEC could be induced to generate mature, functional, tubular cells with phenotypic features of proximal and/or distal tubules, osteogenic cells, adipocytes, and cells that exhibited phenotypic and functional features of neuronal cells. The injection of CD24 + CD133 + PEC but not of CD24 − CD133 − renal cells into SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different portions of the nephron. More important, treatment of acute renal failure with CD24 + CD133 + PEC significantly ameliorated the morphologic and functional kidney damage. This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.
686 citations
TL;DR: Data suggest that 1,25(OH)(2)D(3) is an important regulator of FGF23 production by osteoblasts in bone and may be to act as a counterregulatory phosphaturic hormone to maintain phosphate homeostasis in response to vitamin D.
Abstract: The regulation of the phosphaturic factor fibroblast growth factor 23 (FGF23) is not well understood. It was found that administration of 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) to mice rapidly increased serum FGF23 concentrations from a basal level of 90.6 +/- 8.1 to 213.8 +/- 14.6 pg/ml at 8 h (mean +/- SEM; P < 0.01) and resulted in a four-fold increase in FGF23 transcripts in bone, the predominate site of FGF23 expression. In the Hyp-mouse homologue of X-linked hypophosphatemic rickets, administration of 1,25(OH)(2)D(3) further increased circulating FGF23 levels. In Gcm2 null mice, low 1,25(OH)(2)D(3) levels were associated with a three-fold reduction in FGF23 levels that were increased by administration of 1,25(OH)(2)D(3). In osteoblast cell cultures, 1,25(OH)(2)D(3) but not calcium, phosphate, or parathyroid hormone stimulated FGF23 mRNA levels and resulted in a dose-dependent increase in FGF23 promoter activity. Overexpression of a dominant negative vitamin D receptor inhibited 1,25(OH)(2)D(3) stimulation of FGF23 promoter activity, and mutagenesis of the FGF23 promoter identified a vitamin D-responsive element (-1180 GGAACTcagTAACCT -1156) that is responsible for the vitamin D effects. These data suggest that 1,25(OH)(2)D(3) is an important regulator of FGF23 production by osteoblasts in bone. The physiologic role of FGF23 may be to act as a counterregulatory phosphaturic hormone to maintain phosphate homeostasis in response to vitamin D.
617 citations
TL;DR: Obesity seems to be an important-and potentially preventable-risk factor for CRF, and the strongest association was with diabetic nephropathy, but two- to three-fold risk elevations were observed for all major subtypes of CRF.
Abstract: Few large-scale epidemiologic studies have quantified the possible link between obesity and chronic renal failure (CRF) This study analyzed anthropometric data from a nationwide, population-based, case-control study of incident, moderately severe CRF Eligible as cases were all native Swedes who were aged 18 to 74 yr and had CRF and whose serum creatinine for the first time and permanently exceeded 34 mg/dl (men) or 28 mg/dl (women) during the study period A total of 926 case patients and 998 control subjects, randomly drawn from the study base, were enrolled Face-to-face interviews, supplemented with self-administered questionnaires, provided information about anthropometric measures and other lifestyle factors Logistic regression models with adjustments for several co-factors estimated the relative risk for CRF in relation to body mass index (BMI) Overweight (BMI>or=25 kg/m2) at age 20 was associated with a significant three-fold excess risk for CRF, relative to BMI or=30) among men and morbid obesity (BMI>or=35) among women anytime during lifetime was linked to three- to four-fold increases in risk The strongest association was with diabetic nephropathy, but two- to three-fold risk elevations were observed for all major subtypes of CRF Analyses that were confined to strata without hypertension or diabetes revealed a three-fold increased risk among patients who were overweight at age 20, whereas the two-fold observed risk elevation among those who had a highest lifetime BMI of >35 was statistically nonsignificant Obesity seems to be an important-and potentially preventable-risk factor for CRF Although hypertension and type 2 diabetes are important mediators, additional pathways also may exist
TL;DR: Evidence from an administrative database that the incidence of ARF and ARF-D is rising is provided, despite an increase in the degree of comorbidity, in-hospital mortality has declined.
Abstract: Despite improvements in intensive care and dialysis, some experts have concluded that outcomes associated with acute renal failure (ARF) have not improved significantly over time. ARF was studied in hospitalized patients between 1988 and 2002 using the Nationwide Inpatient Sample, a nationally representative sample of discharges from acute-care, nonfederal hospitals. During a 15-yr period, 5,563,381 discharges with ARF and 598,768 with ARF that required dialysis (ARF-D) were identified. Between 1988 and 2002, the incidence of ARF rose from 61 to 288 per 100,000 population; the incidence of ARF-D increased from 4 to 27 per 100,000 population. Between 1988 and 2002, in-hospital mortality declined steadily in patients with ARF (40.4 to 20.3%; P < 0.001) and in those with ARF-D (41.3 to 28.1%; P < 0.001). Compared with 1988 to 1992, the multivariable-adjusted odds ratio (OR) of death was lower in 1993 to 1997 (ARF: OR 0.62, 95% confidence interval [CI] 0.61 to 0.64; ARF-D: OR 0.63, 95% CI 0.59 to 0.66) and 1998 to 2002 (ARF: OR 0.40, 95% CI 0.39 to 0.41; ARF-D: OR 0.47, 95% CI 0.45 to 0.50). The percentage of patients who had ARF with a Deyo-Charlson comorbidity index of 3 or more increased from 16.4% in 1988 to 26.6% in 2002 (P < 0.001). This study provides evidence from an administrative database that the incidence of ARF and ARF-D is rising. Despite an increase in the degree of comorbidity, in-hospital mortality has declined.
TL;DR: There have been inadequate efforts by the nephrology community to translate the recent advances in molecular and interventional cardiology into therapies for hemodialysis vascular access, and some broad guidelines for future innovative translational and clinical research in this area are offered.
Abstract: Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. The major cause of hemodialysis vascular access dysfunction is venous stenosis as a result of neointimal hyperplasia. Despite the magnitude of the clinical problem, however, there has been a paucity of novel therapeutic interventions in this field. This is in marked contrast to a recent plethora of targeted interventions for the treatment of arterial neointimal hyperplasia after coronary angioplasty. The reasons for this are two-fold. First there has been a relative lack of cellular and molecular research that focuses on venous neointimal hyperplasia in the specific setting of hemodialysis vascular access. Second, there have been inadequate efforts by the nephrology community to translate the recent advances in molecular and interventional cardiology into therapies for hemodialysis vascular access. This review therefore (1) briefly examines the different forms of hemodialysis vascular access that are available, (2) describes the pathology and pathogenesis of hemodialysis vascular access dysfunction in both polytetrafluoroethylene grafts and native arteriovenous fistulae, (3) reviews recent concepts about the pathogenesis of vascular stenosis that could potentially be applied in the setting of hemodialysis vascular access dysfunction, (4) summarizes novel experimental and clinical therapies that could potentially be used in the setting of hemodialysis vascular access dysfunction, and, finally, (5) offers some broad guidelines for future innovative translational and clinical research in this area that hopefully will reduce the huge clinical morbidity and economic costs that are associated with this condition.
TL;DR: Assessment of the effect of statins on change in kidney function and urinary protein excretion found that statin therapy seems to reduce proteinuria modestly and results in a small reduction in the rate of kidney function loss, especially in populations with cardiovascular disease.
Abstract: Statins frequently are used to prevent cardiovascular events. Several recent studies suggest that statins also may have renal benefits, although this is controversial. This systematic review and meta-analysis were performed to assess the effect of statins on change in kidney function and urinary protein excretion. Medline, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings, and the authors' personal files were searched. Published or unpublished randomized, controlled trials or crossover trials of statins that reported assessment of kidney function or proteinuria were included, and studies of individuals with ESRD were excluded. Data were extracted for study design, subject characteristics, type of statin and dose, baseline/change in cholesterol levels, and outcomes (change in measured or estimated GFR [eGFR] and/or urinary protein excretion). Weighted mean differences were calculated for the change in GFR between statin and control groups using a random-effects model. A random-effects model also was used to calculate the standardized mean difference for the change in urinary protein excretion between groups. Twenty-seven eligible studies with 39,704 participants (21 with data for eGFR and 20 for proteinuria or albuminuria) were identified. Overall, the change in the weighted mean differences for eGFR was statistically significant (1.22 ml/min per yr slower in statin recipients; 95% confidence interval [CI] 0.44 to 2.00). In subgroup analysis, the benefit of statin therapy was statistically significant in studies of participants with cardiovascular disease (0.93 ml/min per yr slower than control subjects; 95% CI 0.10 to 1.76) but was NS for studies of participants with diabetic or hypertensive kidney disease or glomerulonephritis. The standardized mean difference for the reduction in albuminuria or proteinuria as a result of statin therapy was statistically significant (0.58 units of SD greater in statin recipients; 95% CI 0.17 to 0.98). Statin therapy seems to reduce proteinuria modestly and results in a small reduction in the rate of kidney function loss, especially in populations with cardiovascular disease.
TL;DR: Patients who receive SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with Cs a.
Abstract: Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.
TL;DR: The finding that chronic ACE2 inhibition increases UAE suggests that ACE2, likely by modulating the levels of glomerular angiotensin II via its degradation, may be a target for therapeutic interventions that aim to reduce albuminuria and glomersular injury.
Abstract: Angiotensin-converting enzyme 2 (ACE2) expression has been shown to be altered in renal tubules from diabetic mice. This study examined the localization of ACE and ACE2 within the glomerulus of kidneys from control (db/m) and diabetic (db/db) mice and the effect of chronic pharmacologic ACE2 inhibition. ACE2 co-localized with glomerular epithelial cell (podocyte) markers, and its localization within the podocyte was confirmed by immunogold labeling. ACE, by contrast, was seen only in glomerular endothelial cells. By immunohistochemistry, in glomeruli from db/db mice, strong ACE staining was found more frequently than in control mice (db/db 64.6 +/- 6.3 versus db/m 17.8 +/- 3.4%; P < 0.005). By contrast, strong ACE2 staining in glomeruli from diabetic mice was less frequently seen than in controls (db/db 4.3 +/- 2.4 versus db/m 30.6 +/- 13.6%; P < 0.05). For investigation of the significance of reduced glomerular ACE2 expression, db/db mice were treated for 16 wk with a specific ACE2 inhibitor (MLN-4760) alone or combined with telmisartan, a specific angiotensin II type 1 receptor blocker. At the end of the study, glomerular staining for fibronectin, an extracellular matrix protein, was increased in both db/db and db/m mice that were treated with MLN-4760. Urinary albumin excretion (UAE) increased significantly in MLN-4760-treated as compared with vehicle-treated db/db mice (743 +/- 200 versus 247 +/- 53.9 microg albumin/mg creatinine, respectively; P < 0.05), and the concomitant administration of telmisartan completely prevented the increase in UAE associated with the ACE2 inhibitor (161 +/- 56; P < 0.05). It is concluded that ACE2 is localized in the podocyte and that in db/db mice glomerular expression of ACE2 is reduced whereas glomerular ACE expression is increased. The finding that chronic ACE2 inhibition increases UAE suggests that ACE2, likely by modulating the levels of glomerular angiotensin II via its degradation, may be a target for therapeutic interventions that aim to reduce albuminuria and glomerular injury.
TL;DR: The excellent performance characteristics of ICD-9-CM codes for ARF-D suggest that administrative data sets may be particularly well suited for research endeavors that involve patients with ARF, although the low sensitivity of ARF codes is an important caveat.
Abstract: Administrative and claims databases may be useful for the study of acute renal failure (ARF) and ARF that requires dialysis (ARF-D), but the validity of the corresponding diagnosis and procedure codes is unknown. The performance characteristics of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for ARF were assessed against serum creatinine-based definitions of ARF in 97,705 adult discharges from three Boston hospitals in 2004. For ARF-D, ICD-9-CM codes were compared with review of medical records in 150 patients with ARF-D and 150 control patients. As compared with a diagnostic standard of a 100% change in serum creatinine, ICD-9-CM codes for ARF had a sensitivity of 35.4%, specificity of 97.7%, positive predictive value of 47.9%, and negative predictive value of 96.1%. As compared with review of medical records, ICD-9-CM codes for ARF-D had positive predictive value of 94.0% and negative predictive value of 90.0%. It is concluded that administrative databases may be a powerful tool for the study of ARF, although the low sensitivity of ARF codes is an important caveat. The excellent performance characteristics of ICD-9-CM codes for ARF-D suggest that administrative data sets may be particularly well suited for research endeavors that involve patients with ARF-D.
TL;DR: At present, the most likely possibility is that a common pathophysiologic process, such as endothelial dysfunction, chronic low-grade inflammation, or increased transvascular leakage of macromolecules, underlies the association between microalbuminuria and cardiovascular disease, but more and prospective studies of these hypotheses are needed.
Abstract: Microalbuminuria is a strong and independent indicator of increased cardiovascular risk among individuals with and without diabetes Therefore, microalbuminuria can be used for stratification of risk for cardiovascular disease Once microalbuminuria is present, cardiovascular risk factor reduction should be more "aggressive" The nature of the link between microalbuminuria and cardiovascular risk, however, remains poorly understood There is no strong evidence that microalbuminuria causes atherothrombosis or that atherothrombosis causes microalbuminuria Many studies have tested the hypothesis that a common risk factor underlies the association between microalbuminuria and cardiovascular disease but, again, have found no strong evidence in favor of this contention At present, the most likely possibility is that a common pathophysiologic process, such as endothelial dysfunction, chronic low-grade inflammation, or increased transvascular leakage of macromolecules, underlies the association between microalbuminuria and cardiovascular disease, but more and prospective studies of these hypotheses are needed
TL;DR: A preoperative, clinical prediction rule to determine fistulas that are likely to fail maturation was created and rigorously validated and applied to predictive risk categories, which predicted risk of FTM to be 24, 34, 50, and 69% and are dependent on age, coronary artery disease, peripheral vascular disease, and race.
Abstract: Fistulas are the preferred permanent hemodialysis vascular access but a significant obstacle to increasing their prevalence is the fistula's high "failure to mature" (FTM) rate. This study aimed to (1) identify preoperative clinical characteristics that are predictive of fistula FTM and (2) use these predictive factors to develop and validate a scoring system to stratify the patient's risk for FTM. From a derivation set of 422 patients who had a first fistula created, a prediction rule was created using multivariate stepwise logistic regression. The model was internally validated using split-half cross-validation and bootstrapping techniques. A simple scoring system was derived and externally validated on 445 different, prospective patients who received a new fistula at five large North American dialysis centers. The clinical predictors that were associated with FTM were aged > or =65 yr (odds ratio [OR] 2.23; 95% confidence interval [CI] 1.25 to 3.96), peripheral vascular disease (OR 2.97; 95% CI 1.34 to 6.57), coronary artery disease (OR 2.83; 95% CI 1.60 to 5.00), and white race (OR 0.43; 95% CI 0.24 to 0.75). The resulting scoring system, which was externally validated in 445 patients, had four risk categories for fistula FTM: low (24%), moderate (34%), high (50%), and very high (69%; trend P < 0.0001). A preoperative, clinical prediction rule to determine fistulas that are likely to fail maturation was created and rigorously validated. It was found to be simple and easily reproducible and applied to predictive risk categories. These categories predicted risk of FTM to be 24, 34, 50, and 69% and are dependent on age, coronary artery disease, peripheral vascular disease, and race. The clinical utility of these risk categories in increasing rates of permanent accesses requires further clinical evaluation.
TL;DR: In this article, longitudinal associations between survival and quarterly (13-wk averaged) hemoglobin values and administered erythropoiesis-stimulating agents (ESA) dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States.
Abstract: Although treating anemia of chronic kidney disease by erythropoiesis-stimulating agents (ESA) may improve survival, most studies have examined associations between baseline hemoglobin values and survival and ignored variations in clinical and laboratory measures over time. It is not clear whether longitudinal changes in hemoglobin or administered ESA have meaningful associations with survival after adjustment for time-varying confounders. With the use of time-dependent Cox regression models, longitudinal associations were examined between survival and quarterly (13-wk averaged) hemoglobin values and administered ESA dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States. After time-dependent and multivariate adjustment for case mix, quarterly varying administered intravenous iron and ESA doses, iron markers, and nutritional status, hemoglobin levels between 12 and 13 g/dl were associated with the greatest survival. Among prevalent patients, the lower range of the recommended Kidney Disease Quality Outcomes Initiative hemoglobin target (11 to 11.5 g/dl) was associated with a higher death risk compared with the 11.5- to 12-g/dl range. A decrease or increase in hemoglobin over time was associated with higher or lower death risk, respectively, independent of baseline hemoglobin. Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, requiring higher doses were surrogates of higher death risk. In this observational study, greater survival was associated with a baseline hemoglobin between 12 and 13 g/dl, treatment with ESA, and rising hemoglobin. Falling hemoglobin and requiring higher ESA doses were associated with decreased survival. Randomized clinical trials are required to examine these associations.
University of Utah1, Wake Forest University2, Cleveland Clinic3, National Institutes of Health4, Emory University5, Baxter International6, Tufts University7, University of Rochester8, Case Western Reserve University9, Vanderbilt University10, Georgia Regents University11, Duke University12, Baylor College of Medicine13
TL;DR: B baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta( 2)M levels at 1 mo of follow-up, and this association is supportive of the potential value of beta(1)M as a marker to guide chronic hemodialysis therapy.
Abstract: In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.
TL;DR: Although blockade of the RAAS with ACE inhibitors, AngII type 1 receptor antagonists, or the combination of both should be part of every strategy to slow progression of renal disease, a better understanding of the novel aspects of theRAAS should contribute to the development of innovative strategies not only to completely halt progression but also to induce regression of human renal disease.
Abstract: Inhibition of the renin-angiotensin-aldosterone system (RAAS) is one of the most powerful maneuvers to slow progression of renal disease. Angiotensin II (AngII) has emerged in the past decade as a multifunctional cytokine that exhibits many nonhemodynamic properties, such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. Many of these deleterious functions are mediated by other factors, such as TGF-β and chemoattractants that are induced in the kidney by AngII. Moreover, understanding of the RAAS has become much more complex in recent years with the identification of novel peptides ( e.g. , AngIV) that could bind to specific receptors, elucidating deleterious effects, and non–angiotensin-converting enzyme (ACE)–mediated generation of AngII. The ability of renal cells to produce AngII in a concentration that is much higher than what is found in the systemic circulation and the observation that aldosterone may be engaged directly in profibrogenic processes independent of hypertension have added to the complexity of the RAAS. Even renin has now been identified to have a “life on its own” and mediates profibrotic effects via binding to specific receptors. Finally, drugs that are used to block the RAAS, such as ACE inhibitors or certain AngII type 1 receptor antagonists, may have properties on cells independent of AngII (ACE inhibitor–mediated outside-inside signaling and peroxisome proliferator–activated receptor-γ stimulatory effects of certain sartanes). Although blockade of the RAAS with ACE inhibitors, AngII type 1 receptor antagonists, or the combination of both should be part of every strategy to slow progression of renal disease, a better understanding of the novel aspects of the RAAS should contribute to the development of innovative strategies not only to completely halt progression but also to induce regression of human renal disease.
TL;DR: Nandrolone decanoate and resistance exercise produced anabolic effects among patients who were on hemodialysis, and exercise was associated with an improvement in self-reported physical functioning compared with nonexercising groups.
Abstract: Patients who are on hemodialysis commonly experience muscle wasting and weakness, which have a negative effect on physical functioning and quality of life. The objective of this study was to determine whether anabolic steroid administration and resistance exercise training induce anabolic effects among patients who receive maintenance hemodialysis. A randomized 2 2 factorial trial of anabolic steroid administration and resistance exercise training was conducted in 79 patients who were receiving maintenance hemodialysis at University of California, San Francisco–affiliated dialysis units. Interventions included double-blinded weekly nandrolone decanoate (100 mg for women; 200 mg for men) or placebo injections and lower extremity resistance exercise training for 12 wk during hemodialysis sessions three times per week using ankle weights. Primary outcomes included change in lean body mass (LBM) measured by dual-energy x-ray absorptiometry, quadriceps muscle cross-sectional area measured by magnetic resonance imaging, and knee extensor muscle strength. Secondary outcomes included changes in physical performance, self-reported physical functioning, and physical activity. Sixty-eight patients completed the study. Patients who received nandrolone decanoate increased their LBM by 3.1 2.2 kg (P < 0.0001). Exercise did not result in a significant increase in LBM. Quadriceps muscle cross-sectional area increased in patients who were assigned to exercise (P 0.01) and to nandrolone (P < 0.0001) in an additive manner. Patients who exercised increased their strength in a training-specific fashion, and exercise was associated with an improvement in self-reported physical functioning (P 0.04 compared with nonexercising groups). Nandrolone decanoate and resistance exercise produced anabolic effects among patients who were on hemodialysis. Further studies are needed to determine whether these interventions improve survival.
TL;DR: It is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-2R antagonists causes rapid and sustained expansion of CD4+CD25+ T cells when cultured with human peripheral blood lymphocytes.
Abstract: T cell-depleting agents are being tested as part of clinical tolerance strategies in humans with autoimmunity and transplantation. The immunosuppressive activity of anti-thymocyte globulin (ATG) has been thought to result primarily from depletion of peripheral lymphocytes. Herein is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-2R antagonists causes rapid and sustained expansion of CD4+CD25+ T cells when cultured with human peripheral blood lymphocytes. These cells display enhanced expression of the regulatory markers glucocorticoid-induced TNF receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and forkhead box P3 and efficiently suppress a direct alloimmune response of the original responder lymphocytes. It is interesting that the cells do not suppress memory responses to the recall antigen mumps. Ex vivo expansion of regulatory T cells is due mainly to conversion of CD4+CD25- into CD4+CD25+ T cells and to a lesser degree to proliferation of natural CD4+CD25+ T cells. The induction of regulatory T cells depends on production of Th2 cytokines in the generating cultures. These novel data suggest that ATG not only may promote expansion/generation of regulatory T cells but also may be useful in future ex vivo expansion of these cells for cellular therapy in autoimmunity and clinical transplantation.
TL;DR: In conclusion, albuminuria seems to be a sensitive marker very early in life for the susceptibility of an individual to CV disease and may be an ideal target for early primary prevention using CV-protective therapy regimens.
Abstract: Excretion of albumin in the urine is highly variable, ranging from nondetectable quantities to milligrams of albumin and even grams of albumin. Microalbuminuria is defined as low levels of urinary albumin excretion of 30 to 300 mg/d. Microalbuminuria is highly prevalent; in hypertensive and diabetic populations, its prevalence varies from 10 to 40%. It is interesting that microalbuminuria also is found frequently in seemingly healthy individuals (5 to 7%). The variable excretion of albumin in the urine is related to the risk for the individual to develop cardiovascular (CV) disease: Absence or very low levels of albuminuria is associated with low CV risk, whereas the CV risk increases markedly with increasing amount of albumin in the urine (even within the now considered normal range). The predictive power of urinary albumin levels for CV risk is independent of other CV risk factors and not only is present in individual with diabetes and/or hypertension but also in healthy individuals. Treatments that lower albuminuria are associated with CV protection, as demonstrated in randomized, controlled trials of patients with diabetes as well as in patients with hypertension. There is preliminary evidence that albuminuria lowering is CV protective in healthy individuals with an elevated albumin excretion rate. Differences between individuals in their level of albumin excretion are already observed at a very early age (just after birth). In fact, the interindividual variability seems to be relatively constant in the first 5 decades of life, indicating that microalbuminuria is not necessarily a consequence of vascular damage at later age. Higher levels of urinary albumin seem to reflect the ordinary interindividual variability in (renal and systemic) endothelial function. Experimental data show that between strains and even within strains, rats at young age show a remarkable difference in individual endothelial function, and this is strongly related to the susceptibility of that rat to organ damage. In conclusion, albuminuria seems to be a sensitive marker very early in life for the susceptibility of an individual to CV disease. It therefore may be an ideal target for early primary prevention using CV-protective therapy regimens.
TL;DR: In the clinical setting, mortality risk stratification in elderly patients should not be based on the same eGFR cut points as for younger age groups and would benefit from finer categorization of the 30- to 59-ml/min per 1.73 m2 eG FR group.
Abstract: Current National Kidney Foundation Kidney Disease Outcomes Quality Initiative staging criteria for chronic kidney disease (CKD) are intended to apply to all age groups. However, it is unclear whether different levels of estimated GFR (eGFR) have the same prognostic significance in older and younger patients. The study cohort was composed of Department of Veterans Affairs (VA) patients who were aged 18 to 100 yr and had at least one outpatient serum creatinine measurement between October 1, 2001, and September 30, 2002 (n=2583,911). Patients with ESRD were excluded. GFR was estimated using the Modification of Diet in Renal Disease equation using each patient's first outpatient creatinine measurement during the study period. The association of eGFR with survival was measured by age group. Twenty percent of cohort patients had an eGFR<60 ml/min per 1.73 m2, ranging from 3% among 18- to 44-yr-olds to as high as 49% among 85- to 100-yr-olds. Fifty-two percent (n=266,421) of cohort patients with an eGFR<60 ml/min per 1.73 m2 had "very" moderate reductions in eGFR into the 50- to 59-ml/min per 1.73 m2 range. The association of eGFR with mortality was weaker in the elderly than in younger age groups: Whereas severe reductions in eGFR were associated with an increased risk for death in all age groups, "very" moderate reductions in eGFR (50 to 59 ml/min per 1.73 m2) were associated with an increased adjusted risk for death only among patients who were younger than 65 yr. Age-related attenuation of the association of eGFR with mortality was also present among women and black patients. In the clinical setting, mortality risk stratification in elderly patients should not be based on the same eGFR cut points as for younger age groups and would benefit from finer categorization of the 30- to 59-ml/min per 1.73 m2 eGFR group.
TL;DR: Results indicate that hMATE2-K is a new human kidney-specific H+/organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes.
Abstract: A cDNA coding a new H + /organic cation antiporter, human kidney-specific multidrug and toxin extrusion 2 (hMATE2-K), has been isolated from the human kidney. The hMATE2-K cDNA had an open reading frame that encodes a 566–amino acid protein, which shows 94, 82, 52, and 52% identity with the hMATE2, hMATE2-B, hMATE1, and rat MATE1, respectively. Reverse transcriptase–PCR revealed that hMATE2-K mRNA but not hMATE2 was expressed predominantly in the kidney, and hMATE2-B was ubiquitously found in all tissues examined except the kidney. The immunohistochemical analyses revealed that the hMATE2-K as well as the hMATE1 was localized at the brush border membranes of the proximal tubules. HEK293 cells that were transiently transfected with the hMATE2-K cDNA but not hMATE2-B exhibited the H + gradient–dependent antiport of tetraethylammonium (TEA). Transfection of hMATE2-B had no affect on the hMATE2-K–mediated transport of TEA. hMATE2-K also transported cimetidine, 1-methyl-4-phenylpyridinium (MPP), procainamide, metformin, and N 1 -methylnicotinamide. Kinetic analyses demonstrated that the Michaelis-Menten constants for the hMATE2-K–mediated transport of TEA, MPP, cimetidine, metformin, and procainamide were 0.83 mM, 93.5 μM, 0.37 mM, 1.05 mM, and 4.10 mM, respectively. Ammonium chloride–induced intracellular acidification significantly stimulated the hMATE2-K–dependent transport of organic cations such as TEA, MPP, procainamide, metformin, N 1 -methylnicotinamide, creatinine, guanidine, quinidine, quinine, thiamine, and verapamil. These results indicate that hMATE2-K is a new human kidney–specific H + /organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes.
TL;DR: This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues.
Abstract: Different types of activated leukocytes play a crucial role in the pathogenesis of most kidney diseases from acute to chronic stages; however, diabetic nephropathy was not considered an inflammatory disease in the past. This view is changing now because there is a growing body of evidence implicating inflammatory cells at every stage of diabetic nephropathy. Renal tissue macrophages, T cells, and neutrophils produce various reactive oxygen species, proinflammatory cytokines, metalloproteinases, and growth factors, which modulate the local response and increase inflammation within the diabetic kidney. Although the precise mechanisms that direct leukocyte homing into renal tissues are not fully identified, it has been reported that intercellular adhesion molecule-1 and the chemokines CCL2 and CX3CL1 probably are involved in leukocyte migration in diabetic nephropathy. This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues.
TL;DR: Findings strongly point to a role for the lectin pathway of complement in glomerular complement activation in IgAN and suggest a contribution for both MBL and L-ficolin in the progression of the disease.
Abstract: IgA nephropathy (IgAN) is characterized by glomerular co-deposition of IgA and complement components. Earlier studies showed that IgA activates the alternative pathway of complement, whereas more recent data also indicate activation of the lectin pathway. The lectin pathway can be activated by binding of mannose-binding lectin (MBL) and ficolins to carbohydrate ligands, followed by activation of MBL-associated serine proteases and C4. This study examined the potential role of the lectin pathway in IgAN. Renal biopsies of patients with IgAN (n=60) showed mesangial deposition of IgA1 but not IgA2. Glomerular deposition of MBL was observed in 15 (25%) of 60 cases with IgAN and showed a mesangial pattern. All MBL-positive case, but none of the MBL-negative cases showed glomerular co-deposition of L-ficolin, MBL-associated serine proteases, and C4d. Glomerular deposition of MBL and L-ficolin was associated with more pronounced histologic damage, as evidenced by increased mesangial proliferation, extracapillary proliferation, glomerular sclerosis, and interstitial infiltration, as well as with significantly more proteinuria. Patients who had IgAN with or without glomerular MBL deposition did not show significant differences in serum levels of MBL, L-ficolin, or IgA or in the size distribution of circulating IgA. Furthermore, in vitro experiments showed clear binding of MBL to polymeric but not monomeric patient IgA, without a significant difference between both groups. Together, these findings strongly point to a role for the lectin pathway of complement in glomerular complement activation in IgAN and suggest a contribution for both MBL and L-ficolin in the progression of the disease.
TL;DR: There is a significant association between hip fracture and moderate to severe degrees of CKD, particularly in younger individuals, that is independent of traditional risk factors for hip fracture.
Abstract: People with ESRD are at a high risk for hip fracture. However, the effect of moderate to severe chronic kidney disease (CKD) on hip fracture risk has not been well studied. As part of the Third National Health and Nutrition Examination Survey, information on both kidney function and history of hip fracture was obtained. This survey is a complex, multistage, probability sample of the US noninstitutionalized civilian population and was conducted between 1988 and 1994. A history of hip fracture was identified from the response to a questionnaire that was administered to all participants. There were 159 cases of hip fracture. There was a significantly increased likelihood of reporting a hip fracture in participants with estimated GFR <60 ml/min (odds ratio [OR] 2.12; 95% confidence interval [CI] 1.18 to 3.80). In younger participants (aged 50 to 74 yr), the prevalence of CKD was approximately three-fold higher in those with a history of hip fracture versus in those without a history of hip fracture (19.0 versus 6.2%, respectively; P = 0.04). In multivariate logistic regression analysis, only the presence of CKD (OR 2.32; 95% CI 1.13 to 4.74), a reported history of osteoporosis (OR 2.52; 95% CI 1.08 to 5.91), and low physical activity levels (OR 2.10; 95% CI 1.03 to 4.27) were associated with a history of hip fracture. There is a significant association between hip fracture and moderate to severe degrees of CKD, particularly in younger individuals, that is independent of traditional risk factors for hip fracture.