Bone Biopsy Results in Chronic Kidney Disease: a Single-Center Experience.

BACKGROUND/AIMS: Although bone histology remains the diagnostic standard in renal osteodystrophy (ROD), biomarkers are used more commonly. Data comparing bone biopsy results and biomarkers of bone metabolism remain sparse. METHODS: This is a single-center retrospective analysis of bone biopsy results (105) stratified by renal function, compared with intact parathyroid hormone (iPTH), bone-specific alkaline phosphatase (BAP) and other biomarkers. We tested associations with high-turnover ostitis fibrosa (OF) and mixed uremic osteodystrophy (MUO), i.e. classes I and III according to Delling's classification. RESULTS: 37% of patients had CKD stage 3-5 not on dialysis (CKD NOD) and 50% CKD stage 5 requiring haemodialysis (CKD 5D). iPTH was significantly higher in CKD 5D with high-turnover ROD, 26 (18) versus 8 (9) pmol/l (p< 0.001). BAP showed no association. In CKD NOD, high-turnover ROD was associated with elevated iPTH, 32 (44) versus 8 (11) pmol/l (p=0.001), and BAP, 39 (32) versus 16 (7) U/l (p=0.01). iPTH achieved receiver operator characteristic (ROC) areas under the curve (AUC) of 0.83 (P=0.003) and 0.91 (P=0.019) for high-turnover ROD among CKD 5D and CKD NOD patients, respectively. An iPTH cutoff of 12.8 (CKD 5D) and 13.5 pmol/l (CKD NOD) reached sensitivities and specificities of 0.83, 0.91 and 1.00, 0.91, respectively. In CKD NOD, BAP achieved an AUC of 0.93 (P=0.013) and with a cutoff at 19.8 U/l a sensitivity and specificity of 1.00, 0.91, respectively. CONCLUSION: In CKD 5D patients, high-turnover ROD was associated with elevated iPTH at a low cutoff but not with BAP. The same diagnosis in CKD NOD was associated both with iPTH and BAP.

Association of Preoperative Urinary Uromodulin with AKI after Cardiac Surgery.

BACKGROUND AND OBJECTIVES: AKI is a serious complication after cardiac surgery. Although high urinary concentrations of the tubular protein uromodulin, a marker of tubular health, are associated with less AKI in animal models, its relationship in humans is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis of a prospective cohort study of 218 adults undergoing on-pump cardiac surgery between 2004 and 2011 was conducted. Multivariable logistic and linear regression analyses were used to evaluate the associations of preoperative urinary uromodulin-to-creatinine ratio with postoperative AKI (defined as a rise in serum creatinine of >0.3 mg/dl or >1.5 times baseline); severe AKI (doubling of creatinine or need for dialysis) and peak postoperative serum creatinine over the first 72 hours. RESULTS: Mean age was 68 years, 27% were women, 95% were white, and the median uromodulin-to-creatinine ratio was 10.0 µg/g. AKI developed in 64 (29%) patients. Lower urinary uromodulin-to-creatinine ratio was associated with higher odds for AKI (odds ratio, 1.49 per 1-SD lower uromodulin; 95% confidence interval, 1.04 to 2.13), which was marginally attenuated after multivariable adjustment (odds ratio, 1.43; 95% confidence interval, 0.99 to 2.07). The lowest uromodulin-to-creatinine ratio quartile was also associated with higher odds for AKI relative to the highest quartile (odds ratio, 2.94; 95% confidence interval, 1.19 to 7.26), which was slightly attenuated after multivariable adjustment (odds ratio, 2.43; 95% confidence interval, 0.91 to 6.48). A uromodulin-to-creatinine ratio below the median was associated with higher adjusted odds for severe AKI, although this did not reach statistical significance (odds ratio, 4.03; 95% confidence interval, 0.87 to 18.70). Each 1-SD lower uromodulin-to-creatinine ratio was associated with a higher adjusted mean peak serum creatinine (0.07 mg/dl per SD; 95% confidence interval, 0.02 to 0.13). CONCLUSIONS: Lower uromodulin-to-creatinine ratio is associated with higher odds of AKI and higher peak serum creatinine after cardiac surgery. Additional studies are needed to confirm these preliminary results.

Atypical case of AL amyloidosis with urinary erythrocyte casts.

We present the case of a 73-year-old man who developed an acute, severe febrile illness with multiorgan dysfunction, featuring renal failure, nephrotic-range proteinuria, microhematuria, and a skin rash. Numerous erythrocyte casts were found on urine microscopy. Typically, the finding of urinary erythrocyte casts indicates the presence of an underlying glomerular inflammatory disease. However, on renal biopsy, only amyloid light-chain (AL) amyloidosis and tubular injury were the predominant findings with no signs of glomerular or vascular inflammation. Photomicrographs of urinary sediment as well as renal biopsy histopathology of the presented case are shown. The unusual combination of findings, is then discussed in light of the existing literature on renal amyloidosis as well as erythrocyte casts in conditions other than glomerulonephritis.

Tumor necrosis factor alpha promoter polymorphism and severity of acute kidney injury.

BACKGROUND: Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). METHODS: We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by level of glomerular filtration (serum cystatin C and creatinine) and tubular injury (urinary NAG, KIM-1, α-GST, and π-GST) markers, in 262 hospitalized adults. RESULTS: In unadjusted analyses, compared with the GG genotype, the TNFA GA and AA genotype groups tended to have higher enrollment (p = 0.08), peak (p = 0.004), and discharge (p = 0.004) serum creatinine levels, and the AA genotype tended to have a higher enrollment serum cystatin C level (p = 0.04). Compared with the GG genotype, the TNFA GA and AA genotype groups tended to have a higher urinary KIM-1 level (p = 0.03), and the AA genotype group tended to have a higher urinary π-GST level (p = 0.03). After adjustment for sex, race, age, baseline estimated glomerular filtration rate, sepsis, and dialysis requirement, compared with the GG genotype, the TNFA minor A-allele group had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; p = 0.001) and a higher urinary KIM-1 (relative ratio: 1.73; 95% CI: 1.16, 2.59; p = 0.008). The TNFA minor A-allele group also had a higher Multiple Organ Failure score of 0.26 (95% CI: 0.03, 0.49; p = 0.024) after adjustment for sex, race, age, and sepsis. CONCLUSIONS: The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Larger studies are needed to confirm these relationships.

Urinary α- and π-glutathione s-transferases for early detection of acute kidney injury following cardiopulmonary bypass.

CONTEXT: Urinary α-GST and π-GST are renal tubular leakage markers. OBJECTIVE: To evaluate the performance characteristics of these markers for the early detection of acute kidney injury (AKI). MATERIALS AND METHODS: Multicenter prospective cohort study of 252 adults undergoing cardiopulmonary bypass (CPB). RESULTS: AKI developed in 72 patients. The 2 h post-CPB π-GST level modestly predicted the development of AKI, including higher stages of severity, whereas α-GST did not. DISCUSSION: Small number of events and absence of subsequent post-operative biomarker measurements. CONCLUSIONS: Among adults undergoing CPB, urinary π-GST outperformed α-GST for predicting AKI, but neither marker displayed good discrimination.

Polymorphisms in the myeloperoxidase gene locus are associated with acute kidney injury-related outcomes.

Myeloperoxidase (MPO) is a lysosomal enzyme that may be involved in oxidative stress-mediated kidney injury. Using a two-step approach, we measured the association of four polymorphisms across the length of the MPO gene with systemic markers of oxidative stress: plasma MPO and urinary 15-F(2t)-isoprostane levels. Adverse outcomes were measured in a primary cohort of 262 adults hospitalized with acute kidney injury, and a secondary cohort of 277 adults undergoing cardiac surgery with cardiopulmonary bypass and at risk for postoperative acute kidney injury. Dominant and haplotype multivariable logistic regression analyses found a genotype-phenotype association in the primary cohort between rs2243828, rs7208693, rs2071409, and rs2759 MPO polymorphisms and both markers of oxidative stress. In adjusted analyses, all four polymorphic allele groups had 2-3-fold higher odds for composite outcomes of dialysis or in-hospital death or a composite of dialysis, assisted mechanical ventilation, or in-hospital death. The MPO T-G-A-T haplotype copy-number was associated with lower plasma MPO levels and lower adjusted odds for the composite outcomes. Significant but less consistent associations were found in the secondary cohort. In summary, our two-step genetic association study identified several polymorphisms spanning the entire MPO gene locus and a common haplotype marker for patients at risk for acute kidney injury.

Vitamin D, chronic kidney disease and survival: a pluripotent hormone or just another bone drug?

It is now about 40 years ago that the mechanism of renal 1-α-hydroxylation of vitamin D was discovered and characterized. After this seminal observation, the key role of the active vitamin D derivative 1, 25-(OH)2-vitamin D (calcitriol) in calcium homeostasis and bone mineralization, and its specific role in the course of chronic kidney disease (CKD) and renal osteopathy, was unraveled step by step, while the precursor 25-OH-vitamin D (calcidiol) was gradually ignored. Calcitriol and its synthetic analogue alfa-calcidol became the first-line standard drug to tackle secondary hyperparathyroidism (sHPT) in CKD. Potential side-effects, including hypercalcemia, hyperphosphatemia, and vascular calcification, were partly abrogated by developing less calcemic substances such as paricalcitol or maxacalcitol. Thus, TIME Magazine surprised when nominating vitamin D, with regard to its newly discovered pleiotropic actions, as one of the "top medical breakthroughs" in the December issue of 2007. This vote was driven by novel and spectacular insights into the pivotal regulatory role of vitamin D with regard to autoimmune diseases, immune defense, cancer development and progression, and cardiovascular function and disease. More than 30 cell types express the vitamin D receptor (VDR), and more than ten organs in addition to the kidney are capable of paracrine 1-α-hydroxylation. More than 200 genes are under the control of calcitriol. A MEDLINE search performed in December 2009 focusing on the keywords "vitamin D-and-kidney-and-2009" yielded 523 hits. This review intends to give a subjective and CKD-related update on novel biological and clinical insights with relevance to the steroid hormone vitamin D.

Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CS/CPB) is associated with increased risk for postoperative complications causing substantial morbidity and mortality. To identify the molecular mechanisms underlying CS/CPB-induced pathophysiology we employed an integrative systems biology approach using the whole blood transcriptome as the sentinel organ. METHODOLOGY/PRINCIPAL FINDINGS: Total RNA was isolated and globin mRNA depleted from whole blood samples prospectively collected from 10 patients at time points prior (0), 2 and 24 hours following CS/CPB. Genome-wide transcriptional analysis revealed differential expression of 610 genes after CS/CPB (p<0.01). Among the 375 CS/CPB-upregulated genes, we found a gene-regulatory network consisting of 50 genes, reminiscent of activation of a coordinated genetic program triggered by CS/CPB. Intriguingly, the highly connected hub nodes of the identified network included key sensors of ischemia-reperfusion (HIF-1alpha and C/EBPbeta). Activation of this network initiated a concerted inflammatory response via upregulation of TLR-4/5, IL1R2/IL1RAP, IL6, IL18/IL18R1/IL18RAP, MMP9, HGF/HGFR, CalgranulinA/B, and coagulation factors F5/F12 among others. Differential regulation of 13 candidate genes including novel, not hitherto CS/CBP-associated genes, such as PTX3, PGK1 and Resistin, was confirmed using real-time quantitative RT-PCR. In support of the mRNA data, differential expression of MMP9, MIP1alpha and MIP1beta plasma proteins was further confirmed in 34 additional patients. CONCLUSIONS: Analysis of blood transcriptome uncovered critical signaling pathways governing the CS/CPB-induced pathophysiology. The molecular signaling underlying ischemia reperfusion and inflammatory response is highly intertwined and includes pro-inflammatory as well as cardioprotective elements. The herein identified candidate genes and pathways may provide promising prognostic biomarker and therapeutic targets.

Plasma cystatin C and acute kidney injury after cardiopulmonary bypass.

BACKGROUND AND OBJECTIVES: Little is known about the performance of plasma cystatin C (CysC) in patients undergoing cardiopulmonary bypass (CPB) and its utility in the early diagnosis of acute kidney injury (AKI). In this post hoc analysis, the goal was to determine whether plasma cystatin C, measured 2 hours after the conclusion of CPB, is a reliable marker of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma CysC was measured in 150 patients undergoing CPB at the following times: preoperatively, 2 hours after the conclusion of CPB, postoperative day 1, and postoperative day 2. Plasma CysC levels were related to the development of AKI as defined by an increase in serum creatinine of >or=50% or >or=0.3 mg/dl from baseline up to 3 days postoperative. Mixed linear models were used to evaluate the relationship of serial plasma CysC values with AKI. The discriminatory capacity of plasma CysC was estimated using receiver operating characteristic curves. Logistic regression was utilized to assess the adjusted relationship between plasma CysC and subsequent AKI. RESULTS: AKI developed in 47 (31.3%) patients. Plasma CysC was higher at all times among patients who developed AKI compared with those who did not (P < 0.0001). The discriminatory capacity of plasma CysC measured preoperatively and 2 hours after the conclusion of CPB was modest. CONCLUSIONS: Serial measures of plasma CysC are highly correlated with the development of AKI. However, the discriminatory capacity of plasma CysC as an early marker of AKI remains limited.

Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case-control pilot study.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery with cardiopulmonary bypass (CPB) causes increased morbidity and mortality. OBJECTIVE: To evaluate the plasma profile of biomarkers potentially involved in AKI development following CPB. METHODS: In a nested case-control study, plasma levels of 27 biomarkers in 11 AKI cases were compared with 25 controls. RESULTS: Pre-CPB, plasma levels of epidermal growth factor and macrophage inflammatory protein-1beta, 2 h following CPB, soluble vascular cell adhesion molecule-1 (sVCAM-1), fractalkine and macrophage inflammatory protein-1alpha, and at later time points, sVCAM-1 and interleukin-6 were associated with AKI. CONCLUSION: Biomarkers associated with AKI following CPB may merit further study.

Serum cystatin C for prediction of dialysis requirement or death in acute kidney injury: a comparative study.

BACKGROUND: Serum cystatin C has emerged as a new and potentially more reliable marker of kidney function. However, its utility and performance in patients with acute kidney injury (AKI), particularly for the prediction of dialysis requirement, is not well known. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Adult patients with AKI enrolled at 2 academic medical centers, at time of nephrology consultation. PREDICTORS: Serum cystatin C (primary predictor), serum creatinine, and serum urea nitrogen levels and 24-hour urine output measured at enrollment. OUTCOMES: The composite of dialysis requirement or in-hospital death. COVARIATES: Acute Physiology and Chronic Health Evaluation II (APACHE II) score, liver disease, sepsis, and mechanical ventilation. RESULTS: 200 participants were enrolled for this analysis. Mean age was 65 years, 55% were men, and mean APACHE II score was 20. In unadjusted analyses, increases in serum cystatin C (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.36 to 2.59), serum creatinine (OR, 1.53; 95% CI, 1.12 to 2.09), and serum urea nitrogen levels (OR, 1.84; 95% CI, 1.34 to 2.54) were associated with a higher odds (per 1-SD increase) for the composite outcome, whereas greater urine output (OR, 0.56; 95% CI, 0.39 to 0.80) was associated with lower odds. These associations persisted after adjustment for APACHE II score. The addition of serum cystatin C, serum creatinine, and serum urea nitrogen levels or urine output to a basic model entailing APACHE II score, liver disease, sepsis, and assisted mechanical ventilation improved its prediction, evidenced by increases in areas under a receiver operator characteristic curve from 0.816 to 0.829, 0.826, 0.837, and 0.836, respectively. However, there was no significant difference between each of these models. LIMITATIONS: Observational study, single serum cystatin C measurement. CONCLUSION: In patients with AKI, serum cystatin C level performs similarly to serum creatinine level, serum urea nitrogen level, and urine output for predicting dialysis requirement or in-hospital death. Larger studies are needed to confirm these findings.

Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass.

The purpose of this study was to compare the performance of six candidate urinary biomarkers, kidney injury molecule (KIM)-1, N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, cystatin C and alpha-1 microglobulin, measured 2 h following cardiopulmonary bypass (CPB) for the early detection of acute kidney injury (AKI) in a prospective cohort of patients undergoing cardiac surgery. A total of 103 subjects were enrolled; AKI developed in 13%. Urinary KIM-1 achieved the highest area under-the-receiver-operator-characteristic curve (AUC 0.78, 95% confidence interval 0.64-0.91), followed by IL-18 and NAG. Only urinary KIM-1 remained independently associated with AKI after adjustment for a preoperative AKI prediction score (Cleveland Clinic Foundation score; p = 0.02), or CPB perfusion time (p = 0.006). In this small pilot cohort, KIM-1 performed best as an early biomarker for AKI. Larger studies are needed to explore further the role of biomarkers for early detection of AKI following cardiac surgery.

A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that mediates many cellular responses to tissue hypoxia, a common feature of acute kidney injury (AKI). Here we studied 241 patients with AKI and determined the relationship to adverse outcome of a non-synonymous polymorphism in the coding region of the HIF-1alpha gene where a C to T substitution occurs at position +85 in exon 12, a change known to enhance transactivation. The baseline characteristics of the patients were not different among genotype groups except for a significantly higher prevalence of shock and number of failed organs in T-allele carriers. A significant genotype-phenotype association was found for plasma levels of vascular endothelial growth factor-A but not angiopoietin-2, two downstream targets of HIF-1alpha. Compared to the CC genotype, T-allele carriers had significantly higher adjusted odds for dialysis requirement or in-hospital death; assisted mechanical ventilation or dialysis requirement; and the composite of assisted mechanical ventilation, dialysis requirement or in-hospital death. The trend for higher plasma angiopoietin-2 levels was associated with significantly higher adjusted odds for in-hospital death; dialysis requirement or in-hospital death; and the composite outcome of assisted mechanical ventilation, dialysis, or in-hospital death. Despite the limited cohort size, our study found this particular HIF-1alpha genetic variant to be associated with disease severity and adverse outcomes in AKI. Larger studies are needed to confirm these relationships.

Protective effect of erythropoietin against radiocontrast-induced renal tubular epithelial cell injury.

BACKGROUND/AIMS: Recombinant human erythropoietin (rhEpo) has been shown to reduce tissue injury following ischemia-reperfusion. We examined whether rhEpo protects in vitro renal tubular epithelial cells against radiocontrast media-induced injury. METHODS: LLC-PK1 renal tubular epithelial cells were exposed to non-ionic radiocontrast agent iohexol (low-osmolar) or iodixanol (iso-osmolar), with or without rhEpo (200 U/ml). Following a 6-hour exposure, cells were incubated for 24 h in radiocontrast-free culture medium. Cell viability was then assessed by the MTT assay. We also assessed cell apoptosis by the TUNEL assay, and activities of caspase-3, caspase-8, and caspase-9 were determined by a luminescence assay. RESULTS: rhEpo improved viability of iohexol-treated LLC-PK1 cells by 27 +/- 6% (88.1 +/- 1.5 vs. 70.8 +/- 3.3%, p = 0.008). Similarly, rhEpo improved the viability of iodixanol-treated LLC-PK1 cells by 26 +/- 4% (82.5 +/- 2.1vs. 65.7 +/- 1.7%, p = 0.028). rhEpo also decreased apoptosis rates of iohexol-treated LLC-PK1 cells (6.4 +/- 0.9/1,000 cells vs. 14.8 +/- 2.4/1,000 cells, p = 0.028), and iodixanol-treated LLC-PK1 cells (8.0 +/- 1.2/1,000 cells vs. 13.5 +/- 1.9/1,000 cells, p = 0.028). In iohexol-treated LLC-PK1 cells, rhEpo attenuated activation of caspase-3 (p = 0.003), caspase-8 (p = 0.033) and caspase-9 (p = 0.055). CONCLUSION: rhEpo attenuates in vitro renal tubular epithelial cell injury induced by low- and iso-osmolar radiocontrast media, possibly by reduction of caspases activation and apoptosis rates.

Acute renal failure after endovascular vs open repair of abdominal aortic aneurysm.

OBJECTIVE: Endovascular aneurysm repair (EVAR) is an increasingly used alternative to open surgical repair of unruptured abdominal aortic aneurysms (AAAs). The effect of EVAR on postprocedure acute renal failure has not been determined. We hypothesized that EVAR would be associated with a lower risk of acute renal failure and acute renal failure requiring hemodialysis. METHODS: A retrospective cohort study was conducted of the 2002 Nationwide Inpatient Sample, the largest all-payer inpatient care database in the United States, reflecting discharges from a representative sample of United States hospitals. We identified 6614 discharges with a primary diagnosis of unruptured AAA and a primary procedure code for open AAA repair or EVAR. We excluded 56 patients with end-stage renal disease and 42 patients who underwent concomitant aortorenal bypass. We compared EVAR vs open repair in this cohort. The main outcome measures were acute renal failure and acute renal failure requiring dialysis. RESULTS: A total of 6516 patient discharges met the inclusion criteria for the study, and postprocedure acute renal failure developed in 439 (6.7%). EVAR was associated with lower odds of acute renal failure (adjusted odds ratio, 0.42; 95% confidence interval, 0.33 to 0.53) and acute renal failure requiring dialysis (adjusted odds ratio, 0.30, 95% confidence interval, 0.15 to 0.63). Results were similar when EVAR and open AAA repair were compared within quintiles of the propensity score for the receipt of EVAR. CONCLUSIONS: Compared with open AAA repair, EVAR is associated with a lower risk of postprocedure acute renal failure.

Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey.

The aim of this study was to provide a broad characterization of the epidemiology of acute renal failure (ARF) in the United States using national administrative data and describe its impact on hospital length of stay (LOS), patient disposition, and adverse outcomes. Using the 2001 National Hospital Discharge Survey, a nationally representative sample of discharges from nonfederal acute care hospitals in the United States, new cases of ARF were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Multivariate regression analyses were used to explore the relation of ARF to hospital LOS and mortality as well as discharge disposition. Review of discharge data on a projected total of 29,039,599 hospitalizations identified 558,032 cases of ARF, with a frequency of 19.2 per 1000 hospitalizations. ARF was more commonly coded for in older patients; men; black individuals; and the setting of chronic kidney disease, congestive heart failure, chronic lung disease, sepsis, and cardiac surgery. ARF was associated with an adjusted prolongation of hospital LOS by 2 d (P < 0.001) and an adjusted odds ratio of 4.1 for hospital mortality and of 2.0 for discharge to short- or long-term care facilities. In a US representative sample of hospitalized patients, the presence of an ICD-9-CM code for ARF in discharge records is associated with prolonged LOS, increased mortality, and, among survivors, a greater requirement for posthospitalization care. These findings suggest that in the United States, ARF is associated with increased in-hospital and post-hospitalization resource utilization.

Cytokine single nucleotide polymorphism. Role in acute renal failure.

Although the pathogenesis of ARF is heterogeneous and results from a combination of different environmental influences and host responses, there is overwhelming data to suggest a common pathway that involves pro- and anti-inflammatory molecules, which in turn, determines the extent of tissue injury. The number of recognized cytokine gene polymorphisms is growing daily. The development of cytokine gene mapping may help identify patients in whom an excessive systemic inflammatory response may follow a therapeutic intervention (e.g. CABG, contrast administration), and who may be at increased risk for developing acute organ dysfunction. Through these advances, tools may be developed to better understand, prevent and treat ARF. Genetic epidemiology studies may help characterize the importance of genetic markers in the development of ARF. This would require large prospective cohort studies aimed at examining associations between genetic markers, urinary (urine KIM-1 and NAG) and circulating (serum creatinine) markers of kidney injury. Once firmly established, the association of a particular genetic profile and outcome could be used to risk stratify patients for the development of ARF (fig. 4). Ultimately, cytokine-modulating therapies could be employed on the basis of genotypic risk stratification with the goal to prevent kidney injury or minimize its deleterious effects on patient outcome.

Polymorphism of immunomodulatory cytokine genes: implications in acute renal failure.

Experimental studies have incriminated cytokines and other immunoregulatory molecules as important mediators of tissue injury in acute renal failure (ARF). The relative importance of genetic factors, e.g. polymorphisms involving cytokine genes, in influencing susceptibility to and severity of ARF is unknown. This review summarizes the existing experimental and clinical studies supporting the role of inflammation in ARF, and critically examines human studies that have examined polymorphism of two critical cytokine genes, tumor necrosis factor-alpha and interleukin-10, as potential determinants of susceptibility to and severity of acute infectious and inflammatory diseases. Conclusions are drawn on the application of genetic epidemiology to the field of ARF and the rationale for further research on the role of genetic markers in ARF.

Soluble Fas: a novel marker of inflammation in uremia.

BACKGROUND: Inflammation has been associated with atherosclerotic cardiovascular disease (CVD) and anemia in patients with end-stage renal disease (ESRD). Recent studies have shown that serum levels of soluble Fas (sFas), an antiapoptotic and proinflammatory molecule, are elevated in patients with cardiac disease and patients with ESRD. We therefore sought to investigate serum levels of sFas in uremic patients and its correlation with known markers of inflammation, anemia and CVD. METHODS: The study included 25 ESRD patients (14 on hemodialysis, 11 on CAPD), 27 patients with chronic kidney disease (CKD; creatinine clearance <50 ml/min/1.73 m2), and 14 normal control subjects. We measured serum levels of sFas, C-reactive protein (CRP), and albumin. We also investigated the association of serum sFas levels with the presence of CVD and with erythropoietin (EPO) dosage. RESULTS: Levels of sFas were elevated in CKD and ESRD patients compared to controls. sFas levels correlated negatively with creatinine clearance. In the dialysis patients, we observed that sFas levels were higher among those with CVD. Serum levels of sFas correlated with serum levels of CRP (r=0.31; P=0.03), serum levels of albumin (r=-0.35, P=0.02), and EPO dosage (r=0.51; P=0.009). CONCLUSION: These results suggest that sFas may be a marker of inflammation in CKD and ESRD patients.

ARF after open-heart surgery: Influence of gender and race.

BACKGROUND: Both acute renal failure (ARF) and female sex are strongly associated with mortality after open-heart surgery. This study analyzes the effect of sex and race on the incidence of ARF after open-heart surgery and its influence on mortality. METHODS: A total of 24,660 patients underwent open-heart surgery at the Cleveland Clinic Foundation (Cleveland, OH) from 1993 to 2000. The primary outcome was ARF defined as ARF requiring dialysis, 50% or greater decline in glomerular filtration rate (GFR) not requiring dialysis, or 50% or greater decline in GFR relative to baseline or requirement of dialysis. The secondary outcome was all-cause hospital mortality. RESULTS: The overall frequency of ARF requiring dialysis after open-heart surgery was 1.82%. The frequency was greater in women (2.36%) than men (1.60%; P < 0.0001) and blacks (2.94%) than nonblacks (1.70%; P < 0.0001) by univariate analysis. By multivariate analysis, risk for ARF requiring dialysis in women was 1.61 (confidence interval [CI], 1.27 to 2.05; P < 0.0001), but race was not a risk factor. The overall postoperative mortality rate was 2.2%, and for patients with ARF requiring dialysis, it was 61.2% (women, 68.6% versus men, 56.5%; P = 0.01) with an odds ratio of 49.29, whereas in patients with ARF not requiring dialysis, it was 14.1% (women, 13.3% versus men 14.6%; P = 0.63) with an odds ratio of 7.18. CONCLUSION: Female sex is an independent risk factor for developing ARF after open-heart surgery. The influence of race on risk for ARF is less clear. Regardless of its definition, ARF is strikingly associated with a high risk for mortality.