Urinary Elafin and Kidney Injury in Hematopoietic Cell Transplant Recipients

Background and objectives

Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.

Design, setting, participants, & measurements

Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry.

Results

Mean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules.

Conclusion

Higher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.     

Urinary Biomarkers and Risk of ESRD in the Atherosclerosis Risk in Communities Study

Background and objectives

Liver fatty acid binding protein (L-FABP), kidney injury molecule 1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and neutrophil gelatinase–associated lipocalin (NGAL) are urinary markers of tubular injury that may also be markers of chronic kidney damage. We evaluated the association of these markers with incident ESRD in a community-based sample from the Atherosclerosis Risk in Communities Study.

Design, setting, participants, & measurements

This was a matched case-control study of 135 patients with ESRD and 186 controls who were matched on sex, race, kidney function, and diabetes status at baseline (Atherosclerosis Risk in Communities Study visit 4, 1996–1998). Urinary KIM-1 indexed to creatinine (Cr), NAG/Cr, NGAL/Cr, and L-FABP/Cr were measured in stored spot urine samples from the baseline examination. Associations of KIM-1/Cr, NAG/Cr, and NGAL/Cr with patients with incident ESRD through 2008 were modeled continuously and categorically (quartiles) using conditional logistic regression. L-FABP/Cr was modeled only categorically because of a large number of measurements below the lower limit of detection for the assay (2.4 ng/ml).

Results

No significant associations were observed for NAG/Cr, NGAL/Cr, or L-FABP/Cr with ESRD. Those in the highest category for KIM-1/Cr had a higher risk of ESRD compared with those with undetectable biomarker levels (reference group) in unadjusted models (odds ratio, 2.24; 95% confidence interval, 1.97 to 4.69; P=0.03) or adjustment for age (odds ratio, 2.23; 95% confidence interval, 1.06 to 4.67; P=0.03). This association was attenuated with additional adjustment for baseline kidney function (odds ratio, 2.02; 95% confidence interval, 0.95 to 4.31; P=0.07 after additional adjustment for eGFR and natural log of the urinary albumin-to-creatinine ratio). No association between KIM-1/Cr and ESRD was found when KIM-1/Cr was analyzed as a continuous variable.

Conclusions

Elevated urinary KIM-1/Cr may be associated with a higher risk of incident ESRD, but it does not add to risk prediction after accounting for traditional markers of kidney function in this population.     

Urinary Biomarkers and Progression of AKI in Patients with Cirrhosis

Background and objectives

AKI is a common and severe complication in patients with cirrhosis. AKI progression was previously shown to correlate with in-hospital mortality. Therefore, accurately predicting which patients are at highest risk for AKI progression may allow more rapid and targeted treatment. Urinary biomarkers of structural kidney injury associate with AKI progression and mortality in multiple settings of AKI but their prognostic performance in patients with liver cirrhosis is not well known.

Design, setting, participants, & measurements

A multicenter, prospective cohort study was conducted at four tertiary care United States medical centers between 2009 and 2011. The study comprised patients with cirrhosis and AKI defined by the AKI Network criteria evaluating structural (neutrophil gelatinase–associated lipocalin, IL-18, kidney injury molecule-1 [KIM-1], liver-type fatty acid–binding protein [L-FABP], and albuminuria) and functional (fractional excretion of sodium [FENa]) urinary biomarkers as predictors of AKI progression and in-hospital mortality.

Results

Of 188 patients in the study, 44 (23%) experienced AKI progression alone and 39 (21%) suffered both progression and death during their hospitalization. Neutrophil gelatinase–associated lipocalin, IL-18, KIM-1, L-FABP, and albuminuria were significantly higher in patients with AKI progression and death. These biomarkers were independently associated with this outcome after adjusting for key clinical variables including model of end stage liver disease score, IL-18 (relative risk [RR], 4.09; 95% confidence interval [95% CI], 1.56 to 10.70), KIM-1 (RR, 3.13; 95% CI, 1.20 to 8.17), L-FABP (RR, 3.43; 95% CI, 1.54 to 7.64), and albuminuria (RR, 2.07; 95% CI, 1.05–4.10) per log change. No biomarkers were independently associated with progression without mortality. FENa demonstrated no association with worsening of AKI. When added to a robust clinical model, only IL-18 independently improved risk stratification on a net reclassification index.

Conclusions

Multiple structural biomarkers of kidney injury, but not FENa, are independently associated with progression of AKI and mortality in patients with cirrhosis. Injury marker levels were similar between those without progression and those with progression alone.     

Temporal Trajectory of B-Type Natriuretic Peptide in Patients with CKD Stages 3 and 4, Dialysis,and Kidney Transplant

Background and objectives

B-type natriuretic peptide (BNP) concentration predicts outcome in patients undergoing dialysis. Because survival and cardiovascular risk change across the CKD continuum, serial changes in BNP were compared in patients at different CKD stages and after kidney transplantation.

Design, setting, participants, & measurements

Patients with CKD stages 3 and 4 (CKD 3–4), dialysis patients, and kidney transplant recipients (KTRs) from one center had two measurements of BNP taken a median of 161 days apart in 2003–2004 and were followed until July 2012. Both BNP-32 (Triage BNP; Biosite Diagnostics) and NT-BNP-76 (proBNP; Roche Diagnostics) were assayed. The interaction between change in log-transformed BNP concentration over time and patient group was tested by fitting regression models on panel data with random effects. Survival after the second measurement was compared by tertile of change in BNP.

Results

Patients with CKD 3–4 (n=48), dialysis patients (n=102), and KTRs (n=73) were followed for a median of 5.7, 4.8, and 5.9 years, respectively. The interaction between patient group and BNP measurements over time was significant for NT-BNP-76 (P<0.001) and BNP-32 (P<0.01). Median NT-BNP-76 increased in dialysis patients and those with CKD 3–4 from 3850 pg/ml (interquartile range [IQR], 1776–12,323 pg/ml) to 18,830 pg/ml (IQR, 6114–61,009 pg/ml; P<0.001) and from 698 pg/ml (IQR, 283–2922 pg/ml) to 2529 pg/ml (IQR, 347–9277 pg/ml; P=0.002), respectively. Change was not significant for KTRs or comparisons made with BNP-32. Survival rate was significantly lower for patients with the highest tertile of change in NT-BNP-76 among patients with CKD 3–4 (P=0.02), but not in the dialysis or KTR groups. In 11 patients who received a kidney transplant during the study, median NT-BNP-76 decreased from 9607 pg/ml (IQR, 2292–31,282 pg/ml) to 457 pg/ml (IQR, 203–863 pg/ml) after transplant (P<0.01).

Conclusions

The temporal trajectory of BNP differs between dialysis patients and those with CKD 3–4 and KTRs. This has important implications for the development of BNP-guided management strategies in CKD.     

Urinary calprotectin and the distinction between prerenal and intrinsic acute kidney injury

Summary

Background and objectives

To date there is no reliable marker for the differentiation of prerenal and intrinsic acute kidney injury (AKI). We investigated whether urinary calprotectin, a mediator protein of the innate immune system, may serve as a diagnostic marker in AKI.

Design, setting, participants, & measurements

This was a cross-sectional study with 101 subjects including 86 patients with AKI (34 prerenal, 52 intrinsic including 23 patients with urinary tract infection) and 15 healthy controls. Assessment of urinary calprotectin concentration was by ELISA and immunohistochemistry of kidney biopsy specimens using a calprotectin antibody. Inclusion criteria were: admission to hospital for AKI stage 1 to 3 (Acute Kidney Injury Network); exclusion criteria were: prior renal transplantation and obstructive uropathy.

Results

Median urinary calprotectin was 60.7 times higher in intrinsic AKI (1692 ng/ml) than in prerenal AKI (28 ng/ml, p <0.01). Urinary calprotectin in prerenal disease was not significantly different from healthy controls (45 ng/ml, p = 0.25). Receiver operating curve curve analysis revealed a high accuracy of calprotectin (area under the curve, 0.97) in predicting intrinsic AKI. A cutoff level of 300 ng/ml provided a sensitivity of 92.3% and a specificity of 97.1%. Calculating urinary calprotectin/creatinine ratios did not lead to a further increase of accuracy. Immunostainings of kidney biopsies were positive for calprotectin in intrinsic AKI and negative in prerenal AKI.

Conclusions

Accuracy of urinary calprotectin in the differential diagnosis of AKI is high. Whereas calprotectin levels in prerenal disease are comparable with healthy controls, intrinsic AKI leads to highly increased calprotectin concentrations.     

HMG–CoA Reductase Activation and Urinary Pellet Cholesterol Elevations in Acute Kidney Injury

Summary

Background and objectives

Experimental acute kidney injury (AKI) activates the HMG–CoA reductase (HMGCR) gene, producing proximal tubule cholesterol loading. AKI also causes sloughing of proximal tubular cell debris into tubular lumina. This study tested whether these two processes culminate in increased urinary pellet cholesterol content, and whether the latter has potential AKI biomarker utility.

Design, setting, participants, & measurements

Urine samples were collected from 29 critically ill patients with (n = 14) or without (n= 15) AKI, 15 patients with chronic kidney disease, and 15 healthy volunteers. Centrifuged urinary pellets underwent lipid extraction, and the extracts were assayed for cholesterol content (factored by membrane phospholipid phosphate content). In vivo HMGCR activation was sought by measuring levels of RNA polymerase II (Pol II), and of a gene activating histone mark (H3K4m3) at exon 1 of the HMGCR gene (chromatin immunoprecipitation assay of urine chromatin samples).

Results

AKI+ patients had an approximate doubling of urinary pellet cholesterol content compared with control urine samples (versus normal; P < 0.001). The values significantly correlated (r, 0.5; P < 0.01) with serum, but not urine, creatinine concentrations. Conversely, neither critical illness without AKI nor chronic kidney disease raised pellet cholesterol levels. Increased HMGCR activity in the AKI+ patients was supported by three- to fourfold increased levels of Pol II, and of H3K4m3, at the HMGCR gene (versus controls or AKI− patients).

Conclusions

(1) Clinical AKI, like experimental AKI, induces HMGCR gene activation; (2) increased urinary pellet cholesterol levels result; and (3) urine pellet cholesterol levels may have potential AKI biomarker utility. The latter will require future testing in a large prospective trial.     

Urinary Biomarkers and Renal Recovery in Critically Ill Patients with Renal Support

Summary

Background and objectives

Despite significant advances in the epidemiology of acute kidney injury (AKI), prognostication remains a major clinical challenge. Unfortunately, no reliable method to predict renal recovery exists. The discovery of biomarkers to aid in clinical risk prediction for recovery after AKI would represent a significant advance over current practice.

Design, setting, participants, & measurements

We conducted the Biological Markers of Recovery for the Kidney study as an ancillary to the Acute Renal Failure Trial Network study. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AKI and received renal replacement therapy (RRT) in the intensive care unit. We explored whether levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary hepatocyte growth factor (uHGF), urinary cystatin C (uCystatin C), IL-18, neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9, and urine creatinine could predict subsequent renal recovery.

Results

We defined renal recovery as alive and free of dialysis at 60 days from the start of RRT. Patients who recovered had higher uCystatin C on day 1 (7.27 versus 6.60 ng/mg·creatinine) and lower uHGF on days 7 and 14 (2.97 versus 3.48 ng/mg·creatinine; 2.24 versus 3.40 ng/mg·creatinine). For predicting recovery, decreasing uNGAL and uHGF in the first 14 days was associated with greater odds of renal recovery. The most predictive model combined relative changes in biomarkers with clinical variables and resulted in an area under the receiver-operator characteristic curve of 0.94.

Conclusions

We showed that a panel of urine biomarkers can augment clinical risk prediction for recovery after AKI.     

Epidemiology and Outcomes in Community-Acquired Versus Hospital-Acquired AKI

Background and objective

Compared with AKI in hospitalized patients, little is known about patients sustaining AKI in the community and how this differs from AKI in hospital. This study compared epidemiology, risk factors, and short- and long-term outcomes for patients with community-acquired (CA) and hospital-acquired (HA) AKI.

Design, setting, participants, & measurements

A total of 15,976 patients admitted to two district general hospitals between July 11, 2011, and January 15, 2012 were studied. Through use of an electronic database and the AKI Network classification, 686 patients with CA-AKI and 334 patients with HA-AKI were identified. Patients were followed up for 14 months, and data were collated on short-term and long-term renal and patient outcomes.

Results

The incidence of CA-AKI among all hospital admissions was 4.3% compared with an incidence of 2.1% of HA-AKI, giving an overall AKI incidence of 6.4%. Patients with CA-AKI were younger than patients with HA-AKI. Risks for developing HA and CA-AKI were similar and included preexisting CKD, cardiac failure, ischemic heart disease, hypertension, diabetes, dementia, and cancer. Patients with CA-AKI were more likely to have stage 3 AKI and had shorter lengths of hospital stay than patients with HA-AKI. Those with CA-AKI had better (multivariate-adjusted) survival than patients with HA-AKI (hazard ratio, 1.8 [95% CI, 1.44–2.13; P<0.001] for HA-AKI group). Mortality for the CA-AKI group was 45%; 43.7% of these deaths were acute in-hospital deaths. Mortality for the HA-AKI group was 62.9%, with 68.1% of these deaths being acute in-hospital deaths. Renal referral rates were low across the cohorts (8.3%). Renal outcomes were similar in both CA-AKI and HA-AKI groups, with 39.4% and 33.6% of patients in both groups developing de novo CKD or progression of preexisting CKD within 14 months, respectively.

Conclusion

Patients with CA-AKI sustain more severe AKI than patients with HA-AKI. Despite having risk factors similar to those of patients with HA-AKI, patients with CA AKI have better short- and long-term outcomes.     

Fluid Balance,Diuretic Use,and Mortality in Acute Kidney Injury

Summary

Background and objectives

Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients.

Design, setting, participants, & measurements

Using data from the Fluid and Catheter Treatment Trial (FACTT), a multicenter, randomized controlled trial evaluating a conservative versus liberal fluid-management strategy in 1000 patients with acute lung injury (ALI), we evaluated the association of post-renal injury fluid balance and diuretic use with 60-day mortality in patients who developed AKI, as defined by the AKI Network criteria.

Results

306 patients developed AKI in the first 2 study days and were included in our analysis. There were 137 in the fluid-liberal arm and 169 in the fluid-conservative arm (P = 0.04). Baseline characteristics were similar between groups. Post-AKI fluid balance was significantly associated with mortality in both crude and adjusted analysis. Higher post-AKI furosemide doses had a protective effect on mortality but no significant effect after adjustment for post-AKI fluid balance. There was no threshold dose of furosemide above which mortality increased.

Conclusions

A positive fluid balance after AKI was strongly associated with mortality. Post-AKI diuretic therapy was associated with 60-day patient survival in FACTT patients with ALI; this effect may be mediated by fluid balance.     

Hospital-acquired Acute Kidney Injury: An Analysis of Nadir-to-Peak Serum Creatinine Increments Stratified by Baseline Estimated GFR

Summary

Background and objectives

Serum creatinine (sCr) increments currently used to define acute kidney injury (AKI) do not take into consideration the baseline level of kidney function. The objective of this study was to establish whether baseline estimated GFR (eGFR) provides additional risk stratification to sCr-based increments for defining AKI.

Design, setting, participants, & measurements

29,645 adults hospitalized at an acute care facility were analyzed. Hospital-acquired AKI was defined by calculating the difference between the nadir and subsequent peak sCr.

Results

Different thresholds of nadir-to-peak sCr were found to be independently associated with increased in-hospital mortality according to baseline eGFR strata. A nadir-to-peak sCr minimum threshold of ≥0.2, ≥0.3, and ≥0.5 mg/dl was required to be independently associated with increased in-hospital mortality among patients with baseline eGFR ≥60 ml/min per 1.73 m² (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.13 to 2.47), 30 to 59 ml/min per 1.73 m² (OR 2.69; 95% CI, 1.82 to 3.97), and <30 ml/min per 1.73 m² (OR 2.15; 95% CI 1.02 to 4.51), respectively. There was a significant interaction between the nadir-to-peak sCr and baseline eGFR for in-hospital mortality (P < 0.001). Using these thresholds, survivors of AKI episodes had an increased hospital length of stay and were more likely to be discharged to a facility rather than home. Sensitivity analyses showed a significant interaction between baseline eGFR strata and relative increases in sCr, as well as absolute and relative decreases in eGFR for in-hospital mortality (P < 0.001).

Conclusions

This study suggests that future sCr-based definitions of AKI should take into consideration baseline eGFR.     

Outcomes After Post-Traumatic AKI Requiring RRT in United States Military Service Members

Background and objectives

Mortality and CKD risk have not been described in military casualties with post-traumatic AKI requiring RRT suffered in the Iraq and Afghanistan wars.

Design, setting, participants, & measurements

This is a retrospective case series of post-traumatic AKI requiring RRT in 51 military health care beneficiaries (October 7, 2001–December 1, 2013), evacuated to the National Capital Region, documenting in-hospital mortality and subsequent CKD. Participants were identified using electronic medical and procedure records.

Results

Age at injury was 26±6 years; of the participants, 50 were men, 16% were black, 67% were white, and 88% of injuries were caused by blast or projectiles. Presumed AKI cause was acute tubular necrosis in 98%, with rhabdomyolysis in 72%. Sixty-day all-cause mortality was 22% (95% confidence interval [95% CI], 12% to 35%), significantly less than the 50% predicted historical mortality (P<0.001). The VA/NIH Acute Renal Failure Trial Network AKI integer score predicted 60-day mortality risk was 33% (range, 6%–96%) (n=49). Of these, nine died (mortality, 18%; 95% CI, 10% to 32%), with predicted risks significantly miscalibrated (P<0.001). The area under the receiver operator characteristic curve for the AKI integer score was 0.72 (95% CI, 0.56 to 0.88), not significantly different than the AKI integer score model cohort (P=0.27). Of the 40 survivors, one had ESRD caused by cortical necrosis. Of the remaining 39, median time to last follow-up serum creatinine was 1158 days (range, 99–3316 days), serum creatinine was 0.85±0.24 mg/dl, and eGFR was 118±23 ml/min per 1.73 m². No eGFR was <60 ml/min per 1.73 m², but it may be overestimated because of large/medium amputations in 54%. Twenty-five percent (n=36) had proteinuria; one was diagnosed with CKD stage 2.

Conclusions

Despite severe injuries, participants had better in-hospital survival than predicted historically and by AKI integer score. No patient who recovered renal function had an eGFR<60 ml/min per 1.73 m² at last follow-up, but 23% had proteinuria, suggesting CKD burden.     

Low Systemic Oxygen Delivery and BP and Risk of Progression of Early AKI

Background and objectives

The optimal hemodynamic management of patients with early AKI is unknown. This study aimed to investigate the association between hemodynamic parameters in early AKI and progression to severe AKI and hospital mortality.

Design, setting, participants, & measurements

This study retrospectively analyzed the data of all patients admitted to the adult intensive care unit in a tertiary care center between July 2007 and June 2009 and identified those with stage 1 AKI (AKI I) per the AKI Network classification. In patients in whom hemodynamic monitoring was performed within 12 hours of AKI I, hemodynamic parameters in the first 12 hours of AKI I and on the day of AKI III (if AKI III developed) or 72 hours after AKI I (if AKI III did not develop) were recorded. Risk factors for AKI III and mortality were identified using univariate and multivariate logistic regression analyses.

Results

Among 790 patients with AKI I, 210 (median age 70 years; 138 men) had hemodynamic monitoring within 12 hours of AKI I; 85 patients (41.5%) progressed to AKI III and 91 (43%) died in the hospital. AKI progressors had a significantly higher Sequential Organ Failure Assessment score (8.0 versus 9.6; P<0.001), lower indexed systemic oxygen delivery (DO₂I) (median 325 versus 405 ml/min per m²; P<0.001), higher central venous pressure (16 versus 13; P=0.02), and lower mean arterial blood pressure (MAP) (median 71 versus 74 mmHg; P=0.01) in the first 12 hours of AKI I compared with nonprogressors. Multivariate analysis confirmed that raised lactate, central venous pressure, and Sequential Organ Failure Assessment score as well as mechanical ventilation were independently associated with progression to AKI III; higher DO₂I and MAP were independently associated with a lower risk of AKI III but not survival. The associations were independent of sepsis, heart disease, recent cardiac surgery, or chronic hypertension.

Conclusions

Higher DO₂I and MAP in early AKI were independently associated with a lower risk of progression.     

Risk of poor outcomes with novel and traditional biomarkers at clinical AKI diagnosis

Summary

Background and objectives

Studies have evaluated acute kidney injury (AKI) using biomarkers in various settings, but their prognostic utility within current practice is unclear. Thus, we sought to determine the prognostic utility of newer biomarkers or traditional markers (fractional excretion of sodium [FeNa] and urea [FeUrea] and microscopy) over clinical assessment alone.

Design, setting, participants, & measurements

This is a prospective cohort study of adults on the first day of meeting AKI criteria. We measured urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and IL-18 and determined FeNa, FeUrea, and microscopy score for casts and tubular cells. Primary outcome was worsened AKI stage from enrollment to peak serum creatinine or in-hospital death.

Results

In 249 recipients, 57% were ≥65 years old, 48% were from intensive care, and mean baseline GFR was 69 ± 30 ml/min per 1.73 m². AKI was considered prerenal in 164 (66%), acute tubular necrosis (ATN) in 51 (20%), and “other” in 34 (14%). All mean protein biomarker concentrations, FeNa, FeUrea, and microscopy scores were statistically different between prerenal and ATN. Seventy-two patients (29%) developed the primary outcome. There was an approximate three-fold increase in adjusted risk for the outcome for upper versus lower values of NGAL, KIM-1, IL-18, and microscopy score (P values <0.05). Net reclassification improved after adding these to baseline clinical assessment. FeNa and FeUrea were not useful.

Conclusions

On the first day of AKI, urine protein biomarkers and microscopy significantly improve upon clinical determination of prognosis, indicating their potential utility in current practice.     

Impact of Acute Kidney Injury on Short- and Long-term Outcomes After Transcatheter Aortic Valve Implantation

Introduction and objectives

Acute kidney injury (AKI) is frequently observed after transcatheter aortic valve implantation (TAVI) and is associated with higher mortality. However, the impact of AKI on long-term outcomes remains controversial. Therefore, we sought to evaluate the impact of AKI on short- and long-term outcomes following TAVI using the Valve Academic Research Consortium 2 criteria.

Acute Respiratory Distress Syndrome and Risk of AKI among Critically Ill Patients

Background and objectives

Increasing experimental evidence suggests that acute respiratory distress syndrome (ARDS) may promote AKI. The primary objective of this study was to assess ARDS as a risk factor for AKI in critically ill patients.

Design, setting, participants, & measurements

This was an observational study on a prospective database fed by 18 intensive care units (ICUs). Patients with ICU stays >24 hours were enrolled over a 14-year period. ARDS was defined using the Berlin criteria and AKI was defined using the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria. Patients with AKI before ARDS onset were excluded.

Results

This study enrolled 8029 patients, including 1879 patients with ARDS. AKI occurred in 31.3% of patients and was more common in patients with ARDS (44.3% versus 27.4% in patients without ARDS; P<0.001). After adjustment for confounders, both mechanical ventilation without ARDS (odds ratio [OR], 4.34; 95% confidence interval [95% CI], 3.71 to 5.10) and ARDS (OR, 11.01; 95% CI, 6.83 to 17.73) were independently associated with AKI. Hospital mortality was 14.2% (n=1140) and was higher in patients with ARDS (27.9% versus 10.0% in patients without ARDS; P<0.001) and in patients with AKI (27.6% versus 8.1% in those without AKI; P<0.001). AKI was associated with higher mortality in patients with ARDS (42.3% versus 20.2%; P<0.001).

Conclusions

ARDS was independently associated with AKI. This study suggests that ARDS should be considered as a risk factor for AKI in critically ill patients.     

Cardiac Resynchronization Therapy in CKD Stage 4 Patients

Background and objectives

Cardiac resynchronization therapy (CRT) is a well established heart failure treatment that has shown to improve renal function. However, landmark CRT trials excluded patients with severe renal dysfunction. Therefore, this study evaluated the effect of CRT on renal function and long-term prognosis in patients with stage 4 CKD.

Design, setting, participants, & measurements

This study evaluated 73 consecutive CRT patients (71±10 years) with stage 4 CKD who underwent echocardiographic and renal function evaluation at baseline and 6-month follow-up between 2000 and 2012. As a control group, 18 patients with stage 4 CKD who received an implantable cardioverter defibrillator (ICD) were selected. CRT recipients with ≥15% reduction in left ventricular end-systolic volume at 6-month follow-up were classified as CRT responders. During long-term follow-up (median, 33 months), appropriate defibrillator therapy, heart failure hospitalizations, and all-cause mortality (combined end point) were recorded.

Results

At 6-month follow-up, a significant reduction in left ventricular end-systolic volume was observed in CRT patients compared with patients with ICD (from 159±78 to 145±78 ml in CRT patients and from 126±54 to 119±49 ml in ICD patients; P=0.05), and CRT response was observed in 22 patients (30%). Compared with ICD patients, eGFR improved among CRT patients (from 25±4 to 30±9 ml/min per 1.73 m²; interaction time and group, P=0.04) and was more pronounced among CRT responders (25±3 to 34±9 ml/min per 1.73 m²; P<0.001). The combined end point was observed in 17 ICD and 62 CRT patients. CRT patients showed superior survival compared with ICD patients (log-rank P=0.03). More importantly, CRT response was independently associated with improved survival free from the combined end point (hazard ratio, 0.51; 95% confidence interval, 0.27 to 0.98; P=0.04) after adjustment for clinical and echocardiographic parameters.

Conclusions

Response to CRT occurs in approximately 30% of patients with stage 4 CKD, which is less than in the average CRT population. CRT was associated with better clinical outcome, and particularly, CRT response was associated with improvement in eGFR and better long-term prognosis.     

Plasma Urate and Risk of a Hospital Stay with AKI: The Atherosclerosis Risk in Communities Study

Background and objectives

Higher urate levels are associated with higher risk of CKD, but the association between urate and AKI is less established. This study evaluated the risk of hospitalized AKI associated with urate concentrations in a large population-based cohort. To explore whether urate itself causes kidney injury, the study also evaluated the relationship between a genetic urate score and AKI.

Design, setting, participants, & measurements

A total of 11,011 participants from the Atherosclerosis Risk in Communities study were followed from 1996–1998 (baseline) to 2010. The association between baseline plasma urate and risk of hospitalized AKI, adjusted for known AKI risk factors, was determined using Cox regression. Interactions of urate with gout and CKD were tested. Mendelian randomization was performed using a published genetic urate score among the participants with genetic data (n=7553).

Results

During 12 years of follow-up, 823 participants were hospitalized with AKI. Overall, mean participant age was 63.3 years, mean eGFR was 86.3 ml/min per 1.73 m², and mean plasma urate was 5.6 mg/dl. In patients with plasma urate >5.0 mg/dl, there was a 16% higher risk of hospitalized AKI for each 1-mg/dl higher urate (adjusted hazard ratio, 1.16; 95% confidence interval, 1.10 to 1.23; P<0.001). When stratified by history of gout, the association between higher urate and AKI was significant only in participants without a history of gout (P for interaction=0.02). There was no interaction of CKD and urate with AKI, nor was there an association between genetic urate score and AKI.

Conclusions

Plasma urate >5.0 mg/dl was independently associated with risk of hospitalized AKI; however, Mendelian randomization did not provide evidence for a causal role of urate in AKI. Further research is needed to determine whether lowering plasma urate might reduce AKI risk.     

Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study

Background and objectives

Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD.

Design, setting, participants, & measurements

Prospective cohort study in adults (n=3939) with CKD aged 21–74 years recruited between 2003 and 2008 and followed for a median of 4.1 years. At baseline, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), apoA-I , apoB, and lipoprotein(a) [Lp(a)] were measured. The outcomes were composite end point of ESRD or 50% decline in eGFR from baseline (rate of change of GFR).

Results

Mean age of the study population was 58.2 years, and the mean GFR was 44.9 ml/min per 1.73 m²; 48% of patients had diabetes. None of the lipid or lipoprotein measures was independently associated with risk of the composite end point or rate of change in GFR. However, there were significant (P=0.01) interactions by level of proteinuria. In participants with proteinuria<0.2 g/d, 1-SD higher LDL-C was associated with a 26% lower risk of the renal end point (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; P=0.01), and 1-SD higher total cholesterol was associated with a 23% lower risk of the renal end point (HR, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In participants with proteinuria>0.2 g/d, neither LDL-C (HR, 0.98; 95% CI, 0.98 to 1.05) nor total cholesterol levels were associated with renal outcomes. Treatment with statins was reported in 55% of patients and was differential across lipid categories.

Conclusions

In this large cohort of patients with CKD, total cholesterol, triglycerides, VLDL-C, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) were not independently associated with progression of kidney disease. There was an inverse relationship between LDL-C and total cholesterol levels and kidney disease outcomes in patients with low levels of proteinuria.     

Relationship between acute kidney injury before thoracic endovascular aneurysm repair and in-hospital outcomes in patients with type B acute aortic dissection

Objective Acute kidney injury (AKI) frequently occurs after catheter-based interventional procedures and increases mortality. However, the implications of AKI before thoracic endovascular aneurysm repair (TEVAR) of type B acute aortic dissection (AAD) remain unclear. This study evaluated the incidence, predictors, and in-hospital outcomes of AKI before TEVAR in patients with type B AAD. Methods Between 2009 and 2013, 76 patients were retrospectively evaluated who received TEVAR for type B AAD within 36 h from symptom onset. The patients were classified into no-AKI vs. AKI groups, and the severity of AKI was further staged according to kidney disease: improving global outcomes criteria before TEVAR. Results The incidence of preoperative AKI was 36.8%. In-hospital complications was significantly higher in patients with preoperative AKI compared with no-AKI (50.0% vs. 4.2%, respectively; P < 0.001), including acute renal failure (21.4% vs. 0, respectively; P < 0.001), and they increased with severity of AKI (P < 0.001). The maximum levels of body temperature and white blood cell count were significantly related to maximum serum creatinine level before TEVAR. Multivariate analysis showed that systolic blood pressure on admission (OR: 1.023; 95% CI: 1.003–1.044; P = 0.0238) and bilateral renal artery involvement (OR: 19.076; 95% CI: 1.914–190.164; P = 0.0120) were strong predictors of preoperative AKI. Conclusions Preoperative AKI frequently occurred in patients with type B AAD, and correlated with higher in-hospital complications and enhanced inflammatory reaction. Systolic blood pressure on admission and bilateral renal artery involvement were major risk factors for AKI before TEVAR.     

Randomized Trial of Bicarbonate or Saline Study for the Prevention of Contrast-Induced Nephropathy in Patients with CKD

Background and objectives

Sodium bicarbonate has been proposed for protection of the kidney from contrast-induced AKI (CIAKI). However, the effects of bicarbonate on long-term important clinical outcomes are uncertain.

Design, setting, participants, & measurements

In a prospective, double-blind, multicenter randomized clinical trial, 391 patients with an eGFR<45 ml/min per 1.73 m² undergoing elective coronary or peripheral angiography were randomized to an infusion with a high dose of isotonic sodium bicarbonate (target 2.0 mEq/kg) or a similar molar amount of isotonic sodium chloride. The primary outcome was a composite of mortality, dialysis, or a sustained 20% reduction in eGFR at 6 months.

Results

There were 391 patients enrolled between March 2010 and May 2012. The incidence of the primary outcome was 14.9% in the bicarbonate group and 16.3% in the control group in the intention-to-treat population (P=0.78). There was also no difference in the incidence of CIAKI between the treatment groups (14.5% versus 12.1%, respectively; P=0.20). CIAKI was associated with a higher incidence of sustained loss of kidney function at 6 months compared with those without CIAKI (21.2% versus 7.7%, respectively; P=0.06).

Conclusions

High-dose sodium bicarbonate infusion in patients with eGFR<45 ml/min per 1.73 m² undergoing angiography did not demonstrate a difference in incidence of the composite of death, dialysis, or sustained 6-month reduction in eGFR or CIAKI compared with sodium chloride.