Nephrolithiasis as a Risk Factor for CKD: The Atherosclerosis Risk in Communities Study

Background and objectives

Previous studies demonstrated a higher risk of CKD in persons with a history of kidney stones, but these studies examined mostly white populations and did not evaluate important potential interactions such as race and plasma uric acid.

Design, setting, participants, & measurements

In 10,678 Atherosclerosis Risk in Communities (ARIC) study participants free of CKD at baseline (ARIC visit 4 in 1996–1998), we assessed the association between a history of nephrolithiasis (a time-varying variable, defined by a combination of self-report and diagnostic codes) and incident CKD (defined by diagnostic codes from linkage to hospitalizations and US Centers for Medicare and Medicaid Services’ records).

Results

At baseline, 856 participants had a history of nephrolithiasis; 322 developed nephrolithiasis during follow-up. Over a mean follow-up of 12 years, there were 1037 incident CKD events. Nephrolithiasis history was associated with a 29% (hazard ratio [HR], 1.29; 95% confidence interval [95% CI], 1.07 to 1.54) higher risk of CKD in demographic-adjusted analyses, but the association was no longer statistically significant after multivariable adjustment (HR, 1.09; 95% CI, 0.90 to 1.32). The multivariable-adjusted association was stronger among participants with plasma uric acid levels ≤6 mg/dl (HR, 1.34; 95% CI, 1.05 to 1.72) compared with those with levels >6 mg/dl (HR, 0.94; 95% CI, 0.70 to 1.28; P_interaction=0.05). There was no interaction of stone disease and race with incident CKD.

Conclusions

In this community-based cohort, nephrolithiasis was not an independent risk factor for incident CKD overall. However, risk of CKD was unexpectedly elevated in participants with stone disease and lower plasma uric acid levels.     

Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus

Summary

Background and objectives

Prior studies have examined long-term outcomes of a single acute kidney injury (AKI) event in hospitalized patients. We examined the effects of AKI episodes during multiple hospitalizations on the risk of chronic kidney disease (CKD) in a cohort with diabetes mellitus (DM).

Design, setting, participants, & measurements

A total of 4082 diabetics were followed from January 1999 until December 2008. The primary outcome was reaching stage 4 CKD (GFR of <30 ml/min per 1.73 m²). AKI during hospitalization was defined as >0.3 mg/dl or a 1.5-fold increase in creatinine relative to admission. Cox survival models examined the effect of first AKI episode and up to three episodes as time-dependent covariates, on the risk of stage 4 CKD. Covariates included demographic variables, baseline creatinine, and diagnoses of comorbidities including proteinuria.

Results

Of the 3679 patients who met eligibility criteria (mean age = 61.7 years [SD, 11.2]; mean baseline creatinine = 1.10 mg/dl [SD, 0.3]), 1822 required at least one hospitalization during the time under observation (mean = 61.2 months [SD, 25]). Five hundred thirty of 1822 patients experienced one AKI episode; 157 of 530 experienced ≥2 AKI episodes. In multivariable Cox proportional hazards models, any AKI versus no AKI was a risk factor for stage 4 CKD (hazard ratio [HR], 3.56; 95% confidence interval [CI], 2.76, 4.61); each AKI episode doubled that risk (HR, 2.02; 95% CI, 1.78, 2.30).

Conclusions

AKI episodes are associated with a cumulative risk for developing advanced CKD in diabetes mellitus, independent of other major risk factors of progression.     

Epidemiology and Clinical Correlates of AKI in Chinese Hospitalized Adults

Background and objectives

Comprehensive epidemiologic data on AKI are particularly lacking in Asian countries. This study sought to assess the epidemiology and clinical correlates of AKI among hospitalized adults in China.

Design, setting, participants, & measurements

This was a multicenter retrospective cohort study of 659,945 hospitalized adults from a wide range of clinical settings in nine regional central hospitals across China in 2013. AKI was defined and staged according to Kidney Disease Improving Global Outcomes criteria. The incidence of AKI in the cohort was estimated using a novel two-step approach with adjustment for the frequency of serum creatinine tests and other potential confounders. Risk factor profiles for hospital-acquired (HA) and community-acquired (CA) AKI were examined. The in-hospital outcomes of AKI, including mortality, renal recovery, length of stay, and daily cost, were assessed.

Results

The incidence of CA-AKI and HA-AKI was 2.5% and 9.1%, respectively, giving rise to an overall incidence of 11.6%. Although the risk profiles for CA-AKI and HA-AKI differed, preexisting CKD was a major risk factor for both, contributing to 20% of risk in CA-AKI and 12% of risk in HA-AKI. About 40% of AKI cases were possibly drug-related and 16% may have been induced by Chinese traditional medicines or remedies. The in-hospital mortality of AKI was 8.8%. The risk of in-hospital death was higher among patients with more severe AKI. Preexisting CKD and need for intensive care unit admission were associated with higher death risk in patients at any stage of AKI. Transiency of AKI did not modify the risk of in-hospital death. AKI was associated with longer length of stay and higher daily costs, even after adjustment for confounders.

Conclusion

AKI is common in hospitalized adults in China and is associated with significantly higher in-hospital mortality and resource utilization.     

Metabolically Healthy Obesity and Risk of Incident CKD

Background and objectives

Metabolically healthy obesity (MHO) is a unique obesity phenotype that apparently protects people from the metabolic complications of obesity. The association between MHO phenotype and incident CKD is unclear. Thus, this study investigated the association between MHO phenotype and incident CKD.

Design, setting, participants, & measurements

A total of 3136 Japanese participants were enrolled in an 8-year follow-up cohort study in 2001. Metabolically healthy status was assessed by common clinical markers: BP, triglycerides, HDL cholesterol, and fasting plasma glucose concentrations. Body mass index ≥25.0 kg/m² was defined as obesity. CKD was defined by proteinuria or eGFR of <60 ml/min per 1.73 m². To calculate the odds ratio for incident CKD, logistic regression analyses were performed.

Results

The crude incidence proportions of CKD were 2.6% (56 of 2122 participants) in participants with the metabolically healthy nonobesity phenotype, 2.6% (8 of 302) in those with the MHO phenotype, 6.7% (30 of 445) in those with the metabolically abnormal nonobesity phenotype, and 10.9% (29 of 267) in those with the metabolically abnormal obesity phenotype. Compared with metabolically healthy nonobesity phenotype, the odds ratios for incident CKD were 0.83 (95% confidence interval [95% CI], 0.36 to 1.72; P=0.64) for MHO, 1.44 (95% CI, 0.80 to 2.57; P=0.22) for metabolically abnormal nonobesity, and 2.80 (95% CI, 1.45 to 5.35; P=0.02) for metabolically abnormal obesity phenotype after adjustment for confounders, including age, sex, smoking statues, alcohol use, creatinine, uric acid, systolic BP, HDL cholesterol, and impaired fasting glucose or diabetes.

Conclusion

MHO phenotype was not associated with higher risk of incident CKD.     

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.     

Plasma Ceruloplasmin,a Regulator of Nitric Oxide Activity,and Incident Cardiovascular Risk in Patients with CKD

Background and objectives

Increased serum levels of the acute-phase reactant ceruloplasmin predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure, but their role in patients with CKD is unclear. This study investigated the relationship of ceruloplasmin with clinical outcomes in CKD, especially with regard to traditional cardiac biomarkers.

Design, setting, participants, & measurements

Serum ceruloplasmin levels in consecutive study participants with CKD (n=654; estimated GFR<60 ml/min per 1.73 m²) as well as a control group of non-CKD participants matched for age and sex (n=250) were measured. Study participants were enrolled during 2001–2006 from a population of patients presenting for elective diagnostic coronary angiography and prospectively followed for 3 years (median follow-up=1095 days) to determine incident major adverse cardiac events (defined as a composite of death, nonfatal myocardial infarction, and stroke).

Results

Serum ceruloplasmin levels in CKD patients were elevated versus controls (median [interquartile range]; 25.5 [21.8–29.6] versus 22.7 [19.7–26.5] mg/dl; P<0.001) and associated with increased risk of future major adverse cardiac events (hazard ratio, 1.35; 95% confidence interval, 1.0 to 1.82; P=0.04). After adjusting for traditional risk factors, higher serum ceruloplasmin was still associated with higher risk of major adverse cardiac events at 3 years (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.25; P=0.01).

Conclusion

In CKD patients, increased serum ceruloplasmin, a regulator of nitric oxide activity, is associated with increased risk of long-term adverse cardiovascular events, even after multivariable model adjustment for traditional clinical and biologic risk factors.     

CKD and Hypertension during Long-Term Follow-Up in Children and Adolescents Previously Treated with Extracorporeal Membrane Oxygenation

Background and objectives

Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined.

Design, setting, participants, & measurements

Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP≥95th percentile of reference values). CKD was suspected in children with either an eGFR<90 ml/min per 1.73 m² or proteinuria (urinary protein-to-creatinine ratio >0.50 for children ages ≤24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membrane oxygenation without preemptive hemofiltration.

Results

Median follow-up of 169 screened participants was 8.2 years (interquartile range=5.2–12.1 years). Nine children had a lower eGFR, but all rates were >60 ml/min per 1.73 m². Proteinuria was observed in 20 children (median=0.26 mg protein/mg creatinine; interquartile range=0.23–0.32 mg protein/mg creatinine), and 32 children had hypertension. Only history of AKI was associated with CKD (P=0.004). Children with RIFLE scores injury and failure had 4.3 times higher odds of CKD signs or hypertension than those without AKI (95% confidence interval, 1.6 to 12.1; P=0.004).

Conclusions

Altogether, 54 participants (32%) had at least one sign of CKD and/or hypertension. However, most values were marginally abnormal, with no immediate consequences for clinical care. Nevertheless, a prevalence of 32% clearly indicates that survivors of neonatal extracorporeal membrane oxygenation, especially those with AKI, are at risk of a more rapid decline of kidney function with increasing age. Therefore, screening for CKD development in adulthood is recommended.     

Utilization of Small Changes in Serum Creatinine with Clinical Risk Factors to Assess the Risk of AKI in Critically lll Adults

Background and objectives

Disease biomarkers require appropriate clinical context to be used effectively. Combining clinical risk factors, in addition to small changes in serum creatinine, has been proposed to improve the assessment of AKI. This notion was developed in order to identify the risk of AKI early in a patient''s clinical course. We set out to assess the performance of this combination approach.

Design, setting, participants, & measurements

A secondary analysis of data from a prospective multicenter intensive care unit cohort study (September 2009 to April 2010) was performed. Patients at high risk using this combination approach were defined as an early increase in serum creatinine of 0.1–0.4 mg/dl, depending on number of clinical factors predisposing to AKI. AKI was defined and staged using the Acute Kidney Injury Network criteria. The primary outcome was evolution to severe AKI (Acute Kidney Injury Network stages 2 and 3) within 7 days in the intensive care unit.

Results

Of 506 patients, 214 (42.2%) patients had early creatinine elevation and were deemed at high risk for AKI. This group was more likely to subsequently develop the primary endpoint (16.4% versus 1.0% [not at high risk], P<0.001). The sensitivity of this grouping for severe AKI was 92%, the specificity was 62%, the positive predictive value was 16%, and the negative predictive value was 99%. After adjustment for Sequential Organ Failure Assessment score, serum creatinine, and hazard tier for AKI, early creatinine elevation remained an independent predictor for severe AKI (adjusted relative risk, 12.86; 95% confidence interval, 3.52 to 46.97). Addition of early creatinine elevation to the best clinical model improved prediction of the primary outcome (area under the receiver operating characteristic curve increased from 0.75 to 0.83, P<0.001).

Conclusion

Critically ill patients at high AKI risk, based on the combination of clinical factors and early creatinine elevation, are significantly more likely to develop severe AKI. As initially hypothesized, the high-risk combination group methodology can be used to identify patients at low risk for severe AKI in whom AKI biomarker testing may be expected to have low yield. The high risk combination group methodology could potentially allow clinicians to optimize biomarker use.     

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.     

Preoperative Hemoglobin and Outcomes in Patients with CKD Undergoing Cardiac Surgery

Background and objectives

Preoperative anemia adversely affects outcomes of cardiothoracic surgery. However, in patients with CKD, treating anemia to a target of normal hemoglobin has been associated with increased risk of adverse cardiac and cerebrovascular events. We investigated the association between preoperative hemoglobin and outcomes of cardiac surgery in patients with CKD and assessed whether there was a level of preoperative hemoglobin below which the incidence of adverse surgical outcomes increases.

Design, setting, participants, & measurements

This prospective observational study included adult patients with CKD stages 3–5 (eGFR<60 ml/min per 1.73 m²) undergoing cardiac surgery from February 2000 to January 2010. Patients were classified into four groups stratified by preoperative hemoglobin level: <10, 10–11.9, 12–13.9, and ≥14 g/dl. The outcomes were postoperative AKI requiring dialysis, sepsis, cerebrovascular accident, and mortality.

Results

In total, 788 patients with a mean eGFR of 43.5±13.7 ml/min per 1.73 m² were evaluated, of whom 22.5% had preoperative hemoglobin within the normal range (men: 14–18 g/dl; women: 12–16 g/dl). Univariate analysis revealed an inverse relationship between the incidence of all adverse postoperative outcomes and hemoglobin level. Using hemoglobin as a continuous variable, multivariate logistic regression analysis showed a proportionally greater frequency of all adverse postoperative outcomes per 1-g/dl decrement of preoperative hemoglobin (mortality: odds ratio, 1.38; 95% confidence interval, 1.23 to 1.57; P<0.001; sepsis: odds ratio, 1.31; 95% confidence interval, 1.14 to 1.49; P<0.001; cerebrovascular accident: odds ratio, 1.31; 95% confidence interval, 1.00 to 1.67; P=0.03; postoperative hemodialysis: odds ratio, 1.38; 95% confidence interval, 1.11 to 1.75; P<0.01). Moreover, preoperative hemoglobin<12 g/dl was an independent risk factor for postoperative mortality (odds ratio, 2.6; 95% confidence interval, 1.1 to 7.3; P=0.04).

Conclusions

Similar to the general population, preoperative anemia is associated with adverse postoperative outcomes in patients with CKD. Whether outcomes could be improved by therapeutically targeting higher preoperative hemoglobin levels before cardiac surgery in patients with underlying CKD remains to be determined.     

NT-ProBNP and Troponin T and Risk of Rapid Kidney Function Decline and Incident CKD in Elderly Adults

Background and objectives

Elevations in N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin T are associated with poor cardiovascular outcomes. Whether elevations in these cardiac biomarkers are associated with decline in kidney function was evaluated.

Design, setting, participants, & measurements

N-terminal pro–B-type natriuretic peptide and troponin T were measured at baseline in 3752 participants free of heart failure in the Cardiovascular Health Study. eGFR was determined from the Chronic Kidney Disease Epidemiology Collaboration equation using serum cystatin C. Rapid decline in kidney function was defined as decline in serum cystatin C eGFR≥30%, and incident CKD was defined as the onset of serum cystatin C eGFR<60 among those without CKD at baseline (n=2786). Cox regression models were used to examine the associations of each biomarker with kidney function decline adjusting for demographics, baseline serum cystatin C eGFR, diabetes, and other CKD risk factors.

Results

In total, 503 participants had rapid decline in serum cystatin C eGFR over a mean follow-up time of 6.41 (1.81) years, and 685 participants developed incident CKD over a mean follow-up time of 6.41 (1.74) years. Participants in the highest quartile of N-terminal pro–B-type natriuretic peptide (>237 pg/ml) had an 67% higher risk of rapid decline and 38% higher adjusted risk of incident CKD compared with participants in the lowest quartile (adjusted hazard ratio for serum cystatin C eGFR rapid decline, 1.67; 95% confidence interval, 1.25 to 2.23; hazard ratio for incident CKD, 1.38; 95% confidence interval, 1.08 to 1.76). Participants in the highest category of troponin T (>10.58 pg/ml) had 80% greater risk of rapid decline compared with participants in the lowest category (adjusted hazard ratio, 1.80; 95% confidence interval, 1.35 to 2.40). The association of troponin T with incident CKD was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.92 to 1.50).

Conclusions

Elevated N-terminal pro–B-type natriuretic peptide and troponin T are associated with rapid decline of kidney function and incident CKD. Additional studies are needed to evaluate the mechanisms that may explain this association.     

The ABO Histo-Blood Group and AKI in Critically Ill Patients with Trauma or Sepsis

Background and objective

ABO blood types are determined by antigen modifications on glycoproteins and glycolipids and associated with altered plasma levels of inflammatory and endothelial injury markers implicated in AKI pathogenesis. We sought to determine the association of ABO blood types with AKI risk in critically ill patients with trauma or sepsis.

Design, setting, participants, & measurements

We conducted two prospective cohort studies at an urban, academic, level I trauma center and tertiary referral center; 497 patients with trauma admitted to the surgical intensive care unit between 2005 and 2010 with an injury severity score >15 and 759 patients with severe sepsis admitted to the medical intensive care unit between 2008 and 2013 were followed for 6 days for the development of incident AKI. AKI was defined by Acute Kidney Injury Network creatinine and dialysis criteria.

Results

Of 497 patients with trauma, 134 developed AKI (27%). In multivariable analysis, blood type A was associated with higher AKI risk relative to type O among patients of European descent (n=229; adjusted risk, 0.28 versus 0.14; risk difference, 0.14; 95% confidence interval, 0.03 to 0.24; P=0.02). Of 759 patients with sepsis, AKI developed in 326 (43%). Blood type A again conferred higher AKI risk relative to type O among patients of European descent (n=437; adjusted risk, 0.53 versus 0.40; risk difference, 0.14; 95% confidence interval, 0.04 to 0.23; P=0.01). Findings were similar when analysis was restricted to those patients who did not develop acute respiratory distress syndrome or were not transfused. We did not detect a significant association between blood type and AKI risk among individuals of African descent in either cohort.

Conclusions

Blood type A is independently associated with AKI risk in critically ill patients with trauma or severe sepsis of European descent, suggesting a role for ABO glycans in AKI susceptibility.     

Serum Creatinine Changes Associated with Critical Illness and Detection of Persistent Renal Dysfunction after AKI

Background and objectives

AKI is a risk factor for development or worsening of CKD. However, diagnosis of renal dysfunction by serum creatinine could be confounded by loss of muscle mass and creatinine generation after critical illness.

Design, setting, participants, & measurements

A retrospective, single center analysis of serum in patients surviving to hospital discharge with an intensive care unit admission of 5 or more days between 2009 and 2011 was performed.

Results

In total, 700 cases were identified, with a 66% incidence of AKI. In 241 patients without AKI, creatinine was significantly lower (P<0.001) at hospital discharge than admission (median, 0.61 versus 0.88 mg/dl; median decrease, 33%). In 160 patients with known baseline, discharge creatinine was significantly lower than baseline in all patients except those patients with severe AKI (Kidney Disease Improving Global Outcomes category 3), who had no significant difference. In a multivariable regression model, median duration of hospitalization was associated with a predicted 30% decrease (95% confidence interval, 8% to 45%) in creatinine from baseline in the absence of AKI; after allowing for this effect, AKI was associated with a 29% (95% confidence interval, 10% to 51%) increase in predicted hospital discharge creatinine. Using a similar model to exclude the confounding effect of prolonged major illness on creatinine, 148 of 700 patients (95% confidence interval, 143 to 161) would have eGFR<60 ml/min per 1.73 m² at hospital discharge compared with only 63 of 700 patients using eGFR based on unadjusted hospital creatinine (a 135% increase in potential CKD diagnoses; P<0.001).

Conclusion

Critical illness is associated with significant falls in serum creatinine that persist to hospital discharge, potentially causing inaccurate assessment of renal function at discharge, particularly in survivors of AKI. Prospective measurements of GFR and creatinine generation are required to confirm the significance of these findings.     

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.     

Association of a Polymorphism in a Gene Encoding a Urate Transporter with CKD Progression

Background and objectives

Hyperuricemia predicts a high risk for CKD progression but there is no large clinical trial in humans indicating that this relationship is causal in nature. The rs734553 single-nucleotide polymorphism (SNP) of the GLUT9 urate transporter gene was strongly associated with uric acid (UA) levels in a large meta-analysis.

Design, setting, participants, & measurements

This prospective study adopted the Mendelian randomization approach. The rs734553 SNP was used as an instrumental variable to investigate the relationship between UA and renal outcomes in a cohort of 755 patients with CKD who were enrolled between October 18, 2005, and October 2, 2008. The association between the polymorphism and UA was preliminary confirmed in a series of 211 healthy volunteers enrolled between January 1, 2001, and July 12, 2011, from the same geographic area as the patients with CKD. The study end point was a composite renal–end point (i.e., >30% decrease in the GFR, dialysis, or transplantation). Patients were followed up for a median of 36 months.

Results

In healthy individuals, serum UA levels were highest in homozygotes for the T allele (risk allele), intermediate in heterozygotes for the same allele, and lowest in those without the risk allele (P<0.001), but no such relationship was found in patients with CKD. In the CKD cohort, homozygotes (TT) and heterozygotes (GT) for the risk allele had a 2.35 times higher risk (hazard ratio, 2.35; 95% confidence interval, 1.25 to 4.42; P=0.008) of CKD progression. The risk for CKD progression by rs734553 remained unmodified in analyses adjusting for proteinuria, GFR, and other classical and CKD-peculiar risk factors.

Conclusions

A GLUT9 polymorphism, which is strongly associated with serum UA levels in healthy individuals of the general population with normal renal function, holds a strong predictive power for CKD progression. These findings are compatible with the hypothesis that the link between UA and CKD progression is causal in nature.     

Peripheral Edema,Central Venous Pressure,and Risk of AKI in Critical Illness

Background and objectives

Although venous congestion has been linked to renal dysfunction in heart failure, its significance in a broader context has not been investigated.

Design, setting, participants, & measurements

Using an inception cohort of 12,778 critically ill adult patients admitted to an urban tertiary medical center between 2001 and 2008, we examined whether the presence of peripheral edema on admission physical examination was associated with an increased risk of AKI within the first 7 days of critical illness. In addition, in those with admission central venous pressure (CVP) measurements, we examined the association of CVPs with subsequent AKI. AKI was defined using the Kidney Disease Improving Global Outcomes criteria.

Results

Of the 18% (n=2338) of patients with peripheral edema on admission, 27% (n=631) developed AKI, compared with 16% (n=1713) of those without peripheral edema. In a model that included adjustment for comorbidities, severity of illness, and the presence of pulmonary edema, peripheral edema was associated with a 30% higher risk of AKI (95% confidence interval [95% CI], 1.15 to 1.46; P<0.001), whereas pulmonary edema was not significantly related to risk. Peripheral edema was also associated with a 13% higher adjusted risk of a higher AKI stage (95% CI, 1.07 to 1.20; P<0.001). Furthermore, levels of trace, 1+, 2+, and 3+ edema were associated with 34% (95% CI, 1.10 to 1.65), 17% (95% CI, 0.96 to 1.14), 47% (95% CI, 1.18 to 1.83), and 57% (95% CI, 1.07 to 2.31) higher adjusted risk of AKI, respectively, compared with edema-free patients. In the 4761 patients with admission CVP measurements, each 1 cm H₂O higher CVP was associated with a 2% higher adjusted risk of AKI (95% CI, 1.00 to 1.03; P=0.02).

Conclusions

Venous congestion, as manifested as either peripheral edema or increased CVP, is directly associated with AKI in critically ill patients. Whether treatment of venous congestion with diuretics can modify this risk will require further study.     

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.     

False-Positive Rate of AKI Using Consensus Creatinine–Based Criteria

Background and objectives

Use of small changes in serum creatinine to diagnose AKI allows for earlier detection but may increase diagnostic false–positive rates because of inherent laboratory and biologic variabilities of creatinine.

Design, setting, participants, & measurements

We examined serum creatinine measurement characteristics in a prospective observational clinical reference cohort of 2267 adult patients with AKI by Kidney Disease Improving Global Outcomes creatinine criteria and used these data to create a simulation cohort to model AKI false–positive rates. We simulated up to seven successive blood draws on an equal population of hypothetical patients with unchanging true serum creatinine values. Error terms generated from laboratory and biologic variabilities were added to each simulated patient’s true serum creatinine value to obtain the simulated measured serum creatinine for each blood draw. We determined the proportion of patients who would be erroneously diagnosed with AKI by Kidney Disease Improving Global Outcomes creatinine criteria.

Results

Within the clinical cohort, 75.0% of patients received four serum creatinine draws within at least one 48-hour period during hospitalization. After four simulated creatinine measurements that accounted for laboratory variability calculated from assay characteristics and 4.4% of biologic variability determined from the clinical cohort and publicly available data, the overall false–positive rate for AKI diagnosis was 8.0% (interquartile range =7.9%–8.1%), whereas patients with true serum creatinine ≥1.5 mg/dl (representing 21% of the clinical cohort) had a false–positive AKI diagnosis rate of 30.5% (interquartile range =30.1%–30.9%) versus 2.0% (interquartile range =1.9%–2.1%) in patients with true serum creatinine values <1.5 mg/dl (P<0.001).

Conclusions

Use of small serum creatinine changes to diagnose AKI is limited by high false–positive rates caused by inherent variability of serum creatinine at higher baseline values, potentially misclassifying patients with CKD in AKI studies.     

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.     

A Prospective International Multicenter Study of AKI in the Intensive Care Unit

Background and objectives

AKI is frequent and is associated with poor outcomes. There is limited information on the epidemiology of AKI worldwide. This study compared patients with AKI in emerging and developed countries to determine the association of clinical factors and processes of care with outcomes.

Design, setting, participants, & measurements

This prospective observational study was conducted among intensive care unit patients from nine centers in developed countries and five centers in emerging countries. AKI was defined as an increase in creatinine of ≥0.3 mg/dl within 48 hours.

Results

Between 2008 and 2012, 6647 patients were screened, of whom 1275 (19.2%) developed AKI. A total of 745 (58% of those with AKI) agreed to participate and had complete data. Patients in developed countries had more sepsis (52.1% versus 38.0%) and higher Acute Physiology and Chronic Health Evaluation (APACHE) scores (mean±SD, 61.1±27.5 versus 51.1±25.2); those from emerging countries had more CKD (54.3% versus 38.3%), GN (6.3% versus 0.9%), and interstitial nephritis (7.0% versus 0.6%) (all P<0.05). Patients from developed countries were less often treated with dialysis (15.5% versus 30.2%; P<0.001) and started dialysis later after AKI diagnosis (2.0 [interquartile range, 0.75–5.0] days versus 0 [interquartile range, 0–5.0] days; P=0.02). Hospital mortality was 22.0%, and 13.3% of survivors were dialysis dependent at discharge. Independent risk factors associated with hospital mortality included older age, residence in an emerging country, use of vasopressors (emerging countries only), dialysis and mechanical ventilation, and higher APACHE score and cumulative fluid balance (developed countries only). A lower probability of renal recovery was associated with residence in an emerging country, higher APACHE score (emerging countries only) and dialysis, while mechanical ventilation was associated with renal recovery (developed countries only).

Conclusions

This study contrasts the clinical features and management of AKI and demonstrates worse outcomes in emerging than in developed countries. Differences in variations in care may explain these findings and should be considered in future trials.