Quantitative morphometrics reveals glomerular changes in patients with infrequent segmentally sclerosed glomeruli.

AIMS: Detection of one segmentally sclerosed glomerulus (SSG) identifies patients with focal segmental glomerulosclerosis (FSGS) but rare SSGs may be missed in kidney biopsies. It is unknown whether alterations of unaffected glomeruli in patients with infrequent SSG can be detected by quantitative morphometrics. METHODS: We determined SSG frequency and obtained quantitative morphometrics in glomeruli without a pathologic phenotype in large kidney sections of non-involved kidney tissue from 137 patients undergoing total nephrectomy. We used multivariate modelling to identify morphometrics independently associated with increasing frequency of SSG and Receiver Operator Curve (ROC) analysis to determine the ability of quantitative morphometrics to identify patients with FSGS. We used the geometric distribution to estimate the sensitivity and specificity of a needle biopsy to identify patients with FSGS. RESULTS: In seventy-one patients (51.8%), at least one SSG was observed, and of those, 39 (54.9%) had an SSG lesion in less than 2% of all glomeruli (mean of 249 glomeruli per specimen). Increasing percent of SSG was independently associated with decreasing podocyte density and increasing mesangial index in multivariate modelling. For infrequent SSG lesions (<1% of glomeruli), kidney biopsy could miss FSGS diagnosis more than 74% of the time, and podocyte density had an area under the curve (AUC) of 0.77, and mesangial index, an AUC of 0.79 to identify patients with FSGS. CONCLUSIONS: More than half of patients had FSGS, although 30% had infrequent SSG. Quantitative morphometrics in glomeruli without pathology, such as podocyte density and mesangial index, identified patients with infrequent SSG and may serve as clinical markers to identify patients with FSGS.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Modelling kidney disease using ontology: insights from the Kidney Precision Medicine Project.

An important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient's phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine.

Systems Biology and Kidney Disease.

The kidney is a complex organ responsible for maintaining multiple aspects of homeostasis in the human body. The combination of distinct, yet interrelated, molecular functions across different cell types make the delineation of factors associated with loss or decline in kidney function challenging. Consequently, there has been a paucity of new diagnostic markers and treatment options becoming available to clinicians and patients in managing kidney diseases. A systems biology approach to understanding the kidney leverages recent advances in computational technology and methods to integrate diverse sets of data. It has the potential to unravel the interplay of multiple genes, proteins, and molecular mechanisms that drive key functions in kidney health and disease. The emergence of large, detailed, multilevel biologic and clinical data from national databases, cohort studies, and trials now provide the critical pieces needed for meaningful application of systems biology approaches in nephrology. The purpose of this review is to provide an overview of the current state in the evolution of the field. Recent successes of systems biology to identify targeted therapies linked to mechanistic biomarkers in the kidney are described to emphasize the relevance to clinical care and the outlook for improving outcomes for patients with kidney diseases.

Atypical Presentation of Pregnancy-Related Hemolytic Uremic Syndrome.

The cause of acute kidney injury during pregnancy and in the postpartum period can be particularly challenging to diagnose, especially when it is necessary to differentiate among preeclampsia; eclampsia; hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome; and thrombotic microangiopathies (TMAs). All these disease entities can present with kidney failure, microangiopathic hemolytic anemia, and thrombocytopenia. We present a teaching case of atypical hemolytic uremic syndrome in the postpartum period in a young woman who was found to have mutations of uncertain clinical significance in the complement cascade, including in C3, CFH, and CFI. We use this as an opportunity to review the clinical presentation and pathophysiology of preeclampsia, eclampsia, and the TMAs. We focus on diagnostic challenges, especially because many patients with TMA do not present with thrombocytopenia, which can delay diagnosis. We additionally review the clinical settings in which administration of eculizumab, a C5 membrane attack complex inhibitor, is appropriate.

A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury.

RATIONALE: Acute kidney injury is a common and severe complication of critical illness and cardiac surgery. Despite significant attempts at developing treatments, therapeutic advances to attenuate acute kidney injury and expedite recovery have largely failed. OBJECTIVES: Identifying genetic loci associated with increased risk of acute kidney injury may reveal novel pathways for therapeutic development. METHODS: We conducted an exploratory genome-wide association study to identify single-nucleotide polymorphisms associated with genetic susceptibility to in-hospital acute kidney injury. MEASUREMENTS AND MAIN RESULTS: We genotyped 609,508 single-nucleotide polymorphisms and performed genotype imputation in 760 acute kidney injury cases and 669 controls. We then evaluated polymorphisms that showed the strongest association with acute kidney injury in a replication patient population containing 206 cases with 1,406 controls. We observed an association between acute kidney injury and four single-nucleotide polymorphisms at two independent loci on metaanalysis of discovery and replication populations. These include rs62341639 (metaanalysis P = 2.48 × 10-7; odds ratio [OR], 0.64; 95% confidence interval [CI], 0.55-0.76) and rs62341657 (P = 3.26 × 10-7; OR, 0.65; 95% CI, 0.55-0.76) on chromosome 4 near APOL1-regulator IRF2, and rs9617814 (metaanalysis P = 3.81 × 10-6; OR, 0.70; 95% CI, 0.60-0.81) and rs10854554 (P = 6.53 × 10-7; OR, 0.67; 95% CI, 0.57-0.79) on chromosome 22 near acute kidney injury-related gene TBX1. CONCLUSIONS: Our findings reveal two genetic loci that are associated with acute kidney injury. Additional studies should be conducted to functionally evaluate these loci and to identify other common genetic variants contributing to acute kidney injury.

Biomarkers of acute kidney injury and associations with short- and long-term outcomes.

Acute kidney injury is strongly associated with increased mortality and other adverse outcomes. Medical researchers have intensively investigated novel biomarkers to predict short- and long-term outcomes of acute kidney injury in many patient care settings, such as cardiac surgery, intensive care units, heart failure, and transplant. Future research should focus on leveraging this relationship to improve enrollment for clinical trials of acute kidney injury.

Amino-Terminal Pro-B-Type Natriuretic Peptide for Diagnosis and Prognosis in Patients With Renal Dysfunction: A Systematic Review and Meta-Analysis.

OBJECTIVES: This study sought to determine if amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has different diagnostic and prognostic utility in patients with renal dysfunction. BACKGROUND: Patients with renal dysfunction have higher NT-proBNP, which may complicate interpretation for diagnosis of acute decompensated heart failure (ADHF) or prognosis. METHODS: We searched MEDLINE and EMBASE through August 2014 for studies with a subgroup analysis by renal function of the diagnostic or prognostic ability of NT-proBNP. RESULTS: For diagnosis, 9 studies were included with 4,287 patients and 1,325 ADHF events. Patients were mostly divided into subgroups with and without renal dysfunction by an estimated glomerular filtration rate of 60 ml/min/1.73 m(2). In patients with renal dysfunction, the area under the curve (AUC) for NT-proBNP ranged from 0.66 to 0.89 with a median cutpoint of 1,980 pg/ml, while the AUC ranged from 0.72 to 0.95 with a cutpoint of 450 pg/ml in patients with preserved renal function. For prognosis, 30 studies with 32,203 patients were included, and mortality in patients with renal dysfunction (25.4%) was twice that of patients with preserved renal function (12.2%). The unadjusted pooled risk ratio for NT-proBNP and mortality was 3.01 (95% confidence interval [CI]: 2.53 to 3.58) in patients with preserved renal function and was similar in patients with renal dysfunction (3.25; 95% CI: 2.45 to 4.30). Upon meta-regression, heterogeneity was partially explained if patients with heart failure or coronary artery disease were enrolled. CONCLUSIONS: NT-proBNP retains utility for diagnosis of ADHF in patients with renal dysfunction with higher cutpoints. Elevated NT-proBNP confers a worse prognosis regardless of renal function.

Perioperative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine whether plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and postoperatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first postoperative log(H-FABP) was associated with severe AKI (adjusted odds ratio (OR) 5.39 (95% confidence interval (CI), 2.87-10.11) per unit increase), while preoperative log(H-FABP) was associated with any AKI (2.07 (1.48-2.89)) and mortality (1.67 (1.17-2.37)). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin. Thus, perioperative plasma H-FABP levels may be used for risk stratification of AKI and mortality following cardiac surgery.

A prospective investigation of coffee drinking and endometrial cancer incidence.

Coffee drinking may be associated with reduced risk of endometrial cancer; however, prospective data are limited. Further, it is not clear whether any association between coffee and endometrial cancer differs according to coffee caffeine content. The association of coffee drinking with incidence of endometrial cancer was evaluated among 226,732 women, aged 50-71, enrolled in the NIH-AARP Diet and Health Study who completed a baseline epidemiologic questionnaire. Following a mean 9.3 years of follow-up, data were available for 1,486 incident endometrial cancer cases. Cox proportional hazards models were used to estimate associations of coffee with endometrial cancer incidence. Sub-group analyses were performed according to smoking status, hormone therapy use (HT) and body habitus. Coffee drinking was inversely related to incidence of endometrial cancer (hazard ratio [HR] comparing drinking of >3 cups/day versus no cups = 0.64, 95% CI, 0.51-0.80; P(trend) = 0.0004). The association of coffee with endometrial cancer risk was apparent for consumption of both regular (HR per cup = 0.90, 95% CI, 0.86-0.95) and decaffeinated coffee (HR per cup = 0.93, 95% CI, 0.87-0.99). The relation of coffee with endometrial cancer incidence varied significantly by HT use (P(interaction) = 0.03) with an association only apparent among HT-never users (HR comparing drinking >3 cups/day versus no cups = 0.54, 95% CI, 0.41-0.72; P(trend) = 0.0005). Endometrial cancer incidence appears to be reduced among women that habitually drink coffee, an association that does not differ according to caffeine content.