Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current ...pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.
Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we ...examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio ≥30 mg/g and/or estimated GFR ≤60 ml/min per 1.73 m(2), was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval 95% CI, 7.0%-8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%-15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%-7.7%), adjusted for demographics, and 3.4% (95% CI, -0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%-37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%-29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%-29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes.
Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of ...59 participants with nondiabetic CKD (mean eGFR =37.6 ml/min per 1.73 m(2)) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemic-euglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (meanSD 3.92.0 versus 5.0 2.0 mg/min per µU/ml; P<0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P<0.001) and was also lower in participants with CKD than controls (876 226 versus 998 212 ml/min; P<0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, -0.7; 95% confidence interval, -1.4 to 0.0 mg/min per µU/ml) and insulin clearance (adjusted difference, -85; 95% confidence interval, -160 to -10 ml/min). Among participants with CKD, eGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65% of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.
Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework ...for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.
The prevalence of chronic kidney disease (CKD) is increasing, leading to significant morbidity and mortality. Kidney biopsy remains the gold standard for diagnosing the underlying etiology of CKD, ...but the procedure carries complication risks. The aim of this study was to identify novel noninvasive biomarkers correlating with kidney function and histopathology in biopsy-proven CKD patients.
We profiled 2402 urinary microRNAs (miRNAs) to identify and confirm differentially expressed miRNAs associated with kidney function and histopathology in patients with diabetic nephropathy (n = 58) or lupus nephritis (n = 89), important etiologies of CKD, compared with healthy controls (n = 93 and 119, respectively). Top performing miRNAs were then measured in 2 independent multi-institutional cohorts of patients with diabetes mellitus with (n = 74) or without nephropathy (n = 71) and systemic lupus erythematosus with (n = 86) or without (n = 37) nephritis.
In patients with diabetic nephropathy, miR-2861, miR-1915-3p, and miR-4532 were down-regulated (>10-fold,
< 0.0001) and were associated with estimated glomerular filtration rate (
< 0.01) and interstitial fibrosis/tubular atrophy (
< 0.05). The
-statistics for miR-2861, miR-1915-3p, and miR-4532 were 0.91, 0.86, and 0.85, respectively. In lupus nephritis patients, miR-3201 and miR-1273e were down-regulated (>3-fold,
< 0.0001) and associated with endocapillary glomerular inflammation (
< 0.01), with
-statistics of 0.97 and 0.91, respectively.
We have identified novel miRNAs that correlate with histopathological lesions and functional markers of kidney damage to facilitate sensitive, specific, and noninvasive detection of diabetic nephropathy and lupus nephritis.
Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of ...underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range−68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction.
•Urinary excretion rate and plasma concentration of 60 metabolites differed significantly in CKD patients versus controls.•Pathway analysis revealed that the citric acid cycle was the most significantly affected.•Expression of genes regulating TCA cycle was significantly reduced in kidney biopsies.
Chronic kidney disease (CKD) is very common and carries a high risk of complications and death. Patients with advanced disease have severe fatigue, organ dysfunction beyond the kidneys, and disturbances in sugar, protein and fat metabolism. We found many metabolites that differed significantly in kidney patients versus healthy controls. Analysis revealed that the citric acid cycle was the most significantly affected metabolic pathway. The citric acid cycle is performed in the cells` mitochondria and is the central metabolic hub where fuel molecules are converted into energy. This supports the view of CKD as a state of mitochondrial dysfunction.
Blacks have high rates of cardiovascular disease and mortality. Diabetes and CKD, risk factors for cardiovascular mortality in the general population, are common among blacks. We sought to assess ...their contribution to cardiovascular disease and mortality in blacks.
This observational cohort study was of 3211 participants in the Jackson Heart Study (enrolled 2000-2004). Rates of incident stroke, incident coronary heart disease, and cardiovascular mortality were quantified in participants with diabetes, CKD (eGFR<60 ml/min per 1.73 m(2), urine albumin-to-creatinine ratio ≥30 mg/g, or both), or both through 2012, with a median follow-up of 6.99 years.
Four hundred fifty-six (14.2%) participants had only diabetes, 257 (8.0%) had only CKD, 201 (6.3%) had both, and 2297 (71.5%) had neither. Diabetes without CKD was associated with excess risks of incident stroke, incident coronary heart disease, and cardiovascular mortality after adjustment for demographic and clinical covariates, including prevalent cardiovascular disease (excess incidence rates, 2.6; 95% confidence interval, 0.5 to 4.7; 2.6; 95% confidence interval, 0.3 to 4.8; and 2.4; 95% confidence interval, 0.4 to 4.3 per 1000 person-years, respectively). CKD without diabetes was associated with comparable nonsignificant excess risks for incident stroke and coronary heart disease (2.5; 95% confidence interval, -0.1 to 5.2 and 2.4; 95% confidence interval, -0.8 to 5.5 per 1000 person-years, respectively) but a larger excess risk for cardiovascular mortality (7.3; 95% confidence interval, 3.0 to 11.5 per 1000 person-years). Diabetes and CKD together were associated with greater excess risks for incident stroke (13.8; 95% confidence interval, 5.3 to 22.3 per 1000 person-years), coronary heart disease (12.8; 95% confidence interval, 4.9 to 20.8 per 1000 person-years), and cardiovascular mortality (14.8; 95% confidence interval, 7.2 to 22.3 per 1000 person-years). The excess risks associated with the combination of diabetes and CKD were larger than those associated with established risk factors, including prevalent cardiovascular disease.
The combination of diabetes and kidney disease is associated with substantial excess risks of cardiovascular events and mortality among blacks.
Diabetes, more frequently type 1, but increasingly also type 2, commonly occurs in childhood. While more advanced diabetic kidney disease (DKD), e.g., loss of glomerular filtration rate (GFR), does ...not occur until adulthood, kidney biopsies show DKD structural changes as early as 1.5–5 years after the onset of type 1 diabetes. Earliest clinical sign of DKD, increased urine albumin excretion, commonly appears during childhood and adolescence and presents an important opportunity to detect and intervene in early DKD, perhaps more successfully than later in the disease course. Longitudinal studies of type 1 diabetes have enriched our understanding of the DKD natural history and modifiable risk factors for DKD progression. These studies have also shown that the presence of DKD marks a subset of people with diabetes who are at the highest risk of early mortality, supporting an enhanced focus on DKD detection, prevention, and treatment. Early studies suggest that youth-onset type 2 diabetes is associated with a higher prevalence of comorbidities and risk factors and follows a more aggressive natural history. A deeper understanding of the natural history, risk factors, underlying mechanisms and therapeutic options for DKD in young-onset type 2 diabetes awaits further studies.
Biomarker discovery approaches in urine have been hindered by concerns for reproducibility and inadequate standardization of proteomics protocols. In this study, we describe an optimized quantitative ...proteomics strategy for urine biomarker discovery, which is applicable to fresh or long frozen samples. We used urine from healthy controls to standardize iTRAQ (isobaric tags for relative and absolute quantitation) for variation induced by protease inhibitors, starting protein and iTRAQ label quantities, protein extraction methods, and depletion of albumin and immunoglobulin G (IgG). We observed the following: (a) Absence of protease inhibitors did not affect the number or identity of the high confidence proteins. (b) Use of less than 20 µg of protein per sample led to a significant drop in the number of identified proteins. (c) Use of as little as a quarter unit of an iTRAQ label did not affect the number or identity of the identified proteins. (d) Protein extraction by methanol precipitation led to the highest protein yields and the most reproducible spectra. (e) Depletion of albumin and IgG did not increase the number of identified proteins or deepen the proteome coverage. Applying this optimized protocol to four pairs of long frozen urine samples from diabetic Pima Indians with or without nephropathy, we observed patterns suggesting segregation of cases and controls by iTRAQ spectra. We also identified several previously reported candidate biomarkers that showed trends toward differential expression, albeit not reaching statistical significance in this small sample set.
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