Browsing by Subject "kidney failure"

Now showing 1 - 4 of 4
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    Molecular mechanisms and therapeutic targets for diabetic kidney disease
    (Elsevier, 2022) Tuttle, Katherine R.; Agarwal, Rajiv; Alpers, Charles E.; Bakris, George L.; Brosius, Frank C.; Kolkhof, Peter; Uribarri, Jaime; Medicine, School of Medicine
    Diabetic kidney disease has a high global disease burden and substantially increases the risk of kidney failure and cardiovascular events. Despite treatment, there is substantial residual risk of disease progression with existing therapies. Therefore, there is an urgent need to better understand the molecular mechanisms driving diabetic kidney disease to help identify new therapies that slow progression and reduce associated risks. Diabetic kidney disease is initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, and fibrotic processes that contribute to disease progression. This review summarizes existing evidence on the molecular drivers of diabetic kidney disease onset and progression, focusing on inflammatory and fibrotic mediators—factors that are largely unaddressed as primary treatment targets and for which there is increasing evidence supporting key roles in the pathophysiology of diabetic kidney disease. Results from recent clinical trials highlight promising new drug therapies, as well as a role for dietary strategies, in treating diabetic kidney disease
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    Prevalence and Persistence of Uremic Symptoms in Incident Dialysis Patients
    (ASN, 2020-02-01) Rhee, Eugene P.; Guallar, Eliseo; Hwang, Seungyoung; Kim, Noori; Tonelli, Marcello; Moe, Sharon M.; Himmelfarb, Jonathan; Thadhani, Ravi I.; Powe, Neil R.; Shafi, Tariq; Medicine, School of Medicine
    Background Uremic symptoms are major contributors to the poor quality of life among patients on dialysis, but whether their prevalence or intensity has changed over time is unknown. Methods We examined responses to validated questionnaires in two incident dialysis cohort studies, the Choices for Health Outcomes in Caring for ESRD (CHOICE) study (N=926, 1995–1998) and the Longitudinal United States/Canada Incident Dialysis (LUCID) study (N=428, 2011–2017). We determined the prevalence and severity of uremic symptoms—anorexia, nausea/vomiting, pruritus, sleepiness, difficulty concentrating, fatigue, and pain—in both cohorts. Results In CHOICE and LUCID, respectively, mean age of the participants was 58 and 60 years, 53% and 60% were male, and 28% and 32% were black. In both cohorts, 54% of the participants had diabetes. Median time from dialysis initiation to the symptoms questionnaires was 45 days for CHOICE and 77 days for LUCID. Uremic symptom prevalence in CHOICE did not change from baseline to 1-year follow-up and was similar across CHOICE and LUCID. Baseline symptom prevalence in CHOICE and LUCID was as follows: anorexia (44%, 44%, respectively), nausea/vomiting (36%, 43%), pruritus (72%, 63%), sleepiness (86%, 68%), difficulty concentrating (55%, 57%), fatigue (89%, 77%), and pain (82%, 79%). In both cohorts, >80% of patients had three or more symptoms and >50% had five or more symptoms. The correlation between individual symptoms was low (ρ<0.5 for all comparisons). In CHOICE, no clinical or laboratory parameter was strongly associated with multiple symptoms. Conclusions The burden of uremic symptoms among patients on dialysis is substantial and has not changed in the past 15 years. Improving quality of life will require identification of the factors that underlie the pathogenesis of uremic symptoms and better ways of removing the toxins that are responsible.
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    Renal C3 complement component: feed forward to diabetic kidney disease
    (Karger, 2015) Kelly, Katherine J.; Liu, Yunlong; Zhang, Jizhong; Dominguez, Jesus H.; Department of Medicine, IU School of Medicine
    BACKGROUND: Diabetic nephropathy is the main cause of end-stage renal disease and has reached epidemic proportions. METHODS: Comprehensive genomic profiling (RNAseq) was employed in the ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) model of diabetic nephropathy. Controls were lean littermates. RESULTS: Diabetic nephropathy in obese, diabetic ZS was accelerated by a single episode of renal ischemia (DI). This rapid renal decline was accompanied by the activation of the renal complement system in DI, and to a lesser extent in sham-operated diabetic rats (DS). In DI there were significant increases in renal mRNA encoding C3, C4, C5, C6, C8, and C9 over sham-operated lean normal controls (LS). Moreover, mRNAs encoding the receptors for the anaphylatoxins C3a and C5a were also significantly increased in DI compared to LS. The classic complement pathway was activated in diabetic kidneys with significant increases of C1qa, C1qb, and C1qc mRNAs in DI over LS. In addition, critical regulators of complement activation were significantly attenuated in DI and DS. These included mRNAs encoding CD55, decay accelerating factor, and CD59, which inhibit the membrane attack complex. C3, C4, and C9 proteins were demonstrated in renal tubules and glomeruli. The complement RNAseq data were incorporated into a gene network showing interactions among C3-generating renal tubular cells and other immune competent migratory cells. CONCLUSIONS: We conclude that local activation of the complement system mediates renal injury in diabetic nephropathy.
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    Renal iron overload in rats with diabetic nephropathy.
    (APS, 2015-12) Dominguez, Jesus H.; Liu, Yunlong; Kelly, Katherine J.; Department of Medicine, IU School of Medicine
    Diabetic nephropathy (DN) remains incurable and is the main cause of end‐stage renal disease. We approached the pathophysiology of DN with systems biology, and a comprehensive profile of renal transcripts was obtained with RNA‐Seq in ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) rats, a model of diabetic nephropathy. We included sham‐operated lean control rats (LS), sham‐operated diabetic (DS), and diabetic rats with induced renal ischemia (DI). Diabetic nephropathy in DI was accelerated by the single episode of renal ischemia. This progressive renal decline was associated with renal iron accumulation, although serum and urinary iron levels were far lower in DI than in LS. Furthermore, obese/diabetic ZS rats have severe dyslipidemia, a condition that has been linked to hepatic iron overload. Hence, we tested and found that the fatty acids oleic acid and palmitate stimulated iron accumulation in renal tubular cells in vitro. Renal mRNAs encoding several key proteins that promote iron accumulation were increased in DI. Moreover, renal mRNAs encoding the antioxidant proteins superoxide dismutase, catalase, and most of the glutathione synthetic system were suppressed, which would magnify the prooxidant effects of renal iron loads. Substantial renal iron loads occur in obese/diabetic rats. We propose that in diabetes, specific renal gene activation is partly responsible for iron accumulation. This state might be further aggravated by lipid‐stimulated iron uptake. We suggest that progressive renal iron overload may further advance renal injury in obese/diabetic ZS rats.