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1.
Kidney Int ; 97(4): 793-804, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32093917

RESUMO

Atherosclerotic renovascular disease (ARVD) reduces tissue perfusion and eventually leads to loss of kidney function with limited therapeutic options. Here we describe results of Phase 1a escalating dose clinical trial of autologous mesenchymal stem cell infusion for ARVD. Thirty-nine patients with ARVD were studied on two occasions separated by three months. Autologous adipose-derived mesenchymal stem cells were infused through the renal artery in 21 patients at three different dose levels (1, 2.5 and 5.0 × 105 cells/kg) in seven patients each. We measured renal blood flow, glomerular filtration rate (GFR) (iothalamate and estimated GFR), renal vein cytokine levels, blood pressure, and tissue oxygenation before and three months after stem cell delivery. These indices were compared to those of 18 patients with ARVD matched for age, kidney function and blood pressure receiving medical therapy alone that underwent an identical study protocol. Cultured mesenchymal stem cells were also studied in vitro. For the entire stem cell treated-cohort, mean renal blood flow in the treated stenotic kidney significantly increased after stem cell infusion from (164 to 190 ml/min). Hypoxia, renal vein inflammatory cytokines, and angiogenic biomarkers significantly decreased following stem cell infusion. Mean systolic blood pressure significantly fell (144 to 136 mmHg) and the mean two-kidney GFR (Iothalamate) modestly but significantly increased from (53 to 56 ml/min). Changes in GFR and blood pressure were largest in the high dose stem cell treated individuals. No such changes were observed in the cohort receiving medical treatment alone. Thus, our data demonstrate the potential for autologous mesenchymal stem cell to increase blood flow, GFR and attenuate inflammatory injury in post-stenotic kidneys. The observation that some effects are dose-dependent and related to in-vitro properties of mesenchymal stem cell may direct efforts to maximize potential therapeutic efficacy.

3.
J Gen Intern Med ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792867

RESUMO

BACKGROUND: People with chronic kidney disease (CKD) are at risk for adverse events and/or CKD progression with use of renally eliminated or nephrotoxic medications. OBJECTIVE: To examine the prevalence of potentially inappropriate medication (PIM) use by U.S. adults by CKD stage and self-reported CKD awareness. DESIGN: Cross-sectional analysis of National Health and Nutrition Examination Surveys, 2011-2016 PARTICIPANTS: Non-pregnant adults with stages 3a (eGFR 45-59 mL/min/1.73 m2), 3b (eGFR 30-44), or 4-5 (eGFR < 30) CKD, stratified as CKD-aware/unaware. MAIN MEASURES: PIMs were identified on the basis of KDIGO guidelines, label information, and literature review. We calculated proportions using any and individual PIMs, assessing for differences over CKD awareness within each CKD stage. Analyses were adjusted for age, sex, race/ethnicity, education, comorbidities, and insurance type. KEY RESULTS: Adjusted proportions of U.S. adults taking any PIM(s) exceeded 50% for all CKD stages and awareness categories, and were highest among CKD-unaware patients with stages 4-5 CKD: 66.6% (95% CI, 55.5-77.8). Proton pump inhibitors, opioids, metformin, sulfonylureas, and non-steroidal anti-inflammatory drugs (NSAIDs) were all used frequently across CKD stages. NSAIDs were used less frequently when CKD-aware by patients with stage 3a CKD (2.2% [95% CI, - 0.3 to 4.7] vs. 10.7% [95% CI, 7.6 to 13.8]) and stages 4-5 CKD (0.8% [95% CI, - 0.9 to 2.5] vs. 16.5% [95% CI, 4.0 to 29.0]). Metformin was used less frequently when CKD-aware by patients with stage 3b CKD (8.1% [95% CI, 0.3-15.9] vs. 26.5% [95% CI, 17.4-35.7]) and stages 4-5 CKD (none vs. 20.8% [95% CI, 1.8-39.8]). The impact of CKD awareness was statistically significant after correction for multiple comparisons only for NSAIDs in stage 3a CKD. CONCLUSIONS: PIMs are frequently used by people with CKD, with some impact of CKD awareness on NSAID and metformin use. This may lead to adverse outcomes or hasten CKD progression, reinforcing the need for improved medication management among people with CKD.

4.
Can Urol Assoc J ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31599719

RESUMO

INTRODUCTION: While medically induced end-stage renal disease (m-ESRD) has been well-studied, outcomes in patients with surgically induced ESRD (s-ESRD) are unknown. We sought to quantitatively compare the non-oncological outcomes for s-ESRD and m-ESRD in a large population-based cohort. METHODS: Medicare patients >65 years old initiating hemodialysis were identified using the U.S. Renal Data System database (2000‒2012). Metastatic cancer, prior transplant history, and nephrectomy for polycystic kidney disease were exclusion criteria. Patients were classified as having s-ESRD or m-ESRD based on hospital and physician claims for nephrectomy within a year preceding the onset of maintenance hemodialysis. Outcomes included non-cancer mortality (NCM), overall survival (OS), cardiovascular event (CVE), and renal transplantation. Time-to-event analyses were performed using Kaplan-Meier and cumulative incidence curves, and multivariable Cox and Fine-and-Grey regression models. RESULTS: The cohort included 312 612 patients, of whom 1648 (0.53%) had s-ESRD. Compared to m-ESRD patients, s-ESRD patients had a significantly lower five-year cumulative incidence of NCM (68% vs. 80%; p<0.001) and CVE (62% vs. 68%; p<0.001), with a correspondingly higher probability of OS (22% vs. 17%; p<0.001) and rate of renal transplantation (3.6% vs. 2.0%; p<0.001). On multivariable analyses, s-ESRD remained associated with lower risks of NCM (p<0.001) and CVE (p<0.001), improved OS (p<0.001), and higher chance of renal transplantation (p<0.001). CONCLUSIONS: While outcomes for s-ESRD appear more favorable than m-ESRD, s-ESRD is still associated with a substantial risk of NCM and CVE, and a low incidence of renal transplantation in Medicare patients >65 years old. These non-oncological outcomes are worth considering in patients potentially facing postoperative ESRD.

5.
EBioMedicine ; 47: 446-456, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31542391

RESUMO

BACKGROUND: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. METHODS: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ±â€¯3·1 years old; 2 female; BMI:33·9 ±â€¯2·3 kg/m2; eGFR:27·0 ±â€¯2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. FINDINGS: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ß-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. INTERPRETATION: "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.


Assuntos
Senescência Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Nefropatias Diabéticas/metabolismo , Quercetina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Idoso , Biomarcadores , Biópsia , Ensaios Clínicos Fase I como Assunto , Dasatinibe/uso terapêutico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Testes de Função Renal , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Quercetina/uso terapêutico
6.
Clin J Am Soc Nephrol ; 14(8): 1213-1227, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31362990

RESUMO

BACKGROUND AND OBJECTIVES: Dialysis is a preference-sensitive decision where prognosis may play an important role. Although patients desire risk prediction, nephrologists are wary of sharing this information. We reviewed the performance of prognostic indices for patients starting dialysis to facilitate bedside translation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Systematic review and meta-analysis following the PRISMA guidelines. We searched Ovid MEDLINE, Ovid Embase, Ovid Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus for eligible studies of patients starting dialysis published from inception to December 31, 2018. SELECTION CRITERIA: Articles describing validated prognostic indices predicting mortality at the start of dialysis. We excluded studies limited to prevalent dialysis patients, AKI and studies excluding mortality in the first 1-3 months. Two reviewers independently screened abstracts, performed full text assessment of inclusion criteria and extracted: study design, setting, population demographics, index performance and risk of bias. Pre-planned random effects meta-analysis was performed stratified by index and predictive window to reduce heterogeneity. RESULTS: Of 12,132 articles screened and 214 reviewed in full text, 36 studies were included describing 32 prognostic indices. Predictive windows ranged from 3 months to 10 years, cohort sizes from 46 to 52,796. Meta-analysis showed discrimination area under the curve (AUC) of 0.71 (95% confidence interval, 0.69 to 073) with high heterogeneity (I 2=99.12). Meta-analysis by index showed highest AUC for The Obi, Ivory, and Charlson comorbidity index (CCI)=0.74, also CCI was the most commonly used (ten studies). Other commonly used indices were Kahn-Wright index (eight studies, AUC 0.68), Hemmelgarn modification of the CCI (six studies, AUC 0.66) and REIN index (five studies, AUC 0.69). Of the indices, ten have been validated externally, 16 internally and nine were pre-existing validated indices. Limitations include heterogeneity and exclusion of large cohort studies in prevalent patients. CONCLUSIONS: Several well validated indices with good discrimination are available for predicting survival at dialysis start.

8.
Transl Res ; 213: 112-123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356770

RESUMO

Obesity and dyslipidemia can be associated with cellular senescence, and may impair kidney function. However, whether senescence contributes to renal dysfunction in these conditions remains unclear. Quercetin is an abundant dietary flavonoid that selectively clears inhibiting PI3K/AKT and p53/p21/serpines and inducing apoptosis. We hypothesized that high-fat-diet-induced obesity causes renal senescence, which would be mitigated by quercetin. C57BL/6J mice fed either standard chow or high-fat diets (HFDs) were treated with quercetin (50 mg/kg) or vehicle 5-days biweekly via oral gavage for 10 weeks. Subsequently, renal function was studied in vivo using magnetic resonance imaging, and renal senescence and histology were evaluated ex vivo. Mice fed with a HFD developed obesity and hypercholesterolemia, whereas renal size remained unchanged. Murine obesity impaired renal function and cortical oxygenation, and induced glomerulomegaly. Renal markers of senescence (eg, expression of p16, p19, and p53) and its secretory phenotype were upregulated in the obese hypercholesterolemic compared to lean mice in renal tubular cells, but attenuated in quercetin-treated murine kidneys, as was renal fibrosis. Quercetin treatment also increased renal cortical oxygenation and decreased plasma creatinine levels in obese mice, whereas body weight and cholesterol levels were unaltered. Therefore, murine obesity and dyslipidemia induce renal tissue senescence and impairs kidney function, which is alleviated by chronic senolytic treatment. These findings implicate senescence in loss of kidney function in murine dyslipidemia and obesity, and support further studies of senolytic therapy in obesity.

9.
Cell Transplant ; 28(9-10): 1271-1278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31250656

RESUMO

Mesenchymal stromal/stem cells (MSCs) belong to the endogenous cellular reparative system, and can be used exogenously in cell-based therapy. MSCs release extracellular vesicles (EVs), including exosomes and microvesicles, which mediate some of their therapeutic activity through intercellular communication. We have previously demonstrated that metabolic syndrome (MetS) modifies the cargo packed within swine EV, but whether it influences their phenotypical characteristics remains unclear. This study tested the hypothesis that MetS shifts the size distribution of MSC-derived EVs. Adipose tissue-derived MSC-EV subpopulations from Lean (n = 6) and MetS (n = 6) pigs were characterized for number and size using nanoparticle-tracking analysis, flow cytometry, and transmission electron microscopy. Expression of exosomal genes was determined using next-generation RNA-sequencing (RNA-seq). The number of EV released from Lean and MetS pig MSCs was similar, yet MetS-MSCs yielded a higher proportion of small-size EVs (202.4 ± 17.7 nm vs. 280.3 ± 15.1 nm), consistent with exosomes. RNA-seq showed that their EVs were enriched with exosomal markers. Lysosomal activity remained unaltered in MetS-MSCs. Therefore, MetS alters the size distribution of MSC-derived EVs in favor of exosome release. These observations may reflect MSC injury and membrane recycling in MetS or increased expulsion of waste products, and may have important implications for development of adequate cell-based treatments.

10.
J Psychosom Res ; 121: 68-73, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003856

RESUMO

OBJECTIVE: Cannabis is the most commonly used non-alcohol intoxicant in the general population. There are no consistent guidelines on the implications of cannabis abuse and dependence (CAD) in kidney transplant candidates. The aims of this study were to characterize kidney transplant candidates with comorbid CAD and examine the implications of CAD on transplant candidacy. METHOD: This was a retrospective cohort study of kidney transplant candidates meeting diagnostic criteria for CAD at a tertiary center from 2012 to 2016. Candidates were reviewed for psychiatric and substance use disorders (SUDs), family history, and medical variables. The cohort was divided by severity of CAD and transplant listing status for comparisons. Statistical analysis included Kruskal-Wallis tests for continuous variables and Fisher's Exact Test for categorical variables. RESULTS: Sixty-one of 2067 (3%) kidney transplant candidates met criteria for CAD, and 13/61 (21%) underwent transplantation. Of 61, 58% smoked cannabis daily, 47% had alcohol dependence history, 31% had other illicit drug dependencies, 38% were smokers, 60% had a SUD family history, and 42% and 27% had depressive and anxiety disorders, respectively. Severity of CAD was inversely associated with transplant listing; those with cannabis abuse were more often listed than those with dependence (67% vs 33%, p = .02) by study end. Three case presentations illustrate cannabis-related issues. CONCLUSION: In this cohort, kidney transplant candidates with comorbid CAD have high prevalence of other substance use disorders, psychiatric comorbidities, and strong family histories of addictions that resemble other SUD populations. These findings have implications for pre-transplant screening and treatment and post-transplant monitoring.

11.
Aging Cell ; 18(3): e12950, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30907060

RESUMO

Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.

12.
Am J Kidney Dis ; 74(3): 417-420, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30910370

RESUMO

We report a case of systemic oxalosis involving the eyes and joints due to long-term use of high-dose vitamin C in a patient receiving maintenance peritoneal dialysis (PD). This 76-year-old woman with autosomal dominant polycystic kidney disease underwent living unrelated kidney transplantation 10 years earlier. The transplant failed 6 months before presentation, and she initiated hemodialysis therapy before transitioning to PD therapy 4 months later. During the month before presentation, the patient noted worsening arthralgias and decreased vision. Ophthalmologic examination revealed proliferative retinopathy and calcium oxalate crystals. Plasma oxalate level was markedly elevated at 187 (reference range, <1.7) µmol/L, and urine oxalate-creatinine ratio was high (0.18mg/mg). The patient reported taking up to 4g of vitamin C per day for several years. Workup for causes of primary and secondary hyperoxaluria was otherwise negative. Vitamin C use was discontinued, and the patient transitioned to daily hemodialysis for 2 weeks. Plasma oxalate level before the dialysis session decreased but remained higher (30-53µmol/L) than typical for dialysis patients. Upon discharge, the patient remained on thrice-weekly hemodialysis therapy with stabilized vision and improved joint symptoms. This case highlights the risk of high-dose vitamin C use in patients with advanced chronic kidney disease, especially when maintained on PD therapy.

13.
Kidney Int ; 95(4): 948-957, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30904069

RESUMO

The relationships between renal blood flow (RBF), tissue oxygenation, and inflammatory injury in atherosclerotic renovascular disease (ARVD) are poorly understood. We sought to correlate RBF and tissue hypoxia with glomerular filtration rate (GFR) in 48 kidneys from patients with ARVD stratified by single kidney iothalamate GFR (sGFR). Oxygenation was assessed by blood oxygenation level dependent magnetic resonance imaging (BOLD MRI), which provides an index for the levels of deoxyhemoglobin within a defined volume of tissue (R2*). sGFR correlated with RBF and with the severity of vascular stenosis as estimated by duplex velocities. Higher cortical R2* and fractional hypoxia and higher levels of renal vein neutrophil-gelatinase-associated-lipocalin (NGAL) and monocyte-chemoattractant protein-1 (MCP-1) were observed at lower GFR, with an abrupt inflection below 20 ml/min. Renal vein MCP-1 levels correlated with cortical R2* and with fractional hypoxia. Correlations between cortical R2* and RBF in the highest sGFR stratum (mean sGFR 51 ± 12 ml/min; R = -0.8) were degraded in the lowest sGFR stratum (mean sGFR 8 ± 3 ml/min; R = -0.1). Changes in fractional hypoxia after furosemide were also absent in the lowest sGFR stratum. These data demonstrate relative stability of renal oxygenation with moderate reductions in RBF and GFR but identify a transition to overt hypoxia and inflammatory cytokine release with severely reduced GFR. Tissue oxygenation and RBF were less correlated in the setting of reduced sGFR, consistent with variable oxygen consumption or a shift to alternative mechanisms of tissue injury. Identifying transitions in tissue oxygenation may facilitate targeted therapy in ARVD.


Assuntos
Aterosclerose/complicações , Taxa de Filtração Glomerular , Inflamação/fisiopatologia , Rim/patologia , Obstrução da Artéria Renal/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/fisiopatologia , Hipóxia Celular , Estudos Transversais , Feminino , Humanos , Inflamação/etiologia , Inflamação/patologia , Rim/diagnóstico por imagem , Rim/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/análise , Oxigênio/sangue , Consumo de Oxigênio , Obstrução da Artéria Renal/etiologia , Obstrução da Artéria Renal/patologia , Circulação Renal
14.
Stem Cell Rev Rep ; 15(3): 427-438, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30338499

RESUMO

Mesenchymal stem cells (MSCs) are currently being tested in several clinical trials. Mitochondria regulate many aspects of MSC function. Mitochondrial preproteins are rapidly translated and trafficked into the mitochondrion for assembly in their final destination, but whether coexisting cardiovascular risk factors modulate this process is unknown. We hypothesized that metabolic syndrome (MetS) modulates mitochondrial protein import in porcine MSCs. MSCs were isolated from porcine abdominal adipose tissue after 16 weeks of Lean or MetS diet (n = 5 each). RNA-sequencing was performed and differentially expressed mitochondrial mRNAs and microRNAs were identified and validated. Protein expression of transporters of mitochondrial proteins (presequences and precursors) and their respective substrates were measured. Mitochondrial homeostasis was assessed by Western blot and function by cytochrome-c oxidase-IV activity. Forty-five mitochondrial mRNAs were upregulated and 25 downregulated in MetS-MSCs compared to Lean-MSCs. mRNAs upregulated in MetS-MSCs encoded for precursor proteins, whereas those downregulated encoded for presequences. Micro-RNAs upregulated in MetS-MSCs primarily target mRNAs encoding for presequences. Transporters of precursor proteins and their substrates were also upregulated, associated with changes in mitochondrial homeostasis and dysfunction. MetS interferes with mitochondrial protein import, favoring upregulation of precursor proteins, which might be linked to post-transcriptional regulation of presequences. This in turn alters mitochondrial homeostasis and impairs energy production. Our observations highlight the importance of mitochondria in MSC function and provide a molecular framework for optimization of cell-based strategies as we move towards their clinical application.

15.
BMJ Open Diabetes Res Care ; 7(1): e000720, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31908790

RESUMO

Objective: Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD. Research design and methods: In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-ß1 or albumin. Results: Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (rs=-0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (rs=0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased. Conclusions: Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

16.
Kidney Int Rep ; 3(6): 1294-1303, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30450456

RESUMO

Introduction: It is unknown whether patients receiving dialysis have a higher morbidity and mortality risk after hip fracture repair conferred by their kidney failure or by the high comorbidity burden often present. Methods: We examined associations of dialysis dependency with postoperative complications, death, and readmission in a matched cohort study of U.S. patients undergoing hip fracture repair, from January 2010 to December 2013, in the American College of Surgeons National Surgical Quality Improvement Program. Matching included sex, age, race, diabetes mellitus, operation year, primary surgery type, and anesthesia technique. Results: Among 22,621 patients, 377 dialysis-dependent patients were matched to 1508 nondialysis patients. Median age was 78 years (interquartile range = 68-85) years, 56% were men, 70% were white, 43% had diabetes, and 47% underwent fracture fixation under mostly (80%) general anesthesia. Dialysis-dependent patients had higher physical status classification, had more heart failure and hypoalbuminemia, and were less often smokers. After adjustment, a greater risk of prolonged postoperative stays beyond 7 days (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09-1.89), higher in-hospital mortality (OR = 3.13, CI = 1.72-5.7), and 30-day death (OR = 2.29, CI = 1.51-3.48) but not 30-day readmission (P = 0.09) was observed with dialysis dependency. Adjusted analyses in the original cohort (n = 22,621) were similar: the dialysis group had greater risk of prolonged postoperative stay (OR = 1.77, CI = 1.42-2.21), in-hospital mortality (OR = 2.65, CI = 1.74-4.05), and 30-day death (OR = 2.03, CI = 1.48-2.80) and 30-day readmission (OR = 1.62, CI = 1.66-2.26). Conclusion: Dialysis dependency is associated with an increased risk of death and postoperative complications after hip fracture repair. These findings have implications for case-mix adjustment and quality metrics.

17.
J Vasc Surg ; 68(5): 1505-1516, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30369411

RESUMO

OBJECTIVE: Patients receiving dialysis are at increased risk for lower extremity amputations (LEAs) and postoperative morbidity. Limited studies have examined differences in 30-day outcomes of mortality and health care use after amputation or the preoperative factors that relate to worsened outcomes in dialysis patients. Our objective was to examine dialysis dependency and other preoperative factors associated with readmission or death after LEA. METHODS: A retrospective cohort study was conducted of dialysis-dependent and nondialysis patients undergoing major LEA in the 2012 to 2013 American College of Surgeons National Surgical Quality Improvement Program. Primary outcomes included death and hospital readmission within 30 days of amputation. RESULTS: Of 6468 patients, 1166 (18%) were dialysis dependent. The dialysis cohort had more blacks (39% vs 23%), diabetes (76% vs 58%), below-knee amputations (62% vs 55%), and in-hospital deaths (8% vs 3%; all P < .001). The 30-day postoperative death rates (15% vs 7%) and readmission rates (35% vs 20% per 30 person-days; both P < .001) were higher in dialysis patients. Among the live discharges, the rate of any readmission or death within 30 days from amputation was highest in those aged ≥50 years (40% per 30 person-days). Multivariable analyses in the dialysis cohort revealed increased age, above-knee amputation, decreased physical status, heart failure, high preoperative white blood cell count, and low platelet count to be associated with death (P < .05; C statistic, 0.75). The only preoperative factor associated with readmission in dialysis patients was race (P = .04; C statistic, 0.58). CONCLUSIONS: Readmission or death after amputation is increased among dialysis patients. Predicting which dialysis patients are at highest risk for death is feasible, whereas predicting which will require readmission is less so. Risk factor identification may improve risk stratification, inform reimbursement policies, and allow targeted interventions to improve outcomes.


Assuntos
Amputação/efeitos adversos , Amputação/mortalidade , Extremidade Inferior/irrigação sanguínea , Readmissão do Paciente , Doença Arterial Periférica/cirurgia , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Bases de Dados Factuais , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etnologia , Doença Arterial Periférica/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
18.
Am J Kidney Dis ; 72(6): 790-797, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30146423

RESUMO

RATIONALE & OBJECTIVES: Kidney stones have been associated with increased risk for end-stage renal disease (ESRD). However, it is unclear whether there is also an increased risk for mortality and if these risks are uniform across clinically distinct categories of stone formers. STUDY DESIGN: Historical matched-cohort study. SETTING & PARTICIPANTS: Stone formers in Olmsted County, MN, between 1984 and 2012 identified using International Classification of Diseases, Ninth Revision codes. Age- and sex-matched individuals who had no codes for stones were the comparison group. PREDICTOR: Stone formers were placed into 5 mutually exclusive categories after review of medical charts: incident symptomatic kidney, recurrent symptomatic kidney, asymptomatic kidney, bladder only, and miscoded (no stone). OUTCOMES: ESRD, mortality, cardiovascular mortality, and cancer mortality. ANALYTICAL APPROACH: Cox proportional hazards models with adjustment for baseline comorbid conditions. RESULTS: Overall, 65 of 6,984 (0.93%) stone formers and 102 of 28,044 (0.36%) non-stone formers developed ESRD over a mean follow-up of 12.0 years. After adjusting for baseline hypertension, diabetes mellitus, dyslipidemia, gout, obesity, and chronic kidney disease, risk for ESRD was higher in recurrent symptomatic kidney (HR, 2.34; 95% CI, 1.08-5.07), asymptomatic kidney (HR, 3.94; 95% CI, 1.65-9.43), and miscoded (HR, 6.18; 95% CI, 2.25-16.93) stone formers, but not in incident symptomatic kidney or bladder stone formers. The adjusted risk for all-cause mortality was higher in asymptomatic kidney (HR, 1.40; 95% CI, 1.18-1.67) and bladder (HR, 1.37; 95% CI, 1.12-1.69) stone formers. Chart review of asymptomatic and miscoded stone formers suggested increased risk for adverse outcomes related to diagnoses including urinary tract infection, cancer, and musculoskeletal or gastrointestinal pain. CONCLUSIONS: The higher risk for ESRD in recurrent symptomatic compared with incident symptomatic kidney stone formers suggests that stone events are associated with kidney injury. The clinical indication for imaging in asymptomatic stone formers, the correct diagnosis in miscoded stone formers, and the cause of a bladder outlet obstruction in bladder stone formers may explain the higher risk for ESRD or death in these groups.


Assuntos
Causas de Morte , Cálculos Renais/epidemiologia , Falência Renal Crônica/epidemiologia , Cálculos da Bexiga Urinária/epidemiologia , Fatores Etários , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Cálculos Renais/diagnóstico , Cálculos Renais/terapia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Masculino , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Análise de Sobrevida , Cálculos da Bexiga Urinária/diagnóstico , Cálculos da Bexiga Urinária/terapia
19.
Clin J Am Soc Nephrol ; 13(8): 1172-1179, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30026285

RESUMO

BACKGROUND AND OBJECTIVES: Withdrawal from maintenance hemodialysis before death has become more common because of high disease and treatment burden. The study objective was to identify patient factors and examine the terminal course associated with hemodialysis withdrawal, and assess patterns of palliative care involvement before death among patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We designed an observational cohort study of adult patients on incident hemodialysis in a midwestern United States tertiary center, from January 2001 to November 2013, with death events through to November 2015. Logistic regression models evaluated associations between patient characteristics and withdrawal status and palliative care service utilization. RESULTS: Among 1226 patients, 536 died and 262 (49% of 536) withdrew. A random sample (10%; 52 out of 536) review of Death Notification Forms revealed 73% sensitivity for withdrawal. Risk factors for withdrawal before death included older age, white race, palliative care consultation within 6 months, hospitalization within 30 days, cerebrovascular disease, and no coronary artery disease. Most withdrawal decisions were made by patients (60%) or a family member (33%; surrogates). The majority withdrew either because of acute medical complications (51%) or failure to thrive/frailty (22%). After withdrawal, median time to death was 7 days (interquartile range, 4-11). In-hospital deaths were less common in the withdrawal group (34% versus 46% nonwithdrawal, P=0.003). A third (34%; 90 out of 262) of those that withdrew received palliative care services. Palliative care consultation in the withdrawal group was associated with longer hemodialysis duration (odds ratio, 1.19 per year; 95% confidence interval, 1.10 to 1.3; P<0.001), hospitalization within 30 days of death (odds ratio, 5.78; 95% confidence interval, 2.62 to 12.73; P<0.001), and death in hospital (odds ratio, 1.92; 95% confidence interval, 1.13 to 3.27; P=0.02). CONCLUSIONS: In this single-center study, the rate of hemodialysis withdrawals were twice the frequency previously described. Acute medical complications and frailty appeared to be driving factors. However, palliative care services were used in only a minority of patients.


Assuntos
Utilização de Instalações e Serviços/estatística & dados numéricos , Cuidados Paliativos/estatística & dados numéricos , Diálise Renal/estatística & dados numéricos , Assistência Terminal/estatística & dados numéricos , Suspensão de Tratamento , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Cuidados Paliativos/métodos , Assistência Terminal/métodos
20.
Prev Med Rep ; 10: 176-183, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29868364

RESUMO

Routine preventive cancer screening is not recommended for patients with end-stage renal disease (ESRD) due to their limited life expectancy. The current extent of cancer screening in this population is unknown. Primary care (PC) reminder systems or performance incentives may encourage indiscriminate cancer screening. We compared rates of cancer screening in patients with ESRD, with and without PC visits. This is a retrospective cohort study using United States Renal Data System (USRDS) billing data and electronic medical record data. Patients aged ≥18 years starting dialysis from 2001 to 2008, Midwest regional dialysis network were categorized with or without a PC visit (defined as an office visit in family practice, internal medicine, pediatrics, geriatrics or preventive medicine during the first two years of dialysis). Cancer screening was based on Current Procedural Terminology codes in USRDS. We identified 2512 incident dialysis patients (60% men, median age 65y). Cancer screening rates were more frequent among those seen in PC: 38% vs 19% (P = 0.0002), for breast; 18% vs 10% (P = 0.047) for cervical; 13% versus 8% (P = 0.024) for prostate; and 18% vs 9% (P = 0.0002) for colon cancer. Multivariable analyses found that those with PC were more likely to be screened after adjusting for age, sex, and comorbidities. In our practice, cancer screening rates among chronic dialysis patients are lower than those previously reported for our general population (64% for breast cancer). However, a sizeable proportion of our ESRD population does receive cancer screening, especially those still seen in primary care.

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