Expression of Urokinase-type Plasminogen Activator Receptor and its Soluble Form in Type 2 Diabetic Kidney Disease

Introduction: Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, has been linked to incident and progressive chronic kidney disease (CKD) in select patient populations, often with few African Americans. Hypothesis: We assessed the hypothesis that higher circulating levels of suPAR are associated with risk for progression of hypertension-attributed CKD in African Americans. Methods: We quantified baseline plasma levels of suPAR in participants of the African-American Study of Kidney Disease and Hypertension (AASK), a clinical trial of African Americans with hypertension-attributed CKD, and regular assessment of measured glomerular filtration rate (mGFR), and proteinuria. We used Cox proportional hazards regression to assess the associations of suPAR with CKD progression (defined as doubling of serum creatinine or end-stage renal disease [ESRD]), ESRD, worsening proteinuria (pre-ESRD doubling of 24-hour urine protein to creatinine ratio [UPCR] to ≥220 mg/g), and all-cause death. Results: Among 955 AASK participants, the median baseline suPAR was 4462 pg/mL (25 th to 75 th percentile: 3425-5923 pg/mL), mean mGFR was 46 mL/min per 1.73 m 2 , and median 24-hour UPCR was 79.6 mg/g. After controlling for baseline demographics, AASK trial arm, mGFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.42-times higher risk for CKD progression per two-fold higher baseline suPAR (HR 1.42, 95% CI: 1.17-1.71, p <0.001). Higher suPAR was also independently associated with ESRD (HR 1.59, 95% CI: 1.26-2.00, p <0.001) and death (HR 1.40, 95% CI: 1.12-1.75, p =0.003). Only in patients with two APOL1 risk alleles was suPAR associated with worsening proteinuria (HR 1.77, 95% CI 1.11-2.82, p =0.016; p interaction =0.008). Conclusion: Our study provides evidence of associations between higher suPAR levels and risk for various adverse outcomes in African Americans with hypertension-attributed CKD, independent of proteinuria and GFR.

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Corrigendum to “Urinary Exosomal MicroRNA Profiling in Incipient Type 2 Diabetic Kidney Disease”

Journal of Diabetes Research ◽

10.1155/2018/5969714 ◽

2018 ◽

Vol 2018 ◽

pp. 1-1 ◽

Cited By ~ 1

Author(s):

Yijun Xie ◽

Yijie Jia ◽

Cuihua Xie ◽

Fang Hu ◽

Meng Xue ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Microrna Profiling ◽

Exosomal Microrna ◽

Type 2 Diabetic

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Diabetic kidney disease: Is there a non-albuminuric phenotype in type 2 diabetic patients?

Nefrología ◽

10.1016/j.nefro.2016.03.025 ◽

2016 ◽

Vol 36 (5) ◽

pp. 503-509 ◽

Cited By ~ 9

Author(s):

Ivo Laranjinha ◽

Patrícia Matias ◽

Sofia Mateus ◽

Filipa Aguiar ◽

Patrícia Pereira ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Diabetic Kidney ◽

Type 2 Diabetic

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Elevated Plasma Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) in Sickle Cell Disease - a Marker of Chronic Kidney Disease

Blood ◽

10.1182/blood-2021-153938 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 968-968

Author(s):

Nowah Kokou Apeadoufia Afangbedji ◽

James G. Taylor ◽

Sergei Nekhai ◽

Marina Jerebtsova

Keyword(s):

Chronic Kidney Disease ◽

Sickle Cell Disease ◽

Kidney Disease ◽

Renal Disease ◽

Plasminogen Activator ◽

Sickle Cell ◽

Cell Disease ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Plasminogen Activator Receptor

Abstract Background: Sickle cell nephropathy (SCN) is one of the most common complications of SCD, leading in most cases to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Despite the high prevalence of CKD in sickle cell disease (SCD) patients, there remains a poor understanding of the pathophysiological mechanism of SCN and a lack of biomarkers for early detection of SCD-associated CKD. Soluble urokinase-type plasminogen activator receptor (suPAR) is an emerging biomarker of CKD. suPAR is a member of the fibrinolytic system, which is dysregulated in SCD patients. Objective: To evaluate suPAR as a biomarker of SCD-associated nephropathy and identify plasma proteases responsible for its increase in SCD. Methods: The study was approved by Howard University review board (IRB) and all subjects provided written inform consent prior to the sample collection. Whole blood and urine samples were collected from 77 SCD patients and 10 healthy individuals, and plasma was isolated. Levels of creatinine and cystatin C in plasma and albumin and creatinine in urine were measured by ELISA. eGFR was calculated using CKD-EPI creatinine-cystatin equation, and CKD stages were assigned. Plasma suPAR was measured by ELISA and was correlated with CKD stages. The activities of candidates uPAR proteases: Neutrophile elastase (NE), urokinase-type plasminogen activator (uPA) and plasmin in plasma samples from SCD patients were measured and compared to healthy participants. Results: The average age of SCD patients was 42.5 years (range 18-67 years). Most patients had HbSS genotype (67.5%),19.5% of patients were HbSC (hemoglobin C sickle cell compound heterozygous), and 13% had HbS β-thalassemia. More than half (53.2 %) were females. We observed an increased level of plasma suPAR (>3ng/ml) in more than 60% of SCA patients without renal disease, representing a risk factor for CKD progression. Plasma suPAR levels further increased in the patients with CKD and positively correlated with stages of CKD (r=0.419, R2=0.1696). Analysis of plasma proteases that cleaved uPAR producing soluble peptides (suPAR) demonstrated increased urokinase-type plasminogen activator (uPA) activity without significant changes in neutrophile elastase. Conclusion: This study validated plasma suPAR as a potential marker of CKD in SCD patients and identified plasma uPA as a uPAR protease that may increase circulating suPAR in SCD. Future longitudinal analysis of suPAR levels in patients with SCA is needed. Acknowledgments: We thank Drs. Namita Kumari and Xiaomei Niu for their help in samples identification. This work was supported by NIH Research Grants 1R01HL125005-06A1, 5U54MD007597, 1P30AI117970-06,1UM1AI26617, and 1SC1HL150685. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Exercise Ameliorates Diabetic Kidney Disease in Type 2 Diabetic Fatty Rats

Antioxidants ◽

10.3390/antiox10111754 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1754

Author(s):

Itaru Monno ◽

Yoshio Ogura ◽

Jing Xu ◽

Daisuke Koya ◽

Munehiro Kitada

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Molecular Mechanisms ◽

Kidney Injury ◽

Male Rats ◽

Fatty Acid Binding ◽

Diabetic Kidney ◽

Beneficial Effects ◽

Type 2 Diabetic

Lifestyle improvement, including through exercise, has been recognized as an important mode of therapy for the suppression of diabetic kidney disease (DKD). However, the detailed molecular mechanisms by which exercise exerts beneficial effects in the suppression of DKD have not yet been fully elucidated. In this study, we investigate the effects of treadmill exercise training (TET) for 8 weeks (13 m/min, 30 min/day, 5 days/week) on kidney injuries of type 2 diabetic male rats with obesity (Wistar fatty (fa/fa) rats: WFRs) at 36 weeks of age. TET significantly suppressed the levels of albuminuria and urinary liver-type fatty-acid-binding protein (L-FABP), tubulointerstitial fibrosis, inflammation, and oxidative stress in the kidneys of WFRs. In addition, TET mitigated excessive apoptosis and restored autophagy in the renal cortex, as well as suppressed the development of morphological abnormalities in the mitochondria of proximal tubular cells, which were also accompanied by the restoration of AMP-activated kinase (AMPK) activity and suppression of the mechanistic target of rapamycin complex 1 (mTORC1). In conclusion, TET ameliorates diabetes-induced kidney injury in type 2 diabetic fatty rats.

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Prevalence and characteristics of diabetic kidney disease in type 2 diabetic patients in Abidjan, Côte d’Ivoire

Journal of Nephropharmacology ◽

10.15171/npj.2018.21 ◽

2018 ◽

Vol 7 (2) ◽

pp. 98-103

Author(s):

Sindou Sanogo ◽

Serge Didier Konan ◽

Kouamé Hubert Yao ◽

Emma Kouassi ◽

Séry Patrick Diopoh ◽

...

Keyword(s):

Kidney Disease ◽

Associated Factors ◽

Diabetic Kidney Disease ◽

University Hospital ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Cross Sectional ◽

Diabetic Kidney ◽

Type 2 Diabetic

Introduction: Diabetes mellitus is a disease whose prevalence has been steadily increasing worldwide. Objectives: To evaluate the prevalence of diabetic kidney disease and to identify the associated factors in type 2 diabetic patients. Material and Methods: This was a descriptive and analytical cross-sectional study. The study was conducted over a period from January to June 2016, among patients with type 2 diabetes, followed up at the Division of Diabetology of the University Hospital of Treichville, Abidjan. Results: Of 154 included patients, diabetic nephropathy (DN) was observed in 40 cases (25.9% prevalence). We observed a female predominance (sex ratio; 0.17) and the mean age of 57.7 ± 11 years. Based on the K/DOQI guidelines, half of our patients had stage 3 kidney disease. Complications such as diabetic retinopathy (100%), hypertension (HT) (75%), dyslipidemia (45%) and obesity (30%) were found. Factors such as female sex (P = 0.001; OR [95% CI] = 4.76 [1.85-12.19]), a range 55-65 years old (P = 0.010; OR [95% CI] = 2.64 [1.26-5.53]), obesity (P = 0.012; OR [95% CI] = 3.06 [1.27-7.36]), hypertension (P = 0.0001; OR [95% CI] = 4.77 [2.12-10.71]) and HbA1c <7% (P = 0.002; OR [94% CI] = 3.42 [1.57-7.44]) were associated with nephropathy by multivariate analysis. Conclusion: the prevalence of diabetic kidney disease is high in our study. The associated factors are non-modifiable such as female gender and age, but also modifiable such as obesity and hypertension.

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Soluble Urokinase‐Type Plasminogen Activator Receptor, Changes of 24‐Hour Blood Pressure, and Progression of Chronic Kidney Disease

Journal of the American Heart Association ◽

10.1161/jaha.120.017225 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Jong Hyun Jhee ◽

Bo Young Nam ◽

Chan Joo Lee ◽

Jung Tak Park ◽

Seung Hyeok Han ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Plasminogen Activator ◽

Interquartile Range ◽

Ckd Progression ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Plasminogen Activator Receptor ◽

The Relationship

Background Soluble urokinase‐type plasminogen activator receptor (suPAR) is associated with cardiovascular risks and poor renal outcomes. However, whether elevated suPAR levels are associated with 24‐hour blood pressure patterns or kidney disease progression in patients with chronic kidney disease (CKD) is unclear. Methods and Results A total of 751 patients with CKD stage 1 to 5 were recruited from CMERC‐HI (Cardiovascular and Metabolic Disease Etiology Research Center–High Risk) cohort study (2013–2018). The relationship of serum suPAR levels to 24‐hour blood pressure parameters and CKD progression was analyzed. The median serum suPAR level was 1439.0 (interquartile range, 1026.2–2150.1) pg/mL, and the mean estimated glomerular filtration rate was 52.8±28.5 mL/min per 1.73 m 2 at baseline. Patients with higher suPAR levels had significantly higher levels of office, 24‐hour, daytime, and nighttime systolic blood pressure and nighttime diastolic blood pressure than those with lower suPAR levels. The highest suPAR tertile was associated with an increased risk of a reverse dipping pattern (odds ratio, 2.93; 95% CI, 1.27–6.76; P =0.01). During a follow‐up of 43.2 (interquartile range, 27.0–55.6) months, the CKD progression occurred in 271 (36.1%) patients. The highest suPAR tertile was significantly associated with higher risk of CKD progression than the lowest tertile (hazard ratio [HR], 2.09; 95% CI, 1.37–3.21; P =0.001). When the relationship was reevaluated with respect to each dipping pattern (dipper, extreme dipper, nondipper, and reverse dipper), this association was consistent only in reverse dippers in whom the risk of CKD progression increased (HR, 1.43; 95% CI, 1.02–2.01; P =0.03) with every 1‐unit increase in serum suPAR levels. Conclusions Elevated suPAR levels are independently associated with CKD progression, and this association is prominent in reverse dippers.

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