FP348SOLUBLE UROKINASE-TYPE PLASMINOGEN ACTIVATOR RECEPTOR (suPAR) IS ASSOCIATED WITH KDIGO CHRONIC KIDNEY DISEASE STAGE IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE

Introduction: Chronic kidney disease (CKD) is common in patients with peripheral arterial disease (PAD), but patients with severe CKD have been excluded from many trials and no objective performance goals exist for patients with PAD and CKD. We sought to analyze the association between severity of CKD and cardiovascular and limb-related outcomes among patients with PAD. Methods: We reviewed records of all patients at our institution who underwent lower extremity angiography between 2006 and 2013. We analyzed outcomes including mortality, major adverse cardiovascular event (MACE) rate, and major adverse limb event (MALE) rate according to clinical stage of CKD, determined by calculating each patient’s glomerular filtration rate using the Cockcroft-Gault equation. We used Cox proportional hazard modeling to account for covariates, along with Bonferroni correction for multiple comparisons. Results: Of 773 patients, 45% had CKD stage 3-5. The patients had a median age of 67, were 58% male, 51% diabetic, and 57% presented with critical limb ischemia (CLI). During a median follow-up time of 3.2 years, patients with higher stages of CKD had an increased rate of death (Figure 1, p<0.001). CKD stages 4 and 5 were significant predictors of mortality in a multivariate model (HR 3.2 and 2.4 vs. CKD 1, P<0.001 and P<0.01, respectively). An analysis of MACE by CKD stage demonstrated similar results (CKD 4 HR 2.2, p<0.01; CKD 5 HR 2.0, p<0.01). CKD stage also predicted MALE in a univariate analysis (p<0.01), driven by increased limb events among patients with CKD stage 5 (p<0.01). However, CKD stage did not demonstrate a significantly increased hazard of MALE in a multivariate Cox model. Conclusions: Patients with PAD who also have CKD have increased rates of adverse outcomes. This relationship seems to be more robust for major cardiovascular events and overall mortality than for major limb events. Future studies should investigate how management of PAD should differ for patients with CKD.

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Abstract MP07: Soluble Urokinase-type Plasminogen Activator Receptor is associated with progression of hypertension-attributed chronic kidney disease in African Americans

Circulation ◽

10.1161/circ.137.suppl_1.mp07 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Shengyuan Luo ◽

Josef Coresh ◽

Adrienne Tin ◽

Casey M Rebholz ◽

Teresa K Chen ◽

...

Keyword(s):

Chronic Kidney Disease ◽

African Americans ◽

Kidney Disease ◽

Plasminogen Activator ◽

Cox Proportional Hazards ◽

Adverse Outcomes ◽

Ckd Progression ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Plasminogen Activator Receptor

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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A systematic review of the effects of Chronic Kidney Disease on lower extremity Peripheral Arterial Disease and Peripheral Neuropathy with recommendations on the development of clinical guidelines

Journal of Foot and Ankle Research ◽

10.1186/1757-1146-3-s1-p14 ◽

2010 ◽

Vol 3 (S1) ◽

Author(s):

Leigh Porter ◽

Wendy Smith

Keyword(s):

Systematic Review ◽

Chronic Kidney Disease ◽

Peripheral Neuropathy ◽

Kidney Disease ◽

Peripheral Arterial Disease ◽

Lower Extremity ◽

Clinical Guidelines ◽

Arterial Disease ◽

Peripheral Arterial

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Subclinical peripheral arterial disease in patients with chronic kidney disease: Prevalence and related risk factors

Kidney International ◽

10.1111/j.1523-1755.2005.09310.x ◽

2005 ◽

Vol 67 ◽

pp. S44-S47 ◽

Cited By ~ 60

Author(s):

Soledad Garcia de Vinuesa ◽

Mayra Ortega ◽

Patricia Martinez ◽

Marian Goicoechea ◽

Francisco Gomez Campdera ◽

...

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Peripheral Arterial Disease ◽

Arterial Disease ◽

Disease Prevalence ◽

Chronic Kidney Disease Prevalence ◽

Related Risk ◽

Peripheral Arterial

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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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