Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis

Harita, Yutaka; Ishizuka, Kiyonobu; Tanego, Atsushi; Sato, Noriko; Chikamoto, Hiroko; Akioka, Yuko; Tsurumi, Haruko; Miura, Kenichiro; Gotoh, Yoshimitsu; Tsujita, Makoto; Yamamoto, Takayuki; Horike, Keiji; Takeda, Asami; Oka, Akira; Igarashi, Takashi; Hattori, Motoshi

doi:10.1007/s00467-014-2808-5

Cited by 31 publications

(20 citation statements)

References 27 publications

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“…Interestingly, lowering of suPAR was associated with a significant reduction in podocyte AP5 levels, suggesting that suPAR drives pathological podocyte β3-integrin activation. Our findings of high suPAR levels during FSGS recurrence are in line with Alachkar et al 10 and Morath et al 27 but in contrast to those by Harita et al 28 Nevertheless, 92% of the patients achieved complete or partial remission using a multimodal therapeutic approach (including extensive PE). Renal function remained stable, and a significant improvement of proteinuria was observed, suggesting that temporary lowering of suPAR-mediated podocyte β3-integrin activity may have been beneficial in a subset of these patients.…”

Section: Discussionsupporting

confidence: 92%

Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor–Mediated Podocyte β3-integrin Activation

Staeck

Slowinski²,

Lieker³

et al. 2015

Transplantation

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Background Primary focal segmental glomerulosclerosis (FSGS) often causes nephrotic proteinuria and frequently results in end-stage renal disease and recurrence after kidney transplantation. Recent studies describe soluble urokinase-type plasminogen activator receptor (suPAR) as a circulating factor implicated in FSGS. Methods This single-center study included 12 adult patients with histologically proven primary FSGS (n = 2) or recurrent FSGS after transplantation (n = 10). The effect of plasma exchange (PE) on clinical outcome, suPAR levels, and in vitro podocyte β3-integrin activation was investigated over a median of 11 (6–18) sessions of PE. Results The course of treatment was monitored in a total of 70 sessions of PE, which partly eliminated suPAR, with a mean reduction of 37 ± 12% of serum concentration per session. However, a substantial rebound was observed between sessions, with suPAR levels reaching 99 ± 22% of the pretreatment levels after a median of 4 days. Podocyte β3-integrin activation dropped significantly after PE but rebounded within 4 days concomitant with a rising suPAR level. In 11 of 12 patients, multimodal treatment (including extensive PE) reduced proteinuria significantly (from 5.3 [2.0–7.8] to 1.0 [0.4–1.6] g/d), indicating clinical efficacy of the therapy. One patient suffered allograft loss due to FSGS recurrence. A persisting response was independent of a lasting reduction in the level of total suPAR because there was no sustained significant change in suPAR levels before and after the course of intensified treatment (3814 ± 908 to 3595 ± 521 pg/mL; P = 0.496). Conclusions We conclude that multimodal therapy including extensive PE was associated with stabilization of recurrent FSGS and a temporary lowering of plasma suPAR as well as podocyte β3-integrin activation. Whether a sustained lowering of total suPAR results in further improved outcomes requires additional study.

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Section: Discussionsupporting

confidence: 92%

Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor–Mediated Podocyte β3-integrin Activation

Staeck

Slowinski²,

Lieker³

et al. 2015

Transplantation

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Section: Supar As a Clinical Marker Of Inflammation And Organ Damagementioning

confidence: 99%

“…However, the postulated central role and direct pathological action of suPAR in FSGS is debated intensively. Several studies report lack of differences in suPAR levels between FSGS and other kidney diseases and suggests rather a reduced glomerular filtration as a major cause of increased suPAR in patients with renal disorders [64][65][66][67][68][69]. suPAR is readily detected in both plasma and serum [50,70] and it is also found in urine [50], cerebrospinal fluid [71] and saliva [72].…”

Section: Supar As a Clinical Marker Of Inflammation And Organ Damagementioning

confidence: 99%

“…After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease Study Group formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.…”

Section: Supar As a Biomarker In Sle And Other Rheumatic Diseasesmentioning

confidence: 99%

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Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Enocsson¹,

Sjöwall²,

Wetterö³

2015

Clinica Chimica Acta

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The expression of uPAR is mainly regulated by growth factors and pro-inflammatory cytokines like basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor, interleukin ( suPAR as a clinical marker of inflammation and organ damagePlasma membrane expression of uPAR as well as the levels of circulating suPAR have been investigated in relation to a broad range of conditions and suPAR has been referred to as a "molecular crystal ball" due to its prognostic value in diseases like tuberculosis, HIV, sepsis and cancer [2,6,13,26,58,59]. Further, it has been reported that it reflects overall immune activation and systemic inflammation [2]. suPAR has also emerged as a potential biomarker of fibrosis in chronic liver diseases of diverse etiology [10,11,[60][61][62].Recently, suPAR attracted significant attention in primary focal segmental glomerulosclerosis (FSGS). data from this pilot study revealed significantly higher suPAR levels among patients with moderately or highly elevated SDI after study inclusion, compared to patients without SDI increase (Figure 2).Furthermore, there were higher death rates among patients in the two groups with SDI increase (Figure 2). However, it is well known that present organ damage predicts further organ damage [17,100], and thus, adjustment for SDI at baseline should be performed to reduce the risk of bias. A stepwise linear multiple regression analysis was therefore performed to evaluate the impact of suPAR on future SDI increase. After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease StudyGroup formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.In line with these findings, elevated suPAR levels have previously been demonstrated to associate with the risk of developing cancer, cardiovascular disease and type 2 diabetes later in life in the general population [7]. Importantly, these associations were independent of CRP, which is known for its predictive value in cardiovascular disease [7,102].7 Potential roles of suPAR in SLE pathogenesisAssessment of circulating suPAR levels at the clinical laboratory could possibly become a future way to estimate organ damage in SLE, and suPAR would be an even more appealing biomarker candidate if the levels could be mechanistically linked to the disease. The pathogenesis of SLE is notoriously complex and not fully understood, but includes disturbances in t...

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“…While the idea of a circulating factor has been established for a long time, the factor itself has not been clearly identified. Recent work suggested that soluble uPAR could be a candidate but doubts have risen (23–26). In summary, the recent pathophysiological and clinical insights suggest that we should aim to clearly identify potentially underlying genetic alterations in children with steroid-resistant nephrotic syndrome to individually adapt treatment.…”

Section: The Glomerular Filtration Barrier and Proteinuric Disorders:mentioning

confidence: 99%

An Emerging Molecular Understanding and Novel Targeted Treatment Approaches in Pediatric Kidney Diseases

Liebau

2014

Front. Pediatr.

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The evaluation and treatment of the heterogeneous group of kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome, and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas, the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches.

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Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis

Abstract: Based on our results, elevated suPAR levels in FSGS patients were attributed mainly to decreased glomerular filtration. These data warrant further analysis for involvement of possible circulating factor(s) in FSGS pathogenesis.

Cited by 31 publications

References 27 publications

Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor–Mediated Podocyte β3-integrin Activation

Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor–Mediated Podocyte β3-integrin Activation

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

An Emerging Molecular Understanding and Novel Targeted Treatment Approaches in Pediatric Kidney Diseases

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