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Prediction of ESRD and long-term remission by proteinuric markers in Primary Focal Segmental Glomerulosclerosis with Nephrotic Syndrome : a review

Claudio Bazzi

D’Amico Foundation for Renal Diseases Research, Milan, Italy

E-mail : aa

DOI: 10.15761/NRD.1000108

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Abstract

In Primary Focal Segmental Glomerulosclerosis (FSGS) with nephrotic syndrome (NS)  the  most  favorable prognostic factor  for long-term stable renal  function  is remission of proteinuria in response to therapy. At present no definitive conclusions have been reached in the treatment of FSGS due to several factors: uncertainty of disease etiology, incomplete knowledge of pathogenetic mechanisms, different response to therapies and a lack of biomarkers allowing risk stratification to predict prognosis and therapy responsiveness. Recent advances in genetics and molecular biology have identified novel biomarkers with a possible pathogenetic role that may be useful for prognostic purposes. A reliable new biomarker would be able to predict remission prior to the start of treatment and outperform traditional ones, e.g. proteinuria. Novel biomarkers (podocyte-secreted angiopoietin-like 4, soluble urokinase-type plasminogen activator receptor, B7-1, urinary CD80, microRNAs) have so far not outperformed the traditional ones and added little value to a simple and   cheap   measurement   of   proteinuria.   In   observational   studies,   proteinuric biomarkers based on high molecular weight protein excretion, such as IgG and α2- macroglobulin, showed  a high predictive value  for  remission and progression  in patients treated with steroids and cyclophosphamide. High levels of urinary apolipoprotein A1 and low levels of α2-macroglobulin are suggestive of steroid- sensitivity. Accordingly new treatments should take into account the predictive value of these biomarkers.

Introduction

Idiopathic Focal Segmental Glomerulosclerosis (FSGS) is a clinicopathological entity characterized by alteration of the molecular architecture of podocytes and slit diaphragms with disruption of the glomerular filtration barrier (GFB) and consequent proteinuria. The diagnosis of idiopathic FSGS is histologically characterized by focal segmental glomerulosclerosis in at least 1 glomerulus, segmental granular deposition of IgM and C3 on immunofluorescence and exclusion of secondary causes of segmental sclerosis. On the basis of various lesions associated with FSGS a classification in 5 histological types has been proposed [1] with differences in presentation, prognosis and response to therapy: the classic lesion  [not otherwise specified (NOS)], perihilar, tip, cellular and collapsing lesions. Studies of animal models and familial forms have elucidated several genetic and molecular defects responsible for podocyte damage [2-4]; increased knowledge of the molecular mechanisms of podocyte damage has not yet led to improved outcome prediction. The etiology of idiopathic FSGS is unknown. Immunological pathogenesis has been hypothesized, at least in some patients, with a clone of T lymphocytes secreting a permeability factor that alters GFB [5]. Recently doubts have been raised regarding the autoimmune pathogenesis of FSGS (review in 6), supported in part by the observation that certain “immunosuppressive” agents (dexamethasone and cyclosporine A) reduce proteinuria by direct stabilization of podocyte cytoskeleton [7-8]. The prognosis of FSGS is associated with the level of proteinuria and at present the most favorable prognostic factor for stable renal function over time and better survival is remission of proteinuria in response to corticosteroids or other treatments [9-11].   On the basis of the immunologic hypothesis, idiopathic FSGS has been treated over time with both older and relatively newer immunosuppressive agents, but treatment is still largely empirical due to variable and unpredictable responses and lack of reliable predictors for drugs responsiveness. The main goal of therapy in idiopathic FSGS with NS is to achieve remission of proteinuria to prevent development  of  interstitial  fibrosis  and  progression  to  end  stage  renal  disease.

(ESRD). To date a definitive conclusion about the treatment of the whole spectrum of patients with idiopathic FSGS and NS has not been reached for several reasons: uncertainty of disease etiology, incomplete knowledge of the pathogenetic mechanisms underlying renal damage, different response to the both older and relatively newer agents. Recent reviews of treatment [12, 13] have analyzed response to therapy in initial episode of NS, in patients relapsing after remission, steroid- dependent  and  steroid-resistant  patients;  some  recent  agents  have  been  mainly utilized only in steroid-unresponsive patients and in mixed cohorts of children and adults, and patients with FSGS and Minimal Change Disease (MCD). To assess outcome prediction and responsiveness to treatment it would be of paramount importance the availability of reliable biomarkers able to define a risk stratification useful to more accurately predict prognosis and response to therapy.

Novel biomarkers

Recent   advances   in  genetics   and   molecular  biology   have   identified  novel biomarkers that may play a pathogenetic role and could be useful for non-invasive diagnosis and prognostication (14). A recent debate published in 2015 in Nephrology, Dialysis and Transplantation on polar views concerning the usefulness of certain novel  biomarkers  in  glomerular  diseases  including  FSGS  reached  contrasting opinions: Ronco [15] summarizes the characteristics of the ideal biomarker: 1) measurement from easily available sources (blood and urine); 2) high sensitivity; 3) high specificity; 4) early detection of disease and response to treatment; 5) predictive value of prognosis and availability for stratification into categories of risk; 6) ability to provide information about the mechanism of disease. Ronco also emphasizes that the contribution of novel biomarkers such as podocyte-secreted angiopoietin-like 4 [16], soluble urokinase-type plasminogen activator receptor (suPAR) (17), B7-1 [18,19] are at present controversial as clinically useful biomarkers. De Vriese and Fervenza (20) underline that novel biomarkers such as suPAR [21], urinary CD80  [22]  and microRNAs  [23]  have little added value to a simple and cheap measurement of proteinuria. “A more useful biomarker would be one that predicts a remission prior to the start of treatment” and “can outperform traditional ones, e.g. proteinuria”. Thus, these Authors’ answer to the question of whether novel biomarkers are better than conventional ones in glomerular diseases, including FSGS, is a categorical NO!

Proteinuria characteristics and proteinuric biomarkers

Proteinuria plays a key role in glomerular diseases as a marker of disease severity, as factor responsible for further renal damage both at the glomerular and tubulo- interstitial level and as an outcome predictor [24, 25]; moreover proteinuria reduction following RAS inhibition is associated with lower progression to renal failure and improvement of kidney survival [26]. Proteinuria is primarily dependent on the GFB alterations responsible for loss of different MW proteins: high MW proteins [IgG, IgM, α2-macroglobulin (α2m)] and medium MW proteins (albumin and transferrin) are markers of alteration of GFB; but the pathophysiology of high and medium MW proteins is different for filtration and tubular reabsorption mechanisms; the tubular reabsorption  of  high  MW  proteins  is  markedly  lower  than  that  of  middle  MW proteins,   as   has   been   recently   demonstrated   [27].   Low   MW   proteins   α1- microglobulin and β2-microglobulin and the lysosomal enzyme β-NAG are markers of  tubulo-interstitial  damage.  Thus  proteinuria  measured  in  the  final  urine  is  a complex mixture of proteins with different MW, pathophysiological determinants and clinical  significance. Notwithstanding the central  role attributed to  proteinuria in glomerular diseases very few studies have evaluated the usefulness of its different components as predictors of functional outcome and response to therapy. In the last few  years  several  studies  have  highlighted  the  usefulness  of  the protein/creatinine/ratio and albumin/creatinine ratio for early diagnosis of clinically silent chronic nephropathies and for predicting progression, cardiovascular events and death [28-30]. Some studies evaluated whether these proteins and this type of proteinuria expression are the most powerful predictors of renal and cardio-vascular outcomes in glomerular diseases and showed that high MW proteins (IgG, IgM, α2m) [31-41] show a higher predictive value than the protein/creatinine and albumin/creatinine ratio. Moreover, the method for expressing urinary protein excretions  may  be  relevant  to  its  predictive  value  and  clinical  usefulness:  the fractional excretion of a protein shows a higher outcome predictive value than the protein/creatinine  ratio;  a  recently  proposed  method  for  indexing  proteinuria  for eGFR [42] more accurately assesses the tubular load of proteins that is one of the main mechanisms responsible for tubulo-interstitial damage and worsening renal function. Moreover, the composition of proteinuria is not stable in the course of the disease:   in   patients   progressing   to   renal   failure   certain   pathophysiological mechanisms such as reduction of nephron mass increase the permeability of GFB mainly  to  high  MW  proteins   and  reduces  the  tubular  reabsorption  as   was demonstrated by Brenner et al in the 5/6 nephrectomy model [43] and by Bazzi et al in IgA Nephropathy (44). Thus, certain properly selected proteinuric biomarkers may at present better meet the requirements suggested by De Vriese and Fervenza [19] for an optimal biomarker that “should be logistically and financially within reach, reproducible, able to predict the clinical course and response to treatment”.

Proteinuric biomarkers in Focal Segmental Glomerulosclerosis

To our knowledge only five published studies have evaluated the clinical significance of certain proteinuric biomarkers in FSGS: three in cohorts of adult patients with FSGS and NS and two in children with idiopathic NS and histologic diagnosis of FSGS or Minimal Change Disease (MCD). The first published study on the outcome predictive value of proteinuric markers in primary FSGS was a pilot study [45] followed by a subsequent study with a larger patients population; thus, only the data from the second study will be described. Bazzi et al [46], with updated follow-up) evaluated  38 patients with idiopathic FSGS and NS who at renal biopsy had measurement of several functional (eGFR), histologic (percentage of global and

segmental glomerulosclerosis, tubulo-interstitial damage score) and proteinuric markers [24 hour proteinuria (24h P)], urinary protein/creatinine ratio (UP/C), α2- macroglobulin/creatinine ratio (α2m/C), Fractional Excretion of IgG (FE IgG) and α1-microglobulin (FE α1m).  Low and high risk groups for all markers were defined by cutoffs assessed by ROC analysis for progression. For the initial episode of NS the first-line therapy for all patients was steroids alone or in combination with cyclophosphamide. Twenty-three patients (61%) went into remission as first event and 9 (24%) progressed to ESRD. Comparing low and high risk groups, by univariate analysis remission was predicted only by FE IgG (77% vs 25%, p=0.016) and α2m/C (81%vs17%, p=0.007) and ESRD at best by FE IgG (0% vs 75%, p<0.0001) and α2m/C (4%vs67%, p<0.0001). By multivariate analysis FE IgG was the only independent predictor of remission and α2m/C the most powerful predictor of ESRD. FE IgG and α2m/C in combination increased the prediction of remission (83%vs11%, p=0.008) and ESRD (0%vs89%, p<0.0001) (Figure 1). Twenty-one out of 23 patients with remission as first event after NS reported sustained remission after a follow up of 147±61 months (range 60-258) obtained with steroids alone (n.5), steroids+CYP (n.13) or other treatments in 3 patients unresponsive to steroids and CYP (n. 2) or steroid-dependent (n. 1); [mycophenolate mofetil (n.1), pentoxifylline (n.1) and cyclosporine A (n.1), respectively. Nineteen (90%) out of 21 patients who attained sustained remission have FE IgG below the cutoff, while all ESRD patients, unresponsive to steroids and cyclophosphamide, had FE IgG above the cutoff. In conclusion  the  most  powerful  outcome  predictors  were  FE  IgG  and  α2m/C,  as markers for the severity of glomerular filtration barrier alterations; their predictive value, if validated in prospective studies, may be useful in clinical practice for therapeutic decisions suggesting alternative first-line treatments in high risk patients and to identify groups for controlled trials that should consist of patients with the same risk profile. Deegens and Wetzels published a study of 35 adult patients with biopsy proven primary FSGS [47]; urinary markers included 24-hour proteinuria, selectivity  index  (SI),  fractional  excretion  of  albumin,  IgG,  transferrin  and  β2-

Figure 1. Probability of ESRD and remission in patients with FE IgG and α2m/C both below (0) or above (1) their respective cutoffs

microglobulin (β2m). Twenty-three patients received immunosuppressive therapy (9 prednisone, 14 prednisone and cyclophosphamide). After a median follow up of 58.3 (4.9-127.6) months, 17 patients were in remission, 6 had persistent NS and 6 had progressed to renal failure. The remission rate was similar in patients with FE IgG below or above 1.40, but more patients with FE IgG > 0.140 received immunosuppressive therapy. The predictive value of FE albumin, transferrin and β2m was lower. This study shows that FE IgG > 0.140 is not invariably associated with poor outcome. However the study is characterized by several limitations: 90% of patients  had  proteinuric  markers  measurements  within  16  months  of  biopsy,  9 patients had already received a course of immunosuppressive therapy and 6 out of 9 untreated patients (67%) developed spontaneous remission, which is a much higher percentage than the 5% spontaneous remission rate reported in the literature. Chehade et al [48] studied 35 children with MCD and 9 with FSGS, of whom 28 in remission and 16 in relapse, and reported that urinary neutrophil-gelatinase-associated lipocalin (uNGAL), whether or not indexed to urinary creatinine, was significantly different between children with NS and healthy children (p = 0.02), between healthy children and those with FSGS (p = 0.007) and between children with MCD and those with FSGS (p = 0.01). uNGAL was not significantly correlated to proteinuria or GFR levels. The ROC curve analysis showed that a cutoff value of 17 ng/mg for the uNGAL/uCreat ratio could be used to distinguish MCD from FSGS with a sensitivity of 77% and specificity of 78%. Only urinary α1-microglobulin, indexed or not to uCreat, was significantly higher (p < 0.001) for patients in relapse compared to those in remission. These results indicate that in this patient cohort uNGAL was a reliable biomarker for differentiating MCD from FSGS independently of proteinuria or GFR levels. The main drawback of this study was its failure to evaluate the predictive value of functional outcome and responsiveness to therapy. Suresh et al [49] studied children with idiopathic NS due to MCD, FSGS and Membranoproliferative Glomerulonephritis (MPGN) and assessed the proteomic profile by isobaric tags for

matrix assisted laser desorption and ionization analysis (iTRAQ/LC/MS) in albumin- and IgG-immunodepleted samples with the aim of identifying differentially expressed urinary biomarkers in children with steroid-sensitive or steroid-resistant NS. For the discovery phase study, 27 patients were analyzed [15 steroid-sensitive NS (SSNS): 5 with first episode of NS (FENS), 5 FENS in long-term remission, 5 relapsing or steroid-dependent (FRNS/SDNS)], 12 steroid-resistant NS (SRNS) and 5 controls. For the validation phase 20 FENS, 20 FENS/SDNS, 20 SRNS and 20 age and gender matched controls were screened by enzyme-linked immunosorbent assay for the biomarkers  apolipoprotein  A1,  α2-macroglobulin, orosomucoid  2,  retinol  binding protein 4 and leucine-rich α2-glycoprotein 1. In the discovery phase, 26 proteins were differentially expressed, between FENS and controls: 23 upregulated and 3 downregulated.  To  discriminate  between  SSNS  and  SRNS  5  biomarkers  were selected and measured.  Significantly higher levels of apolipoprotein A1 (p < 0.001) differentiated  FENS  from  SRNS  (AUC  0.99,  cutoff  <0.48  μg/mg  of  urinary creatinine, 100% sensitivity and specificity 100%). A cutoff value of <0.24 μg/mg of creatinine could differentiate SRNS from frequently relapsing nephrotic syndrome/steroid dependent nephrotic syndrome [AUC 0.99, 100 % sensitivity and

100 % specificity]. α2-macroglobulin could differentiate children with SRNS-FSGS from SRNS-MCD (AUC 0.84, cutoff >3.3 µg/mg creatinine); also orosomucoid 2 and Retinol Binding Protein differentiate SRNS-FSGS from SRNS-MCD. The main clinically useful conclusion to be drawn from this study was that higher levels of urinary apolipoprotein A1 is suggestive of steroid-sensitivity while lower levels identified   patients   with   SRNS;   significantly   higher   levels   of   urinary   α2- macroglobulin (p < 0.001) differentiate SRNS from steroid-sensitive NS; the Authors suggest therefore that α2m is more predictive than other markers.

Discussion

At present there are no definitive conclusions regarding the therapy of idiopathic FSGS with NS; the most favorable prognostic factor for stable renal function over time is still considered to be remission of proteinuria in response to corticosteroids. Until recently, the first-line therapy for an the initial episode of NS was considered to be high dose steroids with variable treatment schedules; the most frequently used schedule was oral prednisone (1 mg/Kg) for 16 weeks followed by taper or iv methylprednisolone pulses followed by oral prednisone (0.5 mg/d) for 8 weeks with subsequent taper. Steroid- resistant patients were usually defined as those who fail to go into remission at the end of 4 months of treatment. Few studies have used alternative therapies for initial episode of NS: prednisone in combination with other immunosuppressive  agents  (cyclophosphamide,  azathioprine,  cyclosporine, tacrolimus, mycophenolate mofetil) achieving variable results (review in 13). Steroid- resistant patients have been treated with the aforementioned immunosuppressive agents with variable results. Recently, Rituximab in steroid-dependent or frequently relapsing idiopathic NS in children and adults with MCD, mesangial proliferative GN and FSGS, effectively and safely prevented recurrences and reduced the need for immunosuppression (50). One major obstacle to defining treatment guidelines is the lack of reliable biomarkers able to predict response to therapy. In the past decade genetic and molecular advances have been made in the understanding of the pathomechanisms of renal damage and novel markers for FSGS have been evaluated. At  present, however,  according  to the opinion  of influential authors  these novel markers have not outperformed traditional ones, e.g. proteinuria. Very few studies in patients with FSGS assessed certain specific proteinuria components such as urinary high MW proteins (IgG, IgM and α2-macroglobulin) or low MW proteins (α1- microglobulin) which have displayed outcome predictive value in other glomerular diseases (IMN, IgAN, Diabetic Nephropathy, Renal Vasculitis). Two recent observational studies evaluated proteinuric components using a different biochemical approach. One study reported that Fractional Excretion of IgG in combination with

analysis showed a high predictive value both of remission (83% vs 11%, p=0.008) and progression to ESRD (0% vs 89%, p < 0.0001) in patients treated mainly with steroids alone or in combination with cyclophosphamide. Another study on the characterization  of  urinary  proteome  reported  that  significantly  higher  levels  of urinary apolipoprotein A1 were suggestive of steroid-sensitivity and lower levels were associated with steroid-resistant NS. Significantly higher levels of urinary α2- macroglobulin  differentiate  steroid-resistant  from  steroid-sensitive  NS.  This  last result confirms the observation of the previous study that showed the usefulness of α2-macroglobulin in combination with FE IgG in predicting remission and ESRD in patients with FSGS and NS. Considering that FSGS is mainly characterized by an alteration of the molecular architecture of podocytes and slit diaphragm, it would be rational to conclude that high MW protein excretion more accurately evaluates the degree of disruption of this component of GFB and that more severe disruption might be  associated  with  progressive  disease.  According  to  these  results,  it  appears warranted to suggest their validation in large controlled trials to evaluate the efficacy of more recent immunosuppressive  agents with risk stratification  based on these simple, cheap and readily available urinary biomarkers not only in steroid-resistant NS patients but also across the whole spectrum of patients with FSGS and NS.

nclusions

Some  novel  biomarkers  are  useful  to  distinguish  FSGS  from  MCD,  to  assess steroid-sensitivity and distinguish  SRNS from SSNS and  to predict relapse after transplantation; but no one of them has been evaluated for prediction of progression to ESRD. The level of urinary excretion of some high MW serum proteins has a high predictive value both of long-term remission and progression to ESRD.

Acknowledgements

Figure 1 and part of the introduction are derived from the Outcome and Responsiveness to Steroids and Cyclophosphamide in Idiopathic Focal Segmental Glomerulosclerosis with Nephrotic Syndrome”, Biomed Res Int 2013; doi.org/10.1155/2013/941831

Conflict of interest

None

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Editorial Information

Editor-in-Chief

Article Type

Review Article

Publication history

Received date: October 18, 2016
Accepted date: November 15, 2016
Published date: November 18, 2016

Copyright

©2016 Bazzi C.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Bazzi C (2016) Prediction of ESRD and long-term remission by proteinuric markers in primary focal segmental glomerulosclerosis with nephrotic syndrome: a review. Nephrol Renal Dis, 2016 doi: 10.15761/NRD.1000108

2021 Copyright OAT. All rights reserv

Corresponding author

Corres Claudio Bazzi

Fondazione D’Amico per la Ricerca sulle Malattie Renali Via Cherubini, 620100 Milano, Italy, Tel: 0039 338 8319049, Fax: 0039 02 48110814,

Table 1. Clinical significance of novel biomarkers in FSGS and MCD

Biomarker

Author/Ref.

Clinical significance

B7-1

Yu et al,

2013 (18)

B7-1 inhibitor Abatacept induces remission of NS.

B7-1

Novelli et al,

2016 (19)

B7-1 is not expressed in podocytes; it has no value as biomarker in

MCD and FSGS.

suPAR

Wei et al,

2011 (21)

suPAR is elevated in 2/3 of primary FSGS, but not in other glomerular diseases; high levels of suPAR before transplantation are associated with increased risk of recurrence after transplantation.

suPAR

Li et al,

2014 (51)

suPAR levels are significantly higher in FSGS vs controls, MCD and

IMN; high levels are associated with steroid-response vs no-response.

Apolipoprotein a-1

Lopez-Hellin et al, 2013 (52)

Urinary Apolipoprotein a-1 found exclusively in FSGS relapsing after transplantation.

CD80

Garin et al,

2009 (22)

Urinary soluble CD80 is significantly higher in relapsed MCD vs MCD

in remission.

Angiopoietin- like-4

Clement et al,

2011 (16)

Ang-l-4 is steroid-sensitive and highly upregulated in experimental model of MCD.

NGAL

Bennet et al,

2012 (53)

NGAL is significantly higher in SRNS vs SSNS and controls and negatively correlated with GFR.

NGAL

Chelade et al,

2013 (48)

Urinary NGAL is significantly different in NS vs controls, FSGS vs controls and FSGS vs MCD.

microRNAs

Zhang et al,

2014 (23)

Urinary miR-196a, miR-30a-5p, and miR-490 discriminate active FSGS from FSGS in remission; urinary miR-30a-5p marginally predicts steroid-responsiveness in patients with active FSGS.

microRNAs

Zhang et al,

2015 (54)

Plasma levels of miR-125b, miR-186, and miR-193-3p are increased in

FSGS patients compared with healthy controls; miR-125b and miR-

186 levels are significantly lower in FSGS in remission than in patients with NS: plasma miR-186 level correlates with proteinuria degree.

microRNAs

Ramezani et al, 2015 (55)

FSGS and MCD patients have a unique circulating and urinary miRNA profile.

Proteomic profile

Wen et al,

2012 (56)

Markedly increased levels of Haptoglobin in serum, but not in urine, are present in SRNS compared with SSNS.

Proteomic profile

Khurana et al, 2006

(57)

Five peaks distinguish SRNS; the peak at m/z 11, 117, 4 has 95% accuracy for classifying SRNS; this peak was identified as β2- microglobulin.

Proteomic profile

Kalantari et al, 2014 (58)

21 urinary proteins (among them apolipoprotein A-1 and Matrix- remodelling protein 8, over- and underrepresented, respectively) had the highest fold changes in steroid-sensitive vs steroid-resistant pts.

18

Figure 1. Probability of ESRD and remission in patients with FE IgG and α2m/C both below (0) or above (1) their respective cutoffs