Background: In glomerulonephritis (GN) with nephrotic syndrome (NS) a proteinuric marker able to predict outcome would very useful in clinical practice. 

Aim of study: verify whether combined excretion of IgG/C and α2m/C, markers of damage of glomerular filtration barrier, assess disease severity, outcome prediction and responsiveness to steroids and cyclophosphamide.

Patients & methods:  84 patients treated with steroids and cyclophosphamide were classified in 4 groups according to excretion of IgG/C and α2m/C: IgG/C ifthan median classified IgG/C0 and IgG/C1; the median of α2m/C calculated independently in IgG/C0 and IgG/C1 and classified as α2m/C0 and α2m/C1 ifthan median. On the basis of these data  4 groups were defined: IgG/C0&α2m/C0, IgG/C0&a2m/C1, IgG/C1&a2m/C0, IgG/C1&a2m/C1(shortly defined 0+0, 0+1, 1+0. 1+1) The outcomes were considered in combination according to similar prognostic significance: Remission combined with persistent NS with long lasting NRF (follow up 80±52 months) indicated as “Remission&NRF”; ESRD,  eGFR ≤ 50%, persistent NS with CRF and progressive eGFR reduction defined as “Progression&progression risk”.

Results: The 4 groups realize a picture of disease severity showing from IgG/C1&α2m/C1 to IgG/C0& α2m/C0 progressive eGFR increase and decrease of histologic and proteinuric parameters.    In 84 treated patients those with IgG/C1&α2m/C1& high BP (n. 14) “Progression&progression risk” is 100% and “Remission&NRF” is 0%; in those with IgG/C0&α2m/C0 & normal BP (n.15): “Remission&NRF” is 100%: “Progression & progression risk”: 0%. 

Conclusions: Urinary  IgG/C and α2m/C in combination with normal or high blood pressure realizes 100% prediction of “Remission&NRF” and 100% of “Progression&progression risk” assessing the responsiveness or unresponsiveness to Steroids and Cyclophosphamide treatment.

In patients with GN and NS some proteinuric biomarkers, mainly low and high molecular weight (MW) urinary proteins (α1-microglobulin, β2-microglobulin, IgG, IgM), have been useful to predict remission and progression to ESRD [1-12]. Fractional Excretion of IgG (FE IgG), according to cut offs assessed by ROC analysis, predicted Remission and ESRD in several types of GN (IMN, FSGS, IgAN, Crescentic IgAN, MPGN) [13-21]; unfortunately no one of these proteinuric markers reachs 100% of outcome. It would be desirable the availability of a marker that may rich 100% prediction of outcome and possibly able to predict the outcome before start of therapy for example with steroids and cyclophosphamide as suggested by a large systematic review and meta-analysis [22] of 36 clinical trials including 1762 patients with  IMN compared several immuno-suppressive treatments (steroids, steroids in combination with alkylating agents, cyclosporine, tacrolimus, mycophenolate mofetil, adreno-corticotropic  hormone, azathioprine and mizoribine) and concluded that corticosteroids in combination with alkylating agents significantly reduced all cause mortality and ESRD.

84 patients with chronic glomerulonephritis (GN) and nephrotic syndrome (NS) were included in the study (Table1); 5 types of outcome were defined: 1) Remission of NS: complete: proteinuria ≤ 0.30 g/24h; partial: proteinuria ≤ 2.0 g/24h; 2) persistent NS with long lasting normal renal function (follow up: 80±52 months); 3) progression to end-stage renal disease (ESRD); 4) eGFR reduction ≤ 50% of baseline; 5) persistent NS with chronic renal failure (PNS CRF) characterized by progressive eGFR reduction (from 49.3 to 39.1 ml/min/1,72 m2). The patients with Remission were not significantly different from patients with PNS and long lasting normal renal function for all functional, proteinuric and histological parameters; thus they may be considered together in an outcome defined “Remission and NRF”. The patients with ESRD, eGFR<50> median);  the median of α2m/C was calculated independently in IgG/C 1 and IgG/C 0 patients, respectively and defined α2m/C 0 and α2m/C 1 if < or> the median; thus 4 groups were  defined:  IgG/C 1 & α2m/C 1, IgG/C 1 & α2m/C 0,  IgG/C 0 & α2m/C 1, IgG/C 0 & α2m/C 0), briefly defined: 0+0, 0+1, 1+0, 1+1.

The 4 groups realize a picture of disease severity showing from IgG/C1&α2m/C1 to IgG/C0& α2m/C0 progressive eGFR increase and decrease of histologic and proteinuric parameters (Table 3). In 84 patients treated with St+Cyc the group 0+0 in combination with normal blood pressure (BP0) (n. 15 patients) predicts 100% of “Remission&NRF” and 0% of “Progression&progression risk”. The group 1+1 in combination with high blood pressure (BP1) (n.14 patients) predicts 100% “Progression & progression risk” and 0% of “Remission&NRF”. The patients of 0+0 group in combination with BP1 show 83% of “Remission&NRF”; thus 29 patients (35%) reach 100% of “Remission” or “Progression”. Very similar results in 30 patients with IMN and NS (Table 4). The patients without the combination 0+0+BP0 (n.15) and 1+1+BP1 (n. 14) were 55; 32 of these patients (58%) show “Remission&NRF”; 23 patients (42%) show “Progression&progression risk”. On the basis of these data all the patients reaching “Remission&NRF” were 47/84 (56%) and the patients reaching “Progression and progression risk” were 37/84 (44%). The 47 patients reaching “Remission&NRF” are associated with 43% of 0+0 group and 9% of 1+1 group. The 37 patients with “Progression and progression risk” were associated with 49% of 1+1 group and 3% of 0+0 group. Thus the IgG/C & α2m/C groups may be useful to suggest responsiveness and indication to treatment.

Prediction of responsiveness and indication to treatment with Steroids and cyclophosphamide in chronic glomerulonephritis and nephrotic syndrome according the combined urinary excretion of IgG/C and α2m/C groups.

In 84 patients treated with St+Cyc the group 0+0 in combination with normal blood pressure (BP0) (n. 15 patients) predicts 100% of Remission and 0% of progression; the group 1+1 in combination with high blood pressure (BP1) (n.14 patients) predicts 100% progression and 0% remission. The group 1+0 predicts 62% of remission and 38% of progression; the group 0+1 predicts 48% of Remission and 52% of progression. Similar results were observed in 30 IMN patients treated with St+Cyc: 0+0 & BP0: 100% remission and 0% progression; 1n 1+1 & BP1 100% progression and 0% remission. In group 1+0 & BP0:  Remission 71% and progression 29%; In group 1+0 &BP1 (n. 14): remission 57%; progression 43%. In group 0+1 & BP0 (n.7): remission 57%, progression 43%: in group 0+1 & BP0 (n. 7) Remission 67%, progression 43%; in Group 0+1 & BP1 (n. 14): remission 0%; progression 100%. Conclusion about treatment: treatment indicated in 0+0 & BP0 (100% remission)

Prediction of responsiveness and selection of patients with indication to treatment with Steroids and cyclophosphamide in chronic glomerulonephritis and nephrotic syndrome according the combined urinary excretion of IgG/C a.

A large systematic review and meta-analysis (27) of 36 clinical trials 

including 1762 patients with  IMN compared several immuno-suppressive treatments (steroids, steroids in combination with alkylating agents, cyclosporine, tacrolimus, mycophenolate mofetil, adreno-corticotropic  hormone, azathioprine and mizoribine) and concluded that corticosteroids in combination with alkylating agents significantly reduced all-cause mortality and ESRD. On the basis of this observation that corticosteroids in combination with alkylating agents significantly reduced all-cause mortality and ESRD it would be very useful in clinical practice to identify a proteinuric marker able to predict before the start of therapy the responsiveness to steroids and Cyclophosphamide in patients with GN and NS. In our previous study we demonstrated that a new proteinuric marker based on the combined urinary excretion of IgG/C and α1m/C that allows to define 4 groupsthat are able to predict from 0% to 100% for the two the main types of functional outcome defined as “Remission & persistent NS with long standing NRF” and “ESRD in combination with eGFR reduction > 50% and with persistent NS with progressive reduction of eGFR”. In 84 patients treated with steroids and Cyclo the Group IgG/C 0 & α2m/C 0 (0+0) in combination with normal Blood pressure (BP0) predict 100% of Remission and PNS with normal renal function and % of progression; by contrast the group IgG/C 1 & α2m/C 1 in combination with high Blood pressure (BP1) predict 100% of Progression and 0% of Remission.

On the basis of groups of combined excretion of IgG/C and α2m/C 15 patients of group 0+0 in combination with BP0 predict 100% of “Remission&NRF” and 0% of “Progression&progression risk”; 14 patients of group 1+1 in combination with BP1 predict 100% of “Progression&progression risk” and 0% of “remission&NRF”, suggesting complete responsiveness and total unresponsiveness to treatment, respectively. The patients without the combination 0+0+BP0 (n.15) and 1+1+BP1 (n. 14) were 55; 32 of these patients (58%) show “Remission&NRF”; 23 patients (42%) show “Progression&progression risk”. The association of “Remission&NRF” mainly with 0+0 group and “Progression and progression risk”mainly with 1+1 group suggest that indication of treatment may be based at least partially on the basis of IgG/C and α2m/C groups.