PREDICTORS OF RENAL OUTCOME IN ANCA- ASSOSIATED GLOMERULONEPHRITIS PREDIKTORI BUBREŽNOG ISHODA KOD ANCA-UDRUŽENIH GLOMERULONEFRITISA

Backgraund/Aim. Primary anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis are chronic multisystemic autoimmune diseases which include microscopic polyangitis (MPA), granulomatosis with polyangitis (WG), eosinophilic granulomatosis with polyangitis (EPGA; churg-strauss syndrome ? CSS), and also a localized forms of ill-ness. In our research, we studied clinical and serological parameters in patients, in order to find out which of them would be the best predictor of renal outcome in ANCA-associated vasculitis. Methods. Data from 42 patients with diagnose of MPA (9), WG (17), EPGA (0), CSS (0), and al-so idiopathic rapidly progressive glomerulonephritis (ROEB) without immune deposits (renal-limited vasculitis ? 16) were analyzed. Cockroft formula was used for calculating the glomerular filtration in the moment of presenting the illness, and also after five year follow-up period. Other factors that were analyzed are: gender, age, type of ANCA antibodies, type of infections, stage of chronic kidney dis-ease, need for heamodialysis and mortality. Results. Of a total of 42 patients, 17 (40.48%) were male. The average age of the patients at the time of diagnosis was 57.8 (? 10.44) years. Seventeen patients (40.48%) had a diagnosis of WG, 9 (21.43%) MPA, and 16 (38.09%) iRPGN. The presence of positive anti-proteinase (anti-PR3) antibodies was confirmed i n 1 8 patients, a nd a nti-MPO antibodies in 17 patients. Three patients had both subtypes of ANCA antibodies (anti-PR3 and anti-MPO). Initially, 12 patients required heamodialysis treatment. Twenty nine patients had a complete and 13 patients had partial remission. Out of the total number of patients, 8 patients (19.04%) developed the terminal renal failure stage, and ended up on a chronic dialysis program. During a five-year follow-up period, 12 patients (28.57%) resulted in death. The age of the patient proved to be statistically significant predictor of glomerular filtration rate (GFR) at the moment of presentation of the disease (p = 0.011). GFR t = 0 was statistically significant (p = 0.000) for the evaluation of kidney function outcomes in ANCA-associated glomerulonephritis. Conclusion. Kidney function in the moment of illness presentation, determined by GFR t = 0, is the most important significant factor for predicting renal outcome in ANCA-associated vasculitis, and also the mortality in these patients.


Introduction
Primary types of vasculitis that are associated with anti-neutrophil cytoplasm antibody (ANCA-associated vasculitis; AAV) are chronic multisystemic autoimmune diseases in which they are counted microscopic polyangitis (MPA), granulomatosis with polyangitis (WG), eosinophilic granulomatosis with polyangitis (EPGA; CSS), and also a localized forms of illness. After receiving the corticosteroid and immunosuppressive therapy, most of the patients experience early remission, but patients with ANCA-associated vasculitis continue to be at increased fatal risk compared with a healthy population 1 .
Kidney affection is one of the most common manifestion of vasculitis and it has a great impact on the outcome of the disease 2,3 . Renal vasculitis is the most common severe manifestation of ANCA-associated vasculitis (AAV) and it is typically presented with rapidly progressive glomerulonephritis (GN). During the diagnostic phase of AAV, dialysis is often needed, but however renal recovery and withdrawal from dialysis after the tretman is possible, in more than 50% patients 4 . Renal impairment at prognosis also is a predictor of poor renal outcome [5][6][7][8] and also of poor patient survival 1,9 .
Treatment of AAV may also cause significant morbidity, and patients with impaired renal function may be particulary prone to treatment-emergent adverse events 4 . Medication based on cyclophosphamide (CYC) and corticosteroids (CS), which have been used since the 1970s 10 , changed the prognosis of AAV from lethal to a chronic relapsing disease.
Around a half of the patients have a relaps within five years after diagnosis 11,12 .
Mortality of the patients with ANCA-associated vasculitis is high 10-15% within the frst year following treatment initiation. These patients have 2.7-fold increase in mortality compared with the general population. Some of the studies have shown that the mortality of the patients with renal involment depends of factors such as: older age, side effects of the therapy, lung haemorrhage, high disease activity score based on the Birmingham Vasculitis Activity Score (BVAS) etc [13][14][15][16][17][18] .
In order to control the inflammation, patients are treated with immunosuppressive and/or cytostatic therapy.
In our study, we used clinical and serological parameters in 42 patients, in order to find out which of them would be the best predictor of renal outcome in ANCA-associated vasculitis.  Table 2 presents the   clinical characteristics of patients after five-year follow up period (Table 2).

Methods
Based on the results of the general significance test (F (1.40) = 7.155, p = 0.011), one can conclude that the predictive GFR model in t = 0 is statistically significant. According to R 2 = 0.152 the model explains 15.2% variation of the dependent variable.
The age of the patient proved to be statistically significant predictor of GFR at the moment of presentation of the disease. Estimated glomerular filtration decreases with the age of patients with a factor of 0.390 (Table 3).
Based on the results of the general significance test (F (4.37) = 16.633, p = 0.000), it is concluded that the predictive GFR model in t = 5 is statistically significant. The corrected determination coefficient shows that the model explains 60.4% of variation of the dependent variable.
Of all potential renal outcome predictors, only GFR t = 0 was statistically significant, which was directly proportional to the factor 0.818 (Table 4).

Discussion
This retrospective study was done with a purpose to identify the best predictors of renal outcome in AAV. Renal dysfunction is known risk factor for mortality in patients with  25 . Other histological research did not prove the difference between antiPR3 and antiMPO antibodies 26 . In our study, we have noticed that the subtypes of ANCA antibodies affect the prognosis. Average GFR t=0 was significantly higher in patients with antiPR3 antibodies than in patients with antiMPO antibodies. The difference was not verified in patients after the five-year follow-up period (GFR t=5). 21 patients (50%) had renal-limmited form of disease, and in 19 patients (70,37%) lung damage was present. Infection are one of the main problems during the treatment of AAV, and also are the main cause of death in immunosuppressed patients 27,28,29 . Unlike the study of Kronbichler et al 30 , in our work, the most frequent were urinary tract infections (26.19%). Also, hospitalization of patients with ANCA vasculitis due to infections was less common than in the published studies so far, where cummulative incidence at 1, 2 and 5 years of any infection was 51, 58 and 65% 1,31,32,33 .
As a conclusion of our study, we can say that the renal function at the moment of presentation of the disease, determined by GFR t = 0, is the most important independent factor for assessing the outcome of renal function in ANCA-associated glomerulonephritis, as well as the mortality of these patients.