TREATMENT OF IgA NEPHROPATHY OF ADULTS PRESENTED BY NEPHROTIC SYNDROME

Th e aim of this retrospective study was to evaluate the results of the immunosuppressive regiment in managing of IgA nephropathy associated with primary nephrotic syndrome at the Nephrology Clinic, University of Sarajevo Clinics Centre in period of -. We studied  patients ( women and  men) with idiopathic nephrotic syndrome, where pathomorphologic changes of IgA nephropathy were proved by kidney biopsy. Th e levels of diuresis, proteinuria, albuminemia, lipidemia and kidney function, as measure of effi ciency of used therapy, were monitored. Th e IgA nephropathy present with the nephrotic syndrome was shown in ,  () patients underwent renal biopsy due to primary nephrotic syndrome in the period of observation. Th e average age of patients with IgA nephropathy was , ± , years. Eight patients from this group were treated with corticosteroid therapy (-, mg/kg of body weight for  weeks, followed by , mg/ kg of body weight until therapeutic response was achieved, and fi nally gradual exclusion of therapy after eight weeks in responsive patients),  patients with corticosteroids and bolus cyclophosphamide ( - mg/kg BW), and in / patients cyclosporine therapy was used ( mg/kg BW). Complete remission of nephrotic syndrome was achieved in , of the patients. In conclusion, in adults patients with primary nephrotic syndrome associated with IgA nephropathy, used immunosuppressive therapy resulted in a high percentage of achieved remissions.


Introduction
IgA nephropathy is the most common glomerular disease which covers - of all types of glomerulonephritis (,).It is characterized by the deposition of immune complexes in mesangial areas, predominantly IgA.Although the most common fi nding of IgA nephropathy on renal biopsy is focal mesangioproliferative glomerulonephritis, IgA nephropathy can be presented by various histological appearances, ranging from minimal lesions to diffuse proliferative and crescend glomerulonephritis.For a very long time this disease was considered to be benign, however, many researchers have shown that chronic renal failure occurs in   of the cases within  years, while - of the cases this disease progress to end-stage renal disease within  years ().Hypertension, severe proteinuria and especially clinical picture of nephrotic syndrome (NS) have shown to be negative prognostic indicators.
As the pathogenesis of IgA nephropathy is obscure, specifi c treatment for this disease still doesn't exist.Th anks to many researchers and analyses, nowadays we have more or less accepted principles of treatment for IgA nephropathy presented by nephrotic syndrome.The aim of this paper was to evaluate the eff ects of applicable therapy protocols in patients with primary nephrotic syndrome at the Nephrology Clinic University of Sarajevo Clinics Centre (CCU) from  to , where IgA nephropathy was proven by renal biopsy.Average observation period for each patient was one year.

Subjects and Methods
Th e retrospective analysis covered  patients ( male and  female), of average age ,±,, with pathohistologically proved IgA nephropathy during the period - at the Nephrology Clinic CCU in Sarajevo.More than a half of the patients with IgA nephropathy (,) were less than  years old.All patients fulfi lled the basic criteria for diagnosing primary NS.Previously, all secondary causes of nephrotic syndrome where IgA deposits in mesangium appeared as a secondary reaction on the basic pathohistological state (Purpura Henoch-Schonlein, Lupus erythematosus systemicus, Hepatitis chr, Nephropathia diabetica, etc), were excluded through relevant clinical investigations.Kidney biopsy was performed under ultrasound control by the usage of biopsy gun with -cm-long needles of G (, mm), during which two cylindrical samples of kidney tissue were taken.Pathohistologic analysis included the light and immunofl uorescent analyses of kidney tissue.Within this patomorphologic entity, patients were divided based on the therapy protocol used.Th e outcome of the used treatment was followed by monitoring the level of total serum proteins, proteinuria and creatinine clearance.Laboratory tests were controlled in intervals no longer than one month, depending on the pace of treatment.Th e outcome of the disease was defi ned as complete remission, partial remission or persistence of NS.Complete remission of NS was defi ned as proteinuria less then , g/day in three consecutive measuring, partial remission of NS as proteinuria between , g/day and , g/day in three consecutive measuring, while persistence of NS was defi ned as proteinuria more than , g/day in three consecutive measuring.Th e test results were statistically processes using descriptive statistics and Student-t test, with the acceptance of statistical signifi cance at the level p<,.The results are shown in graphic and tabular form.

Results
In the period -, IgA nephropathy was pathohistologically proven in , of the cases with primary nephrotic syndrome.Among the observed patients who had IgA nephropathy and nephrotic syndrome, diffuse proliferation of mesangium with more than  of hypercellular glomeruli were found in , of the cases, which classified them in pathohistological subclass IV IgA nephropathy, while , of the cases showed histological appearance of subclass III (focal proliferative glomerulonephritis).Crescend formations were seen in  of the cases with IgA nephropathy.Th e deposits of IgA found in mesangium of glomeruli, ranging between  and +, were in , of the cases + intensity, and in  of the cases + intensity.Interstitial lesions were found in , of the cases.Table  shows the number of patients with IgA nephropathy associated with nephrotic syndrome according to the therapy protocols applied.Corticosteroids (initial dosage -, mg/kg BW/ weeks, then dosage reduction to , mg/kg BW until the achievement of therapeutic response, followed by gradual termination of therapy  weeks after achieved the therapeutic response) were the basis of therapy protocol for patients monitored.The patients with IgA nephropathy associated with nephrotic syndrome, resistant to corticosterods only, were treated with a combination of corticosteroids and pulse therapy of cyclophosphamide (- mg/kg BW), or with cyclosporine ( mg/ kg BW, level of cyclosporine in blood app. ng/ml).
Table  shows the treatment results of patients () with IgA nephropathy and nephrotic syndrome in relation to quantitative values of proteinuria and serum proteins before and after the treatment.Complete remission of nephrotic syndrome was achieved in , of the patients ().Only corticosteroids were used with  patients,  patients were treated with pulse therapy of cyclophosphamide with corticosteroids and  patients were treated with cyclosporine.Partial remission of NS was achieved in , of the cases.The remaining , of the patients also treated, still showed the signs of persistent nephrotic syndrome.
The outcome of the kidney disease in relation to the therapeutically model used is shown in Table .
Th e therapy protocols applied were not followed by the deterioration of kidney function.Creatinine clearance did not change signifi cantly in the period monitored (Table ).

Discussion
Histological appearance of IgA nephropathy can range from minimal lesions to diffuse proliferative crescend glomerulonephritis, which was used by Lee and colleagues () to make the pattern of histological classification of the disease in five subclasses.Many studies have confirmed that IgA nephropathy histological features significantly correlate with the clinical outcome of disease ().
IgA nephropathy was confi rmed in , our patients with primary nephrotic syndrome, with more frequent occurences of this disease in men (,) than in women (,).Most of our patients had histological changes belonging to subclass IV.Immunofl uorescent microscopy showed mesangial hypercellularity with diff erent degrees of mesangial matrix expansion, as well as mesangial IgA deposits with intensity ranging from + to +.
Although some authors () have confirmed that the most common appearance of nephrotic syndrome is within focal segmental glomerulosclerosis as the subclass II of IgA nephropathy, further findings showed that high proteinuria appear in higher subclasses of histological changes (II to V), as observed in our patients.
IgA nephropathy can adversely progress and hasn't an established therapy.In  Nolin and Courteau () suggested, based on results of small randomized controlled studies, the treatment of this form of glomerulonephritis by corticosteroids.A secondary analysis of a multicenter, randomized, controlled trial of  adult IgA nephropathy patients () was shown that ten-year renal survival was significantly better in the group patients who were receiving intravenous methylprednisolone plus oral prednisolone for six months that in the control group ( versus , p=,).However, several studies emphasized need to use cytotoxic drugs in patients with high risk of progressing IgA nephropathy.In , Ballardie and Roberts () published the results of a controlled single-centre study of IgA nephropathy treatment with progressive impairment of kidney function.A signifi cantly better preservation of renal function was observed during the fi ve years follow-up, as well as the reduction of proteinuria during  months in a group of patients treated with corticosteroids and cytotoxic drugs compared to the control group, treated with supportive therapy only.
We used three types of treatment strategy with our patients.Complete remission was achieved in  patients (,) Only corticosteroids were used with  patients,  patients were treated with pulse therapy of cyclophosphamide plus corticosteroids and  patients were treated with cyclosporine.Partial remission of NS was achieved in  patients (,) treated by one of the mentioned strategies, and three patients (,) were resistant to therapy applied.Most of complete and partial remissions achieved were the result of applied corticosteroids ther-apy.Similar results have been reported by other authors.
Katafuchi () recommends the use of high doses of corticosteroids as treatment strategy of IgA nephropathy associate with proteinuria more than , g/day, while others recommend the combination of pulse doses of methylprednisolone and cyclophosphamide i.v.every month, during six months ().Th ere are some opinions that IgA nephropathy associated with NS is often steroid resistant, but that it can respond to cyclosporine treatment (), which was confi rmed in several of our patients.
Recently studies suggest that treatment of IgA nephropathy with new immunosuppressive drugs like mycophenolate mofetil may be eff ective in achieving complete or partial remission of NS in this glomerular disease ().

Conclusion
• Th e greatest number of patients with nephrotic syndrome analyzed had the histological appearance of IgA nephropathy, subclasses IV • Th e use of corticosteroids as a treatment strategy of IgA nephropathy in an initial dose of -. mg/kg BW resulted in the highest number of complete and partial remissions of nephrotic syndrome achieved, along with preserved renal function.
• A good treatment outcome can be achieved in patients with IgA nephropathy associated with nephrotic syndrome, resistant to corticosteroid monotherapy, by adding pulse doses of cyclophosphamide or cyclosporine monotherapy only.

TABLE 1 .
Treatment of primary nephrotic syndrome of IgA

TABLE 2 .
Th erapy eff ects of IgA nephropathy with nephrotic syndrome

TABLE 4 .
Th erapy eff ects on creatinine clearance

TABLE 3 .
Outcome of disease and type of treatment