Steroid Responsiveness of Children with Idiopathic Nephrotic Syndrome in Southeastern Region of Turkey

Abstract

Background. Our aim was to determine the prognostic factors effective in the response to steroid treatment and relapse frequency. Patients and Methods. In this study, we evaluated 84 children with idiopathic nephrotic syndrome followed-up from 1997–2002. The variables were analyzed with respect to medical history, physical examination, laboratory findings, response to treatment, and factors associated with remissions and relapses. Our study group consisted of 62 children with minimal change nephrotic syndrome (MCNS), 11 children with focal segmental glomerulosclerosis (FSGS), and 11 children with diffuse mesangial proliferation (DMP). Results. According to response to steroids; 57.1% were steroid-sensitive with infrequent relapses, 22.6% were steroid-dependent with frequent relapses, and 20.2% were steroid-non-responders. Significantly high non-responder ratios to steroids were found in children with initial hypertension and hematuria (p < 0.05). Although patients older than six years were found to be associated with steroid non-response (p < 0.05), the number of relapses were found to be increased with an increasing number of infections (p < 0.05). The time period for the first relapse was found to be statistically correlated with relapse numbers of the first 6 (p = 0.001) and 12 (p = 0.01) months. Conclusion. The time span between initial presentation and remission and the number of infections were significant for relapse frequency. The existence of hematuria and hypertension and age greater than 6 years at initial presentation were associated with steroid non-responsiveness. The likelihood of developing resistance to the treatment should be emphasized early to the parents of patients bearing these risk factors, and hence the possible disappointment in the family should be prevented.

Keywords:

• idiopathic nephrotic syndrome
• risk factors
• steroid non-responder
• southeast Anatolia

INTRODUCTION

Idiopathic nephrotic syndrome (INS) is a common glomerular disorder in childhood characterized by massive proteinuria, hypoproteinemia, edema, and hyperlipidemia. Estimates of annual incidence range from two to seven new cases in children under 16 years per 100,000 total people.[1],[2] There is epidemiological evidence of a higher incidence of nephrotic syndrome in children from south Asia.[3] This syndrome is of great importance because it tends to become chronic and accelerates the development of end stage renal failure, assuming that it is not followed and treated properly.[4]

The major role in the development of end stage renal failure belongs to chronic proteinuria. Proteinuria in nephrotic level leads to irreversible damages in glomeruli and is a risk factor for tubulointerstitial lesions.[5] Because of the importance of proteinuria, it is essential that in patients in remission, relapses should be avoided if possible, and the proper treatment should be chosen according to the patient's features when relapse develops. However, there are not enough studies related to the prediction of progression of disease, development of resistance to treatment, and frequency of relapse by looking at clinical and laboratory findings of patients.

The purpose of our study was to identify those characteristics at the initial presentation of patients with INS that could predict prognostic factors effective in the response to steroid treatment and relapse frequency.

PATIENTS AND METHODS

In this study, 84 patients who were diagnosed as INS between January 1997 and November 2002 were investigated retrospectively. The study group consisted of patients with MCNS, FSGS, and DMP. Idiopathic nephrotic syndrome was defined as massive proteinuria (urine protein excretion 40 mg/m²/hour), hypoalbuminemia, hyperlipidemia and edema.[4],[6] We excluded patients with underlying secondary causes, including HCV infection, HBV infection, and congenital NS.

The variables were analyzed with respect to medical history, physical examination, laboratory findings, frequency of infection, response to treatment, and factors associated with remission and relapse. Patients with clinical NS who did not undergo biopsy were presumed to have MCNS, and all were treated with prednisone. The response to therapy was classified according to the definitions from the International Study of Kidney Disease in Children (ISKDC).[7] After informed consent was obtained, renal biopsy was performed following the decision of steroid non-responder or -dependent.

Statistical analyses of data were performed by using SPSS 10.0 package program. Remission rates of our patients in the first 15 days and the relation between age and remission were indicated by chi-square test, and the relation between rare and frequent relapse was indicated by Fisher-exact test. The relation between relapse and frequency of infection was determined by using linear regression analysis method. p < 0.05 value was accepted as statistically significant.

RESULTS

In our patients, male to female ratio was 2:1 (56/28) and their ages ranged between 9 months to 15 years with the mean age of 4.8±3.2 years. The mean follow-up time was 35.6±21.9 months. Some clinical and laboratory findings of the patients with INS at first admission are given in Table 1.

Table 1 Some clinical and laboratory findings of the patients with INS at first admission

	Mean ± SD	Median (min-max)
Initial age of NS (year)	4.8 ± 3.2	4 (0.9–15.0)
Total follow-up time (month)	35.6 ± 21.9	29 (12–96)
Initial proteinuria (mg/m^2/h)	117.7 ± 83.3	95 (40–539)
Serum albumin level (mg/dL)	1.6 ± 0.7	1.6 (0.5–4.1)
Serum cholesterol level (mg/dL)	378 ± 145	368 (97–760)
Number of infections developed	2.5 ± 2.0	2.0 (0–10)

The patients were divided into three groups according to response to steroid medication: steroid-responding (n = 48), steroid-dependent (n = 19) and steroid non-responder (n = 17). The rates of steroid response in patients with MCNS, FSGS, and DMP are shown in Figure 1. Factors affecting the response to steroid therapy in patients of our study group are given in Table 2. There was a significant difference between patients with MCNS and patients with FSGS and DMP with respect to going into remission in the first two weeks of the treatment (p = 0.006; see Table 3). Non-responder to steroid therapy in patients over the age of 6 years and in patients with hematuria and hypertension was found statistically significant (p < 0.05; see Table 2).

Figure 1. Response rate of the patients with INS to steroid therapy in our study group.

Table 2 Comparison of steroid response and factors affecting this response

		Steroid response (n = 48), n (%)	Steroid-dependent (n = 19), n (%)	Steroid non-responder (n = 17), n (%)	Total	p
Hypertension	Existing	2 (4.2)	5 (26.4)	6 (35.3)	13	0.003
	Absent	46 (95.8)	14 (73.6)	11 (64.7)	71
Hematuria	Existing	5 (10.4)	4 (21.1)	11 (64.7)	20	<0.001
	Absent	43 (89.6)	15 (78.9)	6 (35.3)	64
Age	≥6 age	7 (14.6)	2 (10.5)	8 (47.1)	17	0.015
	≤6 age	41 (85.4)	17 (89.5)	9 (52.9)	67
Remission in the fifteenth day	Existing	33 (68.7)	5 (26.3)	1 (5.9)	39	<0.001
	Absent	15 (31.3)	14 (73.7)	16 (94.1)	45

Table 3 Remission rates of our patients in the first 15 days of the treatment

Remission in the fifteenth day	Patients with INS, n (%)
	MCNS	FSGS	DMP	Total	p
Yes	35 (66.5)	2 (8.2)	2 (8.2)	45	0.006
No	27 (43.5)	9 (81.8)	9 (81.8)	39	0.006

Abbreviations: MCNS = minimal change nephrotic syndrome, FSGS = focal segmental glomerulosclerosis, DMP = diffuse mesangial proliferation.

The relationship between the duration of initiation of the first remission and the number of relapses in the first six months (r = 0.47; p = 0.001) and in the first 12 months (r = 0.36; p = 0.01) and total number of relapses (r = 0.31; p = 0.024) was significant.

Excluding the patients with steroid non-responder, in 37 of 67 children (55.2%), remission was provided by conventional steroid therapy, and relapse did not occur in the first six months. Over the same period, relapse developed in steroid non-responders once in 26 (38.8%) patients and twice in 4 (6%) patients. The first relapse occurred after 12.1 ± 21.3 months from the initiation of therapy, and the second relapse occurred 7.5 ± 5.8 months after the first relapse. There was no significant difference in terms of frequent and rare relapse development ratios between male and female children (p > 0.05).

A significant relationship was found between the number of relapses of the disease and frequency of infection (r = 0.44; p < 0.05).

DISCUSSION

Idiopathic nephrotic syndrome was defined as the combination of proteinuria of ≥40 mg/m²/h and hypoalbuminemia of ≤2.5 g/dL, usually with edema, in a child between 3 months and 16 years of age without clinical or laboratory evidence of a primary disease known to cause proteinuria.[8]

ISKDC reported that MCNS, FSGS, DMP and other types of glomerulonephritis may be seen in 77%, 10%, 3%, and 10% of children with nephrotic syndrome, respectively.[7] In our series, 74%, 13%, and 13% of our patients had MCNS, FSGS, and DMP, respectively. The ratios of our patients with DMP and FSGS were found parallel to the ISKDC study. However, the higher ratio of the patients with DMP might have resulted from the scarcity of patients or a regional feature that cannot be determined.

In previous studies, the ratio of microscopic hematuria was reported as 22.7% in patients with INS who responded to steroid therapy.[7] However, in our study, that ratio was found to be 10.4%. A lower association of microscopic hematuria detected in our study can result from a scarcity of patients. It is reported that microscopic hematuria is seen in 67%—a relatively high ratio—of patients with INS who resist steroid medication.[9] However in a different study, this ratio has been found as 63% of patients with FSGS who resisted steroid medication.[10] An accompaniment of microscopic hematuria was also determined in our non-responders to steroid therapy (see Table 2).

Of the patients with the diagnosis of MCNS, four had hypertension initially. In the literature, it is declared that blood pressure is usually normal in patients with MCNS responding to steroid medication, and mild hypertension may be seen in 6–13% of cases at the initial period of the disease.[11] We observed frequent relapse and a prevalence toward non-response to steroid therapy in 75% of our patients with hypertension during follow-up.

On the fifteenth day of the treatment with steroid therapy in patients with NS, remission was provided in 46.4% of our patients, whereas in 78.6% of them remission was achieved at the end of the first month of the treatment. According to the data of ISKDC, in 471 patients with NS, remission was achieved in 78.1% at the end of the first month of steroid therapy. It was detected that 91.8% of these patients responding to steroid therapy had MCNS histopathologically. In the same study, while the ratio of response to steroid in patients with FSGS was determined to be 29.7%, this ratio was found to be 55.6% in children with DMP.[12] In our study, the ratio of those responding to steroid therapy of patients was found to be similar to that found in the literature (see Table 2).

Non-response to steroid therapy was determined in about one-fifth of our patients. In the literature, it was reported that approximately 10% of the patients with INS show resistance to steroid therapy.[9] The reason why the ratio of the patients with INS non-response to steroid therapy was higher than ones reported in the literature can be explained with the coordination of the families to the long therapy period.

We observed that children with INS who went into remission in the first two weeks and who responded to initial steroid therapy showed better prognosis. It was shown in a similar study that prognosis would be better in children going into early remission with steroid medication.[13]

Infectious episodes in nephrotic patients are responsible for high morbidity and can also cause an inadequate response to corticosteroid therapy and recurrences among patients in remission.[14] In our patients, similar to the frequency of having infection, frequency of relapse has increased significantly (r = 0.44; p = 0.001). According to Yap et al., in a group of children with INS responding to steroid therapy, frequent relapse and steroid dependence was found significantly higher in children who had upper respiratory tract infection and responded to initial steroid therapy after nine days.[15] Studies have demonstrated that relapse is frequently seen after upper respiratory tract infection occurring in the spring.[16]

Relapse developed at least once in 32.1% of patients having a dependence to or responding to steroid therapy. Most relapses developed in the first year of these patients.

We have not found any relation between high cholesterol levels, low albumin levels, and the amount of protein lost by daily urine with the frequency of relapse or response to steroids. However, Hiraoka et al. showed that mildly associated findings at the initial stage of nephrotic syndrome were the cause of good prognosis.[17] Further investigations regarding the reflection of initial laboratory and clinical findings to the progress are necessary.

We found a significant relationship between the duration of the initiation of the first remission and the number of relapses developed in the first 6 (p = 0.001; r = 0.47) and 12 (p = 0.01; r = 0.36) months. It was observed that patients who did not have any relapse in the first six-month period rarely showed relapse, and prognosis was better both clinically and histopathologically in such patients. In a study by Tarshish et al., it was reported that children who responded to steroid therapy remained in remission during 6 months after therapy, and during the follow-up they either remained in remission or showed rare relapses. Moreover, they observed that the period without relapse was seen after the third year in patients having relapse initially.[18]

In conclusion, patients older than 6 years with initial hematuria and hypertension may develop non-responsiveness to steroids. Moreover, infections may trigger the frequency of relapse. Disappointment over the therapy in the families should be diminished by informing them about the clinical progress.