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Abstract

The aim of this study is to determine response to treatment in terms of remission and relapse, related risk factors, type of management and complications of nephrotic syndrome among studied patients.

Design: Retrospective, analytical study.

Setting: Pediatric nephrology clinic at Althawra Central Teaching Hospital-Albida,

Participants/patients: All patients with idiopathic nephrotic syndrome (INS) were evaluated during 2005- 2016. Patients divided into two groups, group I 46 (39%) is non-relapse and group II 72 (62.7%) is relapse group. Group II are sub divided into group A: frequent relapse steroid dependent (FRNS/SDNS) and group B: infrequent relapse nephrotic syndrome (IRNS).

Results: Records of 118 children with INS were studied and 74 (62.7%) were boys, male to female ratio 1.7:1. There was no significance difference between group I and group II in the following parameters; age group, sex, family history, initial hypertension and hematuria (p value = >0.05). Mean proteinuria was significantly higher in group II (p=0.001), while mean S. albumin, mean s. cholesterol and mean blood urea did not show any significant difference statistically and p value were (0.022), (0.012), (0.116) respectively. Group B showed significant higher frequency than group A regarding sex (p=0.010), age group 1 and positive family history (p=0.050), both groups were comparable regarding gross hematuria and hypertension (p=0.975). Mean S. albumin was significantly low in group A (p=0.03) but no significance difference between both group regarding mean proteinuria, lipid profile and renal function and the p value for the three variables were (0.015) (0.206) (0.257) respectively. The most common complications were hypocalcemia, cushingoid facies and obesity (26.5%, 25.4%, 18.6%) respectively, followed by infections (13.5%), hypertension (11.8%), acute kidney injury (8.4%), chronic kidney disease (1.7%) and death in one patient (0.8%).

Conclusion: Idiopathic nephrotic syndrome is chronic relapsing disease for most steroid-responsive patients especially males between 2 -8 years with different complications of disease and its treatment affecting patient's life.

Keywords: Idiopathic nephrotic syndrome, relapse, steroid sensitive nephrotic syndrome, steroid resistant nephrotic syndrome, nephrotic-range proteinuria, edema, hyperlipidemia, hypoalbuminemia, remission, relapses, cyclosporine, chlorambucil, cyclophosphamide

Abbreviations

SSNS, steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; ISKDC, international study of kidney disease in children; MCNS, minimal change nephrotic syndrome; FSGS, focal segmental glomerulosclerosis; KDIGO, kidney disease improving global outcomes; FRSD, frequent relapse steroid dependent; IFNS, infrequent relapse nephrotic syndrome; SSPS, statistical package for social sciences

Introduction

Pediatric nephrotic syndrome, known as nephrosis and is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia.1 Nephrotic-range proteinuria in children is protein excretion of more than 40 mg/m2/h1 INS and is divided into steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) because response to steroids has a high correlation with histological subtype and prognosis.2 The International Study of Kidney Disease in Children (ISKDC), found that the vast majority of preadolescent children with INS had minimal change nephrotic syndrome (MCNS) on kidney biopsy. Whereas 90% of children with MCNS responded to corticosteroid treatment with remission of their nephrotic syndrome and only 20% of children with focal segmental glomerulosclerosis (FSGS) responded to steroids.2,3 Specific treatment of nephrotic syndrome depends on its type; Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2012 that include recommendations on treatment of nephrotic syndrome in adults and children.4 Despite the generally favorable prognosis in patients who respond to steroids, the ISKDC reported a 60% rate of subsequent relapses, which can lead to complications, increased morbidity, and decreased quality of life.3A longer course of initial steroid treatment (12 week rather than the original ISKDC protocol of 8 week) may reduce the rate of subsequent relapse to 36% which still represents a large percent of patients who undergo repeated courses of immunosuppressant medications other than steroids (i.e., cyclosporine, chlorambucil, cyclophosphamide) with possible co morbidities and more serious side effect.5,6 In fact relapse or remission in nephrotic syndrome is important outcome which reflect the prognosis of treated patients. The periodic follow up of these patients is essential to evaluate the extent of the success of management provided to the patients. The aim of this study is to determine response to treatment in terms of remission and relapse, related risk factors, type of management and complications of nephrotic syndrome among studied patients.

Patient and methods

An analytical retrospective study was conducted on children diagnosed as INS presented to Nephrology clinic Al Thawra Central Teaching Hospital. Medical records of these patients were reviewed from January. 2005 to December 2016. In this study NS was diagnosed according to the criteria of the international study of kidney disease in children (ISKDC). Patients were categorized into two groups: Group I that contains 46 patients (no relapses) and Group II contain 72 patients (with relapses). Group II were subdivided into group A frequent relapse steroid dependent (FRSD), group B infrequent relapse nephrotic syndrome (IFNS).

Demographic characteristics include gender, age investigations that include: total protein, S. albumin, S. cholesterol, renal function test (Urea, S. creatinine), urine 24 protein g/day, history of hematuria, hypertension, family history of nephrotic syndrome, complications, management, outcomes (Remission & Relapses), steroid response (sensitive, resistance or dependent to cytotoxic therapy, other drug and frequency of relapses (frequent and infrequent) were recorded. Relapse is considered when the patients have development of edema and persistent of urinary protein excretion>40 mg/m²/hr, 3+ by dipstick for 3 consecutive days. Remission is considered where the patients have urine protein negative to trace for 3 consecutive days. Frequent relapses was defined as the occurrence of ≥2 relapses in 6 months or ≥3 relapses in 12 months, and steroid dependence as the presence of two consecutive relapses while on tapering doses of prednisolone.7 Failure to show remission of proteinuria despite 4-weeks treatment with prednisolone (2mg/kg/day) was termed as initial resistance when noted at onset of disease, and late resistance if occurring in a patient previously responsive to steroids.7 The disease course, use of alternative therapies and complications were described for patients with minimum 12-months follow up at this center (Study Group). The course of disease during these 12 months was categorized as single episode, infrequent relapses, frequent relapses, steroid dependence or resistance.

Therapy course

Adequate initial treatment for first episode was used prednisolone (2mg/kg/day) for ≥4 weeks followed by 1.5 mg/kg on alternate days for ≥4 weeks and tapering the dose for 3 to 4 months. Relapses were treated with prednisolone, 2mg/kg/d until remission and 1.5 mg/kg on alternate days for 4 weeks. Patients with frequent relapses or steroid dependence received prednisolone (0.3-0.7mg/kg) on alternate days for 9-12 months. Those having relapses or steroid toxicity received one or more alternative agents.7 In this study Mendoza protoclol (high dose methyl prednisolone infusion), cytotoxic chemotherapy drugs (cyclosporin, cyclophosphamid) and levamisol were included as alternative agents after 2010 and lastly adding MMF (mycophenolatemofetil) in 2014.

Often as follows:

  1. levamisole (2 mg/kg on alternate days for 6 months)
  2. oral cyclophosphamide (2 mg/kg/d for 12 weeks)
  3. MMF (600-1000 mg/m2/d)
  4. cyclosporine (4-6 mg/kg/d).8

Kidney biopsies were not done because of unavailability except for few patients who were sending abroad.

Data analysis

Data entry statistical analysis and calculations were performed with the use of Statistical Package for Social sciences (SSPS). The data interpreted in table and figures, the numerical data were shown as percent, mean+ Standard Deviation. To find the significant difference between the studied variable, Chi-Square test and unpaired “t” test were used, p value <0.0 5 was taken as level of significance.

Results

118 children diagnosed as INS, 74(63%) patients were males and 44 (37%) were females, male to female’s ratio1.7:1. The age group was divided into two groups: group 1 (2- 8 years) which represented (82%) and group 2 (< 2 years or >8years) were represented (18%). Among the total studied children 39% showed no relapse, 30% had frequent relapse and 31% with infrequent relapse (Figure 1). Initial steroid resistance (SRNS) was noted in 4 patients (3.38%) and 114 patients (96.6%) were sensitive (Figure 2). Baseline characteristics at initial presentation showed group I (39%) no relapse and group II relapses (61%)and both groups compared with no significant statistical difference regarding age at initial presentation gender, family history hypertension and gross hematuria(p =0.795). Mean proteinuria (24 hour protein excretion) was significantly higher in group II (p=0.001), while mean S. albumin, mean S. cholesterol and mean blood urea did not show any statistical significance P value (0.022, 0.012, 0.116) respectively. Group II (relapses patients) were divided into two subgroups, group A (frequent relapse n=35) and group B (infrequent relapses n=37) showed risk factors for disease course compares the clinical and laboratory characteristics of both groups (Table 1). There was a significantly higher frequency in group B for males, age group 1 and native family history than in group A (p=0.010), (p=0.05), (p=0.05) respectively, both groups were comparable regarding Hematuria and hypertension (p=0.975). Mean S. albumin significantly low in group A (p= 0.03) but no significance difference statistically between both group regarding mean proteinuria, lipid profile and renal function and p value (0.015) (0.206) (0.257) respectively as shown in Table 2. All patients had received first line adequate initial therapy with oral prednisolone treatment and almost one-half of the patients (54%), who were followed are required alternative medications for frequent relapses, steroid dependent and steroid resistant (Table 2).

 

 

Group I

Group II

 

no relapse

relapse

Variable

Parameter

No=46 (39%)

No=72 (61%)

P value

Sex

Male

30

46

0.975

Female

16

26

Age

Group1

37

60

0.975

Group2

9

12

Family history

Yes

2

4

0.975

No

44

68

HTN

Yes

5

11

0.975

No

41

61

Hematuria

Yes

6

8

0.975

No

38

56

No data

2

8

Proteinuria

mean proteinuria (g/24 hr)

4.2±0.7

4.815±1.44

0.001

Hypoalbuminemia

mean S. albumin (g/l)

4.7±23.4

2.11±0.810

0.223

Lipid profile

mean serum cholesterol (mg/dl)

320.5±91.5

340.17±82.7

0.122

RFT

mean blood urea (mg/dl)

29.88±19.94

25.88±12.92

0.116

Table 1 Demographic and laboratory data of idiopathic nephrotic syndrome in relation to relapse

Note: HTN, Hypertension; RFT, renal function test; Proteinuria: urine 24 protein g/day.

Figure 1 Distribution of Relapses of studied children during studied period

Figure 2 Distribution of idiopathic nephrotic syndrome in relation to response and relapse

Note: FRNS, frequent relapse nephrotic syndrome; IRNS, infrequent relapse nephrotic syndrome; SDNS, steroid dependent nephrotic syndrome; SRNS, steroid resistant nephrotic syndrome

 

 

Group A

Group B

 

FRNS, SDNS

IRNS

Variable

Parameter

No=35

No=37

P value

Sex

Male

17

29

0.01

Female

18

8

Age

group1

28

34

0.05

group2

7

3

Family history

Yes

4

9

0.05

No

31

28

HTN

Yes

5

6

0.975

No

30

31

Hematuria

Yes

6

2

0.975

No

27

23

No data

2

12

Proteinuria

mean proteinuria (mg/m2/hr)

4.27±1.35

4.53±1.94

0.015

Hypoalbuminemia

mean S. albumin (mg/dl)

0.68±0.71

1.88±21.82

0.03

lipid profile

mean S. cholesterol(mg/dl)

90.32±96.35

335.34±87.66

0.206

RFT

mean urea

20.62±20.401

26.99±16.21

0.257

Table 2 Factors affect types of relapsing patients

Complications: Hypocalcemia, cushingoid facies and obesity represent (26.2%) (25.4%) (18.6%) respectively, followed by infections (13.5%), hypertension (11.8%), acute renal failure in (8.4%), renal impairment was observed in (1.7%) and death in one patient (0.8%) (Table 3). Distribution of complications according to type of relapses nephrotic syndrome patients with no significant difference regarding hypertension for all groups (p=0.100) but significantly higher frequency observed with frequent relapse steroid dependent nephrotic syndrome patients and p value (0.050) each for renal failure, hypocalcaemia and highly significant (0.001) for peritonitis (Table 4).

Variable

No

%

Hypocalcemia

31

26.2

Cushingoid facies

30

25.4

Infections

16

13.5

Hypertension

14

11.8

Overweight (obesity)

22

18.6

Hyperglycemia

2

1.7

Growth retardation

12

10.1

Acute renal failure

10

8.4

Chronic renal failure

2

1.7

Death

1

0.8

Table 3 Complications of idiopathic nephrotic syndrome and/or steroid therapy among the study population during follow-up of the disease

 

No relapse

IRNS

FRNS/SDNS

Total

 

 Complication

No=46

No=37

No=35

118

P value

a- HTN

3

6

5

14

0.1

b- Renal failure

1

3

6

10

0.05

c- Low S. ca

10

8

13

31

0.05

d- Peritonitis

1

2

13

16

0.001

Table 4 Distribution of complication according to type of relapse nephrotic syndrome patients

Discussion

The findings of the current study support previous published reports that childhood NS is a disease of high morbidity and results in significant healthcare burden.9 INS has highly variable therapeutic managements. Obtaining and maintaining the lowest level of proteinuria, will result in the best quality and quantity of both renal and patient survival.10 The characteristics of our patients were similar to that reported previously including age at onset, male preponderance and low incidence of familial cases.12,13 The extreme age of (age group 2) at presentation of NS in our study was represent (18%), not too far from that reported on a group of children from Saudi Arabia (16.9%).15 The disease was classified based on steroid response and frequency of relapse would be a predictor of increased hospitalizations and complications, as it is an important determinant of disease prognosis. This was substantiated in our analysis on hospitalizations. FRNS/SDNS and SRNS were associated with increased hospitalization rates compared to children with SSNS. In our analysis observed 96.6% were sensitive and the proportion of patients having initial steroid resistance (SRNS) was noted in 4 patients (3.38%) comprising lower proportion of initial resistance was 12.5% seen other studies.16–18 Long-term follow up of studied children 39% showed no relapse, 31% with infrequent relapse and 30% had frequent relapse which in closer extremity to report of ISKDC reported that just 28.1% patients show frequent relapses in the first 6 months of their illness,16 Data from other centers, comprising relatively more than our observation, shows that the proportion of frequent relapses varies from 56-68% .19–21

Children who experienced NS relapse were younger in the present study; the difference was not statistically significant. The lack of any association between age at onset of NS and occurrence of relapse has been reported by other workers.22,23 Similarly, gender and microscopic hematuria enjoy an inconsistent relationship with subsequent relapses, FR or SD in published literature.22,24 while Andersen19 and Suresh Kumar22 reported that male gender as risk factor for subsequent relapses, FR or SD, others did not find such relationship which doesn’t agree with our results we found the opposite as females had higher percentage in FR /SD with statistical significance, the reasons for the inconsistency are unknown but may be related to differences in the study population and design.23,25 Our findings support previous published reports that childhood NS is a disease of high morbidity and Hematuria was found in 11.9% of our patients, which is much less than what was found by Thabet26 (63.6%), Ibadin27 (60%) and Begum28 (45%). The percentage of Hypertension in the current study was 13.56% which lesser than other figures reported by Thabet26 study (26.8%), Ibadin27 study (41.4%), Begum28 (50%) and Srivastava29 were seems to have little effect on the rate of relapse. In this study, patients had normal renal function with no significant difference in blood urea between both relapsed and non relapsed groups. Impaired renal function in accordance to the age and sex were observed in 26.7% in Thabet26 study and 19% of patients in Begum28 study. Takeda30 and Sarker 31 found that, the mean serum albumin level in frequent relapse NS group was significantly lower than that of infrequent relapse NS group which seen in agreement with our results. In this study, complication related to the disease itself as Hypocalcaemia was found the same in the literature;32 that explained by lack of 25-hydroxycholecalciferol (the way that vitamin D is stored in the body) which may lost in the urine or may be relative hypocalcaemia due to hypoalbuminemia as ionized calcium is bound to albumin also other complication related to long-term corticosteroid therapy which increased risk of steroid toxicity including cushingoid features and infections were observed which follow the similar trend in the literature.32 Only one patient died in the current study represent 0.8% which was found the same report by Cohort33 study but lesser than other studies reported by Wingen34 that found 10 deaths was resulting a mortality rate of 1.9% and 17% reported by Wynn35. From the analysis of this work compared to the published studies, one can notice similarities and differences between the reported data, and this may be explained by different design of different studies and could be due small sample size. A larger cohort study is required for a better understanding of these factors and advance management.

Conclusion

Idiopathic nephrotic syndrome is chronic relapsing disease for most steroid-responsive patients especially males between 2-8 years with different complications of disease and its treatment affecting patient's life. Recommendations: Daily prednisolone during episodes of upper respiratory infections remains a relevant intervention aimed to reduce the risk of relapse, also zinc supplements which reduce both the frequency of respiratory tract infections and relapse rates. Prompt search and treatment for URTI should not be overlooked by clinicians managing children with nephrotic syndrome. These relapse-specific interventions can reduce the morbidity associated with frequent relapses and ultimately improve the child’s quality of life.

Acknowledgements

We wish to thank the nephrology clinic nurses at Althawra central teaching hospital for providing the medical records of our patients and to thank Dr Marfoaa S Ali, Dr Salema R Qowaider for their help and Dr Naziha R Rhuma for her help and cooperation and special thank to Professor Ihab El-Hakim, for his constant support.

Conflict of interest

Author declares that there is no conflicts of interests.

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