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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 5  |  Page : 965-972
Long-term outcome of the difficult nephrotic syndrome in children


1 Pediatric Department, College of Medicine, King Saud University and King Khalid University Hospital, Riyadh, Saudi Arabia
2 Pediatric Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

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Date of Web Publication13-Sep-2012
 

   Abstract 

To determine the long-term outcome of nephrotic syndrome (NS) in children, we studied 48 patients with the NS aged seven months to 12 years at onset and followed for a long period (3-9 years). Consanguinity was positive in 31.2%. Patients' history of atopy was present in 25%, while family history of allergy was present in 18 (37.5%) patients. Renal impairment at initial presentation was observed in 12.5% of the patients. Among 32 biopsied patients, 11 (34.3%) had focal segmental glomerulosclerosis and eight (25%) revealed mesangial IgM nephropathy. Outcome at two years of presentation showed 41.6% patients as frequent relapsers, 39.5% as steroid dependent and18.7% as steroid resistant. Forty-three patients were available for follow-up after ten years of presentation, 22 (51%) patients had complete remission, 15 (34.8%) were steroid dependent, two (4.6%) developed chronic renal failure and two (4.6%) died. Two patients (4.6%) developed insulin-dependent diabetes mellitus, two (4.6%) had cataract and one (2.3%) had documented peritonitis. In conclusion, the high incidence of steroid-dependent, frequent relapses and steroid resistance in children can be explained by different factors, including consanguinity, atopy and severe presentation at onset of disease. We suggest longer initial treatment at onset for this group of patients. The low incidence of infection in this group needs to be addressed in future studies.

How to cite this article:
Al Salloum AA, Muthanna A, Bassrawi R, Al Shehab AA, Al Ibrahim A, Islam MZ, Alhasan K. Long-term outcome of the difficult nephrotic syndrome in children. Saudi J Kidney Dis Transpl 2012;23:965-72

How to cite this URL:
Al Salloum AA, Muthanna A, Bassrawi R, Al Shehab AA, Al Ibrahim A, Islam MZ, Alhasan K. Long-term outcome of the difficult nephrotic syndrome in children. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 May 21];23:965-72. Available from: http://www.sjkdt.org/text.asp?2012/23/5/965/100877

   Introduction Top


Nephrotic syndrome (NS) is recognized as a common chronic illness in childhood. [1] The constellation of features that characterize NS develops from primary alterations of the perm selectivity barrier of the glomerular capillary wall, which is no longer able to restrict the loss of protein to less than 100 mg/m 2 body surface per day. [2] The most common form of the NS in childhood is primary idiopathic nephrotic syndrome, with an incidence of 2-7 cases per 100,000 children and prevalence of nearly 16 cases per 100,000. [1] The idiopathic nephrotic syndrome of childhood is characterized by steroid responsiveness in ≥90% of the cases. However, up to 60% of the patients with steroid-sensitive NS develop a frequently relapsing or steroid-dependent course. [4]

Children with NS undergoing long-term and repeated treatment with glucocorticoids are at risk of adverse drug effects, in particular growth retardation and obesity. [5] Furthermore, there are concerns that cytotoxic treatment with cyclophosphamide or chlorambucil may result in infertility and neoplasia. [6]

There are distinct histological variants of primary idiopathic syndrome, including minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS), which may represent opposite ends of one patho-physiological process or distinct disease entities. [1] Although the overall incidence of childhood NS has been generally stable over the past three decades, [7] the histological pattern has changed; [1] the incidence of FSGS seems to be increasing. [8] Ethnic origin may affect the histological variant and the response to immunosuppressive treatment. [9],[10] Moreover, age at initial presentation has an important impact on the disease outcome. [11],[12]

The aim of this study was to obtain detailed data on long-term prognosis of the difficult NS in children.


   Materials and Methods Top


We reviewed all medical records of Saudi children with difficult nephrotic syndrome admitted at our institute from January 1996 to December 2006 and followed-up for a minimum period of three years. Patients with incomplete records and those with follow-up less than three years or aged less than six months at onset were excluded. Forty-eight patients fulfilled the inclusion criteria. We included the following for the analysis in our study:

  1. History and clinical examination at initial presentation and last evaluation.
  2. Laboratory parameters at initial and last presentation, including complete blood count, serum urea, creatinine, cholesterol, triglyceride, total protein, albumin, electrolyte, serum complement C 3 and C 4 levels, hepatitis B surface antigen, erythrocyte sedimentation rate, antistreptolysin O titer, urinalysis, urine albumin:creatinine ratio or 24-h urine protein level and urine dipstick.
  3. The renal histopathology.
  4. The seasons of onset and relapses.
  5. The frequency and type of complications.
  6. The short-term (two years) and long-term (ten years) outcome.
NS was defined as urinary protein excretion of ≥40 mg/m 2 /h and hypoalbuminemia of <25 g/L and edema, according to the criteria of the International Study of Kidney Disease in Children (ISKDC). [3] The Difficult Nephrotic Syndrome was defined as any patient with the NS who was labeled as frequent relapser, steroid dependent or steroid resistant after two years of the initial diagnosis. Remission of the NS was characterized by disappearance of albuminuria (dipstick testing O to trace) for three consecutive days, whereas relapse was defined as reappearance of proteinuria (dipstick testing ≥2+) for at least three consecutive days. Steroid responsiveness was defined as remission of NS during the initial four weeks of steroid treatment. Long-term remission was defined as no relapse of NS for at least three consecutive years. Frequent relapses were defined according to the ISKDC criteria (more than two relapses in the initial six months after presentation or more than four per year during follow-up). [13] Steroid dependency was defined according to the guidelines of the Arbeitsgemeinschafts fur Pediatrische Nephrologie (APN) (at least two relapses during alternate day treatment with prednisone or within two weeks of cessation). [14] Short stature was defined as height less than -2SD compared with normal stature for age and sex. Hypertension was defined as reported by the Second Task Force on Blood Pressure Control in Children. [15] Very low serum albumin was defined as <1.5 g/dL.

The initial episode of NS was treated with the standard initial therapy of the ISKDC, [3] consisting of daily prednisone 60 mg/m 2 body surface area for four weeks, followed by 40 mg/m 2 body surface area on three days per week (intermittent regime).

Relapses were treated with daily prednisone of 60 mg/m 2 until remission (zero or trace dipstick testing on three consecutive days) was achieved, followed by four weeks of 40 mg/m 2 on alternate days. In steroid-dependent patients, maintenance alternate day prednisone was initiated, and the alternate dose was gradually tapered to determine each patient's individual threshold at which relapse occurred.

For alternative treatment, cyclophosphamide was always the first cytotoxic drug and the indications for cyclophosphamide therapy were as follows:

  1. Frequent relapses or mild steroid dependency (i.e. <1 mg/kg per 48 h) and significant psychological, behavioral or somatic side-effects.
  2. Severe steroid dependency (≥1 mg/kg per 48 h).
  3. Steroid resistance.
Cyclophosphamide was administered in a 12- week course with accumulative dose of 160-180 mg/kg/course according to the criteria of APN. [14]

Cyclosporine A has been used at a dose of 5 mg/kg/day, aiming at whole blood trough levels of 100-150 μg/L usually combined with corticosteroids in the first six months. Cyclosporine A was restricted to patients who developed recurrent steroid dependency after a course of cyclophosphamide treatment and performance of renal biopsy. The duration of cyclosporine A treatment ranged between two and six years. Chlorambucil was restricted to patients with treatment failure and administered in a dose of 0.15 mg/kg/day for eight weeks. Levamisole was not used in any patient in the study patients. No patient was given human growth hormone. Pneumococcal vaccine and antibiotic prophylaxis was not a routine practice in our unit.

Salt-poor human albumin was administered intravenously at a dose of 0.5-1.0 g/kg, usually followed by the intravenous infusion of furosemide (1 mg/kg/dose), to children who exhibited massive edema, especially in the presence of reduced urinary volume or elevated level of blood urea nitrogen or creatinine. [12]

Renal biopsy was routinely performed in patients with steroid resistance before the initiation of cyclosporine A treatment or in case of gross hematuria or impaired renal function.


   Statistical Analysis Top


All data are expressed as percentage, median, mean and range.


   Results Top


There were 48 patients with Difficult Nephrotic Syndrome after two years of the diagnosis, including 30 males (62.5%) and 18 females (37.5%); their ages at onset ranged from 0.7 to 11 years (mean 3.6 years) and at the last follow-up ranged from four to 20 years (mean 12.8 years). All patients had nephrotic range proteinuria at onset. Family history of NS was positive in 11 (22.9%) patients only, while history of first-degree consanguinity was present in 15 (31.2%) families. Twelve (25%) patients suffered from active allergy, mainly bronchial asthma. Family history of allergy was positive in 18 (37.5%) patients [Table 1].
Table 1: Demographic and clinical features at presentation of the study patients (n=48).

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The initial presentation of the disease occurred in the winter season in 21 (43.7%) patients, while 19 (39.5%) patients had first onset of the disease in the summer [Table 2]. Hypertension was noted at onset in ten (20.8%) patients, while hematuria was detected in 19 (39.5%) patients. Six (12.5%) patients had evidence of renal impairment at diagnosis. The median serum level of albumin at onset was 14 g/dL (range 4-27 g/dL). Initial attack was precipitated by documented upper respiratory tract infection in four (10.4%) patients, while 16 (33.3%) patients demonstrated systemic lymphocytosis.
Table 2: Season of first onset of the nephrotic syndrome (n=48).

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Regular administration of intravenous salt-poor albumin and diuretics at onset was required in 41 (85.4%) patients because of massive edema and anasarca. Thirty-four (70.8%) patients responded to corticosteroid within four weeks, while 20 patients showed response. Within two to four weeks, 14 patients responded within the first two weeks. Fourteen (29%) patients showed no response to steroids in the first four weeks.

The outcome at two years of presentation was as follows: frequent relapser 20 (41.6%) patients, steroid dependent 19 (39.5%) patients, steroid resistant nine (18.7%) patients, one of the patients with steroid resistance developed chronic renal failure (CRF) and one patient died because of septicemia secondary to end-stage renal disease (ESRD) complications [Table 3]. Renal biopsy was done in 32 patients and the results are shown in [Table 4].
Table 3: The outcome of the nephrotic syndrome at 2 years of presentation (n=48).

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Table 4: Distribution of histopathological diagnosis of biopsied children (n=32).

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In the frequent relapsers group, the mean duration to the first relapse after discontinuation of steroids was 5.1 months. The first relapse was precipitated by upper respiratory tract infection in 18 (90%) patients. The total number of relapses over the first two years for the frequent relapsers was 150 relapses (average 3.75 relapses/patient/year), 50 (33.3%) relapses were severe and required hospitalization. The season for the first four relapses for each patient in the frequent relapsers group was winter in 36 (45%) relapses, summer in 30 (37.5%) relapses, spring in 10 relapses (12.5%) and autumn in four (5%) relapses [Table 5].
Table 5: Season of the first four relapses in the frequent relapser (n=20 patients, n=80 relapses).

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Cyclophosphamide was administered to 35 (72.9%) patients, cyclosporine A was given to 17 (35.4%) patients and chlorambucil was given to only two (4.1%) patients.

Only 43 patients were available for follow-up after ten years of the initial presentation; among them, 22 (51%) patients were in complete remission while 15 (34.8%) patients were steroid dependent, two (4.6%) patients had CRF and two (4.6%) patients on dialysis, one died because of septicemia in the first two years of presentation and one died because of dialysis complications in the fifth year of presentation [Table 6].
Table 6: Outcome of Saudi children with the nephrotic syndrome at 10 years' follow-up (n=43).

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The reported complications of the disease or its treatment in all 43 patients are as follows: short stature in 30 (69.7%) patients, insulin-dependent diabetes mellitus (IDDM) in two (4.6%) patients, cataract that required surgery in two (4.6%) patients, septicemia and death in two (4.6%) patients and peritonitis in one (2.3%) patient. One (2.3%) patient had cellulites in the inguinal region and four patients had mild chicken pox while on steroid with no complications [Table 7].
Table 7: Complications of the nephrotic syndrome or its treatment after 10 years (n=43).

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   Discussion Top


NS in Saudi children, as anywhere in the world, is one of the most common renal problems. [16] A majority of our patients was referred from different parts of the country. Therefore, this constitutes a selected group from which the overall incidence throughout the Kingdom cannot be extrapolated. The male predominance and the age distribution of the illness is similar to children in other countries. [17],[18] The striking predominance of non-minimal change pathology (74%) can be explained by many factors. One cannot ignore the fact that the high incidence of the steroid-dependent, the steroid resistant and the frequently relapsing syndrome was due to MesPGN (40.6%) and FSGS (34.3%). The preponderance of MesPGN has been reported earlier from our institution. [18] The experience so far with NS patients with MesPGN and FSGS indicates that there is still no satisfactory treatment and the prognosis is not encouraging. [9],[19] Family history of the same disease was present in 23% of our patients. This high incidence of familial cases in our population is most probably due to a very high rate of consanguineous marriages. More than one-third (37.5%) of patients had a family history of atopy, and 25% of the patients suffered from active allergic disease, mainly bronchial asthma, at the time of the onset of NS. Some studies showed that the initial episode was associated with allergy in a large number of patients. [20] Upper respiratory tract infection was not the triggering factor for the onset of NS in our patients, but it was the main factor for the relapses in the frequent relapsers group. [5] The role of atopy in the onset of the initial episode of the disease and viral upper respiratory tract infection for ensuing relapses are observed by some investigators. [20],[21],[22] Such observation was confirmed in our study. Prescribing prednisolone daily for seven consecutive days at the same dose as that taken by the patient on alternative-day basis at the onset of a presumed viral upper respiratory tract infection reduces the risk of relapse in children with steroid-dependent NS; [21] that was not a routine practice in our unit until 2005.

Low serum albumin at onset is a risk factor for relapse of childhood NS. [12] A low serum level of albumin indicated an increased probability of relapse in the study by Hiraoka et al; [22] of their 66 patients with steroid-sensitive NS, eight asymptomatic children with higher serum levels of albumin remained in remission for at least one year, while 30 of the 58 symptomatic patients with lower serum levels of albumin relapsed. The majority of our patients had very low serum albumin (<1.4 g/dL) at initial presentations.

We found a decreased GFR in six patients at onset of the disease, which improved after initiation of therapy. The low GFR may be caused by several factors, such as a decreased renal plasma flow, decreased net driving forces, which is represented by the balance between the transcapillary hydraulic pressure gradient and the oncotic pressure differences, and the glomerular ultra-filtration co-efficient, which is the product of the surface area available for filtration and the effective hydraulic permeability of the capillary wall. [23] We believe that low GFR is related to hypoperfusion because of hypoalbuminemia, which was severe at onset in the majority of our patients. Most of our patients received regular salt-poor albumin intravenously at onset (85%) because of severe hypoalbuminemia and manifestations of anasarca. Yoshimura et al [24] demonstrated that albumin infusions may delay the response to corticosteroid therapy and lead to an increased frequency of relapse in the minimal change NS. However, others did not identify the administration of human albumin as an independent risk factor for relapses. [12] We did not record any side-effects or complications of IV albumin infusion, possibly because of the slow infusion of albumin and the administration of diuretics.

Peritonitis associated with low serum albumin (≤1.5 g/dL) at presentation of the NS had been observed by some investigators. [25] In spite of severe hypoalbuminemia (≤1.5 g/dL) in the majority of our patients, only one episode of peritonitis was documented. This very low incidence of peritonitis in our patients has to be investigated in the future. Until recently, pneumococcal vaccinations and antibiotic prophylaxis were not a routine practice in our management. Four patients developed mild uncomplicated varicella infection; they were not vaccinated for chickenpox before steroid therapy. The majority of our patients received cytotoxic drugs, but none to date manifested malignancy. The association of lymphoma and leukemia with NS or its treatment was reported on different occasions. [26]

Children who have NS often require a prolonged, intermittent high dose of systemic corticosteroid therapy. Pediatricians should be aware of the potential risk of developing steroid-related eye complications, especially posterior sub-capsular cataract. The occurrence of cataract as a complication of long-term systemic steroid therapy has been reported; the incidence varies from 14% to 51%. [27] Two (4.6%) of our patients required surgical intervention for cataract.

The co-existence of IDDM and treated and untreated NS was reported previously. [28] Two of our patients with steroid-dependent NS developed IDDM, both in the third year of treatment, and there was no family history of diabetes mellitus in these patients. We correlated this IDDM to the high maintenance dose of steroid. In conclusion, the high incidence of steroid dependent, frequent relapses and steroid resistance among our patients can be explained by different factors, including consanguinity, atopy and severe presentation at onset. We suggest longer initial treatment at onset for this group of patients. The low incidence of infection in this group need to be addressed more in future studies.

 
   References Top

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Takedu A, Matsutani H, Niimura F, Ohgushi H. Risk factors for relapse in childhood nephrotic syndrome, Pediatr Nephrol 1996;10:740-1.  Back to cited text no. 12
    
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A report of the ISKDC early identification of frequent relapsers among children with minimal change nephrotic syndrome. J Pediatr 1982;101:514-8.  Back to cited text no. 13
    
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Abeyagunawardena AS, Trompter RS. Increased the dose of prednisolone during viral infections reduces the risk of relapse in nephrotic syndrome: A randomized controlled trial. Arch Dis Child 2008;93:226-8.  Back to cited text no. 21
    
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Hiraoku M, Takeda N, Tsukaharaa H, et al. Favorable course of steroid-responsive nephrotic children with mild initial attack. Kidney Int 1995;47:1392-3.  Back to cited text no. 22
    
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Lowenborg EK, Berg UB. Influence of serum albumin on renal function in nephrotic syndrome. Pediatr Nephrol 1999;13:19-25.  Back to cited text no. 23
    
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Goldman M, Hebert D, Geary DF. Management of steroid-sensitive nephrotic syndrome in children with type 1 diabetes. Pediatr Nephrol 2002;17:351-4.  Back to cited text no. 28
    

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Correspondence Address:
Abdullah A Al Salloum
Pediatric Department (39), King Saud University, King Khalid University Hospital P.O. Box 2925, Riyadh 11461
Saudi Arabia
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DOI: 10.4103/1319-2442.100877

PMID: 22982908

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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