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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM THE ASIA - AFRICA Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 5  |  Page : 979-990
Childhood idiopathic steroid resistant nephrotic syndrome in Southwestern Nigeria


1 Pediatric Nephrology and Hypertension Unit, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria
2 Department of Morbid Anatomy and Histopathology, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria

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Date of Web Publication31-Aug-2010
 

   Abstract 

Clinical charts of 23 Nigerian children diagnosed with Idiopathic Steroid Resistant Nephrotic Syndrome (iSRNS) between January 2001 and December 2007 were retrospectively re­viewed to determine their clinicopathologic characteristics and outcome. iSRNS (54.8%) was pri­mary in 19 patients (83%) and secondary in four (17%). The mean age at diagnosis was 8.3 ± 3.5 years (2.1-13 years). Histopathology revealed membranoproliferative glomerulonephritis (MPGN) in 43.5%, focal and segmental glomerulosclerosis (FSGS) in 39.1% and mesangial proliferative glo­merulonephritis in 8.7% of the patients while minimal change disease (MCD) and membranous nephropathy accounted for 4.35% each. Routine treatment protocol comprised pulse intravenous (i.v.) cylophosphamide infusion and i.v. dexamethasone ΁ lisinopril or spironolactone. Cumulative Com­plete Remission (CR) rate was 57.12%. The overall median time to CR from start of steroid sparing agents in 12/21 treated patients was 4.5 weeks. CR was better achieved in MPGN than FSGS (P = 0.0186). Five patients had eight relapses with the overall median relapse-free duration being four months. Cumulative renal survival at 36 months was 41.8%. The median follow-up duration was eight months. Our study revealed that there was a high prevalence of iSRNS and preponderance of non-MCD lesions, with MPGN and FSGS being the major morphologic lesions. The outcome with steroid and cyclophosphamide-based treatment for iSRNS was further enhanced with addition of either lisinopril or spironolactone.

How to cite this article:
Olowu WA, Adelusola KA, Adefehinti O. Childhood idiopathic steroid resistant nephrotic syndrome in Southwestern Nigeria. Saudi J Kidney Dis Transpl 2010;21:979-90

How to cite this URL:
Olowu WA, Adelusola KA, Adefehinti O. Childhood idiopathic steroid resistant nephrotic syndrome in Southwestern Nigeria. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Jun 2];21:979-90. Available from: http://www.sjkdt.org/text.asp?2010/21/5/979/68913

   Introduction Top


About 10-20% of children with idiopathic neph­rotic syndrome (INS) have idiopathic steroid re­sistant nephrotic syndrome (iSRNS). [1],[2],[3],[4] It is an en­tity that is difficult to manage. Without treatment, progression to pre-terminal chronic renal failure (CRF) or end-stage kidney disease (ESKD), few years after diagnosis, is almost certain. Diffe­rent aggressive and potentially toxic treatment regimens have been tried to forestall disease progression, with varied outcome. [5],[6],[7],[8],[9],[10] Such is the importance of massive proteinuria that a partial remission is considered a better outcome to no therapeutic response. [6] Results of studies by the International Study of Kidney Disease in Children (ISKDC) revealed focal and segmental glomerulosclerosis (FSGS), mesangial prolifera­tive glomerulonephritis (MesPGN) and minimal change disease (MCD) as the respective mor­phologic lesions seen in 70%, 44% and 7% of children with iSRNS. [11] The glomerular morpho­logic pattern and treatment outcome of iSRNS in Nigerian children have not been previously defined. In this study, we determined the clini­copathological aspects and treatment outcome of childhood iSRNS in southwestern Nigeria where previous data on childhood nephrotic syn­drome were mostly on poor outcome quartan malaria nephropathy (QMN). [12],[13]


   Patients and Methods Top


Clinical charts of consecutive cases of Nigerian children diagnosed with iSRNS between January 2001 and December 2007 and followed-up till June 2008 were reviewed. The diagnostic cri­teria for the nephrotic syndrome (NS) were ede­ma, plasma albumin < 25 g/L, and severe pro­teinuria > 40 mg/m 2 /hour or a urinary protein­creatinine ratio (UPCR) > 200 mg/mmol, [14] by quantitative assessment or dipstick proteinuria > 300 mg/dL. iSRNS was diagnosed based on combination of (i) absence of a specific etio­logy for the NS, and (ii) failure to achieve com­plete remission (CR) using the ISKDC treat­ment protocol for initial therapy of NS; the latter comprised prednisone 60 mg/m 2 /day for four weeks, followed by 40 mg/m 2 /48 hours for another four weeks; [3],[11] prednisolone was used in our patients. Approval of our institution's ethical committee was obtained.

Definitions

CR was defined as proteinuria < 4 mg/m 2 /hour or UPCR < 20 mg/mmol or dipstick proteinuria < 30 mg/dl tested on three consecutive days. [14] Remission was regarded as sustained if no re­lapse occurred for at least six months. Mild to moderate proteinuria (MMP) or partial remission was defined as proteinuria of 4-39 mg/m 2 /hour or a UPCR of 20-199 mg/mmol or 30-100 mg/ dL by dipstick. Relapse was defined as recrude­scence of proteinuria in excess of 40 mg/m 2/hour or UPCR > 200 mg/mmol or > 100 mg/dL by dipstick for three consecutive days after an initial CR. Steroid resistance (SR) was failure to achieve CR following at least four weeks of prednisolone (60 mg/m 2 /day) treatment. Patients who had an initial CR but later developed fre­quent relapses followed by steroid dependence before finally becoming steroid resistant were diagnosed as secondary SR while those who failed to respond to at least four weeks of ste­roid treatment were classified primary SR. The inclusion criteria comprised all confirmed cases of INS in patients aged 2-16 years. Exclusion criteria were identification of a secondary cause for the NS, namely obesity, drugs, heavy metal exposure, congenital cyanotic heart disease, reflux nephropathy and solitary kidney as well as evidence of CRF with the estimated glome­rular filtration rate (eGFR) that was persistently < 60 mL/min/1.73m 2 for at least three months.

Clinical evaluation

Each patient was evaluated for gender, age at onset of NS, age at diagnosis, vital signs, anthro­pometry and presence of hypertension (HTN). HTN was defined according to the update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents. [15] Treat­ment protocol used, treatment complications, co-morbidities, time to remission, remission duration, admission duration, follow-up and out­come were evaluated.

Investigations

These included full blood counts as well as plasma and urinary biochemical evaluation. De­finitive investigations performed to exclude se­condary etiologies were thick and thin blood films for malaria parasites with emphasis on P. malariae; blood films/skin snips for microfila­riae; urine microscopy for schistosoma ova; VDRL test for syphilis; serology for viral he­patitis B and C, and HIV infections. Fasting blood glucose for diabetes mellitus and hemo­globin electrophoresis for sickle cell disease were also performed. Systemic lupus erythema­tosus was excluded based on the American College of Rheumatology diagnostic criteria. [16]

Significant microhematuria and pyuria were defined as urinary red blood cells (RBC) ≥ 5 per high power field (HPF) and white blood cells (WBC) > 10 per HPF, respectively. Neph­rotic proteinuria was determined from either 24-hour urine sample (> 40 mg/m 2 /hour), ran­dom urine sample by UPCR (≥ 200 mg/mmol) or dipstick (≥ 300 mg/dL). eGFR was deter­mined using the Schwartz formula, [17] and a value < 80 mL/ min/1.73m 2 at baseline and during follow-up was regarded as renal insufficiency and indicated poor renal survival when it per­sisted for six months or more.

Microscopic glomerular features were defined along standard lines. [18],[19],[20],[21] Tissue sections were not greater than three microns in thickness. Five or more glomeruli per renal tissue specimen were regarded as adequate for reporting. Tubu­lointerstitial lesions and scores were assessed semi-quantitatively according to the method described by Foster et al. [22] Tubulointerstitial (TI) scores were classified as mild (0-2), moderate (3-5), and severe (6-8).

Treatment

The routine treatment protocol (RTP) received by the patients is defined in [Table 1]. Absence of CR, three months after starting routine treatment, warranted add-on routine treatment (addRT) with lisinopril or spironolactone. Treatment failure was defined as failure to achieve CR after at least six months of addRT. Non-Routine treat­ment (nRT) was prescribed for those who dec­lined RTP [Table 1]. Pulmonary edema, respira­ratory distress from massive ascites and cellu­litis due to skin breakdown warranted slow in­travenous (i.v.) plasma transfusion (10-20 mL/ kg/dose) with i.v. furosemide.
Table 1 :Treatment protocol used for idiopathic steroid resistant nephrotic syndrome in the study patients.

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Follow-up and outcome

Patients were seen in the clinic every 1-3 months depending on distance. At each clinic visit, every patient was evaluated for complica­tions of therapy, weight, height, vital signs, ede­ma, ascites and proteinuria. Twice weekly, pa­rents routinely checked the urine of their chil­dren for proteinuria with dipstick and main­tained the records. Renal ultrasound, UPCR, and eGFR were assessed initially at three months and every six months thereafter if there were no indications for an earlier assessment. The out­come indices were complete remission, partial remission, treatment failure, relapse-free period, patient and renal survival, complications, study exit due to death or voluntary discharge, and lost to follow-up.


   Statistical Analysis Top


The end-point for statistical analysis was at least six months (June 30, 2008) after the last recruited patient; the last recruitment date was December 30, 2007. Both descriptive and com­parative statistics were applied as deemed ap­propriate using the SPSS 15.0 for Window Eva­luation Version statistical software (SPSS 2006 Inc.). Descriptive statistics used comprised mean, standard deviation (SD), median, percentages, and proportions. The comparative statistics were chi-square test, Fisher's exact test, Student's t­test, hazard ratio, regression analysis, correla­tion coefficient, Kaplan-Meier survival analysis, and the log-rank test. In the survival analysis, data of patients lost to follow-up before com­pleting six treatment months, those with incom­plete treatment or those who declined treatment, were censored.


   Results Top


Twenty-three of 42 cases (54.8%) of primary idiopathic nephrotic syndrome managed between January 2001 and June 2008 were diagnosed to have iSRNS. Majority (70%) were over five­years of age at diagnosis. Baseline characteris­tics of the patients are shown in [Table 2]. A total of 685 (7-85) glomeruli were examined. Non­MCD accounted for 95.7% of all glomerular lesions [Figure 1]. Median TI score was 2 (0-6). Mean TI scores for patients with FSGS (2.0 ± 1.73) and MPGN (3.7 ± 1.5) were similar (P = 0.2150). TI scores were mild, moderate, and severe in 12 (52.2%), 10 (43.5%) and 1 (4.3%) patients, respectively.
Table 2 :Baseline characteristics of the study patients.

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Figure 1 :Prevalence of each of the glomerular morphologic lesions in Nigerian children with idiopathic steroid resistant nephrotic syndrome. Non-minimal change disease accounted for 95.7% of all lesions.

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Treatment Outcome

Eighteen (78.3%) patients received the RTP, three (13%) received nRT due to high RTP cost while two declined treatment (8.7%) and took voluntary discharge. Only six of nine patients who were prednisolone-resistant underwent RTP with three attaining CR. Five of the ten patients (50%) with partial prednisolone response attained CR; all four patients with secondary predni­solone resistance attained CR with RTP/addRT or nRT. Proportion of patients with CR fol­lowing treatment with steroid-sparing agents were similar among patients who were prima­rily and secondarily prednisolone resistant (P = 0.1667). Similarly, there was no significant dif­ference between primary prednisolone resis­tance and partial prednisolone response with regard to CR following RTP/addRT or nRT (P = 0.3916). The outcome in the eleven patients who either achieved MMP with RTP or failed to respond to it and who were further treated with addRT is shown in [Table 3].[Figure 2] sum­marizes the outcome in both primary and se­condary iSRNS in relation to the glomerular histopathologic variants; proportions with CR and MMP were similar (P = 0.1277). The over­all cumulative CR rate by Kaplan-Meier survi­val analysis was 57.12% [Figure 3]. [Figure 4] shows the cumulative treatment survival curves for each of the glomerular morphologic types. The number of MPGN patients who achieved CR was significantly more than those with FSGS when data were corrected for lost to follow-up and incomplete treatment (P = 0.0186). The severity of tubulointerstitial injury and time to CR showed no correlation among patients with FSGS and MPGN (r = +0.209; P = 0.514; [Figure 5]).

About 83.0% of the patients attained CR with­in eight weeks of treatment. The overall median time to CR from start of steroid sparing agents in12 of the 21 treated patients was 4.5 weeks (0.43-11.0). The median time to CR in six of 18 patients treated with RTP was 2.9 weeks (0.43­8.7); median time to CR for four of 11 patients that were RTP resistant but who were further treated with addRT was 7.5 weeks (3-11). Time to achieving CR for two of three patients trea­ted with nRT was four and eight weeks, respec­tively. Five patients (41.7%; all MPGN) relapsed with eight relapses overall; they all responded to short courses of daily prednisolone. Relapse was significantly more prevalent among MPGN than non-MPGN patients (P= 0.0265). Overall, the median relapse-free duration was four months (1.9-14). The median relapse-free pe­riods in those who achieved CR with RTP and addRT were 3.9 (2-12) and 3.2 (1.9-4.4) months, respectively. The relapse-free months for the two patients in the nRT group were four and 14 months each. Three patients were in sustained remission at the end of follow-up. Five of 12 (42.0%) CR patients have completed 1-2 years of either RTP or RTP/addRT or nRT treatment; all 12 children remain in CR with normal uri­nalysis and kidney function.
Table 3 :Relationship between the treatment protocols used and outcome in treated patients (n=21).

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Figure 2 :Flow chart showing how each of the morphologic types responded to treatment. All 10 patients
who were partially responsive to prednisolone were also classified as primarily steroid resistant.


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Figure 3 :Kaplan-Meier survival curve showing survival times of all patients; the maximum time to complete remission was 11 weeks. The cumulative probability of remission was 57.12% at 88 weeks

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Figure 4 :The cumulative treatment survival probabilities of patients having different glomerular lesions. Compared to membranoproliferative glomerulonephritis (MPGN; P= 0.002) and focal segmental glomerulosclerosis (FSGS; P= 0.003) but not with the other variants, minimal change disease (MCD) had
significantly shorter treatment survival time. Survival times were similar among MPGN, FSGS,
membranous nephropathy (MN) and mesangial proliferative glomerulonephritis, MesPGN (P> 0.05).


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Figure 5 :Interactive plot showing no significant correlation between tubulointerstitial injury and time to
complete remission.


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Complications

Steroid therapy was complicated by hyperten­sion in 13 (56.5%), oral thrush in nine (39.1%), bacterial infection in six (26%), facial and truncal obesity in four (17.4 %) and cutaneous herpes in one (4.3%); cyclophosphamide was associated with alopecia, vomiting and pancy­topenia in seven (30.4%), four (17.4%) and three (13%) patients, respectively. Lisinopril­related acute kidney injury occurred in one patient.

Follow-up and Renal Survival

Following treatment, eGFR improved signifi­cantly from 57.7 ± 15.4 (27-75) to 101.4 ± 22.0 (82-153; P = 0.0001) mL/min/1.73 m 2 in the 16 patients who had impaired renal function at baseline; however, over the next six to 36 follow-up months, renal function deteriorated persistently (eGFR, 51-75 mL/min/1.73 m 2 ) in three of these patients. The overall cumulative renal survival was 41.8% [Figure 6]. HTN was well controlled in all hypertensive patients. All patients are alive and have been followed-up for a median time of eight months (6-58 months).
Figure 6 :Kaplan-Meier cumulative probability curve showing the renal survival times of all patients. Renal Survival at 6, 12, 24, and 36 follow-up months was 94.1, 83.7, 83.7, and 41.8%, respectively.

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   Discussion Top


Compared to steroid sensitive nephrotic syndrome (SSNS), iSRNS is an uncommon clinical entity and accounts for 10-20% of all cases of INS in Caucasians. [1],[2],[3],[4] The 54.8% prevalence rate of iSRNS in this study is exceptionally high compared to findings in non-Africans; [1],[2],[3],[4] it is similar to the 53% prevalence reported among black South African children. [23] This is due to the preponderance of non-MCD in our patients (95.7%) and South African children (86.5%); [23] non-MCD is significantly less steroid respon­sive than MCD that is highly steroid sensitive and commoner in Caucasians. [1],[2],[3],[4] The mean age at onset of the iSRNS in this and other studies appears to be a function of the glomerular mor­phologic lesion as children with MCD-associa­ted iSRNS tend to be younger (2.2-5.1 years) [4],[24],[25],[26],[27] than those with non-MCD-associated iSRNS who are older (6.2-8.72 years). [28],[29],[30],[31] HTN and he­maturia are common features of non-MCD; [31],[32],[33],[34],[35] respectively, they were found in 30.4% and 21.74% of our patients at baseline; also 70.0% of the patients had baseline kidney insuffi­ciency. All these abnormal features were due to the high prevalence of MPGN and FSGS. Cer­tainly, these are aggressive morphologic va­riants requiring more aggressive, potentially to­xic and expensive combination therapies. The high prevalence of hematuria (26-60%), hyper­tension (23-41%), and immunosuppression re­sistance (31.1-48.3%) in earlier studies from eastern Nigeria [36],[37] further suggest the signifi­cant presence of the aggressive forms of child­hood NS in this country. The pattern of glo­merular lesion seen in this study varies sharply with what is seen elsewhere [25],[28],[38],[39],[40] [Table 4]. While MCD was the predominant lesion in these populations, MPGN and FSGS were the fre­quent lesions in our patients. Children with MPGN have an unfavorable prognosis and de­velop ESKD during late childhood or early ado­lescence. [41],[42],[43] Studies have however shown, that childhood nephrotic MPGN with or without re­nal failure could benefit from a trial of ste­roids. [44] Bergstein and Andreoli [45] demonstrated significant improvement in hematuria, serum albumin, creatinine clearance and reduction in proteinuria among MPGN children within three months of treatment with six pulse i.v. doses of methylprednisolone and alternate-day prednisone for 12-66 months. Although we have not used the same protocol, this study has demonstrated that outcome with regard to proteinuria, hema­turia and impaired kidney function could be sig­nificantly improved in childhood nephrotic MPGN treated with combination of immuno­suppressive and non-immunosuppressive the­rapies. Although FSGS is uncommon in Europe, North America and Japan, [40] it accounted for 39.1% of our patients. However, the emerging trend from Europe, US, Asia and even South Africa shows rising prevalence of FSGS. [23],[25],[28],[31],[38],[39] In the US, FSGS is the most frequently acquired glomerular disease resulting in ESKD. It accounts for 8.3%, 14.3% and 11.4% of chro­nic renal insufficiency, dialysis patients, and transplant recipients, respectively. [46] Compared to MPGN, this study showed that majority of the FSGS patients responded poorly to the im­munosuppressive and non-immunosuppressive protocols; this implies that in the absence of a renal biopsy, failure of a Nigerian child with iSRNS to achieve CR with steroids and cy­clophosphamide combination therapy (oral and i.v.), with or without lisinopril or spironolac­tone, should arouse the suspicion of a FSGS pathology. The prevalence of MesPGN varies from study to study; some studies have reported low prevalence ranging from 2.3 to 7.2% [23],[28],[40] while others have found higher prevalence rates ranging from 17.6 to 44.0%. [25],[31],[38] The preva­lence of MesPGN was low (8.7%) in this study and the response to therapy was just partial. A recent study by Silverstein and Craver [47] showed that steroid resistant nephrotic MesPGN patients achieved 14.8-37.0% complete remission rate depending on whether they received either an alkylating agent or calcineurin inhibitor, alone or in combination. MN is generally rare and the 4.35% prevalence observed in this study is in agreement with this trend. [23],[30],[31],[40] Response to therapy appears good as 80.0% CR was a­chieved with cyclophosphamide in iSRNS due to MN by Valentini et al. [34] The only patient with MN in this study achieved CR with our RTP protocol. Different treatment protocols have been tried by different authors with varied out-come in iSRNS; depending on the protocol used and the morphologic type treated, a CR rate ranging between 14.8 and 80% has been repor­ted by several authors. [5],[24],[25],[34],[39],[47],[48] Mantan et al [25] and Harri et al, [48] respectively achieved 47.8% and 35.1% CR rate using i.v. dexamethasone and oral cyclophosphamide and prednisolone. Bajpai et al 24 achieved a 29.2% CR after six months of monthly pulse i.v. cyclophosphamide and alter­nate day oral prednisolone in iSRNS following failure of eight weeks of daily prednisolone and i.v. pulse doses of dexamethasone. Similarly, we achieved a 33.3% CR after six months of RTP and its follow-up regimen alone; however, with the addition of either lisinopril or spiro­nolactone (addRT), the 33.3% CR rate was in­creased to 47.62%. Altogether, the overall cu­mulative CR rate came to 57.12% with the addition of the two patients who achieved CR with the nRT.
Table 4 :Comparison of glomerular morphologic patterns in other studies with the current study.

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The 41.8% renal survival at 36 months was quite low. While poor renal survival in the pa­tient with primarily steroid resistant FSGS is understandable because of the persistent mild to moderate proteinuria, the other two patients who were in CR cannot be easily explained. The process for continuing renal function insuffi­ciency was probably initiated long before treat­ment was commenced.

There is a high prevalence of non-MCD in this study; MPGN and FSGS were the major mor­phologic lesions. The overall response to com­bined steroid and steroid-sparing agents was significantly better with MPGN than FSGS.

 
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Correspondence Address:
Wasiu A Olowu
Pediatric Nephrology and Hypertension Unit, Obafemi Awolowo University Teaching Hospitals Complex, PMB 5538, Ile-Ife, Osun State
Nigeria
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