Focal Segmental Glomerulosclerosis Variants In Children With Nephrotic Syndrome
Beware when the tiny blood vessels in the kidneys become scarred! This chronic disease called focal segmental glomerulosclerosis or FSGS can lead to kidney failure.
Author:Suleman ShahReviewer:Han JuJan 25, 2024101 Shares16.8K Views
The aim of this study was to determine pathological variants of childhood focal segmental glomerulosclerosisand assess efficacy of prednisolone + methylprednisolone + cyclosporine A treatment.
Nephrotic syndrome constitutes the most common pathological glomerular condition in children, characterized by:
- severe proteinuria
- hypoalbuminemia
- edema
The disease is routinely managed by steroid therapy.
However, these patients may develop focal segmental glomerulosclerosis, the major cause of childhood steroid-resistant nephrotic syndrome (SRNS).
If nephrotic syndrome persists after 6 weeks of prednisolone therapy, the steroid resistance of nephrotic syndrome is confirmed.
In the absence of adequate treatment, SRNS leads to end-stage kidney disease within 5-10 years. Therefore, early diagnosis of focal segmental glomerulosclerosis is essential to provide treatment alternatives and delay progression to end-stage renal disease.
Recent studies identified the podocyte as the predominant site of injury in focal segmental glomerulosclerosis.
Experimental studies identified several factors contributing to podocyte damage:
- stretching
- viral infection
- toxins
- immunological factors
- mitochondriopathies (MCPs)
- genetic mutations
Several genetic mutations of podocyte proteins have been clinically associated with congenital or infantile SRNS, including:
| NPHS1 (nephrin) | PLCE1 (phospholipase C epsylon) |
| NPHS2 (podocin) | WT1 (Wilms’ tumor 1) |
| ACT4 (α-actinin-4) | SMARCAL |
However, few studies have addressed the impact of these mutations on treatment effectiveness in SRNS patients.
Since 1986, the calcineurin inhibitor cyclosporine A (CsA) has been used as a nonsteroidal alternative for the treatment of SRNS.
However, the current protocols have not been optimized for children to avoid CsA-related neurotoxicity.
Concurrently, prolonged treatment for several years with dose tapering is recommended.
Although rare cases of SRNS with focal segmental glomerulosclerosis may develop resistance, almost 100% of patients respond to CsA therapy.
This study also aimed to:
a. test the safety and efficacy of combination immunosuppressive therapy (comprising prednisolone, methylprednisolone, and CsA) in children diagnosed with focal segmental glomerulosclerosis
b. investigate the impact of pathological childhood focal segmental glomerulosclerosis variants associated with genetic mutations in podocytes on treatment outcome
Subjects
A total of 134 nephrotic syndrome patients who were hospitalized in the Nephrology Department of the Republic Children’s Clinical Hospital in Almaty, Kazakhstan, from 2004 to 2011 were included in this retrospective study.
All the patients were native Kazakhs aged 3 months to 17 years.
The study was approved by the institutional Committee on Human Experimentation and performed in agreement with the Helsinki Declaration and subsequent amendments.
Informed consent was obtained from parents (guardians) of all the patients.
Inclusion criteria were age below 18 years and nephrotic syndrome. Exclusion criteria were rapidly progressive renal dysfunction and noncompliance.
Combination Therapy With CsA
After confirmation of focal segmental glomerulosclerosis, all the children received intense 3-drug therapy:
- once-daily CsA (oral; 150 mg/m2)
- 3 to 6 pulses of methylprednisolone (intravenous; 1 g/1.73 m2)
- once-daily prednisolone (oral; 40 mg/m2)
This regimen treatment was administered for 3-6 months, followed by dose tapering after nephrotic syndrome remission, and the maximum duration was 6 years.
Dosages were adjusted to maintain serum CsA concentrations at:
- C0 (80-120 nanograms per milliliter or ng/ml)
- C2 (700-1,200 ng/ml)
Where:
a. C0
- is the baseline level
- reflects dose efficacy
b. C2
- is the level measured 2 hours after drug intake
- reflects dose toxicity
Sample Collection
At present, five pathological FSGS variants are recognized:
- collapsing (COLL)
- cellular (CELL)
- glomerular tip lesion (GTL)
- perihilar
- not otherwise specified (NOS)
The type of focal segmental glomerulosclerosis in each patient with the condition was identified by kidney biopsy analysis.
Normally, biopsy is not recommended for children with nephrotic syndrome because of the high frequency (80%) of minimal change disease.
However, it is indicated when nephrotic syndrome persists after 6 weeks of steroid treatment, given the high risk of developing severe complications such as focal segmental glomerulosclerosis.
In this study, biopsy was performed for patients after ≤12 weeks of unsuccessful steroid treatment.
The procedure was performed using:
- an automatic biopsy gun (from Gallini S.R.L. in Mirandola, Italy)
- 16-18-gauge needles using ultrasound guidance under local or general anesthesia
Two pieces of renal tissue were collected from each patient and fixed in 4% formaldehyde.
Parafilm sections were stained for light microscopic evaluation:
- hematoxylin and eosin
- Masson’s trichrome
- Periodic Acid-Schiff
- methenamine silver
- Congo red stains
Sections were also processed for:
- immunohistochemical microscopy (IgA, IgM, IgG, C1q, C3, and kappa and lambda light chains)
- electron microscopy
Pathological tissue analysis was conducted by experienced nephropathologists from Moscow and Saint Petersburg in Russia.
Statistical Analysis
The reported p values were calculated using:
- natural logarithm-transformed intensities
- Gaussian approximation to the t-distribution
Statistical significance was established at p < 0.05.
Results
The mean period between the onset of nephrotic syndrome and biopsy was 11.7 ± 5.7 months (range: 3-32 months).
The diagnosis of focal segmental glomerulosclerosis was confirmed in 38 children (16 boys and 22 girls; treatment group), with a mean age of 10.9 years (1.4-17 years).
The pathological variants of focal segmental glomerulosclerosis were identified as:
- glomerular tip lesion or GTL (n = 18)
- not otherwise specified or NOS (n = 18)
- collapsing or COLL (n = 2)
All the patients exhibited segmental glomerulosclerosis, and one-third of the patients had total glomerulosclerosis.
They also presented significant focal (57.9%) or diffuse (26.3%) interstitial fibrosis and tubular atrophy.
Most patients were diagnosed with immunoglobulin M (IgM) nephropathy (89.4%), as shown by immunolocalization of IgM + C3 in the renal tissue.
The severity and prognosis of focal segmental glomerulosclerosis were determined on the basis of the extent of proteinuria and decrease in the glomerular filtration rate (GFR).
The mean baseline proteinuria was 7.8 ± 3.5 g/day (range: 1.4-16 g/day), whereas GFR was 79.7 ± 22.6 ml/min (range: 31-110 ml/min).
The symptoms of nephrotic syndrome were associated with:
- persistent hematuria (gross hematuria in 10 children) in 22 (57.9%) patients
- arterial hypertension in 10 (26.3%) patients
All the children were initially treated with prednisone induction (60 mg/m2 for 6-8 weeks) and maintenance therapy (40 mg/m2 for 8 weeks, followed by tapered dosage).
After confirmation of focal segmental glomerulosclerosis, the patients were divided into 3 groups:
a. Treatment group
This group included patients with focal segmental glomerulosclerosis (n = 38).
b. Control (control A) group
This group included patients who did not undergo biopsy and were treated with CsA (n = 30)
c. Another control group (control B)
This group included patients who did not undergo biopsy and were treated with alkylating agents (n = 66), including:
- cyclophosphamide (n = 8)
- azathioprine (n = 58)
The treatment group received combination therapy as described in the earlier section.
Cyclophosphamide (oral; 2-3 mg or kg per day) was administered for 2-3 months:
- with monitoring of the total blood count and proteinuria
- followed by maintenance therapy with 1-1.5 mg/kg/day for 2 months
Azathioprine (oral; 0.2 mg/kg/day) was administered for 2 months, followed by maintenance therapy with 0.1 mg/kg/day for 2 months.
Prednisone was administered together with alkylating agents in moderate doses of 10-20 mg/m2 per 48 hours.
The treatment efficacy in the 3 groups was compared on the basis of proteinuria and GFR levels measured before and after treatment.
The mean treatment duration was 4.7 ± 2.8 years (2.2-7.0 years).
The most significant impact on proteinuria was observed in the treatment group, with a mean decrease of 7.7 ± 2.1 g/day (from 7.8 ± 3.5 g/day before treatment to 0.05 ± 0.03 g/day after treatment).
In the control A group, the mean decrease in PU was 5.8 ± 1.6 g/day (from 7.9 ± 1.8 g/day before treatment to 2.1 ± 1.3 g/day after treatment), which was significant (p < ;0.01) compared with that in the treatment group.
The control B group showed the least significant decrease in proteinuria, i.e., 4.3 ± 1.9 g/day (from 6.8 ± 2.4 g/day before treatment to 2.5 ± 1.1 g/day after treatment).
The most significant decrease in proteinuria was achieved after CsA + methylprednisolone (MP) + prednisone combination therapy was initiated.
This could be related to the presence of other histopathological patterns of nephrotic syndrome, such as membranoproliferative glomerulonephritis in patients in the control groups, where CsA was not so effective because of its podocytotropic effects with no strong effects on cellular proliferation.
After the follow-up period (4.2 ± 3.1 years), the mean decrease in proteinuria in glomerular tip lesion (GTL) patients was 8.9 ± 2.1 g/day (from 9.0 ± 4.5 g/day before treatment to 0.09 ± 0.04 g/day after treatment; p < 0.001), with complete remission of nephrotic syndrome.
In seven patients with NOS without genetic mutations, the mean decrease in proteinuria was 6.7 ± 2.5 g/day (from 6.8 ± 3.2 g/day before treatment to 0.6 ± 0.1 g/day after treatment), and complete remission of nephrotic syndrome was achieved in these patients.
Significant differences were observed:
- between patients with GTL and those with NOS variants associated with genetic mutations (p < 0.01)
- between patients with NOS variants associated with genetic mutations
- those with NOS variants not associated with genetic mutations (p < 0.05)
In patients with NOS variants not associated with genetic mutations, the mean increase in GFR was 5.3 ± 2.2 ml/min (from 92.9 ± 15.4 ml/min before treatment to 98.2 ± 16.1 ml/min after treatment).
In patients with NOS variants associated with genetic mutations, the mean decrease in GFR was 21.5 ± 5.1 ml/min (from 75.0 ± 7.1 ml/min before treatment to 53.5 ± 12.3 ml/min after treatment).
In contrast, the mean increase in GFR was 28 ml/min (from 42 ml/min before treatment to 70 ml/min after treatment) in patients with collapsing (COLL) focal segmental glomerulosclerosis.
Discussion
In this study, 95% patients exhibited either the NOS or GTL variant of focal segmental glomerulosclerosis, whereas the remaining 5% patients exhibited COLL focal segmental glomerulosclerosis.
The absence of the perihilar variant in our patients could be related to its secondary characteristics - arterial hypertension and obesity - which are more frequently encountered in adults.
These data differ from the variant profile of a Chinese cohort of 212 children:
| NOS (40.6%) | COLL (5.6%) |
| perihilar (11.8%) | GTL (14.6%) |
| CELL (27.4%) | -- |
In a cohort of 41 American children, the variant profile was as follows:
| NOS (44%) | COLL (24%) |
| CELL (32%) | -- |
Overall, these studies suggest that the NOS variant dominates in childhood focal segmental glomerulosclerosis, as also reported for adult patients.
The prognosis of focal segmental glomerulosclerosis patients is highly dependent on the type of variant, with reported 10-year renal survival rates of:
- 80% for GTL
- 50% for NOS
- 30% for COLL
Therefore, most patients in this study were considered to have a reasonable prognosis.
However, most patients were diagnosed with IgM nephropathy, which is considered a high-risk factor for SRNS.
Therefore, these patients were excellent candidates for nonsteroidal alternative treatments such as those including CsA.
The CsA + MP + Pred immunosuppressive therapy proposed in this study was significantly more efficient than conventional prednisone treatment, with complete remission achieved in 88.9% patients.
Treatment regimens including CsA require constant monitoring of CsA serum levels to avoid CsA-related nephrotoxicity.
This complication is generally reported for CsA treatments exceeding three years and in patients <5 years old.
We observed two cases of acute CsA-related nephrotoxicity associated with high serum potassium and creatinine levels. These symptoms rapidly resolved after the dose of CsA was decreased.
Notably, CsA-related nephrotoxicity is rare in children.
No other adverse effects were observed in our patients.
The best therapeutic responses were observed in patients with GTL or NOS variants of focal segmental glomerulosclerosis not associated with genetic mutations. All of them achieved complete remission.
Both patients with COLL focal segmental glomerulosclerosis achieved remission when mycophenolate mofetil was added to the immunosuppressive combination therapy.
The weakest response to the immunosuppressive combination therapy was observed in patients with the NOS variant associated with podocyte mutations (NPHS2 and WT1).
After treatment, the immunosuppressive combination therapy was terminated because nephrotic syndrome persisted, while renal function continued to deteriorate.
Proteinuria decreased more significantly in the control A group than in the control B group.
However, this result was less reliable than that for the treatment group because of the lack of histopathological diagnosis in the control groups.
Conclusion
This study demonstrates the safety and efficacy of CsA + MP + Pred therapy for the treatment of childhood focal segmental glomerulosclerosis.
Furthermore, we showed that genetic mutations in podocytes significantly affect treatment success.
This finding emphasizes the importance of genotyping to determine the best course for treating steroid-resistant nephrotic syndrome (SRNS) in children diagnosed with focal segmental glomerulosclerosis (FSGS).
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
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Welcome aboard this journey of insight and exploration, where curiosity leads and music guides.
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