The term FSGS refers to a group of histologic entities that are characterized by the onset of proteinuria or nephrotic syndrome (NS). Patients with FSGS exhibit a variable degree of renal insufficiency depending on the stage of the disease and the cause (1 2 , 3 4 – 8
Histologic variants of primary FSGS have been described in the past several years (9 – 13 et al . (12 5 14 9
Efforts have been directed to clarify the characteristics of the different variants and develop a hierarchy of classification. To this end, the Columbia classification of primary FSGS was recently defined and prioritized into a hierarchy of five distinct pathologic variants: (1 ) Collapsing, (2 ) tip lesion, (3 ) cellular, (4 ) hilar, and (5 ) not otherwise specified (NOS) (9 , 10 1 , 2 , 11 – 13
Pediatric FSGS is a disease of increasing incidence and represents a major cause of chronic kidney disease (CKD) (6 , 7 , 15 , 16 13 17
Systematic study of the clinicopathologic variants according to the Columbia classification, features at presentation, and the clinical course of each variant may improve our understanding of this disease and aid in tailoring therapies to improve the outcome. We assessed the presenting features and clinical course in all children in our center who met the histologic and clinical criteria of primary FSGS.
Materials and Methods
Patients
Inclusion Criteria.
This was a retrospective study of patients who were aged 1 to 18 yr at diagnosis, presented to our institution from 1995 to 2004, and underwent renal biopsy for one or more of the following: (1 ) Fixed proteinuria, (2 ) unexplained hematuria, and (3 ) NS that was unresponsive to 1 mo of corticosteroid therapy. Inclusion criteria were histologic diagnosis of primary FSGS as defined by the Columbia FSGS classification system (9 , 10
Exclusion Criteria.
Patients in whom complete data at presentation or last follow-up were not available, those who received previous dialysis or renal transplant, those whose renal biopsy contained inadequate sample (fewer than five glomeruli), and those with secondary FSGS (e.g ., chronic hypertension, reflux nephropathy, HIV, morbid obesity, heroin nephropathy, unilateral renal agenesis or renal atrophy, or genetic disease with predisposition to FSGS) or other glomerular disease with sclerotic lesions were excluded.
Follow-Up Data
Data were collected on disease presentation on each outpatient visit. On each patient encounter, we obtained a history, vital signs, casual BP, urinalysis, and information regarding immunosuppression treatment. Serum electrolytes and albumin and random urine protein and creatinine were measured intermittently according to the clinical circumstance. GFR was calculated by the Schwartz formula. NS was defined according to the International Study of Kidney Disease in Children (ISKDC) criteria: Proteinuria with protein >40 mg/m2 per h (or at least 2+ protein on urine dipstick) and hypoalbuminemia (<3.5 g/dl). Remission was defined as three consecutive days of absent or trace proteinuria (4
Treatment of NS
Patients who presented with NS were treated according to ISKDC guidelines (4 2 per d, up to a maximum of 80 mg/d), in either two or three divided doses for 1 mo, after which they were treated with oral corticosteroids (40 mg/m2 every other day) for an additional month. All relapses of NS were treated with oral corticosteroids (60 mg/m2 per d, up to a maximum of 80 mg/d, in either two or three divided doses) until the urinalysis dipstick was negative or trace for 3 consecutive days. Thereafter, they were treated with oral corticosteroids (40 mg/m2 every other day) for an additional month.
Patients who were steroid resistant (SR) were treated with calcineurin inhibitors (CNI; tacrolimus or cyclosporine) according to the individual physician's preference. Tacrolimus was started at a dosage of 0.1 mg/kg per d, with target trough level of 5 to 9 ng/dl, and titrated to achieve partial or complete remission of NS. Cyclosporine was started at a dosage of 4 mg/kg per d, with the target trough level of 150 to 250 ng/dl, and titrated to achieve partial or complete remission of NS.
Patients who presented with proteinuria but without NS were treated with an angiotensin-converting enzyme inhibitor (ACEI), angiotensin-receptor blocker (ARB), or a combination of these agents. A majority of patients who were treated with either corticosteroids or CNI were simultaneously treated with ACEI and/or ARB.
Assessment of BP
Casual BP was measured by oscillometry on validated devices. Use of proper size cuff on the right arm and in a calm atmosphere in the presence of a nurse was performed in our clinic. All patients were instructed to reduce salt intake. BP was defined according to the Fourth Report of Blood Pressure in Children (18
Kidney Biopsy Methods
Kidney biopsy specimens were evaluated by (1 ) light microscopy on B-5–fixed, paraffin-embedded tissue using hematoxylin and eosin, Jones, periodic acid Schiff, and Masson trichrome staining; 2.5% glutaraldehyde fixed tissue; embedded with Spur (EMS, Hatfield PA); and stained with toluidine blue and epoxy tissue stain (EMS); (2 ) immunofluorescence microscopy on frozen tissue using fluoresceinated antibodies to IgG, IgA, IgM, C3, and C1q (Ventana, Tucson, AZ) and fibrin; and (3 ) transmission electron microscopy on tissue fixed in 2.5% glutaraldehyde and spur-embedded. Patients with any of the structural expressions of FSGS were entered into the registry. Pathologic findings in the vascular, glomerular, and interstitial compartments, including arteriosclerosis, glomerular sclerosis, interstitial fibrosis, interstitial leukocyte infiltrate, and tubular injury or atrophy, were scored using a semiquantitative scale of 0 = normal, 1 = mild, 2 = moderate, 3 = moderately severe, and 4 = severe. A global chronicity score was calculated by the sum of the individual scores for arteriosclerosis, glomerular sclerosis, interstitial fibrosis, and tubular atrophy with a maximum score of 16 (11 9 , 10
Classification of FSGS
All variants had segmental consolidation of at least one glomerulus that was either predominantly sclerotic or cellular. Glomerular sclerosis was defined as the extracellular accumulation or condensation of matrix that impinged on or obliterated capillary lumens. We used the Columbia classification system in which the following variants are described (9 , 10 1 ) Cellular, (2 ) hilar, (3 ) collapsing, (4 ) tip lesion, and (5 ) NOS.
Statistical Analyses
Comparison between two groups was achieved by the t test. Comparison among more than two groups was achieved by ANOVA with Bonferroni post hoc test. Correlation between groups was determined by linear regression analysis.
Results
General Demographics
Forty-one patients were included in the study; 14 (34.1%) were female, 27 (65.9%) were male, 33 (80.5%) were black, and eight (19.5%) were white. At presentation, the mean age was 10.9 ± 0.9 yr. The time of follow-up was 3.9 ± 0.5 yr (range 1 to 17 yr).
Clinical Features and Prescribed Therapy at Presentation
The most common initial presenting symptom was NS (63.4%). A minority (31.7%) of patients presented with fixed proteinuria, one (2.4%) patient with hematuria alone, and one (2.4%) with ESRD. The majority (67.6%) had blood on the initial urinalysis. A total of 80.4% received oral corticosteroids alone as initial therapy, one (2.4%) received high-dosage intravenous corticosteroids, 12.2% were treated with an ACEI alone, and one (2.4%) received a CNI alone.
Clinical Data at Presentation and Last Follow-up
At first presentation, approximately one half had elevated systolic BP (SBP), approximately one quarter had elevated diastolic BP (DBP), serum albumin (Alb) was low, and the GFR was slightly low. At the end of the observation period, the SBP and DBP remained stable, the serum albumin was significantly higher, and the GFR had declined slightly. The minority of patients achieved clinical remission after the initial treatment; however, the majority were in remission at last follow-up (Table 1 ). Among those who received corticosteroids, 21.2 achieved an initial remission with corticosteroid therapy.
Clinical Features and Therapy at Last Follow-Up
At last follow-up, 29.3% were receiving corticosteroids, 63.4% were receiving an ACEI and/or an ARB, 31.7% were being treated with a CNI, and two (4.9%) were receiving mycophenolate mofetil; 14.6% were not receiving any therapy. On last follow-up, 29 (70.7%) of 41 were in remission. At last observation, the distribution according to CKD stage (19
Outcome in Patients Observed for at Least 3 Yr
Among these patients, the mean follow-up period was 6.6 yr. In these patients, we observed no significant change in SBP (120.0 ± 3.5 [initial] versus 124.4 ± 4.1 [end] mmHg; P = 0.4), SBP percentile (87.7 ± 4.0 [initial] versus 83.6 ± 4.7 [end]; P = 0.5), DBP (69.2 ± 2.1 [initial] versus 73.3 ± 2.4 [end] mmHg; P = 0.2), or DBP percentile (80.1 ± 3.9 [initial] versus 75.7 ± 4.4 [end]; P = 0.5); a similar percentage of patients had SBP or DBP >95th percentile at presentation and last observation. GFR (114.3 ± 5.8 [initial] versus 106.0 ± 8.9 [end] ml/min per 1.73 m2 ; P = 0.5) was stable over the entire observation period. A higher percentage of patients achieved remission at the end of the study: 38.9% [initial] versus 55.6 [end].
Outcome in Patients Depending on Initial Response to Oral Corticosteroids
As shown in Table 2 , approximately one fifth of the patients were initially steroid sensitive (SS). There were no differences in the clinical and laboratory data at presentation regarding response to steroids, although elevated BP was more common in SR patients. The time of observation was longer in the SS patients: 6.4 yr (SS) versus 3.7 yr (SR). GFR remained almost identical throughout the observation period in SS patients (P = 0.4) but trended downward in SR patients (P = 0.07). The mean change in GFR over the entire observation period (in ml/min per 1.73 m2 ) in SS patients was 6.4 compared with −17.1 in SR patients; when GFR is plotted against time (in years), the slopes were: 1.0 (SS) versus −4.5 (SR).
Clinical Data on Presentation and Last Follow-Up According to Pathologic Variants
Renal biopsy demonstrated the presence of three of the five previously described pathologic variants: Cellular (29.3%), collapsing (26.8%), and NOS (43.9%). The majority (81.8%) of patients with the cellular variant presented with NS; the rest had fixed proteinuria. A total of 54.5% of those with the collapsing variant initially had NS, 36.4% had fixed proteinuria, and one (9.1%) had ESRD. The presenting features for those with the NOS variant were as follows: 55.6% NS, 38.9% fixed proteinuria, and 5.6% hematuria alone. The chronicity scores were similar in patients with the cellular (4.3) and NOS (4.0) variants but significantly (P = 0.02) higher in those with the collapsing (6.4) variant compared with the NOS variant.
As shown in Table 3 , at presentation, the SBP and DBP were significantly higher in patients with the collapsing versus the NOS variant. The serum albumin was similar in all groups at presentation. The GFR was significantly lower at presentation in patients with the collapsing versus NOS variant, whereas that of patients with the cellular variant fell in between. Finally, a higher percentage of patients with the cellular or NOS variant achieved initial remission compared with those with the collapsing variant.
At last follow-up, the SBP, SBP percentile, DBP, and DBP percentile were significantly higher in patients with the collapsing versus NOS variant. The GFR trended lower in patients with the collapsing versus NOS variant, but this did not reach statistical significance.
When we assessed the GFR according to Kidney Disease Outcomes Quality Initiative (K/DOQI) CKD stage, we observed diverse distribution patterns among the three variant subtypes. At the end of the observation period, the majority of patients with either the cellular or the NOS variant had stage 1 (GFR >90 ml/min per 1.73 m2 ) CKD compared with only 36.4% of the patients with the collapsing variant (Table 4 ). A higher percentage of patients with the collapsing variant reached stages 3 to 5 CKD (46%) compared with the cellular (16.7%) or NOS (11.1%) variants. In addition, compared with the response to initial therapy, a higher percentage of patients with all variants were in remission at last observation. Finally, as shown in Figure 1 , the chronicity score correlated with GFR at presentation (r = 0.36, P = 0.03). GFR trended lower in patients with a higher chronicity score at last follow-up (r = 0.26, P = 0.1), but this did not reach statistical significance.
Clinical Data on Presentation and Last Follow-Up According to Ethnicity
The distribution of histologic variant was as follows: Cellular: black, nine (27.3%) of 33, white, three (37.5%) of eight; collapsing: black, 10 (30.3%) of 33, white, one (12.5%) of eight; NOS: black, 14 (42.2%) of 33, white, four (50.0%) of eight. In summary, the distribution among the variants was equal for black patients, whereas white patients tended to exhibit either the cellular or the NOS variant.
At presentation, BP and BP percentile were almost identical in the two groups. At last follow-up, BP and BP percentile trended higher in black patients, but the differences were not statistically significant. Serum albumin was the same in the two groups at both time points. The random urine protein/creatinine was twice as high in black compared with white patients at last observation, but this was not statistically significant. Finally, the GFR trended lower in black patients at both time periods, but these differences were not statistically significant. In summary, ethnicity had no effect on the clinical data at first presentation and final observation (Table 5 ).
Discussion
FSGS is a disease that usually is characterized at onset by fixed proteinuria or NS. There has been a rising incidence of FSGS in children and adults in the past two decades (6 , 7 , 15 , 16 , 20 , 21 7 et al . (13 21 et al . (8
There are five variants of FSGS: (1 ) Collapsing, (2 ) tip lesion, (3 ) cellular, (4 ) hilar, and (5 ) NOS (9 , 10 5 , 12 11
Because of the controversy regarding the overall prognosis and impact of the histologic variant on renal survival, we studied the presenting features, short-term outcome, and impact of pathologic variant on outcome in childhood primary (idiopathic) FSGS. The most common presenting features among our patients were NS and fixed proteinuria. Our studies also show that the short-term outcome in pediatric primary FSGS is generally favorable, with more than three quarters showing no or mild change in GFR over several years. In a subgroup in which the mean follow-up period was almost 7 yr, the clinical features remained generally favorable during the entire observation period. These results are consistent with those of Abrantes et al . (13 et al . (17
We assessed the effect of the response to therapy on remission rates and renal survival. Similar to most studies of pediatric FSGS (reviewed in reference [22 , 23 et al . (13 versus SR patients (1.0 [SS] versus −4.5 [SR]), confirming the prognostic significance of initial steroid sensitivity. Indeed, our data show that GFR remains stable (and normal) in patients who are initially SS, whereas it declines in those who are initially SR. Owing to our frequent use of ACEI, ARB, and CNI in SR patients, a relatively high proportion of these patients were in remission at last observation. These results are consistent with recent studies showing that there are higher rates of clinical remission in childhood SR FSGS with the use of either alkylating agents (24 – 26 27 – 30
One major aim of our study was to assess the impact of the FSGS variant on presenting features and renal survival. Three variants were observed among our patients: Cellular, collapsing, and NOS. Similar to recent studies in adult FSGS (11 , 12 11 7 , 11 – 13
The distribution of pathologic variants was also different between ours and other recent pediatric studies. The most common pathologic variant that we observed was the NOS variant, with the remainder equally divided between the cellular and collapsing variants. The proportion of patients with the collapsing variant was higher in our cohort compared with that reported by Abrantes et al . (13 versus 16%). Similar to our report, Paik et al . (17
Our results show that the type of variant affects clinical and laboratory features at presentation and during the course of the disease. Compared with patients with the collapsing or NOS variant, patients with the cellular variant more commonly presented with NS. In addition, the collapsing variant was heralded by higher SBP and DBP and lower GFR. The NOS variant carried the most favorable prognosis, the cellular variant portended a generally favorable prognosis, and those with the collapsing variant carried the most guarded prognosis. Unlike the results reported by Abrantes et al . (13 et al . (17 11
Finally, we studied the impact of ethnicity on outcome in primary FSGS, prompted by reports showing that renal survival is shorter in pediatric black versus white patients with FSGS (8 versus white (12.5%) patients with the collapsing variant, we did not observe any short-term differences in the outcome according to ethnicity.
Our study has several limitations. First, this was a retrospective study in which the patients were cared for by a group of physicians. Although bias was not inherent in the study design, individual patient outcome may have been affected by each physician's treatment preference. Second, we did not perform ambulatory BP monitoring, which may minimize conclusions regarding the prevalence (and impact) of hypertension. Finally, the average time of observation was only approximately 4 yr, a relatively short time span for a disease that may take up to 10 yr to show significant progression.
Conclusion
Our results show, first, that, overall, the short-term outcome of pediatric primary FSGS is generally promising but more guarded for patients with the collapsing variant. Second, the distribution of pathologic FSGS variants is different in children compared with adults. Finally, although our study did not focus on treatment outcomes, our impression is that more aggressive treatment with CNI, in combination with ACEI/ARB or with mycophenolate mofetil, may provide more favorable prognosis for renal survival in pediatric FSGS.
Disclosures
None.
Figure 1: Correlation between chronicity score (CS) on renal biopsy and GFR at presentation. There was a significant (P = 0.03) inverse relationship between the CS and GFR.
Table 1: Clinical features and laboratory data at presentation and last follow-upa
Table 2: Clinical features and laboratory data at presentation according to the response to corticosteroids: SS and SRa
Table 3: Clinical features and laboratory data at presentation according to histologya
Table 4: Distribution of CKD stage according to FSGS variant at last observationa
Table 5: Clinical features and laboratory data at presentation according to ethnicity: Black and white patientsa
We thank Dr. V. Matti Vehaskari, Dr. Diego H. Aviles, Dr. Flavia F. Jung, Dr. Kimberly Irwin, Pamela LeBlanc, David Seymour, and Linda Dublin for dedicated care of the patients.
Published online ahead of print. Publication date available at www.cjasn.org
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