Indian Journal of Pathology and Microbiology
Home About us Instructions Submission Subscribe Advertise Contact e-Alerts Ahead Of Print Login 
Users Online: 2064
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size

ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 2  |  Page : 248-252
Morphological features and prognostic significance of tip variant of focal segmental glomerulosclerosis: Study of an Indian cohort

1 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
2 Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Click here for correspondence address and email

Date of Web Publication12-Jun-2010


Context: Several attempts have been made to formulate a morphologic classification of focal segmental glomerulosclerosis (FSGS) variants with therapeutic and prognostic implications. Differences in study populations such as racial profile or therapy offered have hampered attempts to define prognostic variables in FSGS. Literature reveals conflicting results regarding the prognostic significance of tip variant of FSGS in different populations. Aims: To study the clinical and pathologic parameters in tip and not otherwise specified (NOS) variants of FSGS, in subjects from the Indian subcontinent with prognostic significance. Materials and Methods: First we performed a retrospective analysis of patients with biopsy proven primary FSGS, diagnosed between January 2004 and December 2008. Twenty cases of tip variant were encountered in adult population and similar numbers of adult cases of NOS variant were randomly selected. Renal biopsies were studied using light and immunofluorescence microscopy. Medical records for clinical data at presentation, biopsy and three monthly follow-up intervals were reviewed and compared between two groups. Results: At presentation, clinical profiles for the two groups were similar; however, significant differences in histological parameters and clinical outcome in tip and NOS variant cases were noted. Interstitial fibrosis and tubular atrophy were significantly higher in NOS variant. Greater response rate to steroid therapy was observed in tip variant cases while higher proportion of NOS variant cases showed renal failure. Conclusion: Analysis of histological parameters is important in assessing the outcome of tip and NOS variants. Tip variant signifies a better prognostic subset for a population of Indian origin affected by FSGS.

Keywords: Focal segmental glomerulosclerosis, histologic variants, prognosis, renal biopsy, tip variant

How to cite this article:
Malhotra KP, Prasad N, Jain M. Morphological features and prognostic significance of tip variant of focal segmental glomerulosclerosis: Study of an Indian cohort. Indian J Pathol Microbiol 2010;53:248-52

How to cite this URL:
Malhotra KP, Prasad N, Jain M. Morphological features and prognostic significance of tip variant of focal segmental glomerulosclerosis: Study of an Indian cohort. Indian J Pathol Microbiol [serial online] 2010 [cited 2022 Sep 29];53:248-52. Available from:

   Introduction Top

Focal segmental glomerulosclerosis (FSGS) is a clinico-pathologic entity characterized by affection of some, but not all, glomeruli by segmental sclerosing lesions. It may occur in a primary form of unknown cause or secondary to many other underlying conditions. An increasing incidence of primary FSGS has recently been reported in several countries. Racial variation in incidence of FSGS has also been reported.

In the United States, FSGS is the most common cause of nephrotic syndrome and end stage renal disease (ESRD) in Black and White adults with primary glomerulonephritis. [1],[2],[3] A similar trend has been noted in Latin America. [4],[5],[6]

Since the first descriptions by Fahr. [7] and Rich., [8] several attempts have been made to formulate a morphologic classification of FSGS variants with prognostic and therapeutic implications. Differences in study populations, such as racial profile or therapy and lack of a standardized morphologic classification, have hampered attempts to define prognostic variables in FSGS. A recent consensus conference of renal pathologists held in New York city has described five variants of FSGS based on light microscopic analysis, namely classic or NOS, perihilar, cellular, tip and collapsing variants. [9]

Some variants e.g. the collapsing variant, are known for their aggressive course, but the prognostic implications of the tip variant are shrouded in mystery. [10],[11] Since its initial description by Howie et al.[12] it has been variously reported as having a prognosis better than, similar to or poorer than other variants. [13],[14],[15],[16],[17],[18],[19] A previous Indian study has assessed the duration of optimal therapy for FSGS, however, treatment response was not analyzed according to histological variants. [20] The paucity of data regarding FSGS in Asian countries and the relevance of tip lesion as a separate prognostic entity have formed the basis of our present study.

   Materials and Methods Top

We retrospectively reviewed patient records of all 146 adult cases of biopsy proven FSGS, diagnosed between January 2004 and December 2008 at a tertiary care center in North India. Patients younger than 16 years of age, those with secondary FSGS including human immune deficiency virus (HIV) nephropathy and biopsy specimens with fewer than eight glomeruli were excluded from the study. Perihilar, cellular and collapsing variants were also excluded. Twenty cases of tip variant were encountered during the said period and similar numbers of adult cases of NOS variant were randomly selected for comparison. The biopsy specimens were reviewed separately by two pathologists blinded to the clinical outcome . The histological and clinical outcome differences between the two groups were compared.

Renal biopsies for light microscopy were formalin-fixed and paraffin-embedded. Sections were cut at three micron thickness. A total of four slides with serial sections stained with hematoxylin and eosin, periodic acid Schiff (PAS), silver methenamine and Masson's trichrome stain were studied in each case. Further, serial sections stained with PAS were used as and when required.

The light microscopic analysis included evaluation of total number of glomeruli, proportion of glomeruli with global and segmental sclerosis and presence or absence of glomerular foam cells. Semi-quantitative assessment of percentage of total glomerular area involved by segmental sclerosis was done and graded as: grade 1 (0- 25%) and grade 2 (greater than 25%) sclerosis. Cortical area showing tubular atrophy and interstitial fibrosis were also graded semi-quantitatively as: grade 1 (0-25%) and grade 2 (greater than 25%).

For the immunofluorescence study, the tissue was frozen at minus 40ΊC, cut into five ΅m sections in a cryostat and incubated with fluorescein-labeled antibodies against IgG, IgM, IgA, C3, C1q and fibrin.

The diagnostic criteria for FSGS variants were in accordance with Columbia classification. [9],[21] The tip variant was defined by the presence of at least one glomerulus with a segmental lesion involving the tip domain (i.e. the peripheral 25% of the glomerular tuft next to the origin of the proximal tubule). Either adhesion between the capillary tuft and Bowman's capsule or prolapse into the tubular lumen was a requisite. FSGS - NOS lesions should show at least one glomerulus with segmental sclerosis.

The demographic and clinical characteristics of all patients in terms of age, sex, blood pressure, renal failure, serum albumin, total and LDL cholesterol concentrations, 24-hour timed protein and creatinine excretion and microscopic urine sediment analysis were recorded. The profiles of the two groups were compared. Normal serum creatinine was defined as less than 1.4 mg/dL and renal insufficiency as greater than 1.4 mg/dL. Nephrotic range proteinuria was defined as greater than 3.5 gm/24hr/1.73m 2 and sub-nephrotic proteinuria was defined as less than 3.5 gm/24hr/1.73m 2 body surface area. Hematuria was defined as greater than five red blood cells (RBC) per high power field. Hypertension was defined as systolic blood pressure (SBP) greater than 140 mmHg or diastolic blood pressure (DBP) greater than 90 mmHg.

All the patients were treated with prednisolone at a dosage of one mg/kg daily for 16 weeks. In the non-responder group the treatment duration was increased up to six months. In patients who had shown intolerance to steroids, the steroid dosage was reduced to 0.5 mg/kg/day. At the end of the study period, the response to therapy was defined as: (1) Complete remission (urine protein less than two300 mg/day); (2) Partial remission (urine protein greater than 300 mg/day but less than two g/day or decrease in proteinuria of greater than 50% from baseline in the case of non nephrotic patients); and (3) No response (persistent proteinuria greater than two g/day).

Data was analyzed on SPSS 10.0 statistical software. Student's t test was used to compare the mean between two groups and chi square test was used to compare proportions between two groups. Pearson's correlation was used to assess the correlation between histologic parameters and creatinine and proteinuria levels.

   Results Top

The demographic and clinical characteristics of patients in the two groups, at presentation, are shown in [Table 1]. The age ranged from 16 to 60 years with a mean age of 35.7 years for cases with tip variant and 16 to 44 years with a mean of 28 years for cases with NOS variant. The average durations from initial presentation to biopsy were 9.5 months and 20.3 months in tip and NOS variants respectively. The patients with tip variant were followed up for a mean duration of 15.2 months and those with NOS variant for a mean duration of 27.3 months. There was no significant difference between the two groups with regard to the number of patients presenting with nephrotic syndrome and hypertension or the mean levels of proteinuria per day and levels of total and LDL cholesterol. Mean serum creatinine at presentation was higher in tip variant cases, but the levels were not statistically significant. Active sediments were found with similar frequency in the two groups [Table 1].

At biopsy, the mean number of glomeruli was 14.7 in tip lesion and 14.2 in NOS variant. Globally sclerosed glomeruli were more frequent in NOS variant (7.74%) compared to tip variant (2.58%). The percentage of glomeruli affected by segmental sclerosis was higher in the NOS variant cases (16.69% in tip versus 25.78% in NOS variant). The proportion of glomerular area involved by sclerosis in the segmental sclerosed glomeruli was also higher in NOS variant cases. All patients of tip variant had grade 1 glomerulosclerosis lesion (less than 25%), while 17 patients in NOS variant had grade 1, and three patients had grade 2 (greater than 25%) glomerulosclerosis [Table 2]. Majority of glomeruli in cases with tip variant had only small segment of sclerosis and synechiae formation at tubular pole [Figure 1], [Figure 2] and [Figure 3].

On analysis, interstitial fibrosis was found to be significantly higher in patients with NOS variant compared to tip variant. All patients with tip lesion had grade 1 interstitial fibrosis while in NOS variant cases, 14 patients had grade 1 and six patients had grade 2 interstitial fibrosis [P is equal to 0.020]. Of the 20 patients with tip lesion, all had grade 1 tubular atrophy, while 15 patients of NOS variant had grade 1 and five had grade 2 tubular atrophy [P is equal to 0.022]. The grading of histologic parameters in the two subsets is shown in [Table 2].

Presence of foam cells was noted in four cases with tip variant and one case with NOS variant. Immunofluorescent deposits of IgM and C3 were noted in the sclerosed glomerular segments in both variants with equal frequency.

For outcome analysis, clinical variables were evaluated at three monthly intervals. All the patients were treated with steroids (prednisolone 1mg/kg/day) for an average of 16 weeks post diagnosis, along with antihypertensives and other supportive treatment as necessary.

Amongst the tip lesion cases, 15 patients responded (11 [55%] cases complete remissions and four partial remissions) while five showed no response [25%] to therapy. Of the 11 patients with complete remission, three relapsed at the end of follow-up. Non-responder patients were treated with cyclophosphamide (two mg/kg) for three months. Of the five non-responder patients, one achieved complete remission, another achieved partial remission and remaining three remained non-responsive.

Amongst NOS lesion cases, 11 patients had remission [six complete remissions [30%] and five partial remissions] and nine patients [45%] showed no response to therapy. All non-responder patients in NOS variants were also treated with cyclophosphamide (two mg/kg). Of the nine non-responder patients, two patients achieved complete remission, one partial remission while six remained non-responders. Of the five patients with complete remission, two had relapsed by the end of follow-up. The outcome after 16 weeks of treatment and at the end of the study period is presented in [Table 3].

The creatinine level at end of follow-up period, highly correlated (Pearson's correlation) with glomerulosclerosis (r is equal to 0.719 and P is equal to 0.001), interstitial fibrosis (r is equal to 0.412 and P is equal to 0.008) and tubular atrophy (r is equal to 0.667and P is equal to 0.001). However, proteinuria did not show significant correlation with glomerulosclerosis (r is equal to 0.109 and p is equal to 0.50), interstitial fibrosis (r is equal to 0.161and P is equal to 0.32) or tubular atrophy (r is equal to 0.255 and P is equal to 0.11).

   Discussion Top

Literature search reveals conflicting data on the demographic and histologic profile as well as the clinical outcome of patients with various histologic variants of FSGS. Several studies conducted in the Western countries have reported tip lesion as a marker of benign course and better response to therapy. [13],[14],[15],[16],[17] Conflictingly, tip variant patients have also been shown to have a poorer renal survival as compared to all other histological variants put together. [19] From the data available to us, ours is the first study which compares the prognostic value of the tip and NOS histologic variants of FSGS in an Indian subset of patients.

We observed significant differences in the histologic parameters and clinical outcome in tip and NOS variants while clinical profile at presentation was similar. There was no significant difference in the demographic profile, age group affected or sex ratio. The average duration between initial presentation and biopsy was greater in NOS group (20.3 months) as compared to tip lesion (9.5 months). Deegan et al.[22] as well as Chun et al.[18] and Stokes et al.[16] revealed that tip lesion presented earlier than FSGS-NOS variant.

The frequency of nephrotic syndrome, proteinuria excretion and degree of hypoalbuminemia and hypertension did not differ among our study groups. In a study conducted on an adult Dutch population, nephrotic syndrome at presentation was more common in tip variant cases. [22] In another study conducted in Chicago, hypoalbuminemia was more common in tip variant cases, but severity of proteinuria was similar. [18] Higher degree of proteinuria and greater incidence of nephrotic syndrome has also been reported in tip variant cases in a study from China. [23] Serum creatinine was comparatively higher in patients with tip variant but the difference was not statistically significant in our study population. Active urine sediment was a common finding in both groups in our study.

Biopsy characteristics revealed notable variability among the two groups. Area involved by interstitial fibrosis and tubular atrophy was significantly higher in NOS variant biopsies in our study. Lesser tubulointerstitial injury was also noted in tip variant cases in a study by Thomas et al. [24] However, a study on an adult population in Chicago revealed no difference in cortical interstitial fibrosis in the two groups. [18] Tip variant cases revealed fewer global and segmental scarred glomeruli and also lesser proportion of glomerular area affected by sclerosis. Deegens et al. and Chun et al. have reported similar findings. [19],[20] According to literature, all other variants of FSGS including tip lesion may evolve to FSGS NOS variant in the course of disease progression. [9]

In our study none of the tip lesion or FSGS NOS cases had overlaps in morphogical features and the diagnosis of FSGS NOS was made after the exclusion of the tip lesion. None of the tip lesion or NOS case had follow up biopsy to assess the progression of tip lesion to FSGS NOS subtype. Greater response rate after 16 weeks of steroid therapy was noted in tip variant cases in our study. This difference in outcome was maintained at the end of follow-up period. Higher proportion of patients with NOS lesion showed renal failure at the end of follow-up period as compared to tip variant. Renal outcome in terms of creatinine levels showed high correlation with the histologic parameters studied, despite similar levels of proteinuria remission in the two groups. Howie et al. [25] also analyzed the histologic evidence of chronic damage and suggested that increasing fibrosis and tubular atrophy is associated with shortened renal survival in FSGS.

In conclusion, NOS cases have more severe histologic damage and poorer renal outcome than tip variant cases. Analysis of histologic variants and the severity of glomerular and tubulointerstitial damage hence remain important parameters in assessing the clinical outcome of these patients. We summarize from the results of our study that tip variant signifies a better prognostic subset for a population of Indian origin affected by FSGS.

   References Top

1.Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephritic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 1997;30:621-31.  Back to cited text no. 1      
2.Dragovic D, Rosenstock JL, Wahl SJ, Panagopoulos G, DeVita MV, Michelis MF. Increasing incidence of focal segmental glomerulosclerosis and an examination of demographic patterns. Clin Nephrol 2005;63:1-7.  Back to cited text no. 2      
3.Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 2004;44:815-25.  Back to cited text no. 3      
4.Bahiense-Oliveira M, Saldanha LB, Mota EL, Penna DO, Barros RT, Romγo-Junior JE, et al. Primary glomerular diseases in Brazil (1979-1999): is the frequency of focal and segmental glomerulosclerosis increasing? Clin Nephrol 2004;61:90-7.  Back to cited text no. 4      
5.Malafronte P, Mastroianni-Kirsztajn G, Betonico GN, Romao JE Jr, Alves MA, Carvalho MF, et al. Paulista registry of glomerulonephritis: 5-year data report. Nephrol Dial Transplant 2006;21:3106-14.  Back to cited text no. 5      
6.Mazzuchi N, Acosta N, Caorsi H, Schwedt E, Di Martino LA, Mautone M, et al. Frequency of diagnosis and clinical presentation of glomerulopathies in Uruguay. Nefrologνa 2005;25:113-20.  Back to cited text no. 6      
7.Fahr T. Pathologische Anatomie des morbus brightii. In: Henke F, Lubarsch O, editors. Handbuch der speziellen pathologischen Anatomie und Histologie. Berlin: Springer;1925. p.156.  Back to cited text no. 7      
8.Rich AR. A hitherto undescribed vulnerability of the juxta-medullary glomeruli in lipoid nephrosis. Bull Johns Hopkins Hosp 1957;100:73.  Back to cited text no. 8      
9.Agati VD. Pathologic classification of focal segmental glomerulosclerosis. Seminars in Nephrology 2003;23:117-34.  Back to cited text no. 9      
10.Detwiler RK, Falk RJ, Hogan SL, Jennette JC. Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int 1994;45:1416-24.  Back to cited text no. 10      
11.Valeri A, Barisoni L, Appel GB, Seigle R, D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int 1996;50:1734-46.  Back to cited text no. 11      
12.Howie AJ, Brewer DB. The glomerular tip lesion: a previously undescribed type of segmental glomerular abnormality. J Pathol 1984;42:205-20.  Back to cited text no. 12      
13.Howie AJ, Brewer DB. Further studies on the glomerular tip lesion: early and late stages and life table analysis. J Pathol 1985;147:245-55.  Back to cited text no. 13      
14.Beaman M, Howie AJ, Hardwicke J, Michael J, Adu D. The glomerular tip lesion: a steroid responsive nephrotic syndrome. Clin Nephrol 1987;27:217-21.  Back to cited text no. 14      
15.Huppes W, Hene RJ, Kooiker CJ. The glomerular tip lesion: a distinct entity or not? J Pathol 1988;154:187-90.  Back to cited text no. 15      
16.Stokes MB, Markowitz GS, Lin J, Valeri AM, D'Agati VD. Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum. Kidney Int 2004;65:1690-702.  Back to cited text no. 16      
17.Howie AJ, Pankhurst T, Sarioglu S, Turhan N, Adu D. Evolution of nephrotic associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion. Kidney Int 2005;67:987-1001.  Back to cited text no. 17      
18.Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. In nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 2004;15:2169-77.   Back to cited text no. 18      
19.Roja JR, Pιrez M, Hurtado A, Asato C. Factors predicting for renal survival in primary focal segmental glomerulosclerosis. Nefrologia 2008;28:439-46.   Back to cited text no. 19      
20.Pokhariyal S, Gulati S, Prasad N, Sharma RK, Singh U, Gupta RK, et al. Duration of optimal therapy for idiopathic focal segmental glomerulosclerosis. J Nephrol 2003;16:691-6.  Back to cited text no. 20      
21.D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 2004;43:368-82.  Back to cited text no. 21      
22.Deegens JK, Steenbergen EJ, Borm GF, Wetzels JF. Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population-epidemiology and outcome. Nephrol Dial Transplant 2008;23:186-92.  Back to cited text no. 22      
23.Shi SF, Wang SX, Zhang YK, Zhao MH, Zou WZ. Clinicopathologic study of different variants of focal segmental glomerulosclerosis. Zhonghua Bing Li Xue Za Zhi. 2007;36:11-4.  Back to cited text no. 23      
24.Thomas DB, Franceschini N, Hogan SL, Ten Holder S, Jennette CE, Falk RJ, et al. Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 2006;69:920-6.  Back to cited text no. 24      
25.Howie AJ, Ferreira MA, Adu D. Prognostic value of simple measurement of chronic damage in renal biopsy specimens. Nephrol Dial Transplant 2001;16:1163-9.  Back to cited text no. 25      

Correspondence Address:
Manoj Jain
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226 014, UP
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.64339

Rights and Permissions


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 Relationship between Serum Soluble Urokinase Plasminogen Activator Receptor Level and Steroid Responsiveness in FSGS
Furong Li,Chunxia Zheng,Yongzhong Zhong,Caihong Zeng,Feng Xu,Ru Yin,Qi Jiang,Minlin Zhou,Zhihong Liu
Clinical Journal of the American Society of Nephrology. 2014; 9(11): 1903
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  

    Materials and Me...
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded209    
    Comments [Add]    
    Cited by others 1    

Recommend this journal