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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 1  |  Page : 8-14
Focal and segmental glomerulosclerosis in renal allograft recipients: A clinico-pathologic study of 37 cases

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India

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Date of Web Publication22-Jan-2013


Focal and segmental glomerulosclerosis (FSGS) in renal allografts may occur as a recurrence of primary FSGS, as a de novo phenomenon or as a complication of calcineurin inhibitor toxicity. There are very few studies in the literature describing the clinico-pathologic characteristics of FSGS in renal allografts. To the best of our knowledge, no such study exists from the Indian subcontinent. Thirty-seven cases showing FSGS, of 426 transplant biopsies performed over a 4-year period (2006-2009), were included in this study. The pre- and post-transplant clinical data were noted. FSGS was classified as per the Columbia scheme. Appropriate statistical tests were applied. The age of the study patients ranged from 13 to 54 years, with a male preponderance. Thirty-five patients (94.6%) were diagnosed as FSGS more than 12 months after transplantation. All the patients presented with renal dysfunction (median serum creatinine 2.8 mg/dL) and detectable proteinuria at the time of diagnosis. Histologically, FSGS-NOS (70.3%) was observed as the most common subtype, followed by collapsing and perihilar varieties (13.5% each). Most of the biopsies (83.7%) showed grade-2 to -3 interstitial fibrosis and tubular atrophy. Follow-up data were available in 27 patients (73%), of whom 12 (44.4%) had graft loss with dialysis-dependent state at last follow-up. FSGS is one of the important causes of graft dysfunction, especially late in the post-transplantation period in cases of de novo FSGS. The long-term outcome of renal allografts developing this glomerular pathology is quite dismal, with a significant proportion of patients suffering graft loss.

How to cite this article:
Gupta R, Sharma A, Mahanta PJ, Agarwal SK, Dinda AK. Focal and segmental glomerulosclerosis in renal allograft recipients: A clinico-pathologic study of 37 cases. Saudi J Kidney Dis Transpl 2013;24:8-14

How to cite this URL:
Gupta R, Sharma A, Mahanta PJ, Agarwal SK, Dinda AK. Focal and segmental glomerulosclerosis in renal allograft recipients: A clinico-pathologic study of 37 cases. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Jun 6];24:8-14. Available from: http://www.sjkdt.org/text.asp?2013/24/1/8/106231

   Introduction Top

Renal transplantation in patients with end-stage renal disease (ESRD) secondary to focal and segmental glomerulosclerosis (FSGS) carries a 20-30% risk of recurrence of FSGS in the renal allograft. [1] In addition, FSGS may be seen in the renal allografts as a de novo occurrence or secondary to chronic calcineurin inhibitor (CNI) toxicity. [2] The distinction between recurrent and de novo FSGS in the renal allograft is complicated by the frequent absence of a pre-transplant biopsy diagnosis in many patients. However, clinical features may be helpful to some extent in this distinction. Recurrent FSGS usually presents in the early post-transplantation period with re-emergence of proteinuria and progressive graft dysfunction. On the other hand, de novo FSGS is generally detected more than 12 months after transplantation. [3] Although the pathogenesis of FSGS involving the renal allograft is not amply clear, glomerular hyperfiltration due to nephron loss or size discrepancy has been implicated in the pathogenesis of de novo FSGS. [4]

Early detection and appropriate management of FSGS in the renal allograft may be difficult in centers where urinalysis is not utilized in the routine post-transplantation surveillance. [2] The earliest manifestation of FSGS in the renal allograft is proteinuria; hence, routine urinalysis allows for timely detection of urinary abnormality and subsequent renal allograft biopsy for an accurate diagnosis. Appropriate therapeutic modality for FSGS in renal allograft is debatable, although a number of approaches have been tried.

An extensive literature search yielded only a few studies of FSGS in the renal allografts. [1],[3],[5],[6],[7] To the best of our knowledge, no such study of FSGS in renal allograft biopsies has been reported from the Indian sub-continent. This study describes the detailed clinical, biochemical and histological data of 37 patients with FSGS diagnosed on renal allograft biopsies, with particular emphasis on the clinical significance of this entity.

   Materials and Methods Top

Case identification

All patients with a histological diagnosis of FSGS on renal allograft biopsy performed over four-year study duration (2006-2009) were included in the study.

Clinical data

All the pertinent pre- and post-transplant clinical and laboratory data were retrieved from the medical records of these patients. The clinical details included age, gender, date of transplant and date of biopsy on which a diagnosis of FSGS was rendered, previous episodes of acute rejection, presenting clinical features, degree of proteinuria (spot dipstick and/or 24-hour urinary protein) and serum creatinine. The time to occurrence of FSGS was defined as the interval between renal transplantation and biopsy diagnosis of FSGS. Graft loss was defined as a requirement of dialysis in post-transplant cases.

Histological analysis

The biopsy slides consisted of three routine stains in all cases: hematoxylin and eosin (H&E), periodic acid Schiff (PAS) and silver methenamine (SM). The slides were reviewed by three independent renal pathologists (RG, AS and AKD), who confirmed the diagnosis of FSGS along with classification as collapsing or non-collapsing and other changes scored according to updated Banff 2007 criteria. [8] The histological criteria used for the diagnosis of FSGS were: Segmental sclerosis of glomerular capillaries with associated hyaline and/or lipid deposition and with variable prominence of overlying visceral epithelial cells and segmental adhesion to a mildly thickened bowman capsule. The collapsing variant of FSGS (cFSGS) was defined by wrinkling and retraction of the glomerular capillary wall, collapse of the underlying tuft with marked hyperplasia and hypertrophy of the overlying visceral epithelial cells, often accompanied by prominent intra-cytoplasmic protein reabsorption droplets. A diagnosis of cFSGS was made if at least one glomerulus demonstrated these typical changes of collapsing FSGS. The FSGS lesions were categorized according to the Columbia classification. [9]

   Statistical Analysis Top

Student's t-test and Mann-Whitney test were utilized to analyze numeric data, with normal and non-normal distribution, respectively. Chi-square test was applied for categorical variables. An attempt was made to analyze the significance of difference between the various subtypes of FSGS with respect to their clinical and histological features. Also, an attempt was made to assess the difference between the patient group with graft loss and those with functioning graft at the last follow-up.

   Results Top

Demographic and clinical data

A total of 37 cases of FSGS were identified in the study period. In the same period, 426 renal allograft biopsy samples were received in our department. Thus, FSGS constituted 8.7% of the renal transplant biopsies at our institute. There was a wide age range, from 13 to 54 years (mean 32 ± 8.8 years).

Of the 37 patients, 86.5% patients were males (male:female ratio of 6.4:1). All the transplants were from live-related adult donors, with a median time to occurrence of FSGS of 36.5 months (range 4-192 months). Native kidney disease was documented in only five patients: two each with diabetes mellitus and polycystic kidney disease and one patient with FSGS in the native kidney. Of the 37 patients, nine presented with pedal edema or anasarca while 28 (75.6%) were detected to have asymptomatic graft dysfunction (evident by rise in serum creatinine) on a follow-up visit in the renal transplant clinic. Thus, all these 37 biopsies were performed for clinical indications rather than being performed for routine surveillance. On examination, 17 patients (45.9%) were receiving antihypertensive agents with controlled hypertension. Systemic examination was unremarkable in all patients.

Serum creatinine at the time of allograft biopsy ranged between 1.5 and 13.9 mg/dL (median 2.8 mg/dL). All the patients had significant detectable proteinuria on dipstick urine examination, with a mean 24-h urinary protein excretion of 2.2-10.4 g/24 h. Serum trough levels of CNIs (cyclosporine A or tacrolimus) were within reference ranges for the duration of transplant in all patients. All these patients were negative for serological evidence of infection with the human immunodeficiency virus (HIV). The salient clinical and biochemical parameters are summarized in [Table 1].
Table 1: Clinical features of the 37 cases of focal and segmental glomerulosclerosis in renal allograft biopsy.

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All the patients were receiving a steroid-based triple-drug immunosuppressive regimen including CNIs, steroids and mycophenolate mofetil or azathioprine. None of the patients was on sirolimus at the time of biopsy diagnosis of FSGS.

Histopathological features

The median number of glomeruli was eight, with a range of 4-32. Global glomerulosclerosis was noted in a median of 16.7% glomeruli (range 0-77.8%). FSGS lesion was seen in a variable number of glomeruli, with a median of two (range 1-5), constituting 25% (range 8.3-57.1%) of the total number of glomeruli. The type of FSGS lesion was NOS in 26 (70.3%), collapsing and perihilar in five biopsies each (13.5%) and apical in location in one case (2.7%) [Figure 1] and [Figure 2].
Figure 1: The upper panel of photomicrographs demonstrates a case of FSGS-NOS showing segmental sclerosis involving multiple tufts of the same glomerulus (a, H&E ×200 and b, Periodic acid Schiff (PAS) stain ×200). The lower panel shows a glomerulus with visceral epithelial cell hyperplasia associated with collapse of the underlying tuft (c, H&E ×200), which is better highlighted on silver methenamine (SM) stain (d, SM ×200).

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Figure 2. Photomicrographs from a case of perihilar FSGS (a, H&E ×200), highlighted on SM stain (b, SM ×200). The lower panel demonstrates a case of apical FSGS (tip lesion) with the sclerotic lesion opposite the afferent arteriole (c, H&E ×200 and d, PAS ×200).

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In addition, acute cellular rejection (ACR) was noted in ten biopsies (27%). The grade of ACR, as per the Banff 2007 update, was grade-1 in six, grade-2 in three and grade-3 in one biopsy. The chronic tubulo-interstitial changes (interstitial fibrosis and tubular atrophy) were also graded according to the Banff 2007 criteria. The changes were grade-1 in six, grade-2 in 17 and grade-3 in 14 biopsies. Moderate to marked hyaline arteriolosclerosis was noted in 30 biopsies (81.1%). Thickening of the glomerular basement membrane with focal reduplication, evident on SM stain (suggestive of chronic antibody-mediated rejection) was noted in 12 cases. These histological features are summarized in [Table 2].
Table 2: Histopathological findings in the renal allograft biopsy specimen.

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None of the allograft biopsies showed the characteristic isometric vacuolization of tubular epithelial cells, or "striped" pattern of tubular atrophy/interstitial fibrosis or nodular arteriolar hyalinosis of CNI toxicity.

Follow-up data

Consequent to the biopsy diagnosis of FSGS, angiotensinogen-convertase inhibitors (ACE inhibitor) or angiotensin receptor blockers (ARB) were added to the therapeutic regime in these patients. Patients showing concurrent ACR received intravenous pulse methylprednisone therapy. Follow-up data were available in 27 patients, with a mean follow-up period of 15 months (6-28 months). Of these, 12 progressed to become dialysis dependent (graft loss). The remaining 15 patients had a serum creatinine ranging between 1.4 and 4.0 mg/dL at the last follow-up visit.

Statistical analysis

Clinical parameters including age at diagnosis of FSGS, gender, duration of transplant, baseline serum creatinine or creatinine at current presentation or degree of proteinuria did not correlate with the graft outcome. Histological features like degree of focal sclerosis, type of FSGS, degree of interstitial fibrosis/tubular atrophy and concurrent acute rejection also did not show any correlation with the outcome.

   Discussion Top

FSGS is a common cause of ESRD both in children and in adults. In patients undergoing renal transplantation for ESRD due to FSGS, there is a 20-30% risk of recurrence in the allograft. [1] The risk is reported to be as high as 50% in series that include only pediatric or young adults with primary FSGS. [10],[11] It has been shown that familial forms of FSGS do not recur after renal transplantation, highlighting that the genetic defect is intrinsic to the kidney. [12] In addition to the recurrence, FSGS may be seen in renal allografts as a de novo phenomenon or secondary to CNI toxicity. [2],[5] Unfortunately, the distinction between recurrent and de novo FSGS is not always possible, especially in the absence of diagnosis of native kidney disease in many cases. In the present series, native kidney disease was known in only five patients. This may be due to the fact that our institution is a tertiary referral center and that most patients are registered with ESRD for dialysis and renal transplantation. In such patients, renal biopsy is usually avoided due to the risk of potentially life-threatening hemorrhage and a lower rate of characterization of cause of renal disease. [2]

Recurrence of FSGS in the renal allograft occurs quite early in the post-transplantation period, with proteinuria being observed within weeks of renal transplantation. [13] Patients with recurrent FSGS present with heavy proteinuria and progressive renal insufficiency soon after renal transplantation. In the present study, one patient had a biopsy-proven FSGS in the native kidney. In this patient, FSGS was diagnosed in the allograft biopsy 81 months after transplantation. Such a long duration to recurrence of FSGS in the renal allograft, although reported previously, is uncommon. De novo FSGS, in contrast to recurrent FSGS, is frequently seen in late allograft biopsies, months or years after transplantation. This form of FSGS in renal allografts has been described in several settings: (a) long standing grafts where gradual nephron loss and fibrosis result in glomerular hyperfiltration; (b) pediatric kidneys transplanted in adult patients with resultant hyperfiltration; (c) grafts with severe vascular disease resulting in secondary collapsing FSGS; (d) grafts with transplant glomerulopathy or CNI-induced glomerulopathy; and (e) as new-onset primary FSGS in allograft. [4] The pathogenesis of de novo FSGS in renal allografts is not clear; however, changes like progresssive nephron loss and glomerular hyperfiltration, or sometimes hypo-perfusion, have been postulated to play a role in this development. [14] In our series, the median time to diagnosis of FSGS was 36.5 months. Hence, majority of our cases are likely to be de novo FSGS, considering the long time to diagnosis of FSGS post-transplantation. However, we cannot completely exclude the possibility of recurrent FSGS in the absence of primary diagnosis. Majority of the allograft biopsies in our study showed moderate to marked arteriolar hyalinosis along with significant degree of interstitial fibrosis and tubular atrophy. It is difficult to clearly indicate the contribution of these histological changes in the pathogenesis of FSGS in allograft biopsies as vascular changes are postulated to be the reason of FSGS developing in CNI toxicity. [4]

cFSGS, initially described as a variant of FSGS occurring in association with HIV infection, has been recently reported in a number of cases with no evidence of HIV infection. As with other subtypes of FSGS, cFSGS is known to occur in renal allografts both as recurrent and as de novo phenomena. [7] Few studies in the available literature have compared cFSGS and non-cFSGS in renal allografts. [5],[7] These studies reveal that post-transplant cFSGS is associated with more severe vascular changes in renal allograft biopsy, higher degree of proteinuria and renal insufficiency with higher rate of graft loss. [7] In the present study, cFSGS constituted 13.5% of cases of FSGS in renal allograft biopsies. Because the number of cFSGS was relatively small, a comparison with non-collapsing FSGS was not attempted. Among the histological features, the proportion of glomeruli showing global sclerosis and FSGS was comparable in cFSGS and non-cFSGS. Similar results were observed for tubulo-interstitial fibrosis and arteriolar hyalinosis. Of the five patients with cFSGS, three had functioning grafts, with serum creatinine ranging between 1.5 and 3.3 mg/dL at last follow-up, while two patients had failed grafts, one at three months and another six months after diagnosis.

Therapy of recurrent FSGS in renal allografts has been based on the theory of clearance of a proposed circulating factor and, hence, includes plasma exchange, immunoadsorption and high-dose cyclosporine, with varying success rates. [2] Other drugs that have been tried include rituximab (anti-CD20 antibody), ACE inhibitors and ARBs. However, the effectiveness of these therapeutic strategies has not been studied in a prospective controlled manner. In our study, ACE inhibitors and/or ARBs were added to the therapeutic regime after diagnosis of FSGS. The rate of graft loss in our patients was similar to previous results in the literature. [7] Hence, the appropriate therapeutic modality for FSGS in renal allografts needs to be explored further.

To the best of our knowledge, this is the first large series of 37 patients from the Indian subcontinent describing the occurrence of FSGS in the renal allografts, majority of which were de novo. The follow-up data in this series underscore the importance of detection of this glomerular pathology in renal allograft biopsies, especially those cases that have detectable proteinuria.

In conclusion, FSGS is not uncommon in renal allografts, both in recurrent and in de novo forms. Because FSGS is an important cause of graft dysfunction and late graft loss, its detection by the presence of proteinuria and by renal allograft biopsy would help in appropriate therapeutic modification and improving the long-term outcome of the affected allografts.

   Acknowledgment Top

Dr. Ruchika Gupta and Dr. Alok Sharma acknowledge the CSIR for their research grant support as research associates.

   References Top

1.Cosio FG, Frankel WL, Pelletier RP, Pesavento TE, Henry ML, Fergusen RM. Focal segmental glomerulosclerosis in renal allografts with chronic nephropathy: implications for graft survival. Am J Kidney Dis 1999;34: 731-8.   Back to cited text no. 1
2.Golgert WA, Appel GB, Hariharan S. Recurrent glomerulonephritis after renal transplantation: An unsolved problem. Clin J Am Soc Nephrol 2008;3:800-7.   Back to cited text no. 2
3.Tejani A, Stablein DH. Recurrence of focal segmental glomerulosclerosis post-transplantation: A special report of the North American Pediatric Renal Transplant Cooperative Study. J Am Soc Nephrol 1992;2:S258-63.  Back to cited text no. 3
4.Colvin RB, Nickeleit V. Renal transplant pathology. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall's Pathology of the Kidney, 6 th ed. Philadelphia, USA: Lippincott Williams & Wilkins; 2007. p. 1452-3.  Back to cited text no. 4
5.Meehan SM, Pascual M, Williams WW, et al. De novo collapsing glomerulopathy in renal allografts. Transplantation 1998;65:1192-7.  Back to cited text no. 5
6.Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F. Recurrent focal glomerulosclerosis: Natural history and response to therapy. Am J Med 1992;92:375-83.  Back to cited text no. 6
7.Swaminathan S, Lager DJ, Qian X, Stegall MD, Larson TS, Griffin MD. Collapsing and noncollapsing focal segmental glomerulosclerosis in kidney transplants. Nephrol Dial Transplant 2006;21:2607-14.  Back to cited text no. 7
8.Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: Updates and future directions. Am J Transplant 2008;8:753-60.  Back to cited text no. 8
9.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. 9
10.Baum MA, Ho M, Stablein D, Alexander SR, North American Pediatric Renal Transplant Cooperative Study: Outcome of renal transplantation in adolescents with focal segmental glomerulosclerosis. Pediatr Transplant 2002;6:488-92.   Back to cited text no. 10
11.Briggs JD, Jones E. Recurrence of glomerulonephritis following renal transplantation: Scientific advisory board of the ERA-EDTA registry. European Renal Association - European Dialysis and Transplant Association. Nephrol Dial Transplant 1999;14:564-5.   Back to cited text no. 11
12.Winn M. Approach to the evaluation of heritable diseases and update on familial focal segmental glomerulosclerosis. Nephrol Dial Transplant 2003;18:vi14-20.   Back to cited text no. 12
13.Ivanyi B. A primer on recurrent and de novo glomerulonephritis in renal allografts. Nature Clin Pract Nephrol 2008;4:446-57.   Back to cited text no. 13
14.Nadasdy T, Allen C, Zand MS. Zonal distribution of glomerular collapse in renal allografts: Possible role of vascular changes. Hum Pathol 2002;33:437-41.  Back to cited text no. 14

Correspondence Address:
Amit Kumar Dinda
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029
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DOI: 10.4103/1319-2442.106231

PMID: 23354185

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