| Abstract|| |
Introduction: Minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) are the two common causes of nephrotic syndrome (NS) in both children and adults with overlapping clinical features, but with distinct prognostic and therapeutic implications. The distinction between these relies entirely on histopathology, which can sometimes be difficult. CD44 is expressed by activated parietal epithelial cells, plays a role in matrix deposition and thus in the pathogenesis of FSGS. Aims: To assess the expression of CD44 in MCNS and FSGS and to evaluate its association with the known clinical and histopathological prognostic factors. Methods: Thirty cases each of MCNS and FSGS were studied. The clinical, laboratory, histopathological, and CD 44 immunohistochemical data were recorded. The findings were analyzed and correlated. A P value of < 0.05 was considered statistically significant. Results: Statistical association was noted between CD44 positivity and serum creatinine (p = 0.031), estimated glomerular filtration rate (p = 0.040), segmental sclerosis (p < 0.001), tubular atrophy (p = 0.027), interstitial fibrosis (p = 0.027), and histological diagnosis (p < 0.001). The sensitivity, specificity, positive predictive, and negative predictive values were 90%, 76.67%, 79.41% and 88.46%, respectively. Conclusions: CD44 immunostain can effectively distinguish MCNS from FSGS. The congruent results of CD44 positivity with known prognostic factors support the possibility of using the CD44 marker as a predictive tool in selecting high-risk patients and offering appropriate therapeutic measures.
Keywords: Activated parietal epithelial cells, CD44, focal segmental glomerulosclerosis, minimal change nephrotic syndrome
|How to cite this URL:|
Paul E N, Satish S, Kelur KK, Shetty MS. Glomerular parietal epithelial expression of CD44 in minimal change nephrotic syndrome and primary focal segmental glomerulosclerosis: A clinico-pathological study. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Jan 29]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=345886
| Introduction|| |
Primary focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome in all age groups and has a high risk of progression to end stage renal disease (ESRD) and is characterized histologically by the presence of mesangial sclerosis, obliteration of glomerular capillaries with adhesions along with epithelial cell hypertrophy and hyperplasia. Minimal change nephrotic syndrome (MCNS), a major cause of nephrotic syndrome in adults and children, in contrast, displays no abnormalities of the glomeruli when observed using light microscopy.
Given the similar clinical presentation in MCNS and FSGS, the diagnosis of MCNS versus primary FSGS relies exclusively on the histological findings in the biopsy, emphasizing the clinical relevance of the pathologic analysis. The distinction between the entities is usually made by the presence or absence of sclerotic lesions in glomerular tuft which may be difficult, particularly when biopsies are small and diagnostic segmental lesions are not adequately sampled or when the glomerular injury is in an early pre-sclerotic stage., This differentiation has profound implications for treatment and prognosis.
In the initial stages of glomerular injury, parietal epithelial cells (PECs) can become activated and express CD44 de novo. CD44 can be present within FSGS lesions and on Bowman's capsule, often in the proximity of adhesion and plays a role in matrix deposition. CD44 is the main receptor for osteopontin and hyaluronic acid and is involved in cell adhesion, matrix interaction, and migration. Accordingly, CD44 is considered a marker of activated PECs that may distinguish FSGS from minimal change disease.
By immuno-histological detection of CD44, even small FSGS lesions can be detected which might otherwise be missed on histological sections.
| Methods|| |
The present study included 30 patients each of biopsy proven MCNS and FSGS. Patients with histological and immunofluorescent diagnoses of MCNS and primary FSGS with a minimum of eight glomeruli for light microscopy and five for immunofluorescence were included in the study.
Biopsies of primary FSGS with glomerulosclerosis and tubulo-interstitial damage (both more than 25%) were excluded from the study.
Data was collected as per case-report forms. Variables of interest were measured at a fixed point of time.
For light microscopy, step serial sections from the renal core were stained and studied using hematoxylin and eosin (H&E), periodic acid Schiff (PAS), Masson trichrome (MTS), and Jones methenamine silver (JMS) stains. The histopathological parameters include the total number of glomeruli, number of globally sclerotic glomeruli, number of segmentally sclerotic glomeruli, the presence of podocyte hypercellularity, and mesangial hypercellularity were recorded. The total percentage cortical area with tubular atrophy and interstitial fibrosis along with arterial changes were documented.
For Immunofluorescence, 2-3-μ thin sections were cut and stained with fluorescein-isothiocyanate conjugated [FITC] antibodies to immunoglobulins G, A, M, C3, C1q, kappa, and lambda light chains and viewed under an immunofluorescent microscope - Olympus BX 41.
Immunohistochemistry (IHC) was performed on 3 μm thick sections on poly-l-lysine coated slides. Sections were then incubated with anti-CD44 antibody (Mouse anti-human anti-CD44 Std./HCAM Monoclonal Antibody Ref: PM380AA (Clone: BC8), Biocare, Lot no: 052420) for 30 minutes at room temperature followed by secondary antibody (MACH 1 Detection kit, M1U539G Biocare) for 30 minutes. Sections from tonsil were taken as a positive control, whereas sections treated with the tris-buffer solution instead of the primary antibody were used as a negative control. In each biopsy, all glomeruli, except for those with global sclerosis, were evaluated individually for the number of CD44-positive epithelial cells in an anatomical PEC location. CD44 staining in PECs or in VECs was scored positive when at least one cell showed brown membrane positivity for CD44. Patients were classified into two groups according to the presence or absence of CD44 staining.
The study protocol was approved by the Ethics Committee of JSS Medical College and Hospital, JSS Academy of Higher Education and Research, India (JSS/MC/PG/4623/2018-19).
The statistical analyses were performed using a statistical package for social sciences IBM SPSS© version 23 (SPSS Inc, Chicago, IL, USA). Continuous data were expressed as mean values ± standard deviation and categorical variables as a percentage. Comparisons between groups were performed with student's t-test for continuous data and the Chi-square test (χ2) for categorical data. Associated P values were reported for each of the baseline predictors. P < 0.05 was considered statistically significant. All graphs were generated using windows excel 2019.
| Results|| |
The demographic, clinical, and laboratory parameters are included in [Table 1]. The urine protein: creatinine ratio was calculated using a conversion tool suggested by Van Der Velde et al. Out of the 39 patients for which data was available, one (2.6%), seven (17.9%), 11 (28.2%), and 20 (51.3%) patients belonged to the respective categories of <0.05, (0.051-0.10), (0.11-1.00), and >1.00. Twenty-six of 39 patients showed CD44 positivity, out of which 1 (2.6%), 4 (10.3%), 9 (23.1%), and 12 (30.8%) were found in the above respective categories.
|Table 1: Demographic, clinical, laboratory and histopathological parameters|
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eGFR was sub-grouped into categories of ≤50, (51-100), (101-150), and (151-200), with 10 (23.25%), 21 (48.8%), 10 (23.25%), and two (4.7%) patients, respectively. Twenty-five of 43 were CD44 positive, which included nine (20.9%), 12 (27.9%), four (9.3%), and no patients in the above respective categories.
Out of the 30 cases of histologically diagnosed MCNS, seven cases (23.3%) showed CD44 positivity and three (10.0%) of 30 cases of FSGS were CD44 negative [Figure 1].
|Figure 1: a: Negative CD 44 immunostaining in MCNS (CD44, X 100). b: Positive CD 44 immunostaining in MCNS (CD44, X200). c: Focal and segmental glomerulosclerosis (JMS, X200). d: Positive CD 44 immunostaining in FSGS (CD44, X200)|
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Segmental sclerosis in FSGS was graded into categories based on the percentage of glomeruli involved as: Nil, (1-10), (11-20), (21-30), and > 30%. There were 30 (50.0%), one (1.7%), seven (11.7%), 14 (23.3%), and eight (13.3%) cases in these categories. Out of 34 CD44 positive cases, seven (11.7%), one (1.7%), seven (11.7%), 11 (18.3%), and eight (13.3%) patients were present in the above groups.
The sample was sub-grouped into categories based on the percentage of involvement of tubulo-interstitium in the form of tubular atrophy (TA) or interstitial fibrosis (IF) as: Nil, (1-5%), (6-10%), (11-15%), (16-20%), and (20-25%). There were 36 (60.0%), six (10.0%), eight (13.3%), five (8.3%), four (6.7%), and one (1.7%) patients, respectively.
The statistical correlation of the variables studied in MCNS and FSGS with CD44 positivity is given in [Table 2]. The statistical measures of the performance of CD 44 are highlighted in [Table 3].
|Table 2: Correlation of CD44 positivity with clinico-pathological parameters|
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|Table 3: Correlation of CD 44 immunostaining with histopathology - an observation and evaluation|
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| Discussion|| |
The diagnosis and evaluation of MCNS and FSGS rely on the integration of the clinical history, laboratory findings along with renal histopathology. While overt FSGS can be picked up with PAS stain under light microscopy, early pre-scarring stages and poor representation in core biopsies are diagnostic challenges for the pathologist. Even high-end ancillary investigations like electron microscopy rarely help as effacement of foot processes can be seen in both these entities, and other subtle changes may be absent in early FSGS.
The need to differentiate these entities calls for use of markers for activated PECs, which are implicated in the pathogenesis of FSGS. The distinction between MCNS and FSGS has both prognostic and therapeutic implications, as FSGS is most likely to progress to ESRD and can even recur in renal transplants, while MCNS is usually a reversible entity.
Age of onset
The mean age of onset of NS among FSGS patients was in agreement with other studies. The mean age of MCNS patients was not correlating with some studies. An earlier age of diagnosis in MCNS predicts steroid responsiveness, a lesser number of relapses, and is inversely related to the duration of the disease, which was not reflected in our study. The reason behind this contradiction was the fewer number of patients we could analyze from the pediatric population.
No statistical significance for the prognostic relevance of age of onset in FSGS was observed in various other studies including the present study.,,, This could be because FSGS invariably has a poor outcome, no matter the age of onset of disease.
Various studies demonstrated a male preponderance in MCNS which was corresponding to the present study., The female predominance in FSGS was correlating with the study done by Pei et al. However, most of the other studies showed a male predominance., The variation in the sex ratio of incidence among the studies is indicative of the geographical and ethnic variation of the disease entity.
Peripheral pitting pedal edema was the most common clinical sign in the present study. Edema is not a well-documented prognostic factor for nephrotic syndrome. It lacked any statistical significance with CD44 positivity in the current study too.
Hypertension is found in increased proportion in both steroid sensitive and steroid resistant NS. Studies have shown a bidirectional relationship between albuminuria and blood pressure (BP), implying that elevated albuminuria led to higher BP and higher systolic BP predicted an increase in albuminuria.
Patients with hypertension and NS are at risk for dyslipidemia, left ventricular hypertrophy, left ventricular dysfunction, atherosclerosis, and aortic stiffness, all leading to premature death. Studies have found prognostic significance for hypertension in NS., However, no prognostic significance was seen between CD44 positivity and hypertension in the present study and other recent studies.,,, This discrepancy needs to be validated in long-term longitudinal studies.
Hematuria was noted in six (42.8%) FSGS patients, and three (16.6%) MCNS patients, which was far less compared to other studies., The non-availability of clinical data could be the reason for this discrepancy and not all asymptomatic NS patients with microscopic hematuria undergo a renal biopsy. The absence of correlation between CD44 positivity and hematuria in the present study was supported by other studies too.,,,
Loss of negative charge of the glomerular capillary wall causes excretion of albumin and no other high molecular weight (HMW) proteins in urine which is selective proteinuria. However, the presence of HMW proteins in urine indicates an increased number of large pores or structural changes of the glomerular barrier called non-selective proteinuria. It is the type of proteinuria and not albuminuria that can predict the rate of progression of renal injury. Thus, it's not the proteinuria per se that has prognostic significance, but the excretion of HMW proteins that contributes to tubulo-interstitial sclerosis and consequently deranged renal function.
The studies which showed significant prognostic significance for proteinuria had all the variants of FSGS. It is well documented that collapsing and cellular variants of FSGS have a higher prevalence of significant proteinuria and are more likely to progress to ESRD. However, the present study included tip and NOS variants of FSGS.
The lack of association between 24-hour urinary protein excretion and CD44 positivity was in agreement with other studies., However, several studies have shown that a significant baseline 24-hour proteinuria is associated with a grave prognosis.,,,
The lack of statistical significance between serum albumin and CD44 positivity in the present study was also reflected in other studies. Hypoalbuminemia in NS can be attributed to increased capillary permeability causing increased loss, uncompensated by increased synthesis by the liver. Also, the half-life of albumin has been found to be reduced in NS.
Serum creatinine is a less expensive way to estimate the GFR. It is usually normal in uncomplicated MCNS. Even in FSGS, a baseline increased creatinine level indicates the level of renal injury that has occurred. Alterations in serum creatinine can be due to either hemodynamic changes or chronic and irreversible renal damage. The present study had comparatively higher baseline serum creatinine which further strengthens the hemodynamic alteration hypothesis.
A statistical significance was noted between serum creatinine and CD44 positivity in the current study. Hunt et al. proposed that an elevated plasma creatinine, either at onset or at 1 year and heavy urinary protein loss persisting at 1 year were the factors most significantly related to eventual ESRD, thus indicating the prognostic significance. Korbet et al. could demonstrate that increased baseline creatinine value of >1.3 mg/dl as a poor prognostic factor, and also 30% of patients with renal insufficiency (serum creatinine ≥3.5 mg/dl) ended up with ESRD.
Estimated GFR (eGFR)
GFR represents the flow of plasma into the Bowman's space over a specified period. It is a chief measure of kidney function. A decrease in GFR is considered a poor prognostic factor in NS.
There was a statistical association between eGFR and CD44 positivity in the present study which correlated with other studies., These studies demonstrated that CD44 positive cases had lower baseline eGFR, and on follow up had a significant fall in eGFR. Martinelli et al. could not demonstrate any prognostic significance for eGFR. However, a reduced baseline GFR, indeed predicts the progression of the disease.
Mesangial changes following a glomerular injury include the production of chemoattractants for inflammatory cells, proliferation of mesangial cells, and increased ECM production. Mesangial expansion with or without hypercellularity can cause compression of glomerular capillaries causing decreased GFR which results in disease progression.
The lack of association between mesangial hypercellularity and CD44 positivity as in other studies could be due to a smaller sample size.,,
Six of the 30 FSGS patients (20.0%) had podocyte hypercellularity. There was no statistical association between CD44 positivity and podocyte hypercellularity. This is not at all surprising because glomerulomegaly in FSGS following a podocyte injury causes an increase in GBM surface area. In order to maintain coverage, podocyte tries to hypertrophy initially but gets arrested in the G1 phase of the cell cycle leading to actin rearrangement, detachment, and finally cell death. Podocytes may die by apoptosis, necrosis, necroptosis, and death due to decreased autophagy. Podocyte depletion is well documented in both experimental animals and human kidneys. Thus the six cases with podocyte hypercellularity in the current study may be due to the reparative mechanisms in play.
Segmental sclerosis can occur due to post compensatory hemodynamic changes following nephron loss or by primary podocyte damage due to mediators released from mesangial cells following a glomerular injury. The association between segmental sclerosis and CD44 positivity was in line with the findings by Paik et al. The more advanced the injury to the podocytes, the more decline in the renal function and progression to ESRD ensues.
Tubular atrophy/interstitial fibrosis
Regardless of the etiology, TA is defined as the disappearance of either individual tubular epithelial cells or entire tubules, often in conjunction with interstitial fibrosis. TA is found to be a better predictor of the progression of renal failure.
Fibrosis on renal biopsy is an index of functional renal impairment and a predictor of disease progression. Studies have shown that IF > 50% are poor candidates for therapy effectiveness.
There was a statistical association between TA/IF with CD44 positivity (p = 0.027). This was correlating with other studies.,, Studies have shown that TA/IF > 20/30% is associated with a poor prognosis., However, some studies failed to demonstrate any prognostic significance., TA/IF due to any disease process carries a worse prognosis.
Several possible explanations are given for the decreased yield in histological diagnosis of FSGS: (1) if glomerular scars are uniformly distributed in a biopsy with 10–30 glomeruli, the diagnostic accuracy for the detection of at least one scarred glomerulus will be 80% when at least 10% of juxtamedullary glomeruli or 20% of other cortical glomeruli are scarred. (2) With an average of 20 glomeruli with 20%–60% glomerular sclerosis, the predicte error rate is ± 50% for the extent of glomerular involvement. Thus the distinction of MCD versus early FSGS may be difficult, particularly when biopsies are small and diagnostic segmental lesions are not adequately sampled or when the glomerular injury is in an early pre-sclerotic stage. This is where activated PECs come into the picture. Activated PECs show de novo expression of CD44 and thus help pick up early FSGS lesions surpassing the limitations mentioned above.
A statistical association was established between CD44 positivity and histological diagnosis. This was corroborated by Hunt et al. However, Martinelli et al. could not establish any prognostic significance with morphological diagnosis.
The 90% CD44 positivity in FSGS biopsies makes it a sensitive marker. But we did encounter CD44 negative FSGS cases. This has decreased the specificity of the marker to 76.67%. This could be explained by the fact that the sclerotic lesions could have been lost on serial sectioning of the biopsies used for immuno-histological assessment.
Regarding the absence of sclerotic lesions in CD44 positive histologically diagnosed MCNS cases, several explanations are possible. Studies have shown that the small sclerotic lesions in CD44 positive MCNS cases were not detectable in consecutive PAS-stained sections, prepared after the immunohistologic analysis. Thus, the cells expressing CD44 on the glomerular tuft could be an earlier marker than overt sclerosis; whether these patients follow a course indicative of FSGS could not be evaluated in those studies due to the lack of follow up. In the present study, the original diagnosis was made on the sections of the same biopsy analyzed for immunohistochemistry. Although we examined only those biopsies with eight or more glomeruli, the sclerotic lesions could still be present in other glomeruli or in different planes of sectioning. We could not demonstrate any sclerotic lesions in these CD44 positive MCNS cases even after reviewing the slides. Surprisingly, the original diagnosis is normally based on 32 serial sections of a single biopsy, thereby examining several planes of sectioning. We stained and analyzed only one biopsy section per PEC marker staining, and still, it could pick up these CD 44 positive cells which were missed in the earlier 32 sections. This highlights the sensitivity of CD44. Immunohistologic staining for PEC markers could detect sclerotic lesions in 25% of the biopsies originally diagnosed as MCNS in a recent study, which was reflected in the present study too.
The differentiation of MCNS from primary FSGS relies exclusively on the histologic findings in the biopsy, emphasizing the relevance of the pathologic analysis. In general, the lesions detected by PEC markers were small and often located close to the glomerular tip. The focal and segmental nature of FSGS, especially for these small lesions, may explain why the lesions were missed in the original sections. In fact, it is a well-known fact that small lesions particularly at the glomerular tip may be missed in biopsies initially diagnosed as MCNS. Another explanation is that CD44 could stain migrated PECs even before overt sclerosis develops, reiterating that diagnosis made by light microscopy alone may be insufficient.
The positivity of CD44 favors the view that MCNS and FSGS are a continuum of the same entity and that in steroid responsive MCNS too prognosis can be uncertain because of morphological transition to FSGS on repeat biopsy and subsequent renal impairment develops later.
A hypothesis that a greater number of glomeruli present in the renal biopsies could be a reason why CD44 positivity could be demonstrated in those histologically diagnosed MCNS cases, has been disproved by several studies.,, Present study also failed to demonstrate any statistical significance between these variables (p = 0.131). In fact, CD44 positivity in MCNS was seen more in biopsies with less than 25 glomeruli in them.
Next, we compared the proven poor prognostic factors with CD44 positivity in the MCNS group to speculate possible poor prognosis and thus indirectly to a diagnosis of FSGS. The mean serum creatinine among the CD44 positive MCNS cases was 1.466 ± 0.641 mg/dl, which is not significantly high. Even other parameters both clinical and laboratory parameters could not give a hint towards FSGS. Five biopsies did not show any TA or IF. Even the remaining two cases also had TA/IF < 15%. However, the glomeruli in the vicinity of TA/IF were histologically unremarkable. There was no podocyte hypercellularity in any of these cases, again ruling out another histological clue that could have made the pathologist think of an alternative diagnosis. This further underscores the fact that CD44 can prove to be a game-changer to detect activated PECs when light microscopy does not show any sclerotic lesion.
| Conclusion|| |
FSGS and MCNS have similar clinical presentations, and hence the onus of diagnosis lies on the pathologist to look for the presence of sclerotic lesions in the glomerular tuft. By immuno-histologic detection of CD44, even small and early segmental lesions could be detected. This provides us with a less expensive alternative in diagnosis, at a stage when even electron microscopy reveals only subtle changes.
The present study adds valuable data from Southern India that correlates findings with established results from other studies in different parts of the world. The role of correlating international data with regional data is to help clinicians formulate treatment plans confidently. This study fulfills the much-needed knowledge deficit.
The study had its limitations. This was a cross-sectional study; hence follow up data was not collected. Moreover, the pediatric group was inadequately represented. The addition of CD45 to mark the inflammatory cells would have refined the results. Long-term studies with large cohorts and evaluation of treatment outcomes will be the logical next step. This will provide valuable prognostic data and help make a real difference in treatment and outcome for this subset of patients with nephrotic syndrome.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]