—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 3 - Focal, Segmental Glomerulosclerosis, Collapsing Type
Severe Hypertensive Arteriosclerosis

Robert B. Colvin
Massachusetts General Hospital
Boston, MA


Click on each slide thumbnail image for an enlarged view
Clinical History
57 y.o. white woman had a transplant 10 years ago from a cadaveric donor. She experienced no episodes of rejection. Beginning 3 years ago pregressive renal dysfunction developed with creatinines 1.9-2.9 mg/dl and with the new onset of 3+ proteinuria. A recent urine protein was 1.2 grams/24 hours. Has been maintained on cyclosporine (225 mg/d), azathioprine (75 mg/d) and prednisone 5 mg/d). Has difficult to control hypertension (on Atenolol and Losartan) and hyperlipidemia. History of glomerulonephritis at age 19 (no further information). Physical: BP 145/89. Labs: Blood cyclosporine 239 ng/ml., Cr 7.5 mg/dl., albumin 3.3 gm/dl.


Case 3 - Figure 4 - Nodular hyaline in arterioles in the outer media, typical, if not pathognomonic, of calcineurin inhibitor toxicity as described by Mihatsch. This early, distinctive lesion was rare, although the hyalinosis was widespread and severe. PAS
Case 3 - Figure 5 - Small artery with severe hyaline and foam cells. The foam cells correlate with the severe hyperlipidemia. PAS.
Case 3 - Figure 6 - Immunofluorescence shows segmental IgM and C3 deposition in glomeruli. IgG and IgA are negative.



Case 3 - Figure 7 - Low power electron micrograph shows collapse of a glomerulus and hyaline deposits (dense), The podocyte is lifted from the GBM (top) multiple lamina of basement membrane separate it from the GBM.
Case 3 - Figure 8 - Higher power EM shows widespread foot process effacement and no deposits. The GBM is segmentally wrinkled but otherwise unremarkable.
Case 3 - Figure 9 - High power view of the area of podocyte separation from Figure 7. This finding is typical of the collapsing variant of FSGS.

Past Medical History:
No history of diabetes mellitus, IV drug abuse or infections. Splenectomy post- trauma at age 38 and partial thyroidectomy for a benign thyroid nodule 2 years previously.

She was put on hemodialysis. Two months later she received a living unrelated kidney transplant. The sample for review is a nephrectomy performed as part of the transplant procedure (PAS stain, photos of EM and IF).

Pathology:
By LM the nephrectomy shows widespread collapse and marked hyperplasia of podocytes, with reabsorption droplets, segmental and global scarring, hyaline and adhesions. The GBM is normal on PAS stains, except for the collapse. A geographic distribution of the sclerosis (e.g., by vascular tree or corticomedullary junction) was not evident. Tubules show marked focal dilation with proteinaceous casts, reactive epithelial cells and anoikis (sloughing of epithelium= "homeless" in Greek); occasional tubules have neutrophils, but there is no other evidence of pyelonephritis and this is a common finding in end-stage kidneys. A nodular interstitial mononuclear infiltrate is present. Arteries have severe intimal fibrosis, attributed to the longstanding hypertension. Arterioles have marked hyalinosis, often circumferential, and sometimes nodular on the external aspect of the arteriole. Several arterioles are occluded by hyaline and foam cells. IF shows segmental IgM and C3; other stains were unremarkable (IgA, IgG). EM shows widespread foot process effacement, no deposits except for hyaline and no tubuloreticular structures. The GBM showed abundant newly formed subepithelial laminations where the podocytes are separated from the GBM. The endothelial cells are reactive and have lost fenestrations.

Diagnosis:
Focal, segmental glomerulosclerosis, collapsing type, associated with severe hyaline arteriolopathy, probably due to chronic cyclosporine toxicity (other potential factors include hyperlipidemia and hypertension). Severe hypertensive arteriosclerosis.

Note:
The nephrectomy sample is the native kidney. The patient's prior transplant 10 years ago was a heart-lung transplant for primary pulmonary hypertension (I never said the first transplant was a kidney!). The lack of complicating effects of renal allograft rejection makes this case unusually instructive. No studies are available on HIV or parvovirus B-19, although the patient has never had evidence of either infection.

Followup:
The patient is doing well with her three allografts. Six years post-renal transplant, on CsA 200 mg/d, MMF 500 mg/d and Prednisone (10 mg/d), and now including Zocor, her Cr is 0.8 mg/dl and she has no evidence of recurrence.

Discussion
The differential diagnosis includes focal, segmental glomerular sclerosis (FSGS) and its subtypes. The biopsy shows adhesions in all parts of the tuft ranging from the tip to the base. However the collapse and marked podocyte reaction puts it into the collapsing category. Even one glomerulus with this lesion is considered sufficient by one group for the collapsing designation .

The collapsing variant of focal, segmental glomerulosclerosis (CV-FSGS), originally described by Mark Weiss and associates [1], is a form of glomerular injury defined by capillary collapse and visceral epithelial hypercellularity, and often associated with nephrotic range proteinuria and a rapid, progressive decline in renal function [2]. CV-FSGS is a pattern of injury that has several different etiologies, including HIV, pamidronate [3], heroin abuse, parvovirus B-19 [4], as well as a substantial portion without known cause. The common pathogenetic mechanism(s) if any, are obscure.

The present case falls into the idiopathic category, although I believe that the vascular disease is the likely basis of the glomerular change. The arteriolar lesions are quite dramatic, showing severe degree of hyalinosis, with the unusual feature of occlusion by hyaline and foam cells in numerous arterioles. The cause of the arteriolar lesions are likely to be a combination of chronic CsA toxicity, hyperlipidemia and hypertension. A component of thrombotic microangiopathy cannot be excluded. Occasional peripheral nodules of hyaline characteristic of CsA toxicity are present, but not common. The lack of recurrence in the present case argues against a systemic infection such as HIV or parvovirus. The glomerulonephritis at age 19 resolved, and is not related to the present disease.

Chronic CsA arteriolopathy is characterized by replacement of the degenerated media smooth muscle cells with hyalinosis deposits, which are classically in a beaded pattern in the media [5]. The lesion begins and predominates in the afferent arterioles but may progress to the small arteries and efferent arterioles [6]. The CsA-associated arteriolopathy has been described as "an extensive eosinophilic lumpy and smudgy deposit which replaces the pericytes of the arteriole" [7] or as "nodular protein deposits (hyalin deposits) replacing necrotic smooth muscle cells of the media.." [8].."occasionally in a pearl-like pattern" [6]. The current evidence supports the view that the arteriolopathy is specific for CsA. A thorough analysis of changes in native kidneys at autopsy has been made of bone marrow and heart transplant patients, comparing the lesions in 141 patients treated with CsA with those in 26 patients who were not [9]. CsA arteriolopathy was found only in patients on CsA (55% with CsA vs 0% without CsA), strongly arguing for the specificity of the lesion. Tacrolimus causes similar lesions [10].

Glomerular collapse has also been noted in native kidneys of patients on CsA at autopsy (present in 59% of the patients on CsA vs 8% of those not on CsA) [9] . Renal biopsies in heart transplant recipients have shown that over half of the glomeruli can be collapsed [7]. Electron microscopy in cardiac transplant recipients showed the most striking glomerular abnormality to be a diffuse expansion of the mesangial matrix, with little hypercellularity [7]. No significant GBM or podocyte abnormality was appreciated. Mild GBM thickening and wrinkling with normal podocytes were described in liver transplant patients with chronic CsA toxicity [11]. One patient had glomerular changes suggestive of thrombotic microangiopathy, with "fairly extensive" separation of the endothelium from the GBM by loose granular amorphous material, although the patient did not have clinical signs of TMA [11]. However, none of these descriptions is sufficient for the classification of the lesions as CV-FSGS.

De novo FSGS (type not otherwise specified) was found in 30% of 293 patients on CsA with chronic allograft nephropathy 6 months or more after transplantation and was associated with arteriolar hyalinosis, black race, hyperlipidemia, high grade proteinuria, and increased risk of graft loss [12]. The association with hyalinosis suggested an etiologic role for CsA. It should be noted, however, that CsA is an effective treatment of idiopathic FSGS [13]. The use of lipid lowering agents was associated with improved survival [12]. De novo FSGS has also been reported in the absence of rejection [14].

Several cases of CV-FSGS have been described in renal transplants since 1993. In a 1998 review of 892 allograft biopsies, Shane Meehan et al. (Massachusetts General Hospital) found five cases of de novo CV-FSGS (3.2% since 1993-none occurred before 1993) [15]. The patients were 31-66 years of age and presented 6 to 25 months after transplantation. Protein ranged from 1.8 to 11.8 g/24 hours. All patients were on CsA and were negative for HIV. Diffuse or focal, global or segmental collapse of glomerular capillaries, swelling and hypercellularity of the visceral epithelium, hyaline arteriolosclerosis, intimal fibrosis and interstitial fibrosis were characteristic histologic features. Two had concomitant glomerular immune complex deposits. Progressive decline in allograft function occurred within 2-24 months after diagnosis, culminating in return to dialysis in all patients. These authors raised the possibility that the vascular disease contributed to the lesions.

Nadasdy et al [16] (Hopkins) reported 3 allograft nephrectomy specimens that showed a zonal distribution of collapsing glomerular changes. All had obliterative vascular changes: chronic obliterative transplant arteriopathy, acute vascular rejection, or thrombotic microangiopathy. None had severe proteinuria. Similar results were reported by Stokes and colleagues (Univ. Washington) [17] in seven patients that developed CV-FSGS in renal allografts. Two had proteinuria >3.5 g/24 h), but the others had only modest proteinuria. Five had other lesions that probably contributed to graft dysfunction: microvascular injury, acute rejection, recurrent diabetic nephropathy, and immune complex glomerulonephritis; 3 had features of chronic rejection. The development of CV-FSGS in these series was associated with graft dysfunction and a high rate of graft loss.

De novo allograft CV-FSGS differs in certain features from idiopathic or HIV-related CV-FSGS, which have a preponderance of black males, severe proteinuria, and the rapid course to renal failure. In these respects, allograft CV-FSGS resembles pamidronate CV-FSGS. Allografts with CV-FSGS often have mild proteinuria (our case had 1.2 gm/d) and almost always have severe vascular disease (as in our case). Renal failure is the rule, although with a slower course (> 1 year). The consensus view of several authors is that hemodynamic disturbances, probably at the arteriolar level, are important in the collapsing lesions [15, 16] .

Non-vascular causes can also promote CV-FSGS in allografts. One transplant patient (UCLA) lost a renal allograft due to de novo CV-FSGS associated with red cell hypoplasia and parvovirus B-19. Eradication of Parvovirus B-19 with IVIG and discontinuation of immunosuppression was followed by a successful retransplant and no recurrence [18]. Also idiopathic CV-FSGS can recur in allografts [19, 20, 21, 22] .

References

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