1
1 CASEREPORTS
Course of Renal Transplantation Immunotactoid Glomerulopathy STEPHENM. KORBET,M.D., Chicago,///inois,B~~~~~~F. EDMUNDJ. LEWIS, M.D., Chicago, ///inois
in
ROSENBERG, M.D.,
glomerulopathy [1,2] is a primary Itionmmunotactoid glomerulopathy that has gained increasing recogniduring the past 6 years. To date, 43 cases of immunotactoid glomerulopathy have been reported (Table I) [2-121. The diagnosis is established at renal biopsy by the presence of glomerular extracellular microtubules, which have been shown to contain immunoglobulins. Because of the highly organized structure of the immune deposits demonstrated in the glomeruli of these patients, we adopted the term “immunotactoid glomerulopathy” in order to differentiate the clinicopathologic entity from that of cryoglobulinemia, amyloid, and other lesions associated with glomerular deposits that also have a highly organized tubular or fibrillar characteristic. Clinically, this entity is characterized by proteinuria, which has been in the nephrotic range in 60% of cases, microscopic hematuria (80%), and hypertension (80%). In more than 50% of patients, progressive renal insufficiency leading to long-term dialysis occurs within 4 years [2,3,5,6]. Little information regarding the course of renal transplantation in patients with immunotactoid glomerulopathy is available in the literature. We, therefore, present the course of renal transplantation in two patients whose primary diagnosis in their native kidneys was immunotactoid glomerulopathy.
MATERIALSAND METHODS The two patients were identified by the unique immunofluorescence and ultrastructural features of their native renal biopsy specimens. Both patients had undergone renal transplants and neither had had pretransplant nephrectomies. Systemic lupus erythematosus, amyloidosis, cryoglobulinemia, or a paraproteinemia had been excluded in both patients. Renal tissue obtained at biopsy was divided and processed for light, fluorescence, and electron microscopy as previously described [2].
CASEREPORTS Patient 1 A 66-year-old woman presented in May 1973 with hypertension and a urinalysis with 3+ protein. In December 1973, she was admitted for further evaluation. On physical examination, the following were found: blood pressure 140/80 mm Hg, normal fundi, and no pretibial edema. Laboratory data were as follows: seFrom the Section of Nephrology, Department of Medicine and Pathology, Rush Medical College and Rush-Presbyterian St. Luke’s Medical Center (SMK, MMS, EJL), Chicago, Illinois, and the Department of Pathology, William Beaumont Hospital (BFR), Royal Oak, Michigan. Requests for reprints should be addressed to Stephen M. Korbet. M.D.. Rush-Presbyterian-St. Luke’s Medical Center, 1653 West Congress Parkway, Chicago, lllinois 60612. Manuscript submitted June 27,1989, and accepted January 2. 1990.
RoyalOak,
Michigan,
MELVIN M.~CHWARTZ,M.D.,
rum creatinine 1.8 mg/dL, serum albumin 2.8 g/dL, and total protein of 4.3 g/dL. Urinalysis detected 2+ protein with microscopic hematuria and no abnormal casts. The creatinine clearance was 57 ml/minute, with a urine protein of 1.06 g/24 hours. The antinuclear antibody was negative, and the C3 and C4 levels were normal at 182 mg/dL (normal: 80 to 180 mg/dL) and 67 mg/dL (normal: 15 to 50 mg/dL), respectively. The cryocrit was negative. She underwent a percutaneous renal biopsy, which demonstrated organized microtublar deposits containing IgG. However, it was originally believed to be renal amyloidosis even though the Congo red preparation was negative. In October 1980, her serum creatinine level was 6.7 mg/ dL with a urine protein of 10 g/24 hours. She was treated with oral prednisone 80 mglday and melphalan 12 mg/day for 4 days. Her blood urea nitrogen and creatinine continued to increase, and by April 1981, they were 105 mg/dL and 11.0 mg/dL, respectively. Hemodialysis was started and continued until May 1983, at which time the patient received a cadaveric renal transplant. Immunosuppressive therapy consisted of azathioprine, prednisone, and Minnesota antilymphocyte globulin. Her post-transplant course was complicated by allograft rejection, but no evidence of recurrent disease was observed on biopsy examination of her allograft. Her renal function improved and stabilized at 1.5 mg/dL by September 1983. Over the course of the next 5 years, she has had no evidence of recurrent disease. At last follow-up in June 1988, her serum creatinine level was 1.6 mg/dL, serum albumin was 4.4 g/dL, urinalysis had no protein and no abnormal sediment, and the urine protein was 0.4 g/24 hours. Her antinuclear antibody, C3, C4, and cryocrit were all normal. Urine and serum for immunofixation were negative for monoclonal proteins and free light chains. Patient 2 A 52-year-old man presented in 1979 with hypertension (132/98 mm Hg) and proteinuria. His serum creatinine level was 1.6 mg/dL, and urinalysis showed 3+ protein with microscopic hematuria and no abnormal casts. A urine protein was 900 mg/24 hours. The patient was lost to follow-up until May 1982, at which time he presented with severe hypertension (180/110 mg/dL) and renal failure. The serum creatinine and serum albumin levels were 10.8 mg/dL and 3.2 g/dL, respectively. The urine protein was 20 g/24 hours. C3 and C4 levels were normal, and electrophoresis of urine and serum samples was negative for monoclonal proteins or free light chains. A bone marrow examination yielded normal results as well. Renal biopsy demonstrated immunotactoid glomerulopathy. In August 1982, the patient received a renal allograft from his July 1990
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Patients(n)
t:::;
Synonyms Non-amyloidotic fibrillary glomerulopathy Fibrillary nephritis Fibrillary glomerulonephritis
::,
151
7
El ty
2 2 1
t::\
1 1
(71
Total
Amyloid-like glomerulopathy Congo Red-negative amyloid-lrke glomerulopathy Amyloid-stain-negative glomerulopathy
microfibrillary
43
TABLEII Summaryof Morphology
Patient 1 2
PostTransplant (months)
Renal Biopsy Native kidney transplant Native kidney transplant :
;21 53
IgG (+/-) +Mes +GCW +GCW +GCW + Mes
Chronic Rejection (+/-) -
Microtubule Diameter (nanometers) 19.4 f 3 24.&
3
22&
5
es = mesangial; GCW = glomerular capillary wall.
son. After transplant, his serum creatinine level stabilized at 1.0 mg/dL and his urine protein was 264 mg/24 hours. After 1% years, he became hypertensive and the serum creatinine level was 2.0 mg/dL with 12.3 g/24 hours proteinuria. Urinalysis demonstrated 4+ protein with no abnormal sediment, and serum samples were negative for cryoglobulins. De nouo membranous glomerulopathy was found on biopsy examination of the transplanted kidney. Hepatitis B surface antigen and antibody were negative. The patient’s course was stable over the next 2l/2 years until December 1986 when he developed increasing fatigability and edema. The urine protein was 5.4 g/24 hours and the serum creatinine level was 4.6 mg/dL. A second biopsy examination of the allograft demonstrated more advanced glomerular disease with scarring. Evidence of recurrent immunotactoid glomerulopathy was also present. His renal function continued to deteriorate, and by March 1987, long-term dialysis was initiated. His course was further complicated by severe coronary artery disease, resulting in unstable angina and several myocardial infarctions. In May 1988, he died after a cardiopulmonary arrest. RESULTS (TABLE II) Patient 1 The native kidney had increased mesangial matrix, which was periodic acid-Schiff (PAS)-positive with normal cellularity. The basement membranes were thin and delicate and the capillaries were patent. The Congo red stain for amyloid was negative. The mesangium contained deposits of IgG and C3 by immunoflu-
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orescence microscopy; electron microscopy demonstrated masses of randomly oriented microtubles (19.4 f 3 nanometers in diameter), which diffusely expanded the mesangium and focally permeated and replaced the basal lamina (Figure 1). A transplant biopsy specimen, obtained during a clinical rejection episode at 1 month, had evidence of acute cellular rejection. Although the mesangium was mildly expanded by PASpositive matrix, the Congo red stain was negative; there were no glomerular deposits of immunoglobulins or complement components, and there were no electron-dense deposits or microtubules. Thus, the allograft biopsy specimen showed no evidence of recurrent immunotactoid glomerulopathy.
TABLEI lmmunotactoid Glomerulopathy:ReportedCases References
/ KORBET
89
Patient 2 The original renal biopsy specimen had advanced glomerulosclerosis, and the surviving glomeruli had massive mesangial expansion by PAS-positive material with normal cellularity. The glomerular basement membranes were focally thickened, and the Congo red stain was negative. Mesangial and granular capillary deposits of IgG, kappa, lambda, and C3 were demonstrated by fluorescence microscopy. Electron microscopy showed randomly oriented subendothelial, mesangial, and focal subepithelial microtubules measuring 24.9 f 3 nanometers in diameter (Figure 2). The first biopsy specimen of the donor kidney taken 13/4 years after transplant had early membranous glomerulonephritis with mild thickening and focal complexities of the glomerular basement membranes, granular deposits of IgG, kappa, and lambda exclusively in a granular capillary pattern, and subepithelial electron-dense deposits. No microtubules were seen in the deposits or in the mesangium. The Congo red stain was negative. The second biopsy specimen taken 4l/2 years after transplant had recurrent immunotactoid glomerulopathy superimposed upon the membranous lesion seen previously. Although only one of 12 glomeruli was hyalinized, all had diffuse thickening of glomerular basement membranes and moderate mesangial expansion. There were granular mesangial and glomerular basement membrane deposits of IgG, and electron microscopy showed persistence and expansion of the subepithelial electrondense deposits seen previously. In addition, mesangial and subendothelial masses of microtubules measuring 22.5 i 5 nanometers in diameter were present. In some areas, the microtubules infiltrated the glomerular basement membranes, but they were not seen within the subepithelial deposits (Figure 3). There was diffuse interstitial fibrosis, focal tubular atrophy, and a mild mononucular cell infiltrate. The blood vessels were normal. Although the tubular atrophy was disproportionate with the extent of glomerulosclerosis in the second transplant biopsy, the lesion had progressed to involve 90% of the glomeruli with sclerosis at autopsy. Since the two transplant biopsy specimens had only mild rejection, the patient’s progressive renal failure most likely was caused by the deleterious effect of the two glomerular lesions and not by rejection. At autopsy, there was no ultrastructural evidence of systemic immunotactoid deposition in randomly examined sections of spleen, liver, skin, and heart. In addition, there was no evidence of a systemic disease or lymphoproliferative disorder.
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Figure 1. Original renal biopsy specimen from Patient 1. The nlomerular capillary wall is distoried by intramembranous electrondense deposits (arrowhead). The mesangium is greatly expanded by similar deposits (asterisks). M = mesangial cell nucleus (uranyl acetate and lead citrate stain; original magnification X 7,000, reduced by 30%). Inset, at high magnification, the morphology and random arrangement of the microtubules that comprise the electron-dense deposits are demonstrated. P = mesangial cell process (uranyl acetate and lead citrate stain; original magnification X 34,000, reduced by 30%).
Figure 2. Original renal biopsy specimen from Patient 2. A, the glomerulus is distorted by microfibrils (asterisks) that expand the mesangium. CL = capillary lumen (uranyl acetate and lead citrate stain; original magnification X 11,000, reduced by 30%). B, capillary wall with microfibrils permeating the glomerular basement membrane and deposited under the glomerular epithelial cell. EPI = epithelial cell (uranyl acetate and lead citrate stain; original magnification X 42.000. reduced by 30%). C, fluorescent micrograph demonstrating irregular granular deposits in the glomerular walls and mesangium. (FITC goat antihuman IgG, original magnification X 400, reduced by 30%).
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Flgure 3. Second transplant biopsy specimen fiom Patient 2. A, the glomerular architecture is distorted by irregular subepithelial deposits, subendothelial expansion, and mesangial deposits. CL = capillary Iucell nucleus: men: M = mesangial EPI = epithelial cell (uranyl acetate and lead citrate stain; original magnification X 7,000, reduced by 30%). Inset, at high power, the random orientation of the microfibrils and their morphologic characteristics are apparent (uranyl acetate and lead citrate stain: original magnification X 34,000, reduced by 30%). B, the subepithelial deposits are comprised of subepithelial electron-dense deposits (asterlsk) and separate deposits of randomly arranged microfibrils (arrow). Similar fibrillar deposits are present between the endothelial cell (ENDO) and the glomerular basement membrane and in the mesangium (not shown) (uranyl acetate and lead citrate stain; original magnification X 34,000, reduced by 30%).
TABLE III Post-Transplant Course of lmmunotactoid Glomerulopathy FolloWUp Patient Age/Race/ Sex
Study [ii Present study Patient 1 Patient 2
Serum Creatinine @w/W
Recurrence (months)
19/B/F NA
Yes (60) No
2.0
66/W/F 52/W/M
No Yes (21-53)
1.6 ESRD
NA
Proteinurla (g/24 hours) Ii: 0.4 5.4
SRD = end-stage renal disease; NA = not available.
COMMENTS We initially reported the morphologic features of immunotactoid glomerulopathy in 1980 [l]. In 1985, we increased our understanding of this lesion by describing the morphology and clinical course in 11 patients with this clinicopathologic entity [2]. Since our initial observation, 42 additional cases of immunotactoid glomerulopathy have been described (Table I). Unlike other primary glomerulopathies, little is known about the course of renal allografts in patients with immunotactoid glomerulopathy. In addition to our experience, only two other patients [4,6] who have 94
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received renal transplants have been described (Table III). Alpers et al [6] described a patient who presented at 19 years of age with proteinuria and who experienced progression to end-stage renal disease. She received a renal allograft 7 years after her initial presentation. Recurrent glomerular disease developed 5 years after transplant accompanied by 17 g/24 hours proteinuria. Morphologic and immunofluorescent findings in the renal allograft were reported to be similar to those of the native kidney. Furthermore, the size of fibrils (14 to 15 nm) was the same in both the native kidney and the allograft. Mild renal insufficiency was
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present at the time of last follow-up. Sturgill and Bolton [4] also described a patient 2 years after transplant who is without evidence of recurrence. Taken together, there is experience with only four cases of renal transplants in patients with immunotactoid glomerulopathy (Table III). Recurrent disease in two of the cases was heralded clinically by the nephrotic syndrome, which presented at 21 and 60 months after transplantation. Morphologically, organized immune deposits, similar to those found in the native kidney, were identified 53 and 60 months after transplant. The initial post-transplant biopsy (21 months) in our second case did not demonstrate any organization of the immune deposits. It is possible that two glomerular processes could have occurred in this patient, with his initial allograft lesion representing a de nouo membranous glomerulopathy. This concept is supported in the second biopsy specimen in which deposits with and without organization coexisted. Due to the lack of adequate follow-up in the case reported by Alpers et al [6] and the complexity of the condition of our Patient 2, we cannot know the rate of progression to end-stage renal failure in patients with recurrent disease. In the remaining two cases, there was no evidence or report of clinical or morphologic recurrence after 24 and 61 months of follow-up. Immunotactoid glomerulopathy appears to represent a primary glomerulopathy, as patients with this entity do not have clinical or serologic evidence of a systemic disease [2]. This contrasts with other diseases associated with organized immune deposits such as amyloidosis, paraproteinemia (light-chain deposition disease), cryoglobulinemia, or systemic lupus erythematosus. The lack of systemic involvement was further substantiated morphologically by the autopsy findings in our Patient 2, since no ultrastructural evidence of immunotactoid deposition could be found in sections of the spleen, liver, skin, or the heart. Due to the extremely poor prognosis associated with primary amyloidosis [13], the latter has been a relative contraindication for renal transplantation. It is, therefore, of practical importance to differentiate renal amyloid and immunotactoid glomerulopathy because the prognoses of these entities are vastly different. The
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diagnosis of amyloidosis should be firmly established by histochemical methods, as well as by the subtle but different ultrastructural characteristics that have been reported in these two entities [2,13]. Immunotactoid glomerulopathy appears to have the potential to lead to progressive renal insufficiency in a significant number of affected patients. As a result, many of these patients are potential candidates for renal transplantation. Experience thus far demonstrates that these patients can undergo successful renal transplantation but may have a recurrence of immunotactoid glomerulopathy. Recurrence of immunotactoid glomerulopathy, based on clinical grounds, appears to occur many months after the graft is placed.
ACKNOWLEDGMENT We thank Dr. Stephen Jensik for assistance secretarial support.
with Pabent 1 and Susan Parks for
REFERENCES 1. Schwartz MM, Lewis EJ: The quarterly case: nephrotic syndrome in a middleaged man. Ultrastruct Pathol 1980; 1: 575-582. 2. Korbet SM. Schwartz MM, Rosenberg BF, Sibley RK. Lewis EJ: lmmunotactoid glomerulopathy. Medicine (Baltimore) 1985; 64: 228-243. 3. Sturgill BC, Bolton WK, Griffith KM: Congo red-negative amyloid-like glomerulopathy. Hum Pathol 1985; 16: 220-224. 4. Sturgill BC, Bolton WK: Non-amyloidotic fibrillary glomerulopathy (abstr). Kidney Int 1989: 35: 233. 5. Duffy JL, Khurana E. Susin M, Gomez-Leon G. Churg J: Fibrillary renal deposits and nephrms. Am J Pathol 1983; 113: 279-290. G.Alpers CE. Rennke HG. Hopper J, Biava CG: Fibrillary glomerulonephritis: an entity with unusual rmmunofluorescence features. Kidney Int 1987; 31: 781-789. 7. Olesnicky L, Doty SB, Bertani T. Pirani CL: Tubular mtcrofibrils in the glomeruli of membranous nephropathy. Arch Pathol Lab Med 1984; 108: 902-905. 8. Rosenmann E. Eliakim M: Nephrotic syndrome associated with amylord-like glomerular deposits. Nephron 1977; 18: 301-308. 9. Rosenmann E. Brisson M-L, Bercovitch DD. Rosenberg A: Atypical membranous glomerulonephritis with fibrillar subepithelial deposits in a patient with malignant lymphoma. Nephron 1988; 48: 226-230. 10. Sadladi JA. Sobel HJ: Congo red-negative amyloidosis-like glomerulopathy: report of a case. Am J Kidney Dis 1987; 9: 231-234. 11. Schifferli SA, Merot Y, Cruchaud A, Chatelanat F: lmmunotactoid glomerulopathy with leucocytoclastic skin vasculitis and hypocomplementemia: a case report. Clin Nephrol 1987; 27: 151-155. 12. Kobayashi Y. Fufii K. Kurokawa A, Kamiyama M. Miyazawa H: Glomerulonephropathy with amyloid-stain-negative microfibrillar glomerular deposits. Nephron 1988; 48: 33-39. 13. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58: 665683.
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1 CASEREPORTS
Course of Renal Transplantation Immunotactoid Glomerulopathy STEPHENM. KORBET,M.D., Chicago,///inois,B~~~~~~F. EDMUNDJ. LEWIS, M.D., Chicago, ///inois
in
ROSENBERG, M.D.,
glomerulopathy [1,2] is a primary Itionmmunotactoid glomerulopathy that has gained increasing recogniduring the past 6 years. To date, 43 cases of immunotactoid glomerulopathy have been reported (Table I) [2-121. The diagnosis is established at renal biopsy by the presence of glomerular extracellular microtubules, which have been shown to contain immunoglobulins. Because of the highly organized structure of the immune deposits demonstrated in the glomeruli of these patients, we adopted the term “immunotactoid glomerulopathy” in order to differentiate the clinicopathologic entity from that of cryoglobulinemia, amyloid, and other lesions associated with glomerular deposits that also have a highly organized tubular or fibrillar characteristic. Clinically, this entity is characterized by proteinuria, which has been in the nephrotic range in 60% of cases, microscopic hematuria (80%), and hypertension (80%). In more than 50% of patients, progressive renal insufficiency leading to long-term dialysis occurs within 4 years [2,3,5,6]. Little information regarding the course of renal transplantation in patients with immunotactoid glomerulopathy is available in the literature. We, therefore, present the course of renal transplantation in two patients whose primary diagnosis in their native kidneys was immunotactoid glomerulopathy.
MATERIALSAND METHODS The two patients were identified by the unique immunofluorescence and ultrastructural features of their native renal biopsy specimens. Both patients had undergone renal transplants and neither had had pretransplant nephrectomies. Systemic lupus erythematosus, amyloidosis, cryoglobulinemia, or a paraproteinemia had been excluded in both patients. Renal tissue obtained at biopsy was divided and processed for light, fluorescence, and electron microscopy as previously described [2].
CASEREPORTS Patient 1 A 66-year-old woman presented in May 1973 with hypertension and a urinalysis with 3+ protein. In December 1973, she was admitted for further evaluation. On physical examination, the following were found: blood pressure 140/80 mm Hg, normal fundi, and no pretibial edema. Laboratory data were as follows: seFrom the Section of Nephrology, Department of Medicine and Pathology, Rush Medical College and Rush-Presbyterian St. Luke’s Medical Center (SMK, MMS, EJL), Chicago, Illinois, and the Department of Pathology, William Beaumont Hospital (BFR), Royal Oak, Michigan. Requests for reprints should be addressed to Stephen M. Korbet. M.D.. Rush-Presbyterian-St. Luke’s Medical Center, 1653 West Congress Parkway, Chicago, lllinois 60612. Manuscript submitted June 27,1989, and accepted January 2. 1990.
RoyalOak,
Michigan,
MELVIN M.~CHWARTZ,M.D.,
rum creatinine 1.8 mg/dL, serum albumin 2.8 g/dL, and total protein of 4.3 g/dL. Urinalysis detected 2+ protein with microscopic hematuria and no abnormal casts. The creatinine clearance was 57 ml/minute, with a urine protein of 1.06 g/24 hours. The antinuclear antibody was negative, and the C3 and C4 levels were normal at 182 mg/dL (normal: 80 to 180 mg/dL) and 67 mg/dL (normal: 15 to 50 mg/dL), respectively. The cryocrit was negative. She underwent a percutaneous renal biopsy, which demonstrated organized microtublar deposits containing IgG. However, it was originally believed to be renal amyloidosis even though the Congo red preparation was negative. In October 1980, her serum creatinine level was 6.7 mg/ dL with a urine protein of 10 g/24 hours. She was treated with oral prednisone 80 mglday and melphalan 12 mg/day for 4 days. Her blood urea nitrogen and creatinine continued to increase, and by April 1981, they were 105 mg/dL and 11.0 mg/dL, respectively. Hemodialysis was started and continued until May 1983, at which time the patient received a cadaveric renal transplant. Immunosuppressive therapy consisted of azathioprine, prednisone, and Minnesota antilymphocyte globulin. Her post-transplant course was complicated by allograft rejection, but no evidence of recurrent disease was observed on biopsy examination of her allograft. Her renal function improved and stabilized at 1.5 mg/dL by September 1983. Over the course of the next 5 years, she has had no evidence of recurrent disease. At last follow-up in June 1988, her serum creatinine level was 1.6 mg/dL, serum albumin was 4.4 g/dL, urinalysis had no protein and no abnormal sediment, and the urine protein was 0.4 g/24 hours. Her antinuclear antibody, C3, C4, and cryocrit were all normal. Urine and serum for immunofixation were negative for monoclonal proteins and free light chains. Patient 2 A 52-year-old man presented in 1979 with hypertension (132/98 mm Hg) and proteinuria. His serum creatinine level was 1.6 mg/dL, and urinalysis showed 3+ protein with microscopic hematuria and no abnormal casts. A urine protein was 900 mg/24 hours. The patient was lost to follow-up until May 1982, at which time he presented with severe hypertension (180/110 mg/dL) and renal failure. The serum creatinine and serum albumin levels were 10.8 mg/dL and 3.2 g/dL, respectively. The urine protein was 20 g/24 hours. C3 and C4 levels were normal, and electrophoresis of urine and serum samples was negative for monoclonal proteins or free light chains. A bone marrow examination yielded normal results as well. Renal biopsy demonstrated immunotactoid glomerulopathy. In August 1982, the patient received a renal allograft from his July 1990
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Patients(n)
t:::;
Synonyms Non-amyloidotic fibrillary glomerulopathy Fibrillary nephritis Fibrillary glomerulonephritis
::,
151
7
El ty
2 2 1
t::\
1 1
(71
Total
Amyloid-like glomerulopathy Congo Red-negative amyloid-lrke glomerulopathy Amyloid-stain-negative glomerulopathy
microfibrillary
43
TABLEII Summaryof Morphology
Patient 1 2
PostTransplant (months)
Renal Biopsy Native kidney transplant Native kidney transplant :
;21 53
IgG (+/-) +Mes +GCW +GCW +GCW + Mes
Chronic Rejection (+/-) -
Microtubule Diameter (nanometers) 19.4 f 3 24.&
3
22&
5
es = mesangial; GCW = glomerular capillary wall.
son. After transplant, his serum creatinine level stabilized at 1.0 mg/dL and his urine protein was 264 mg/24 hours. After 1% years, he became hypertensive and the serum creatinine level was 2.0 mg/dL with 12.3 g/24 hours proteinuria. Urinalysis demonstrated 4+ protein with no abnormal sediment, and serum samples were negative for cryoglobulins. De nouo membranous glomerulopathy was found on biopsy examination of the transplanted kidney. Hepatitis B surface antigen and antibody were negative. The patient’s course was stable over the next 2l/2 years until December 1986 when he developed increasing fatigability and edema. The urine protein was 5.4 g/24 hours and the serum creatinine level was 4.6 mg/dL. A second biopsy examination of the allograft demonstrated more advanced glomerular disease with scarring. Evidence of recurrent immunotactoid glomerulopathy was also present. His renal function continued to deteriorate, and by March 1987, long-term dialysis was initiated. His course was further complicated by severe coronary artery disease, resulting in unstable angina and several myocardial infarctions. In May 1988, he died after a cardiopulmonary arrest. RESULTS (TABLE II) Patient 1 The native kidney had increased mesangial matrix, which was periodic acid-Schiff (PAS)-positive with normal cellularity. The basement membranes were thin and delicate and the capillaries were patent. The Congo red stain for amyloid was negative. The mesangium contained deposits of IgG and C3 by immunoflu-
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orescence microscopy; electron microscopy demonstrated masses of randomly oriented microtubles (19.4 f 3 nanometers in diameter), which diffusely expanded the mesangium and focally permeated and replaced the basal lamina (Figure 1). A transplant biopsy specimen, obtained during a clinical rejection episode at 1 month, had evidence of acute cellular rejection. Although the mesangium was mildly expanded by PASpositive matrix, the Congo red stain was negative; there were no glomerular deposits of immunoglobulins or complement components, and there were no electron-dense deposits or microtubules. Thus, the allograft biopsy specimen showed no evidence of recurrent immunotactoid glomerulopathy.
TABLEI lmmunotactoid Glomerulopathy:ReportedCases References
/ KORBET
89
Patient 2 The original renal biopsy specimen had advanced glomerulosclerosis, and the surviving glomeruli had massive mesangial expansion by PAS-positive material with normal cellularity. The glomerular basement membranes were focally thickened, and the Congo red stain was negative. Mesangial and granular capillary deposits of IgG, kappa, lambda, and C3 were demonstrated by fluorescence microscopy. Electron microscopy showed randomly oriented subendothelial, mesangial, and focal subepithelial microtubules measuring 24.9 f 3 nanometers in diameter (Figure 2). The first biopsy specimen of the donor kidney taken 13/4 years after transplant had early membranous glomerulonephritis with mild thickening and focal complexities of the glomerular basement membranes, granular deposits of IgG, kappa, and lambda exclusively in a granular capillary pattern, and subepithelial electron-dense deposits. No microtubules were seen in the deposits or in the mesangium. The Congo red stain was negative. The second biopsy specimen taken 4l/2 years after transplant had recurrent immunotactoid glomerulopathy superimposed upon the membranous lesion seen previously. Although only one of 12 glomeruli was hyalinized, all had diffuse thickening of glomerular basement membranes and moderate mesangial expansion. There were granular mesangial and glomerular basement membrane deposits of IgG, and electron microscopy showed persistence and expansion of the subepithelial electrondense deposits seen previously. In addition, mesangial and subendothelial masses of microtubules measuring 22.5 i 5 nanometers in diameter were present. In some areas, the microtubules infiltrated the glomerular basement membranes, but they were not seen within the subepithelial deposits (Figure 3). There was diffuse interstitial fibrosis, focal tubular atrophy, and a mild mononucular cell infiltrate. The blood vessels were normal. Although the tubular atrophy was disproportionate with the extent of glomerulosclerosis in the second transplant biopsy, the lesion had progressed to involve 90% of the glomeruli with sclerosis at autopsy. Since the two transplant biopsy specimens had only mild rejection, the patient’s progressive renal failure most likely was caused by the deleterious effect of the two glomerular lesions and not by rejection. At autopsy, there was no ultrastructural evidence of systemic immunotactoid deposition in randomly examined sections of spleen, liver, skin, and heart. In addition, there was no evidence of a systemic disease or lymphoproliferative disorder.
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Figure 1. Original renal biopsy specimen from Patient 1. The nlomerular capillary wall is distoried by intramembranous electrondense deposits (arrowhead). The mesangium is greatly expanded by similar deposits (asterisks). M = mesangial cell nucleus (uranyl acetate and lead citrate stain; original magnification X 7,000, reduced by 30%). Inset, at high magnification, the morphology and random arrangement of the microtubules that comprise the electron-dense deposits are demonstrated. P = mesangial cell process (uranyl acetate and lead citrate stain; original magnification X 34,000, reduced by 30%).
Figure 2. Original renal biopsy specimen from Patient 2. A, the glomerulus is distorted by microfibrils (asterisks) that expand the mesangium. CL = capillary lumen (uranyl acetate and lead citrate stain; original magnification X 11,000, reduced by 30%). B, capillary wall with microfibrils permeating the glomerular basement membrane and deposited under the glomerular epithelial cell. EPI = epithelial cell (uranyl acetate and lead citrate stain; original magnification X 42.000. reduced by 30%). C, fluorescent micrograph demonstrating irregular granular deposits in the glomerular walls and mesangium. (FITC goat antihuman IgG, original magnification X 400, reduced by 30%).
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Flgure 3. Second transplant biopsy specimen fiom Patient 2. A, the glomerular architecture is distorted by irregular subepithelial deposits, subendothelial expansion, and mesangial deposits. CL = capillary Iucell nucleus: men: M = mesangial EPI = epithelial cell (uranyl acetate and lead citrate stain; original magnification X 7,000, reduced by 30%). Inset, at high power, the random orientation of the microfibrils and their morphologic characteristics are apparent (uranyl acetate and lead citrate stain: original magnification X 34,000, reduced by 30%). B, the subepithelial deposits are comprised of subepithelial electron-dense deposits (asterlsk) and separate deposits of randomly arranged microfibrils (arrow). Similar fibrillar deposits are present between the endothelial cell (ENDO) and the glomerular basement membrane and in the mesangium (not shown) (uranyl acetate and lead citrate stain; original magnification X 34,000, reduced by 30%).
TABLE III Post-Transplant Course of lmmunotactoid Glomerulopathy FolloWUp Patient Age/Race/ Sex
Study [ii Present study Patient 1 Patient 2
Serum Creatinine @w/W
Recurrence (months)
19/B/F NA
Yes (60) No
2.0
66/W/F 52/W/M
No Yes (21-53)
1.6 ESRD
NA
Proteinurla (g/24 hours) Ii: 0.4 5.4
SRD = end-stage renal disease; NA = not available.
COMMENTS We initially reported the morphologic features of immunotactoid glomerulopathy in 1980 [l]. In 1985, we increased our understanding of this lesion by describing the morphology and clinical course in 11 patients with this clinicopathologic entity [2]. Since our initial observation, 42 additional cases of immunotactoid glomerulopathy have been described (Table I). Unlike other primary glomerulopathies, little is known about the course of renal allografts in patients with immunotactoid glomerulopathy. In addition to our experience, only two other patients [4,6] who have 94
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received renal transplants have been described (Table III). Alpers et al [6] described a patient who presented at 19 years of age with proteinuria and who experienced progression to end-stage renal disease. She received a renal allograft 7 years after her initial presentation. Recurrent glomerular disease developed 5 years after transplant accompanied by 17 g/24 hours proteinuria. Morphologic and immunofluorescent findings in the renal allograft were reported to be similar to those of the native kidney. Furthermore, the size of fibrils (14 to 15 nm) was the same in both the native kidney and the allograft. Mild renal insufficiency was
RENAL
TRANSPLANTATION
present at the time of last follow-up. Sturgill and Bolton [4] also described a patient 2 years after transplant who is without evidence of recurrence. Taken together, there is experience with only four cases of renal transplants in patients with immunotactoid glomerulopathy (Table III). Recurrent disease in two of the cases was heralded clinically by the nephrotic syndrome, which presented at 21 and 60 months after transplantation. Morphologically, organized immune deposits, similar to those found in the native kidney, were identified 53 and 60 months after transplant. The initial post-transplant biopsy (21 months) in our second case did not demonstrate any organization of the immune deposits. It is possible that two glomerular processes could have occurred in this patient, with his initial allograft lesion representing a de nouo membranous glomerulopathy. This concept is supported in the second biopsy specimen in which deposits with and without organization coexisted. Due to the lack of adequate follow-up in the case reported by Alpers et al [6] and the complexity of the condition of our Patient 2, we cannot know the rate of progression to end-stage renal failure in patients with recurrent disease. In the remaining two cases, there was no evidence or report of clinical or morphologic recurrence after 24 and 61 months of follow-up. Immunotactoid glomerulopathy appears to represent a primary glomerulopathy, as patients with this entity do not have clinical or serologic evidence of a systemic disease [2]. This contrasts with other diseases associated with organized immune deposits such as amyloidosis, paraproteinemia (light-chain deposition disease), cryoglobulinemia, or systemic lupus erythematosus. The lack of systemic involvement was further substantiated morphologically by the autopsy findings in our Patient 2, since no ultrastructural evidence of immunotactoid deposition could be found in sections of the spleen, liver, skin, or the heart. Due to the extremely poor prognosis associated with primary amyloidosis [13], the latter has been a relative contraindication for renal transplantation. It is, therefore, of practical importance to differentiate renal amyloid and immunotactoid glomerulopathy because the prognoses of these entities are vastly different. The
IN IMMUNOTACTOlD
GLOMERULOPATHY
/ KORBET
ET AL
diagnosis of amyloidosis should be firmly established by histochemical methods, as well as by the subtle but different ultrastructural characteristics that have been reported in these two entities [2,13]. Immunotactoid glomerulopathy appears to have the potential to lead to progressive renal insufficiency in a significant number of affected patients. As a result, many of these patients are potential candidates for renal transplantation. Experience thus far demonstrates that these patients can undergo successful renal transplantation but may have a recurrence of immunotactoid glomerulopathy. Recurrence of immunotactoid glomerulopathy, based on clinical grounds, appears to occur many months after the graft is placed.
ACKNOWLEDGMENT We thank Dr. Stephen Jensik for assistance secretarial support.
with Pabent 1 and Susan Parks for
REFERENCES 1. Schwartz MM, Lewis EJ: The quarterly case: nephrotic syndrome in a middleaged man. Ultrastruct Pathol 1980; 1: 575-582. 2. Korbet SM. Schwartz MM, Rosenberg BF, Sibley RK. Lewis EJ: lmmunotactoid glomerulopathy. Medicine (Baltimore) 1985; 64: 228-243. 3. Sturgill BC, Bolton WK, Griffith KM: Congo red-negative amyloid-like glomerulopathy. Hum Pathol 1985; 16: 220-224. 4. Sturgill BC, Bolton WK: Non-amyloidotic fibrillary glomerulopathy (abstr). Kidney Int 1989: 35: 233. 5. Duffy JL, Khurana E. Susin M, Gomez-Leon G. Churg J: Fibrillary renal deposits and nephrms. Am J Pathol 1983; 113: 279-290. G.Alpers CE. Rennke HG. Hopper J, Biava CG: Fibrillary glomerulonephritis: an entity with unusual rmmunofluorescence features. Kidney Int 1987; 31: 781-789. 7. Olesnicky L, Doty SB, Bertani T. Pirani CL: Tubular mtcrofibrils in the glomeruli of membranous nephropathy. Arch Pathol Lab Med 1984; 108: 902-905. 8. Rosenmann E. Eliakim M: Nephrotic syndrome associated with amylord-like glomerular deposits. Nephron 1977; 18: 301-308. 9. Rosenmann E. Brisson M-L, Bercovitch DD. Rosenberg A: Atypical membranous glomerulonephritis with fibrillar subepithelial deposits in a patient with malignant lymphoma. Nephron 1988; 48: 226-230. 10. Sadladi JA. Sobel HJ: Congo red-negative amyloidosis-like glomerulopathy: report of a case. Am J Kidney Dis 1987; 9: 231-234. 11. Schifferli SA, Merot Y, Cruchaud A, Chatelanat F: lmmunotactoid glomerulopathy with leucocytoclastic skin vasculitis and hypocomplementemia: a case report. Clin Nephrol 1987; 27: 151-155. 12. Kobayashi Y. Fufii K. Kurokawa A, Kamiyama M. Miyazawa H: Glomerulonephropathy with amyloid-stain-negative microfibrillar glomerular deposits. Nephron 1988; 48: 33-39. 13. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58: 665683.
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