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Recurrent dense deposit disease in renal allograft
RECURRENT
DENSE
DEPOSIT
DISEASE
IN
RENAL ALLOGRAFT ALINA F. JUKKOLA, TERESA
M.D.
MANTARING,
M.D.
SHANE ROY, III, M.D. WILLIAM
M. MURPHY,
M.D.
From the Departments of Pathology and Pediatrics, University of Tennessee Center for the Health Sciences, Memphis, Tennessee
ABSTRACT - This report documents the recurrence of dense deposit disease in a renal allograft thirty-three days post-transplantation and stresses the usefulness of immunofluorescence in early detection. -
Dense deposit disease (DDD) is currently classified on clinical and light microscopic grounds a subtype of membranoproliferative iyomerulonephritis (MPGN, type II).’ The cliffering immunofluorescence, ultrastructure, and complement profiles of MPGN type I subendothelial deposits (SED) and type 1I raise questions as to (DDD), however, their kinship. l-6 Studies on the chemistry of the electron-dense alteration of basement membranes in DDD have revealed few differences from normal,‘*8 but documentation o.f the natural history of the disease might lead to increased understanding. The constant recurrence of DDD in renal allografts offers a unique opportunity in this regard. Unfortunately, early biopsies (< six months post-transplant) of allografts are rarely done in the absence of specific clinical symptoms. It is the purpose of this report to document the earliest known recurrence of DDD in an allograft and to emphasize the role of immunofluorescence in its detection. Case Report This ten-year-old white female was admitted to LeBonheur Children’s Hospital, Memphis, Tennessee, with the sudden onset of renal failure. Urinalysis on admission revealed 4 plus protein and 50 to 75 red blood cells per highpower field of sediment. There were no casts.
UROLOGY
I
APRIL 1978
!
VOLUME XI, NUMBER 4
Other pertinent laboratory values included: blood urea nitrogen 143 mg. per deciliter, creatinine clearance 11 ml. per minute per 1.73m2, C3 31 mg. per deciliter; negative antistreptolysin 0 and streptozyme titers. A renal biopsy performed on the fifth hospital day revealed features characteristic of DDD (MPGN, type II) (Fig. 1). On light microscopy, the glomerular tufts were compressed by large epithelial crescents. There was mesangial cell proliferation with increased mesangial matrix and lobulation. The capillary walls were thickened and many were intensely periodic acidSchiff (PAS) positive. With silver stains, “double contouring” of basement membranes was minimal and there were no “spikes.” These glomerular changes were accompanied by severe interstitial fibrosis and tubular atrophy and marked acute and chronic inflammation. Many tubular basement membranes were strongly PAS positive. Immunofluorescence revealed linear deposition of C3 along glomerular, Bowman’s capsular, and tubular basement membranes. Focal granular deposition of immunoglobulin M occurred in a few glomerular segments and fibrin reactive products were identified in crescents. Electron microscopic examination confirmed the light microscopic findings. In addition, the ribbonlike, electron-dense basement membrane alterations diagnostic of DDD were prominent.
FIGURE 1. Original renal (A) Thickening of biopsy. glomerular capillary loops, mesangial cell hyperplasia, diffuse mesangial matrix increase, and circumferential epithelial crescent formation; (hematoxylin and eosin) (B) discontinuous linear deposits of C3 along glomerular, Bowman’s capsular, and tubular basement membranes as well as scattered granular deposits within mesangium of glomerulus; (C) extensive electron-dense alteration of glomerular capilla y basement membrane; (original magnijications x 250, X 250, and x 2,400, respectively.)
FIGURE 2. Allograft biopsy at thirty-three days. (A) Few darkly staining segments of the glomerular (arrowhead) and Bowman’s capsular (arrow) basement membranes are visible; most basement membranes are unremarkable, (toluidine blue, reduced from x 250); (B) no discernible glomerular basement membrane or me(PAS, sangial abnormalities reduced from x 250); (C) immunofluorescence pattern of C3 deposition similar to that seen in original renal biopsy (Fig. 1B) (reduced from X 250); (D) segmental electrondense alteration of glomerular and Bowman’s capsular basement membranes (X 5,500).
Over the ensuing three months, the patient’s renal function continued to deteriorate despite intensive chemotherapy. She required hemodialysis and, eventually, a cadaver allograft. Poor graft function raised the question of transplant rejection, and a percutaneous biopsy was performed thirty-three days post-
396
transplantation. The pathologic findings are illustrated in Figure 2. Except for findings consistent with acute tubular necrosis, the tissue was unremarkable by light microscopy. Immunofluorescence, however, revealed diffuse linear deposition of C3 in glomerular, Bowman’s capsular, and tubular basement membranes.
UROLOGY
/ APRIL1978 / VOLUMEXI,
NUMBER4
The corresponding ultrastructural electrondense alterations were focal and in many areas equivocal. The graft continued to fail despite increased clinical efforts, and it was removed three months post-transplantation. Pathologic examination at that time revealed the characteristic findings of DDD.
Since its first description in 1962, DDD has remained an enigma. g Despite clinical and light microscopic features relating it to MPGN @ED), the etiology and pathogenesis of this entity remain obscure. ‘,l” Its almost universal recurrence in allografts and the failure to find similar pathology in allografts placed in patients with other glomerular diseases implicate factor(s) unique to the host rather than any induced by the graft. ‘Al Indeed, the rapidity of recurrence in the case herein reported would indicate that little sensitization to donor tissue is required. This case documents the earliest recurrence of DDD in an allograft. The frequency of early recurrence is difficult to ascertain since histologic changes may occur in the absence of clinical manifestations, and follow-up renal biopsies have not usually been performed prior to six months post-transplantation.‘,” Furthermore, the paucity of light and electron microscopic changes in early stages might be misleading if immunofluorescence were not available. The
I
APRIL
1978
/
VOLUME
Department of Pathology 858 Madison Avenue Memphis, Tennessee 38163 (DR. MURPHY) References
Comment
UROLOGY
prognostic importance of early recurrence is unknown but until dense deposit disease is better understood, early pathologic evaluation of allografts in these patients might be valuable.
XI, NUMBER
4
1. Habib R, et al: Idiopathic membranoproliferative glomerulonephritis in children: report of 195 cases, Clin. Nephrol. 1: 194 (1973). 2. Habib R, et 02: Dense deposit disease: a variant of membranoproliferative glomerulonephritis, Kidney Int. 7: 204 (1975). 3. West CD: Pathogenesis and approaches to therapy of membranoproliferative glomerulonephritis, ibid. 9: 1 (1976). 4. Ooi YM, Vallota EH, and West CD: Classical complement pathway activation in membranoproliferative glomerulonephritis, ibid. 9: 46 (1976). 5. Barbiano Di Belgiojoso G, et al: Immunofluorescence patterns in chronic membranoproliferative glomerulonephritis (MPGN), Clin. Nephrol. 6: 363 (1976). 6. Vargas AR, et al: Mesangiocapillary glomerulonephritis with dense “denosits” in the basement membranes of the kidnev., ibid. 5: 73 (1976). 7. Galle P, and Mahieu P: Electron dense alteration of kidney basement membranes, Am. J. Med. 58: 749 (1975). 8. Mahieu P, and Winand RJ: Biochemical studies of the glomerular basement membrane of the diseased kidney, in Hamburger, J., et al., Eds.: Advances in Nephrology, Chicago, Year Book Medical Publishers, 1972, pp. 2, 25. 9. Galle P: Mise en evidence au microscope electronique dune lesion singuliere des membranes basales du rein et de la substance hyaline, Thesis Med. Paris, 1962. 10. Antoine B, Faye C: The clinical course associated with dense deposits in the kidney basement membranes, Kidney Int. 1: 420 (1972). 11. Turner DR, el al: Transplantation in mesangiocapillary glomerulonephritis with intramembmnous dense “deposits”: re^_ . . __ ~~.. currence of disease, ibid. 9: 439 (1976).
397
DENSE
DEPOSIT
DISEASE
IN
RENAL ALLOGRAFT ALINA F. JUKKOLA, TERESA
M.D.
MANTARING,
M.D.
SHANE ROY, III, M.D. WILLIAM
M. MURPHY,
M.D.
From the Departments of Pathology and Pediatrics, University of Tennessee Center for the Health Sciences, Memphis, Tennessee
ABSTRACT - This report documents the recurrence of dense deposit disease in a renal allograft thirty-three days post-transplantation and stresses the usefulness of immunofluorescence in early detection. -
Dense deposit disease (DDD) is currently classified on clinical and light microscopic grounds a subtype of membranoproliferative iyomerulonephritis (MPGN, type II).’ The cliffering immunofluorescence, ultrastructure, and complement profiles of MPGN type I subendothelial deposits (SED) and type 1I raise questions as to (DDD), however, their kinship. l-6 Studies on the chemistry of the electron-dense alteration of basement membranes in DDD have revealed few differences from normal,‘*8 but documentation o.f the natural history of the disease might lead to increased understanding. The constant recurrence of DDD in renal allografts offers a unique opportunity in this regard. Unfortunately, early biopsies (< six months post-transplant) of allografts are rarely done in the absence of specific clinical symptoms. It is the purpose of this report to document the earliest known recurrence of DDD in an allograft and to emphasize the role of immunofluorescence in its detection. Case Report This ten-year-old white female was admitted to LeBonheur Children’s Hospital, Memphis, Tennessee, with the sudden onset of renal failure. Urinalysis on admission revealed 4 plus protein and 50 to 75 red blood cells per highpower field of sediment. There were no casts.
UROLOGY
I
APRIL 1978
!
VOLUME XI, NUMBER 4
Other pertinent laboratory values included: blood urea nitrogen 143 mg. per deciliter, creatinine clearance 11 ml. per minute per 1.73m2, C3 31 mg. per deciliter; negative antistreptolysin 0 and streptozyme titers. A renal biopsy performed on the fifth hospital day revealed features characteristic of DDD (MPGN, type II) (Fig. 1). On light microscopy, the glomerular tufts were compressed by large epithelial crescents. There was mesangial cell proliferation with increased mesangial matrix and lobulation. The capillary walls were thickened and many were intensely periodic acidSchiff (PAS) positive. With silver stains, “double contouring” of basement membranes was minimal and there were no “spikes.” These glomerular changes were accompanied by severe interstitial fibrosis and tubular atrophy and marked acute and chronic inflammation. Many tubular basement membranes were strongly PAS positive. Immunofluorescence revealed linear deposition of C3 along glomerular, Bowman’s capsular, and tubular basement membranes. Focal granular deposition of immunoglobulin M occurred in a few glomerular segments and fibrin reactive products were identified in crescents. Electron microscopic examination confirmed the light microscopic findings. In addition, the ribbonlike, electron-dense basement membrane alterations diagnostic of DDD were prominent.
FIGURE 1. Original renal (A) Thickening of biopsy. glomerular capillary loops, mesangial cell hyperplasia, diffuse mesangial matrix increase, and circumferential epithelial crescent formation; (hematoxylin and eosin) (B) discontinuous linear deposits of C3 along glomerular, Bowman’s capsular, and tubular basement membranes as well as scattered granular deposits within mesangium of glomerulus; (C) extensive electron-dense alteration of glomerular capilla y basement membrane; (original magnijications x 250, X 250, and x 2,400, respectively.)
FIGURE 2. Allograft biopsy at thirty-three days. (A) Few darkly staining segments of the glomerular (arrowhead) and Bowman’s capsular (arrow) basement membranes are visible; most basement membranes are unremarkable, (toluidine blue, reduced from x 250); (B) no discernible glomerular basement membrane or me(PAS, sangial abnormalities reduced from x 250); (C) immunofluorescence pattern of C3 deposition similar to that seen in original renal biopsy (Fig. 1B) (reduced from X 250); (D) segmental electrondense alteration of glomerular and Bowman’s capsular basement membranes (X 5,500).
Over the ensuing three months, the patient’s renal function continued to deteriorate despite intensive chemotherapy. She required hemodialysis and, eventually, a cadaver allograft. Poor graft function raised the question of transplant rejection, and a percutaneous biopsy was performed thirty-three days post-
396
transplantation. The pathologic findings are illustrated in Figure 2. Except for findings consistent with acute tubular necrosis, the tissue was unremarkable by light microscopy. Immunofluorescence, however, revealed diffuse linear deposition of C3 in glomerular, Bowman’s capsular, and tubular basement membranes.
UROLOGY
/ APRIL1978 / VOLUMEXI,
NUMBER4
The corresponding ultrastructural electrondense alterations were focal and in many areas equivocal. The graft continued to fail despite increased clinical efforts, and it was removed three months post-transplantation. Pathologic examination at that time revealed the characteristic findings of DDD.
Since its first description in 1962, DDD has remained an enigma. g Despite clinical and light microscopic features relating it to MPGN @ED), the etiology and pathogenesis of this entity remain obscure. ‘,l” Its almost universal recurrence in allografts and the failure to find similar pathology in allografts placed in patients with other glomerular diseases implicate factor(s) unique to the host rather than any induced by the graft. ‘Al Indeed, the rapidity of recurrence in the case herein reported would indicate that little sensitization to donor tissue is required. This case documents the earliest recurrence of DDD in an allograft. The frequency of early recurrence is difficult to ascertain since histologic changes may occur in the absence of clinical manifestations, and follow-up renal biopsies have not usually been performed prior to six months post-transplantation.‘,” Furthermore, the paucity of light and electron microscopic changes in early stages might be misleading if immunofluorescence were not available. The
I
APRIL
1978
/
VOLUME
Department of Pathology 858 Madison Avenue Memphis, Tennessee 38163 (DR. MURPHY) References
Comment
UROLOGY
prognostic importance of early recurrence is unknown but until dense deposit disease is better understood, early pathologic evaluation of allografts in these patients might be valuable.
XI, NUMBER
4
1. Habib R, et al: Idiopathic membranoproliferative glomerulonephritis in children: report of 195 cases, Clin. Nephrol. 1: 194 (1973). 2. Habib R, et 02: Dense deposit disease: a variant of membranoproliferative glomerulonephritis, Kidney Int. 7: 204 (1975). 3. West CD: Pathogenesis and approaches to therapy of membranoproliferative glomerulonephritis, ibid. 9: 1 (1976). 4. Ooi YM, Vallota EH, and West CD: Classical complement pathway activation in membranoproliferative glomerulonephritis, ibid. 9: 46 (1976). 5. Barbiano Di Belgiojoso G, et al: Immunofluorescence patterns in chronic membranoproliferative glomerulonephritis (MPGN), Clin. Nephrol. 6: 363 (1976). 6. Vargas AR, et al: Mesangiocapillary glomerulonephritis with dense “denosits” in the basement membranes of the kidnev., ibid. 5: 73 (1976). 7. Galle P, and Mahieu P: Electron dense alteration of kidney basement membranes, Am. J. Med. 58: 749 (1975). 8. Mahieu P, and Winand RJ: Biochemical studies of the glomerular basement membrane of the diseased kidney, in Hamburger, J., et al., Eds.: Advances in Nephrology, Chicago, Year Book Medical Publishers, 1972, pp. 2, 25. 9. Galle P: Mise en evidence au microscope electronique dune lesion singuliere des membranes basales du rein et de la substance hyaline, Thesis Med. Paris, 1962. 10. Antoine B, Faye C: The clinical course associated with dense deposits in the kidney basement membranes, Kidney Int. 1: 420 (1972). 11. Turner DR, el al: Transplantation in mesangiocapillary glomerulonephritis with intramembmnous dense “deposits”: re^_ . . __ ~~.. currence of disease, ibid. 9: 439 (1976).
397