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Membranoproliferative Injury Pattern in a Renal Allograft
KIDNEY BIOPSY TEACHING CASE
Membranoproliferative Injury Pattern in a Renal Allograft Neriman Gökden, MD, Michele Rossini, MD, Jayant Kumar, MD, and Agnes B. Fogo, MD INDEX WORDS: Membranoproliferative glomerulonephritis; acute transplant glomerulitis; acute vascular rejection.
M
EMBRANOPROLIFERATIVE glomerulonephritis (MPGN), caused by subendothelial immune-complex deposits, can occur as a de novo or recurrent disease in the transplantation setting. When an MPGN-like injury pattern with endocapillary proliferation and double contours of the capillary wall is seen by means of light microscopy in the allograft biopsy, the differential diagnosis includes recurrent MPGN, de novo MPGN, acute transplant glomerulitis, transplant glomerulopathy, and chronic thrombotic microangiopathy, among others. Careful integration of immunofluorescence and electron microscopic findings is essential for accurate diagnosis. We present the case of a renal transplant recipient with MPGN-like injury pattern detected by means of light microscopy. With careful correlation of immunofluorescence and electron microscopic findings, a specific diagnosis was made and appropriate treatment was rendered. CASE REPORT
Clinical History A 59-year-old African-American woman presented for cadaveric kidney transplantation. Her past medical history was significant for polycystic kidney disease diagnosed in 1986, type 2 diabetes mellitus for 12 years, and hypertension. She also had hepatic cysts associated with polycystic kidney disease and chronic cholecystitis. She had been on dialysis therapy for 6 years. On admission, blood urea nitrogen level was 36 mg/dL (12.9 mmol/L), and serum creatinine level was 1.9 mg/dL (168 mol/L). Other laboratory tests showed normal sodium and potassium levels, with a glucose level of 186 mg/dL (10.3 mmol/L). The patient underwent successful cadaveric transplantation, along with bilateral native nephrectomies and cholecystectomy. Immunosuppression consisted of prednisone, mycophenolate mofetil, FK506, and induction with basiliximab pretransplantation and on day 4. Her postoperative course was complicated by delayed graft function, with urine output of 1 to 2 L/d and slowly improving creatinine levels. She required 3 sessions of hemofiltration on days 3, 4, and 5 for volume overload. Serum creatinine level improved to 2.3 mg/dL (203 mol/L) by day 14 without hemodialysis. The patient was maintained on prednisone, mycophenolate mofetil, and FK506 therapy as an outpatient. Her serum creatinine level stabilized at 1.8 mg/dL (159 mol/L) at 6 weeks posttransplantation. During a routine laboratory
workup, she was noted to have persistently elevated proteinuria on dipstick (protein, 300 mg/dL). Spot urine proteincreatinine ratio was 1.95. Proteinuria persisted despite treatment of an episode of urinary tract infection with an appropriate antibiotic. She underwent a diagnostic transplant kidney biopsy.
Renal Biopsy The biopsy specimen consisted of 2 pieces of cortex and medulla containing 15 glomeruli, 1 of which was globally sclerosed. There was diffuse glomerulitis with endocapillary proliferation and many mononuclear cells and rare polymorphonuclear leukocytes in the capillary lumens (Fig 1). Glomeruli showed an increase in mesangial matrix and cellularity without mesangiolysis. Podocytes were unremarkable. Glomerular basement membranes did not have spikes, holes, or corrugation, but there was frequent splitting. There were no crescents, adhesions, or fibrin thrombi in Bowman space. There was mild interstitial fibrosis involving 10% of the biopsy tissue, with proportional tubular atrophy. There was minimal lymphocytic infiltrate involving 3 tubules/highpower field (Fig 2). There were several interlobular arteries showing activated endothelium, 1 showing adherent lymphocyte and 1 showing endothelialitis, diagnostic of acute vascular rejection Collaborative Clinical Trials in Transplantation (CCTT) type 21 (Fig 3). Immunofluorescence microscopy showed trace mesangial staining for immunoglobulin M and trace mesangial and trace arteriolar staining for C3. Immunoglobulin G, immunoglobulin A, C1q, and polyvalent antisera were negative. C4d staining showed diffuse 2⫹ peritubular capillary staining (Fig 4). The control worked appropriately. Electron microscopy showed endocapillary proliferation with polymorphonuclear leukocytes and mononuclear cells in the capillary lumen and swelling of endothelial cells, but no reticular aggregates in endothelial cells. The glomerular
From the Department of Pathology, Vanderbilt University Medical Center, Nashville, TN; Department of Pathology, and Department of Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR. Received February 15, 2005; accepted as submitted March 18, 2005. Originally published online as doi:10.1053/j.ajkd.2005.03.026 on August 2, 2005. Address reprint requests to Agnes B. Fogo, MD, Department of Pathology, C3310, Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2561. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4603-0023$30.00/0 doi:10.1053/j.ajkd.2005.03.026
American Journal of Kidney Diseases, Vol 46, No 3 (September), 2005: pp 573-576
573
574
GÖKDEN ET AL
Fig 1. A glomerulus shows global endocapillary proliferation with numerous mononuclear cells in the capillary lumens (Jones silver stain; original magnification ⴛ200).
basement membrane showed normal thickness. There were no subendothelial or subepithelial deposits. There was 50% to 75% foot-process effacement. Visceral epithelial cells showed cytoplasmic vacuolization. The mesangium showed normal matrix and cellularity, no mesangial immunecomplex deposits, and no mesangial interposition. There was interstitial edema and infiltrate. Tubules were unremarkable.
Final Diagnosis The final diagnosis was acute rejection, CCTT type 2, with glomerulitis and C4d peritubular capillary staining, suggestive of a possible antibody-mediated component.1
Clinical Follow-Up On the day of the biopsy, the patient was treated with 1 dose of intravenous methylprednisolone sodium succinate, 250 mg. After biopsy results were known, she was treated with 7 daily doses of antithymocyte globulin (rabbit), 1.5 mg/kg/d, in addition to intravenous ganciclovir. She tolerated the therapy well and was discharged home on therapy with prednisone, FK506, and mycophenolate mofetil, with oral valganciclovir for cytomegalovirus prophylaxis. Her serum creatinine level has improved to 1.0 mg/dL (88 mol/L) and proteinuria has decreased, with a spot urinary protein-creatinine ratio less than 0.25.
Fig 2. A tubular profile shows 2 lymphocytes within the tubular epithelium (ie, tubulitis) (Jones silver stain; original magnification ⴛ400).
Fig 3. (A) An arteriole shows activated endothelium with an adherent lymphocyte (Jones silver stain; original magnification ⴛ1,000). (B) An interlobular artery shows 2 lymphocytes underneath the endothelial layer (ie, endothelialitis) (Jones silver stain; original magnification ⴛ400).
DISCUSSION
Our case represents a patient 6 weeks posttransplantation with endothelialitis and diffuse acute transplant glomerulitis characterized by an increased number of mononuclear cells and rare polymorphonuclear leukocytes in glomerular cap-
Fig 4. Immunofluorescence for C4d shows diffuse 2ⴙ positivity along the peritubular capillaries (anti-C4d antibody; original magnification ⴛ400).
MPGN PATTERN IN ALLOGRAFT
illary lumina, resulting in diminished capillary patency. In addition, there was endocapillary proliferation, increase in mesangial matrix, and cellularity with diffuse splitting of glomerular basement membranes reminiscent of MPGN. The initial differential diagnosis based on light microscopy in this patient included acute transplant glomerulitis or de novo MPGN, in addition to the acute rejection. Immunofluorescence microscopy did not show evidence of immune complex– mediated glomerulonephritis, excluding MPGN. Immunofluorescence for C4d was strongly positive in peritubular capillaries, which, along with the acute glomerulitis, suggests an antibodymediated component of the acute rejection.2 Acute transplant glomerulitis has been variously called transplant glomerulitis,3 endocapillary glomerulitis,4 acute allograft glomerulopathy,5 and early allograft glomerulitis.6 The incidence is reported to be 4% to 10% of renal allograft biopsies. In approximately 2% to 4% of biopsies, a severe diffuse form of glomerular injury is evident and dominates the histological pattern.7 The first detailed description of acute glomerulitis was made in 1981 by Richardson et al,8 who found an association with cytomegalovirus viremia. However, several other studies could not confirm this correlation between glomerulitis and active cytomegalovirus infection.9-12 Glomerular endothelial cell hypercellularity has been described at an early stage after transplantation in the early renal allograft7,8 and has been proposed as a particular pattern of glomerular rejection.9 However, the cause of acute transplant glomerulitis remains uncertain. Acute transplant glomerulitis is characterized morphologically by enlargement of the glomerular tuft, with swollen endothelial cells and accumulation of mononuclear cells in glomerular capillaries, resulting in closure of the capillary lumina. A significant increase in the relative number of mesangial cells also has been reported in acute transplant glomerulitis.13 Visceral epithelial cell proliferation is observed rarely, and when present, was only mild. Polymorphonuclear cells in glomeruli in acute transplant glomerulitis are rare. A fine web of periodic acid–Schiff–positive fibrils has been described in the capillary lumina between intracapillary cells and in areas of mesangiolysis. Occasional endothelial cell necrosis in glomeruli can be found,
575
and endothelial cells appear activated. The infiltrating mononuclear cells also have an activated appearance. Crescents are not found, and thrombi are rare.7 Acute transplant glomerulitis can be scored according to criteria of the Banff system. All glomeruli are affected in a global manner in the severe form (G3), but the lesion can be segmental and focal (G1). G2 is defined as segmental or global glomerulitis in 25% to 75% of glomeruli.14 The evolution of morphologically distinct changes in acute transplant glomerulitis has been described. The earliest stage is called evolving glomerulitis and is recognizable by swelling of endothelial and mesangial cells. The intermediate stage is characterized by enlarged glomeruli with lobular simplification, spongy matrix, and glomerular basement membrane deformities. In the advanced stage, the glomerular basement membrane shows reduplication and interposition with monocytes.15 Thus, our patient showed predominantly advanced stage lesions. The importance of acute transplant glomerulitis in the prognosis of renal allograft outcome is controversial. An association with poor graft survival was reported in earlier series.5,10,15 There was some correlation with conventional type 1 acute rejection, but 40% of all biopsy specimens with glomerulitis showed no rejection by standard criteria, and 53% of all biopsy specimens with rejection showed no glomerulitis.4 In a retrospective cohort study, acute transplant glomerulitis was associated significantly with a trend toward earlier rejection episodes, greater serum creatinine level at the time of the index biopsy, greater prevalence of vascular rejection, and less improvement in mean reciprocal serum creatinine level at 1 to 2 weeks after biopsy, but was not an independent predictor of graft survival.15 The association of acute transplant glomerulitis with a greater prevalence of variable degrees of endothelialitis/“vascular rejection” has been documented.14,15 In our case, acute transplant glomerulitis was associated with acute “vascular” rejection (CCTT type 2) and also strong C4d peritubular staining, a finding linked to humoral mechanisms of rejection. Conversely, there was only minimal lymphocytic infiltrate involving less than 5% of biopsy tissue, with occasional tubulitis, not diagnostic of acute “cellular” rejection (CCTT type 1). However, earlier studies
576
GÖKDEN ET AL
showed that acute transplant glomerulitis is not an independent predictor of graft survival. This graft lesion is not included in the Banff or CCTT classification systems as a criterion for the presence or grading of rejection. In summary, acute transplant glomerulitis may be a peculiar pattern of rejection with a pathogenesis different from that of conventional rejection, but present data do not show independent adverse effects on graft function or prognosis.4,11 Differentiation from other causes of MPGN-like pattern injury is important. This case illustrates the utility of immunofluorescence and electron microscopic study for workup in transplant recipients with unusual light microscopic findings. The association between vascular rejection and acute transplant glomerulitis should direct a very careful examination of sampled arteries in biopsy specimens with glomerulitis to ensure that endothelialitis, which may be focal, is detected when present and timely appropriate aggressive therapy is initiated. REFERENCES 1. Colvin RB, Cohen AH, Saiontz C, et al: Evaluation of pathologic criteria for acute renal allograft rejection: Reproducibility, sensitivity, and clinical correlation. J Am Soc Nephrol 8:1930-1941, 1997 2. Racusen LC, Colvin RB, Solez K, et al: Antibodymediated rejection criteria—An addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 3:708-714, 2003 3. Marcussen N, Solez K, Spencer E, Cockfield S, Olsen S: Early transplant glomerulitis; Glomerular size and ultrastructure. Transplant Proc 28:468-469, 1996
4. Olsen S, Spencer E, Cockfield S, Marcussen N, Solez K: Endocapillary glomerulitis in the renal allograft. Transplantation 59:1421-1425, 1995 5. Tuazon TV, Schneeberger EE, Bhan AK, et al: Mononuclear cells in acute transplant glomerulopathy. Am J Pathol 129:119-132, 1987 6. Racusen LC, Solez K, Colvin RB, et al: The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713-723, 1999 7. Colvin RB: Renal transplant pathology, in Jennette JC, Olson JL, Schwartz MM, Silva FG (eds): Heptinstall’s Pathology of the Kidney, vol 2 (ed 5). Philadelphia, PA, Lippincott-Raven, 1998, pp 1417-1418 8. Richardson WP, Colvin RB, Cheeseman SH, et al: Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med 305:57-63, 1981 9. Axelsen RA, Seymour AE, Mathew TH, Canny A, Pascoe V: Glomerular transplant rejection: A distinctive pattern of early graft damage. Clin Nephrol 23:1-11, 1985 10. Herrera AG, Alexander RV, Cooley CF, et al: Cytomegalovirus glomerulopathy: A controversial lesion. Kidney Int 29:725-733, 1986 11. Messias NC, Eustace JA, Zachary AA, Tucker PC, Charney D, Racusen LC: Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts. Transplantation 72:655-660, 2001 12. Boyce N, Hayes K, Gee D, et al: Cytomegalovirus infection complicating renal transplantation and its relationship to acute transplant glomerulopathy. Transplantation 45:706-709, 1988 13. Hanberg FS: A quantitative study of the renal corpuscles in acute renal allograft rejection. Acta Pathol Microbiol Scand (A) 85:367-372, 1977 14. Solez K, Axelsen R, Benediktsson H, et al: International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int 44:411-422, 1993 15. Maryniak RK, First MR, Weiss MA: Transplant glomerulopathy: Evolution of morphologically distinct changes. Kidney Int 27:799-806, 1985
Membranoproliferative Injury Pattern in a Renal Allograft Neriman Gökden, MD, Michele Rossini, MD, Jayant Kumar, MD, and Agnes B. Fogo, MD INDEX WORDS: Membranoproliferative glomerulonephritis; acute transplant glomerulitis; acute vascular rejection.
M
EMBRANOPROLIFERATIVE glomerulonephritis (MPGN), caused by subendothelial immune-complex deposits, can occur as a de novo or recurrent disease in the transplantation setting. When an MPGN-like injury pattern with endocapillary proliferation and double contours of the capillary wall is seen by means of light microscopy in the allograft biopsy, the differential diagnosis includes recurrent MPGN, de novo MPGN, acute transplant glomerulitis, transplant glomerulopathy, and chronic thrombotic microangiopathy, among others. Careful integration of immunofluorescence and electron microscopic findings is essential for accurate diagnosis. We present the case of a renal transplant recipient with MPGN-like injury pattern detected by means of light microscopy. With careful correlation of immunofluorescence and electron microscopic findings, a specific diagnosis was made and appropriate treatment was rendered. CASE REPORT
Clinical History A 59-year-old African-American woman presented for cadaveric kidney transplantation. Her past medical history was significant for polycystic kidney disease diagnosed in 1986, type 2 diabetes mellitus for 12 years, and hypertension. She also had hepatic cysts associated with polycystic kidney disease and chronic cholecystitis. She had been on dialysis therapy for 6 years. On admission, blood urea nitrogen level was 36 mg/dL (12.9 mmol/L), and serum creatinine level was 1.9 mg/dL (168 mol/L). Other laboratory tests showed normal sodium and potassium levels, with a glucose level of 186 mg/dL (10.3 mmol/L). The patient underwent successful cadaveric transplantation, along with bilateral native nephrectomies and cholecystectomy. Immunosuppression consisted of prednisone, mycophenolate mofetil, FK506, and induction with basiliximab pretransplantation and on day 4. Her postoperative course was complicated by delayed graft function, with urine output of 1 to 2 L/d and slowly improving creatinine levels. She required 3 sessions of hemofiltration on days 3, 4, and 5 for volume overload. Serum creatinine level improved to 2.3 mg/dL (203 mol/L) by day 14 without hemodialysis. The patient was maintained on prednisone, mycophenolate mofetil, and FK506 therapy as an outpatient. Her serum creatinine level stabilized at 1.8 mg/dL (159 mol/L) at 6 weeks posttransplantation. During a routine laboratory
workup, she was noted to have persistently elevated proteinuria on dipstick (protein, 300 mg/dL). Spot urine proteincreatinine ratio was 1.95. Proteinuria persisted despite treatment of an episode of urinary tract infection with an appropriate antibiotic. She underwent a diagnostic transplant kidney biopsy.
Renal Biopsy The biopsy specimen consisted of 2 pieces of cortex and medulla containing 15 glomeruli, 1 of which was globally sclerosed. There was diffuse glomerulitis with endocapillary proliferation and many mononuclear cells and rare polymorphonuclear leukocytes in the capillary lumens (Fig 1). Glomeruli showed an increase in mesangial matrix and cellularity without mesangiolysis. Podocytes were unremarkable. Glomerular basement membranes did not have spikes, holes, or corrugation, but there was frequent splitting. There were no crescents, adhesions, or fibrin thrombi in Bowman space. There was mild interstitial fibrosis involving 10% of the biopsy tissue, with proportional tubular atrophy. There was minimal lymphocytic infiltrate involving 3 tubules/highpower field (Fig 2). There were several interlobular arteries showing activated endothelium, 1 showing adherent lymphocyte and 1 showing endothelialitis, diagnostic of acute vascular rejection Collaborative Clinical Trials in Transplantation (CCTT) type 21 (Fig 3). Immunofluorescence microscopy showed trace mesangial staining for immunoglobulin M and trace mesangial and trace arteriolar staining for C3. Immunoglobulin G, immunoglobulin A, C1q, and polyvalent antisera were negative. C4d staining showed diffuse 2⫹ peritubular capillary staining (Fig 4). The control worked appropriately. Electron microscopy showed endocapillary proliferation with polymorphonuclear leukocytes and mononuclear cells in the capillary lumen and swelling of endothelial cells, but no reticular aggregates in endothelial cells. The glomerular
From the Department of Pathology, Vanderbilt University Medical Center, Nashville, TN; Department of Pathology, and Department of Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR. Received February 15, 2005; accepted as submitted March 18, 2005. Originally published online as doi:10.1053/j.ajkd.2005.03.026 on August 2, 2005. Address reprint requests to Agnes B. Fogo, MD, Department of Pathology, C3310, Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2561. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4603-0023$30.00/0 doi:10.1053/j.ajkd.2005.03.026
American Journal of Kidney Diseases, Vol 46, No 3 (September), 2005: pp 573-576
573
574
GÖKDEN ET AL
Fig 1. A glomerulus shows global endocapillary proliferation with numerous mononuclear cells in the capillary lumens (Jones silver stain; original magnification ⴛ200).
basement membrane showed normal thickness. There were no subendothelial or subepithelial deposits. There was 50% to 75% foot-process effacement. Visceral epithelial cells showed cytoplasmic vacuolization. The mesangium showed normal matrix and cellularity, no mesangial immunecomplex deposits, and no mesangial interposition. There was interstitial edema and infiltrate. Tubules were unremarkable.
Final Diagnosis The final diagnosis was acute rejection, CCTT type 2, with glomerulitis and C4d peritubular capillary staining, suggestive of a possible antibody-mediated component.1
Clinical Follow-Up On the day of the biopsy, the patient was treated with 1 dose of intravenous methylprednisolone sodium succinate, 250 mg. After biopsy results were known, she was treated with 7 daily doses of antithymocyte globulin (rabbit), 1.5 mg/kg/d, in addition to intravenous ganciclovir. She tolerated the therapy well and was discharged home on therapy with prednisone, FK506, and mycophenolate mofetil, with oral valganciclovir for cytomegalovirus prophylaxis. Her serum creatinine level has improved to 1.0 mg/dL (88 mol/L) and proteinuria has decreased, with a spot urinary protein-creatinine ratio less than 0.25.
Fig 2. A tubular profile shows 2 lymphocytes within the tubular epithelium (ie, tubulitis) (Jones silver stain; original magnification ⴛ400).
Fig 3. (A) An arteriole shows activated endothelium with an adherent lymphocyte (Jones silver stain; original magnification ⴛ1,000). (B) An interlobular artery shows 2 lymphocytes underneath the endothelial layer (ie, endothelialitis) (Jones silver stain; original magnification ⴛ400).
DISCUSSION
Our case represents a patient 6 weeks posttransplantation with endothelialitis and diffuse acute transplant glomerulitis characterized by an increased number of mononuclear cells and rare polymorphonuclear leukocytes in glomerular cap-
Fig 4. Immunofluorescence for C4d shows diffuse 2ⴙ positivity along the peritubular capillaries (anti-C4d antibody; original magnification ⴛ400).
MPGN PATTERN IN ALLOGRAFT
illary lumina, resulting in diminished capillary patency. In addition, there was endocapillary proliferation, increase in mesangial matrix, and cellularity with diffuse splitting of glomerular basement membranes reminiscent of MPGN. The initial differential diagnosis based on light microscopy in this patient included acute transplant glomerulitis or de novo MPGN, in addition to the acute rejection. Immunofluorescence microscopy did not show evidence of immune complex– mediated glomerulonephritis, excluding MPGN. Immunofluorescence for C4d was strongly positive in peritubular capillaries, which, along with the acute glomerulitis, suggests an antibodymediated component of the acute rejection.2 Acute transplant glomerulitis has been variously called transplant glomerulitis,3 endocapillary glomerulitis,4 acute allograft glomerulopathy,5 and early allograft glomerulitis.6 The incidence is reported to be 4% to 10% of renal allograft biopsies. In approximately 2% to 4% of biopsies, a severe diffuse form of glomerular injury is evident and dominates the histological pattern.7 The first detailed description of acute glomerulitis was made in 1981 by Richardson et al,8 who found an association with cytomegalovirus viremia. However, several other studies could not confirm this correlation between glomerulitis and active cytomegalovirus infection.9-12 Glomerular endothelial cell hypercellularity has been described at an early stage after transplantation in the early renal allograft7,8 and has been proposed as a particular pattern of glomerular rejection.9 However, the cause of acute transplant glomerulitis remains uncertain. Acute transplant glomerulitis is characterized morphologically by enlargement of the glomerular tuft, with swollen endothelial cells and accumulation of mononuclear cells in glomerular capillaries, resulting in closure of the capillary lumina. A significant increase in the relative number of mesangial cells also has been reported in acute transplant glomerulitis.13 Visceral epithelial cell proliferation is observed rarely, and when present, was only mild. Polymorphonuclear cells in glomeruli in acute transplant glomerulitis are rare. A fine web of periodic acid–Schiff–positive fibrils has been described in the capillary lumina between intracapillary cells and in areas of mesangiolysis. Occasional endothelial cell necrosis in glomeruli can be found,
575
and endothelial cells appear activated. The infiltrating mononuclear cells also have an activated appearance. Crescents are not found, and thrombi are rare.7 Acute transplant glomerulitis can be scored according to criteria of the Banff system. All glomeruli are affected in a global manner in the severe form (G3), but the lesion can be segmental and focal (G1). G2 is defined as segmental or global glomerulitis in 25% to 75% of glomeruli.14 The evolution of morphologically distinct changes in acute transplant glomerulitis has been described. The earliest stage is called evolving glomerulitis and is recognizable by swelling of endothelial and mesangial cells. The intermediate stage is characterized by enlarged glomeruli with lobular simplification, spongy matrix, and glomerular basement membrane deformities. In the advanced stage, the glomerular basement membrane shows reduplication and interposition with monocytes.15 Thus, our patient showed predominantly advanced stage lesions. The importance of acute transplant glomerulitis in the prognosis of renal allograft outcome is controversial. An association with poor graft survival was reported in earlier series.5,10,15 There was some correlation with conventional type 1 acute rejection, but 40% of all biopsy specimens with glomerulitis showed no rejection by standard criteria, and 53% of all biopsy specimens with rejection showed no glomerulitis.4 In a retrospective cohort study, acute transplant glomerulitis was associated significantly with a trend toward earlier rejection episodes, greater serum creatinine level at the time of the index biopsy, greater prevalence of vascular rejection, and less improvement in mean reciprocal serum creatinine level at 1 to 2 weeks after biopsy, but was not an independent predictor of graft survival.15 The association of acute transplant glomerulitis with a greater prevalence of variable degrees of endothelialitis/“vascular rejection” has been documented.14,15 In our case, acute transplant glomerulitis was associated with acute “vascular” rejection (CCTT type 2) and also strong C4d peritubular staining, a finding linked to humoral mechanisms of rejection. Conversely, there was only minimal lymphocytic infiltrate involving less than 5% of biopsy tissue, with occasional tubulitis, not diagnostic of acute “cellular” rejection (CCTT type 1). However, earlier studies
576
GÖKDEN ET AL
showed that acute transplant glomerulitis is not an independent predictor of graft survival. This graft lesion is not included in the Banff or CCTT classification systems as a criterion for the presence or grading of rejection. In summary, acute transplant glomerulitis may be a peculiar pattern of rejection with a pathogenesis different from that of conventional rejection, but present data do not show independent adverse effects on graft function or prognosis.4,11 Differentiation from other causes of MPGN-like pattern injury is important. This case illustrates the utility of immunofluorescence and electron microscopic study for workup in transplant recipients with unusual light microscopic findings. The association between vascular rejection and acute transplant glomerulitis should direct a very careful examination of sampled arteries in biopsy specimens with glomerulitis to ensure that endothelialitis, which may be focal, is detected when present and timely appropriate aggressive therapy is initiated. REFERENCES 1. Colvin RB, Cohen AH, Saiontz C, et al: Evaluation of pathologic criteria for acute renal allograft rejection: Reproducibility, sensitivity, and clinical correlation. J Am Soc Nephrol 8:1930-1941, 1997 2. Racusen LC, Colvin RB, Solez K, et al: Antibodymediated rejection criteria—An addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 3:708-714, 2003 3. Marcussen N, Solez K, Spencer E, Cockfield S, Olsen S: Early transplant glomerulitis; Glomerular size and ultrastructure. Transplant Proc 28:468-469, 1996
4. Olsen S, Spencer E, Cockfield S, Marcussen N, Solez K: Endocapillary glomerulitis in the renal allograft. Transplantation 59:1421-1425, 1995 5. Tuazon TV, Schneeberger EE, Bhan AK, et al: Mononuclear cells in acute transplant glomerulopathy. Am J Pathol 129:119-132, 1987 6. Racusen LC, Solez K, Colvin RB, et al: The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713-723, 1999 7. Colvin RB: Renal transplant pathology, in Jennette JC, Olson JL, Schwartz MM, Silva FG (eds): Heptinstall’s Pathology of the Kidney, vol 2 (ed 5). Philadelphia, PA, Lippincott-Raven, 1998, pp 1417-1418 8. Richardson WP, Colvin RB, Cheeseman SH, et al: Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med 305:57-63, 1981 9. Axelsen RA, Seymour AE, Mathew TH, Canny A, Pascoe V: Glomerular transplant rejection: A distinctive pattern of early graft damage. Clin Nephrol 23:1-11, 1985 10. Herrera AG, Alexander RV, Cooley CF, et al: Cytomegalovirus glomerulopathy: A controversial lesion. Kidney Int 29:725-733, 1986 11. Messias NC, Eustace JA, Zachary AA, Tucker PC, Charney D, Racusen LC: Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts. Transplantation 72:655-660, 2001 12. Boyce N, Hayes K, Gee D, et al: Cytomegalovirus infection complicating renal transplantation and its relationship to acute transplant glomerulopathy. Transplantation 45:706-709, 1988 13. Hanberg FS: A quantitative study of the renal corpuscles in acute renal allograft rejection. Acta Pathol Microbiol Scand (A) 85:367-372, 1977 14. Solez K, Axelsen R, Benediktsson H, et al: International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int 44:411-422, 1993 15. Maryniak RK, First MR, Weiss MA: Transplant glomerulopathy: Evolution of morphologically distinct changes. Kidney Int 27:799-806, 1985