- Email: [email protected]
Focal segmental glomerulosclerosis in one of two “en bloc” pediatric transplanted kidneys
Focal Segmental Glomerulosclerosis in One of Two “En Bloc” Pediatric Transplanted Kidneys Azemi Barama, MD, Rekka Gupta, MD, FRCPC, and Allan S. MacDonald,
MD, FRCSC
0 Focal segmental glomerulosclerosis (FSGS) is thought to have several causes, including hypertension, reduction of nephron mass, or immunologic processes. Experimental studies have underlined the role of glomerular adaptation to capillary pressure in the growing kidney after partial nephrectomy. We report here the occurrence of FSGS in one of two “en bloc” pediatric kidneys transplanted in an adult recipient. One of the kidneys sustained early ureteral obstruction requiring reoperation and subsequently developed pathological changes on biopsy consistent with FSGS, whereas the mate kidney did not, although both kidneys grew at equal rates and to equivalent sizes. 0 1997 by the National Kidney Foundation, Inc. INDEX WORDS: Focal segmental glomerulosclerosis;
ureteral obstruction;
F
OCAL segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome comprising proteinuria, hypertension, and azotemia. Based on hypothetical physiopathological mechanisms, diseases with primary alteration of glomerular epithelial cells, termed primary FSGS, are distinguished from diseases in which FSGS is a consequence of renal structural and hemodynamic changes, termed secondary FSGS.’ In the primary disorder, an undefined circulating factor has been postulated. In the secondary, reduction of functioning nephron units caused by conditions such as congenital deficit of nephrons, reflux nephropathy, and partial nephrectomy are believed to be involved. Since the first report by Hoyer et al2 in 1972, in patients in whom kidney transplantation was performed for FSGS-induced renal failure, recurrence in the grafted kidney has been reported with an incidence between 9% and 50%3-6 in single-center reports, and from 37%’ to 52%8 in multicenter studies with subsequent graft loss rates of 23% and 19%, respectively. De novo FSGS in kidney transplants has been associated with chronic rejection,’ as well as with kidney transplants that failed because of reflux nephropathy.” However, the pathophysiology of the glomerular sclerosis is unclear. We report the occurrence of FSGS in one of two “en bloc” pediatric kidney transplants. The pathological features of de novo FSGS were present only in the one kidney, which experienced an early posttransplantation obstruction of the ureter. CASE REPORT A 27-year-old, 40-kg, 140-cm tall woman with chronic renal failure secondary to Henoch-Schonlein glomerulopathy diagnosed at age 9, hypertensive for 12 years, started on peritoneal dialysis in August 1993. In December 1994, she American
Journal
of Kidney
Diseases,
Vol 30, No 2 (August),
%n bloc” pediatric kidney transplantation.
received an “en bloc” kidney transplant from a 2-year-old multiorgan donor. The donor and the recipient were mismatched at two human lymphocyte antigen (HLA) B and one HLA DR loci. Postoperative immunosuppression consisted of rapamycin (0.08 mg/kg/d), cyclosporine A (5 mg/kg/d), and prednisone. Two weeks later, she developed ureter obstruction in one of the transplanted kidneys. At reoperation, the obstructed kidney looked no different than its mate except for a twist in the ureter. To correct this, the graft renal pelvis was connected to the native ureter. An open biopsy of the unobstructed kidney was performed, and it showed mild acute rejection (grade I by Banff criteria) (Fig 1). One week later, she required reoperation because of a urinary leak from the ureteropelvic anastomosis. A necrotic area of renal pelvis was excised, and reanastomosis with the native ureter was done over a double pigtail stent. It was noted that both kidneys had increased substantially in size, but equally. The postoperative course was subsequently uneventful, with serum creatinine level stable at 164 pmol/L. The patient was started on metoprolol and nifedipine and discharged 27 days after transplantation. One month later, proteinuria of 0.3 g was noticed, rapidly increasing to 1.00 g and remaining stable. Microscopic hematuria was present. Her lipid profile was abnormal, with increased triglycerides to 456.1 mg/dL and cholesterol to 339.9 mg/dL. Nifedipine was replaced by enalaprll, and the patient was started on pravastatin sodium. The serum creatinine reached its nadir in July (1.16 mg/dL). Her blood pressure was well controlled and serum cyclosporine levels stable (150 to 250 ng/mL) at clinic visits every 2 months. In September, 10 months after transplantation, the patient presented with severe hypertension and a seizure. On admission, blood pressure was 240/130 mm Hg, proteinuria 5 g/L (11 g/total volume), serum creatinine 1.59 mg/dL, tri-
From the Kidney Transplant Program, the Department of Pathology, and the Department of Surgery, QE II Health Sciences Center, Dalhousie University, Halifax, Nova Scotia, Canada. ReceivedAugust 16,1996; accepted in revisedform March 3, 1997. Address reprint requests to AS. MacDonald, MD, FRCSC, QE II Health Sciences Center (VG site), Room 4134, Dickson Center, 1278 Tower Rd, Halifaw, NS, Canada B3H 2Y9. 0 1997 by the National Kidney Foundation, Inc. 0272-6386/97/3002-0016$3.00/O 1997:
pp 271-274
271
BARAMA,
272
~ i 1
glycerides 658 mg/dL, and cholesterol 417.2 mg/dL. A biopsy of the lower pole of the transplanted kidney, which had experienced the early obstruction, showed histological features of FSGS in four of eight glomendi, associated with moderate tubular atrophy. Electron microscopy showed segmental fusion of epithelial foot processes (Fig 2). Immunofluorescence showed granular immunoglobulin M (IgM), C3, and properdin in the glomerular capillaries. A biopsy of the mate kidney performed 2 weeks later showed six glomeruli with fibrin thrombi in glomerular capillaries and cytoplasmic vacuolization of tubular epithelial cells consistent with cyclosporine toxicity (Fig 3). No evidence of FSGS was noted. The enalapril was replaced by nifedipine, and the cyclosporine dose
Fig 2. Glomerulus FSGS (hematoxylin sin stain; original cation x400).
with and eomagnifi-
GUPTA,
AND
MACDONALD
Fig 1. Biopsy specimen from unobsbucted kidney. Mled inter&W and lymphocltic tubuliis. Acute rejection BanffgradsI@ematoxylinand eosin stain; original magnification x400).
was tapered, resulting in both a dramatic improvement in hypertension and a significant amelioration of proteinuria (1 .OOg/L), and improvement of hyperlipidemia (triglyceride, 264 mg/dL; cholesterol, 263.3 mg/dL), which has been monitored for the ensuing 12 months, now 24 months posttransplantation. DISCUSSION
It is commonly believed that the glomerular changes after renal transplantation are attributable to immune complexes, and recurrence where the primary disease is FSGS would therefore not
FSGS IN TRANSPLANTED
KIDNEYS
273
Fig 3. Kidney biopsy specimen from mate kidney. Note fibrin thrombi in arteriolar and glomerular capillary lumena, a lymphoid aggregate, and mild tubular cell degeneration (hematoxylin and eosin stain; original magnification x100).
be surprising. However, in this case of “de novo” FSGS, the histopathological changes in the kidney that experienced urinary complication and their absence in its mate suggest an alternate mechanism for the induction of the disease. The occurrence of FSGS in congenital deficits of nephron units in patient with unilateral agenesis, oligomeganephronia, and segmental hypoplasia has been reported.” The constant feature of FSGS seems to be glomerular hypertrophy and subsequent hemodynamic adaptation, as induced experimentally by five-sixths nephrectomy in animal experimentation.” The process of glomerulosclerosis in rats with subtotal nephrectomy is accompanied by an increase in glomerular size and ultrastructural alteration and ultimately sclerosis of remnant glomeruli. Increased renal flow caused by a discrepancy between the size of the graft and the recipient may play a key role in the occurrence of pathological changes in such kidneys. However, with pediatric kidneys, the number of nephrons is the same as in the adult, although their size is substantially smaller. Whether the initial blood flow in a pediatric kidney transplanted into an adult is greater than in the appropriate-sized child is unknown. Kidney grafts from pediatric donors transplanted into adult recipients undergo hypertrophy within 4 to 6 weeks posttransplantation.’ However, the incidence of FSGS in this group has not been reported to be excessive.
Among antihypertensive drugs, angiotensinconverting enzyme inhibitors (ACEIs), as renoprotective agents that reduce proteinuria, have been shown to be unable to control FSGS progression.14 In the current case, despite ACEIs, proteinuria persisted and the histological change of FSGS developed. Conversely, control of blood pressure by nifedipine and reduction in cyclosporine dose resulted in improvement in function, emphasizing the importance of blood pressure control. Urinary tract obstruction, which occurred early after transplantation in one kidney, was likely the pathophysiological mechanism in this case. What is unique in this case is that a second simultaneously transplanted kidney from the same donor was available to act as a control organ. It was spared the ureteral obstruction, but the discrepancy between pediatric organ size and adult blood flow was presumably the same for each graft, and it was exposed to the same degree of hypertension but did not develop FSGS. This case provides evidence that, in a growing kidney, the occurrence of a urinary tract obstruction alone can induce histological changes consistent with FSGS. REFERENCES 1. Rennke HG, Klein PS: Pathogenesis and significance of nonprimary focal segmantal glomerulosclerosis. Am J Kidney Dis 13:443-456, 1989
274 2. Hoyer JR, Vernier RL, Najarian J, Raij L, Simmons RL, Michael AI? Recurrence of idiopathic nephrotic syndrome renal transplantation. Lancet 2:343-348, 1972 3. Maize1 SE, Sibley RK, Horstman JP, Kjellstrand CM, Simmons RL: Incidence and significance of recurrent focal segmental glomerulosclerosis in renal allograft recipients. Transplantation 32512516, 1981 4. Cameron JS: Glomerulonephritis in renal transplants. Transplantation 34:237-245, 1982 5. Banfi G, Colturi C, Montagnino G, Ponticelli C: The recurrence of focal segmental glomerulosclerosis in kidney transplant patients treated with cyclosporine. Transplantation 50:594-596, 1990 6. Pinto J, Lacerda G, Cameron J, Turner DR. Bewick M, Ogg CS, and the Physicians, Pediatricians, and Pathologists of the South East Thames Renal Units: Recurrence of focal segmental glomerulosclerosis in renal allografts. Transplantation 32:83-89, 1981 7. Leumann EP, Briner J, Donckerwolcke RAM, Kuijten R, Largieder F: Recurrence of focal segmental glomerulosclerosis in the transplanted kidney. Nephron 25:65-71, 1980
BARAMA,
GUPTA,
AND
MACDONALD
8. Zimmerman CE: Renal transplantation for focal segmental glomerulosclerosis. Transplantation 29:172, 1980 9. Ettenger RB, Heuser ET, Malekzadeh MH, Pennisi AJ, Uittenbogaart CH, Fine RN: Focal glomerulosclerosis in renal allograft. Am J Dis Child 131:1347-1352, 1977 10. Mathew TH, Km&d-Smith P, Kraman P: Risk of vesicoureteric reflux in the transplanted kidney. N Engl J Med 297:414-418, 1977 11. Bhathena DB, Julian BA, McMormw RG, Baehler RW: Focal sclerosis of hyperttophied glomeruh in solitary functioning kidneys of humans. Am J Kidney Dis 5:226-232, 1985 12. Shimamura T, Morrison AB: A progressive glomerulosclerosis occurring in partial five-sixths nephrectomy. Am J Path01 79:95-101, 1975 13. Nghiem DD, Hsia S, Schlosser JD: Growth and function of en bloc infant kidney transplants: A preliminary study. J Urol 153:326-329, 1995 14. Tejani A, Butt K, Trachtman H, Suthanhiran M, Rosenthal CJ, Khamar MR: Cyclosporine A induced remission of relapsing nephrotic syndrome in children. Kidney Int 331729-734, 1988
MD, FRCSC
0 Focal segmental glomerulosclerosis (FSGS) is thought to have several causes, including hypertension, reduction of nephron mass, or immunologic processes. Experimental studies have underlined the role of glomerular adaptation to capillary pressure in the growing kidney after partial nephrectomy. We report here the occurrence of FSGS in one of two “en bloc” pediatric kidneys transplanted in an adult recipient. One of the kidneys sustained early ureteral obstruction requiring reoperation and subsequently developed pathological changes on biopsy consistent with FSGS, whereas the mate kidney did not, although both kidneys grew at equal rates and to equivalent sizes. 0 1997 by the National Kidney Foundation, Inc. INDEX WORDS: Focal segmental glomerulosclerosis;
ureteral obstruction;
F
OCAL segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome comprising proteinuria, hypertension, and azotemia. Based on hypothetical physiopathological mechanisms, diseases with primary alteration of glomerular epithelial cells, termed primary FSGS, are distinguished from diseases in which FSGS is a consequence of renal structural and hemodynamic changes, termed secondary FSGS.’ In the primary disorder, an undefined circulating factor has been postulated. In the secondary, reduction of functioning nephron units caused by conditions such as congenital deficit of nephrons, reflux nephropathy, and partial nephrectomy are believed to be involved. Since the first report by Hoyer et al2 in 1972, in patients in whom kidney transplantation was performed for FSGS-induced renal failure, recurrence in the grafted kidney has been reported with an incidence between 9% and 50%3-6 in single-center reports, and from 37%’ to 52%8 in multicenter studies with subsequent graft loss rates of 23% and 19%, respectively. De novo FSGS in kidney transplants has been associated with chronic rejection,’ as well as with kidney transplants that failed because of reflux nephropathy.” However, the pathophysiology of the glomerular sclerosis is unclear. We report the occurrence of FSGS in one of two “en bloc” pediatric kidney transplants. The pathological features of de novo FSGS were present only in the one kidney, which experienced an early posttransplantation obstruction of the ureter. CASE REPORT A 27-year-old, 40-kg, 140-cm tall woman with chronic renal failure secondary to Henoch-Schonlein glomerulopathy diagnosed at age 9, hypertensive for 12 years, started on peritoneal dialysis in August 1993. In December 1994, she American
Journal
of Kidney
Diseases,
Vol 30, No 2 (August),
%n bloc” pediatric kidney transplantation.
received an “en bloc” kidney transplant from a 2-year-old multiorgan donor. The donor and the recipient were mismatched at two human lymphocyte antigen (HLA) B and one HLA DR loci. Postoperative immunosuppression consisted of rapamycin (0.08 mg/kg/d), cyclosporine A (5 mg/kg/d), and prednisone. Two weeks later, she developed ureter obstruction in one of the transplanted kidneys. At reoperation, the obstructed kidney looked no different than its mate except for a twist in the ureter. To correct this, the graft renal pelvis was connected to the native ureter. An open biopsy of the unobstructed kidney was performed, and it showed mild acute rejection (grade I by Banff criteria) (Fig 1). One week later, she required reoperation because of a urinary leak from the ureteropelvic anastomosis. A necrotic area of renal pelvis was excised, and reanastomosis with the native ureter was done over a double pigtail stent. It was noted that both kidneys had increased substantially in size, but equally. The postoperative course was subsequently uneventful, with serum creatinine level stable at 164 pmol/L. The patient was started on metoprolol and nifedipine and discharged 27 days after transplantation. One month later, proteinuria of 0.3 g was noticed, rapidly increasing to 1.00 g and remaining stable. Microscopic hematuria was present. Her lipid profile was abnormal, with increased triglycerides to 456.1 mg/dL and cholesterol to 339.9 mg/dL. Nifedipine was replaced by enalaprll, and the patient was started on pravastatin sodium. The serum creatinine reached its nadir in July (1.16 mg/dL). Her blood pressure was well controlled and serum cyclosporine levels stable (150 to 250 ng/mL) at clinic visits every 2 months. In September, 10 months after transplantation, the patient presented with severe hypertension and a seizure. On admission, blood pressure was 240/130 mm Hg, proteinuria 5 g/L (11 g/total volume), serum creatinine 1.59 mg/dL, tri-
From the Kidney Transplant Program, the Department of Pathology, and the Department of Surgery, QE II Health Sciences Center, Dalhousie University, Halifax, Nova Scotia, Canada. ReceivedAugust 16,1996; accepted in revisedform March 3, 1997. Address reprint requests to AS. MacDonald, MD, FRCSC, QE II Health Sciences Center (VG site), Room 4134, Dickson Center, 1278 Tower Rd, Halifaw, NS, Canada B3H 2Y9. 0 1997 by the National Kidney Foundation, Inc. 0272-6386/97/3002-0016$3.00/O 1997:
pp 271-274
271
BARAMA,
272
~ i 1
glycerides 658 mg/dL, and cholesterol 417.2 mg/dL. A biopsy of the lower pole of the transplanted kidney, which had experienced the early obstruction, showed histological features of FSGS in four of eight glomendi, associated with moderate tubular atrophy. Electron microscopy showed segmental fusion of epithelial foot processes (Fig 2). Immunofluorescence showed granular immunoglobulin M (IgM), C3, and properdin in the glomerular capillaries. A biopsy of the mate kidney performed 2 weeks later showed six glomeruli with fibrin thrombi in glomerular capillaries and cytoplasmic vacuolization of tubular epithelial cells consistent with cyclosporine toxicity (Fig 3). No evidence of FSGS was noted. The enalapril was replaced by nifedipine, and the cyclosporine dose
Fig 2. Glomerulus FSGS (hematoxylin sin stain; original cation x400).
with and eomagnifi-
GUPTA,
AND
MACDONALD
Fig 1. Biopsy specimen from unobsbucted kidney. Mled inter&W and lymphocltic tubuliis. Acute rejection BanffgradsI@ematoxylinand eosin stain; original magnification x400).
was tapered, resulting in both a dramatic improvement in hypertension and a significant amelioration of proteinuria (1 .OOg/L), and improvement of hyperlipidemia (triglyceride, 264 mg/dL; cholesterol, 263.3 mg/dL), which has been monitored for the ensuing 12 months, now 24 months posttransplantation. DISCUSSION
It is commonly believed that the glomerular changes after renal transplantation are attributable to immune complexes, and recurrence where the primary disease is FSGS would therefore not
FSGS IN TRANSPLANTED
KIDNEYS
273
Fig 3. Kidney biopsy specimen from mate kidney. Note fibrin thrombi in arteriolar and glomerular capillary lumena, a lymphoid aggregate, and mild tubular cell degeneration (hematoxylin and eosin stain; original magnification x100).
be surprising. However, in this case of “de novo” FSGS, the histopathological changes in the kidney that experienced urinary complication and their absence in its mate suggest an alternate mechanism for the induction of the disease. The occurrence of FSGS in congenital deficits of nephron units in patient with unilateral agenesis, oligomeganephronia, and segmental hypoplasia has been reported.” The constant feature of FSGS seems to be glomerular hypertrophy and subsequent hemodynamic adaptation, as induced experimentally by five-sixths nephrectomy in animal experimentation.” The process of glomerulosclerosis in rats with subtotal nephrectomy is accompanied by an increase in glomerular size and ultrastructural alteration and ultimately sclerosis of remnant glomeruli. Increased renal flow caused by a discrepancy between the size of the graft and the recipient may play a key role in the occurrence of pathological changes in such kidneys. However, with pediatric kidneys, the number of nephrons is the same as in the adult, although their size is substantially smaller. Whether the initial blood flow in a pediatric kidney transplanted into an adult is greater than in the appropriate-sized child is unknown. Kidney grafts from pediatric donors transplanted into adult recipients undergo hypertrophy within 4 to 6 weeks posttransplantation.’ However, the incidence of FSGS in this group has not been reported to be excessive.
Among antihypertensive drugs, angiotensinconverting enzyme inhibitors (ACEIs), as renoprotective agents that reduce proteinuria, have been shown to be unable to control FSGS progression.14 In the current case, despite ACEIs, proteinuria persisted and the histological change of FSGS developed. Conversely, control of blood pressure by nifedipine and reduction in cyclosporine dose resulted in improvement in function, emphasizing the importance of blood pressure control. Urinary tract obstruction, which occurred early after transplantation in one kidney, was likely the pathophysiological mechanism in this case. What is unique in this case is that a second simultaneously transplanted kidney from the same donor was available to act as a control organ. It was spared the ureteral obstruction, but the discrepancy between pediatric organ size and adult blood flow was presumably the same for each graft, and it was exposed to the same degree of hypertension but did not develop FSGS. This case provides evidence that, in a growing kidney, the occurrence of a urinary tract obstruction alone can induce histological changes consistent with FSGS. REFERENCES 1. Rennke HG, Klein PS: Pathogenesis and significance of nonprimary focal segmantal glomerulosclerosis. Am J Kidney Dis 13:443-456, 1989
274 2. Hoyer JR, Vernier RL, Najarian J, Raij L, Simmons RL, Michael AI? Recurrence of idiopathic nephrotic syndrome renal transplantation. Lancet 2:343-348, 1972 3. Maize1 SE, Sibley RK, Horstman JP, Kjellstrand CM, Simmons RL: Incidence and significance of recurrent focal segmental glomerulosclerosis in renal allograft recipients. Transplantation 32512516, 1981 4. Cameron JS: Glomerulonephritis in renal transplants. Transplantation 34:237-245, 1982 5. Banfi G, Colturi C, Montagnino G, Ponticelli C: The recurrence of focal segmental glomerulosclerosis in kidney transplant patients treated with cyclosporine. Transplantation 50:594-596, 1990 6. Pinto J, Lacerda G, Cameron J, Turner DR. Bewick M, Ogg CS, and the Physicians, Pediatricians, and Pathologists of the South East Thames Renal Units: Recurrence of focal segmental glomerulosclerosis in renal allografts. Transplantation 32:83-89, 1981 7. Leumann EP, Briner J, Donckerwolcke RAM, Kuijten R, Largieder F: Recurrence of focal segmental glomerulosclerosis in the transplanted kidney. Nephron 25:65-71, 1980
BARAMA,
GUPTA,
AND
MACDONALD
8. Zimmerman CE: Renal transplantation for focal segmental glomerulosclerosis. Transplantation 29:172, 1980 9. Ettenger RB, Heuser ET, Malekzadeh MH, Pennisi AJ, Uittenbogaart CH, Fine RN: Focal glomerulosclerosis in renal allograft. Am J Dis Child 131:1347-1352, 1977 10. Mathew TH, Km&d-Smith P, Kraman P: Risk of vesicoureteric reflux in the transplanted kidney. N Engl J Med 297:414-418, 1977 11. Bhathena DB, Julian BA, McMormw RG, Baehler RW: Focal sclerosis of hyperttophied glomeruh in solitary functioning kidneys of humans. Am J Kidney Dis 5:226-232, 1985 12. Shimamura T, Morrison AB: A progressive glomerulosclerosis occurring in partial five-sixths nephrectomy. Am J Path01 79:95-101, 1975 13. Nghiem DD, Hsia S, Schlosser JD: Growth and function of en bloc infant kidney transplants: A preliminary study. J Urol 153:326-329, 1995 14. Tejani A, Butt K, Trachtman H, Suthanhiran M, Rosenthal CJ, Khamar MR: Cyclosporine A induced remission of relapsing nephrotic syndrome in children. Kidney Int 331729-734, 1988