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The different patterns of response to plasmapheresis of recurrent focal and segmental glomerulosclerosis
EVALUATION OF AND ALLOCATION TO CANDIDATES
The Different Patterns of Response to Plasmapheresis of Recurrent Focal and Segmental Glomerulosclerosis C. Ponticelli, M. Campise, and A. Tarantino
F
OCAL AND SEGMENTAL glomerulosclerosis (FSGS) is a renal disease that can affect both children and adults. The clinical course is characterized by nephrotic syndrome (NS) and frequent progression to end-stage renal failure. The possibility that FSGS may recur after transplantation was first demonstrated by Hoyer et al.1 Since then, a number of articles confirmed this possibility and pointed out a poor graft prognosis for patients with recurrence.2– 6 The observation that, in most cases of recurrence, proteinuria appears within a few hours after transplantation suggested the possibility that a circulating factor was responsible for increased glomerular permeability, proteinuria, and eventually FSGS. Savin et al7 identified in the plasma of patients with recurrent FSGS a substance that causes an immediate increase in the glomerular permeability of isolated rat glomeruli. This substance might be a plasma protein bound to immunoglobulins, which can be removed by plasmaexchange with consequent improvement of proteinuria.7,8 On the basis of these results, several trials with plasmapheresis (PP) or immunoadsorption by protein A have been conducted in transplant recipients with recurrent FSGS.9 –13 Unfortunately, most of the available studies reported only short-term follow-up periods of patients treated with PP or protein A immunoadsorption. In this article, we report the long-term outcomes of three cases of posttransplantation recurrence of FSGS treated with PP to show the different and unpredictable response to this treatment.
PATIENTS AND METHODS Patient 1 A 21-year-old man was diagnosed with biopsy-proven FSGS associated with full-blown NS. In spite of high-dose prednisone and cyclophosphamide, his renal function rapidly deteriorated and he started hemodialysis approximately 30 months after the clinical onset. Fifteen months later, in April 1986, he received a cadaveric renal transplant. Immunosuppressive treatment consisted of cyclosporine (CsA), azathioprine (Aza), and prednisone. On day 4, a nephrotic proteinuria appeared. The patient was given angiotensinconverting enzyme (ACE) inhibitors without improvement of proteinuria. On day 45, he underwent a graft biopsy that showed a recurrence of FSGS. His serum creatinine level progressively increased and the patient had to restart dialysis 63 months after transplantation. After 10 months of hemodialysis, the patient received a second cadaveric renal transplantation in May 1992. He was treated with CsA and prednisone. Graft function recovered immediately but nephrotic proteinuria appeared on the day 5. Proteinuria spontaneously reduced, however, and eventually disappeared after a few days. The patient remained without proteinuria until the end of the first posttransplantation year when nephrotic proteinuria reappeared (5 g/d). A graft biopsy showed a typical FSGS with extensive effacement of foot processes at electron microscopy. A course of PP was started, 9 over the first 15 days followed by 1 to 2 PP per From the U.O. Nefrologia IRCCS Ospedale Maggiore, Milano, Italy. Address reprint requests to Claudio Ponticelli, MD, U.O. Nefrologia IRCCS Ospedale Maggiore, Via della Commenda, 15 20122, Milano, Italy. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03655-2
Transplantation Proceedings, 34, 3069 –3071 (2002)
3069
3070 week for 7 months. Proteinuria rapidly improved and completely disappeared 5 months’ later. After 7 months from PP discontinuation, nephrotic proteinuria (6 g/d) reappeared. PP was restarted: three sessions per week for 2 weeks, then two sessions per week for 2 months, then one session per week for 2 months, and eventually one session every fortnight until discontinuation. At the end of the PP course, a mild proteinuria (0.5 g/d) was still present but progressively decreased until complete and definitive disappearance. At the most recent follow-up, 10 years after the second transplantation, the serum creatinine level was 0.8 mg/dL and proteinuria was 0.02 g/d.
Patient 2 An 18-year-old man developed severe proteinuria and microhematuria. Renal biopsy showed a typical pattern of FSGS. In spite of treatment with high-dose prednisone, cyclophosphamide, and CsA, his renal function progressively worsened and he had to start hemodialysis 2 years after the diagnosis. Six months later in May 1995 he received a living donor kidney transplantation from his mother. Immunosuppression consisted of CsA, Aza, and prednisone. Renal function promptly recovered but 3 days after transplantation NS developed. PP was started (once a day for the first week gradually tapered to once a week for the next 2 months), Csa dosage was increased from 10 to 12 mg/kg/d, and enalapril, 20 mg/d, was added. Proteinuria decreased to 1 g/d whereas plasma creatinine level remained unchanged, ranging around 1.3 mg/dL. One month later he developed an upper respiratory tract infection, followed by a relapse of nephrotic proteinuria and an increase in plasma creatinine level to 1.7 mg/dL. A graft biopsy showed a typical FSGS. The patient was treated with a further course of PP gradually tapered to one session every fortnight. Proteinuria decreased to 1 g/d and plasma creatinine level reduced to 1.5 mg/dL. In February 2001 after a flu-like syndrome, the patient had a relapse of full-blown NS (proteinuria 15 g/d) with an increase of plasma creatinine level to 2.1 mg/dL. A second graft biopsy showed segmental and diffuse sclerotic lesions of the glomeruli associated with severe tubulo-interstitial damage. The PP rhythm was increased to three sessions per week for 2 weeks, then to one session per week. Proteinuria improved (from 16 to 2 g/d). He continued with one PP a week Seven years after transplantation the patient voluntarily interrupted the PP. Proteinuria and plasma creatinine level increased. He now has nephrotic proteinuria (4.5 g/d) and a plasma creatinine level of 2.1 mg/dL. Recently, he has been tested for the permeability factor, which was positive (0.65).
Patient 3 A 19-year-old woman underwent renal biopsy because of a NS. A diagnosis of minimal change glomerulonephritis was made. She was treated with prednisone and then with cyclophospamide without any responese. A few months later, she underwent a second renal biopsy, which showed a FSGS. A treatment with CsA obtained a partial remission of the NS but was interrupted after 14 weeks because of an increase in plasma creatinine level. In the following years, renal failure continued to progress and the patient had to start chronic hemodalysis in May 1995. On June 1997 she underwent a living donor kidney transplantation from her mother. She was treated with CsA and prednisone. On day 4, the patient had an acute rejection which was treated with three intravenous high-dose metylprednisolone pulses. Plasma creatinine levels rapidly improved from 1.8 to 1.4 mg/dL but
PONTICELLI, CAMPISE, AND TARANTINO proteinuria appeared and progressively increased up to 10 g/d. PP was started and after three sessions proteinuria decreased to 0.26 g/d. PP was interrupted. Six months later, enalapril also was withdrawn because of anemia. At the most recent observation 5 years after transplantation, the patient is without proteinuria. Her plasma creatinine level is 1.4 mg/dL.
DISCUSSION
The recurrence of FSGS after transplantation ranges between 20% and 30%,14,15 but is almost constant in retransplanted patients who lost the previous graft for recurrent FSGS.16 –18 The prognosis is poor for patients with recurrence as half of them lose their allograft within a few months after the diagnosis of recurrence.6,14 Sporadic cases of success have been reported in children with high-dose CsA19 or cyclophosphamide,20 but in most cases pharmacological treatment is of little if any help. The best results have been reported with PP or with immunoadsorption with protein A. The rationale for such a treatment rests on the evidence that patients with recurrence of FSGS have a circulating permeability factor that can be removed by plasma exchange. Moreover, a recent study showed that the injection of a human FSGS factor to normal Sprague-Dawley rats induces proteinuria.21 A review of the literature found remission of proteinuria in 32 of 44 patients with recurrent FSGS. Only the presence of sclerosis at the time of biopsy of the graft predicted treatment failure.22 In most cases, however, the follow-up was short, thus it is difficult to assess the impact of plasma exchange on the long-term outcome. In this article we described three different examples of effectiveness of PP. Case 1, partially reported elsewhere,23 has several peculiar characteristics. As expected, this patient who lost his first graft because of recurrent FSGS, had another recurrence after retransplantation. NS spontaneously disappeared, however, and the patient remained without proteinuria for almost 1 year. Spontaneous remission of nephrotic proteinuria after recurrent FSGS is possible17 but exceptional. At any rate, the patient had a relapse of NS that reverted after intensive PP. He had a relapse of proteinuria a few months later. A new course of PP obtained stable remission. The patient is still without proteinuria after 10 years. The analysis of this case gives several messages: (1) spontaneous remission may occur even in re-recurrent FSGS, (2) although early PP must be recommended in recurrent FSGS, late PP also may obtain remission of NS in some transplant recipients with already established histological lesions on the allograft, and (3) PP also can obtain long-term remission in patients with repeated relapses of NS after transplantation. Case 2 is an example of PP-dependence. This young patient had recurrence of severe proteinuria whenever PP was interrupted. Eventually it was decided to continue PP. Proteinuria maintained in a subnephrotic range and plasma creatinine level remained stable. The voluntary interruption of plasmapheresis after 7 years of treatment led to an overt
PATTERNS OF RESPONSE TO PLASMAPHERESIS
NS and a graft function deterioration. Nevertheless, the transplanted kidney is still working. A few cases of PPdependence have been reported already.8,9,11 Whether or not one should insist on PP in these patients is still unclear. The example of our patient may support the decision of offering a prolonged PP treatment to patients with frequent relapses or who are PP-dependent. Such a strategy may maintain proteinuria within an acceptable range and may help in protecting from graft dysfunction caused by FSGS progression itself. Case 3 represents the most optimistic example of an excellent response to PP. This woman had an onset of nephrotic proteinuria after an early acute rejection. Although graft biopsy was not performed, it is likely that the increase in proteinuria was due to a recurrence of FSGS. In fact, proteinuria continued to increase while plasma creatinine level rapidly improved after a short course of intravenous methylprednisolone pulses. Of interest, she had complete and stable remission of proteinuria after three PP. We cannot exclude a spontaneous remission, although it is very unusual in patients with recurrence. In summary, we have presented three cases of patients with recurrent FSGS who had different responses to PP. The transplant physician should be aware of the potential of such a treatment. Some patients may show an early, complete, and stable response. Other patients become PPdependent. Finally, although there is general agreement that plasma exchange or protein A immunoadsorption should be applied as early as possible, a good response may be obtained even in some cases of late treatment. REFERENCES 1. Hoyer JR, Raij L, Vernier RL, et al: Lancet 2:343, 1972
3071 2. Leuman EP, Briner J, Donckerwolcke RAM, et al: Nephron 25:65, 1980 3. Pinto J, Lacerda G, Cameron JS, et al: Transplantation 32:81, 1981 4. Axelsen RA, Seymur AE, Mathew TH, et al: Clin Nephrol 21:110, 1984 5. Striegel JE, Sibley RK, Fryd DS, et al: Kidney Int 30:S44, 1986 6. Banfi G, Colturi C, Montagnino G, et al: Transplantation 50:594, 1990 7. Savin VJ, Sharma R, Sharma M, et al: N Engl J Med 334:878, 1996 8. Dantal J, Goodfrin Y, Koll R, et al: J Am Soc Nephrol 9:1709, 1998 9. Andresdottir MB, Ajubi N, Croockewit S, et al: Nephrol Dial Transplant 14:2650, 1999 10. Franke D, Zimmering M, Wolfish N, et al: Pediatr Nephrol 14:965, 2000 11. Matalon A, Markowitz GS, Joseph RE, et al: Clin Nephrol 56:271, 2001 12. Bosh T, Wendler T: Ther Apheresis 5:155, 2001 13. Ohta T, Kawaguchi H, Hattori M, et al: Transplantation 71:628, 2001 14. Dantal J, Baatard R, Hourmant M, et al: Transplantation 52:827, 1991 15. Baum MA, Stablein DM, Panzarino VM, et al: Am J Kidney Dis 59:328, 2001 16. Artero M, Biava C, Amend W, et al: Am J Med 92:375, 1992 17. Stephanian E, Matas AJ, Mauer SM, et al: Transplantation 53:755, 1992 18. Dall’Amico R, Ghiggeri G, Carraro M, et al: Am J Kidney Dis 34:1048, 1999 19. Ingulli E, Tejani A: Transplantation 51:401, 1991 20. Cochat P, Kassir A, Colon S, et al: Pediatr Nephrol 7:50, 1993 21. Sharma M, Sharma R, Reddy SR, et al: Transplantation 73:366, 2002 22. Davenport RD: J Clin Apheresis 16:175, 2001 23. Montagnino G, Tarantino A, Banfi G, et al: Transplant Int 13:166, 2000
The Different Patterns of Response to Plasmapheresis of Recurrent Focal and Segmental Glomerulosclerosis C. Ponticelli, M. Campise, and A. Tarantino
F
OCAL AND SEGMENTAL glomerulosclerosis (FSGS) is a renal disease that can affect both children and adults. The clinical course is characterized by nephrotic syndrome (NS) and frequent progression to end-stage renal failure. The possibility that FSGS may recur after transplantation was first demonstrated by Hoyer et al.1 Since then, a number of articles confirmed this possibility and pointed out a poor graft prognosis for patients with recurrence.2– 6 The observation that, in most cases of recurrence, proteinuria appears within a few hours after transplantation suggested the possibility that a circulating factor was responsible for increased glomerular permeability, proteinuria, and eventually FSGS. Savin et al7 identified in the plasma of patients with recurrent FSGS a substance that causes an immediate increase in the glomerular permeability of isolated rat glomeruli. This substance might be a plasma protein bound to immunoglobulins, which can be removed by plasmaexchange with consequent improvement of proteinuria.7,8 On the basis of these results, several trials with plasmapheresis (PP) or immunoadsorption by protein A have been conducted in transplant recipients with recurrent FSGS.9 –13 Unfortunately, most of the available studies reported only short-term follow-up periods of patients treated with PP or protein A immunoadsorption. In this article, we report the long-term outcomes of three cases of posttransplantation recurrence of FSGS treated with PP to show the different and unpredictable response to this treatment.
PATIENTS AND METHODS Patient 1 A 21-year-old man was diagnosed with biopsy-proven FSGS associated with full-blown NS. In spite of high-dose prednisone and cyclophosphamide, his renal function rapidly deteriorated and he started hemodialysis approximately 30 months after the clinical onset. Fifteen months later, in April 1986, he received a cadaveric renal transplant. Immunosuppressive treatment consisted of cyclosporine (CsA), azathioprine (Aza), and prednisone. On day 4, a nephrotic proteinuria appeared. The patient was given angiotensinconverting enzyme (ACE) inhibitors without improvement of proteinuria. On day 45, he underwent a graft biopsy that showed a recurrence of FSGS. His serum creatinine level progressively increased and the patient had to restart dialysis 63 months after transplantation. After 10 months of hemodialysis, the patient received a second cadaveric renal transplantation in May 1992. He was treated with CsA and prednisone. Graft function recovered immediately but nephrotic proteinuria appeared on the day 5. Proteinuria spontaneously reduced, however, and eventually disappeared after a few days. The patient remained without proteinuria until the end of the first posttransplantation year when nephrotic proteinuria reappeared (5 g/d). A graft biopsy showed a typical FSGS with extensive effacement of foot processes at electron microscopy. A course of PP was started, 9 over the first 15 days followed by 1 to 2 PP per From the U.O. Nefrologia IRCCS Ospedale Maggiore, Milano, Italy. Address reprint requests to Claudio Ponticelli, MD, U.O. Nefrologia IRCCS Ospedale Maggiore, Via della Commenda, 15 20122, Milano, Italy. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03655-2
Transplantation Proceedings, 34, 3069 –3071 (2002)
3069
3070 week for 7 months. Proteinuria rapidly improved and completely disappeared 5 months’ later. After 7 months from PP discontinuation, nephrotic proteinuria (6 g/d) reappeared. PP was restarted: three sessions per week for 2 weeks, then two sessions per week for 2 months, then one session per week for 2 months, and eventually one session every fortnight until discontinuation. At the end of the PP course, a mild proteinuria (0.5 g/d) was still present but progressively decreased until complete and definitive disappearance. At the most recent follow-up, 10 years after the second transplantation, the serum creatinine level was 0.8 mg/dL and proteinuria was 0.02 g/d.
Patient 2 An 18-year-old man developed severe proteinuria and microhematuria. Renal biopsy showed a typical pattern of FSGS. In spite of treatment with high-dose prednisone, cyclophosphamide, and CsA, his renal function progressively worsened and he had to start hemodialysis 2 years after the diagnosis. Six months later in May 1995 he received a living donor kidney transplantation from his mother. Immunosuppression consisted of CsA, Aza, and prednisone. Renal function promptly recovered but 3 days after transplantation NS developed. PP was started (once a day for the first week gradually tapered to once a week for the next 2 months), Csa dosage was increased from 10 to 12 mg/kg/d, and enalapril, 20 mg/d, was added. Proteinuria decreased to 1 g/d whereas plasma creatinine level remained unchanged, ranging around 1.3 mg/dL. One month later he developed an upper respiratory tract infection, followed by a relapse of nephrotic proteinuria and an increase in plasma creatinine level to 1.7 mg/dL. A graft biopsy showed a typical FSGS. The patient was treated with a further course of PP gradually tapered to one session every fortnight. Proteinuria decreased to 1 g/d and plasma creatinine level reduced to 1.5 mg/dL. In February 2001 after a flu-like syndrome, the patient had a relapse of full-blown NS (proteinuria 15 g/d) with an increase of plasma creatinine level to 2.1 mg/dL. A second graft biopsy showed segmental and diffuse sclerotic lesions of the glomeruli associated with severe tubulo-interstitial damage. The PP rhythm was increased to three sessions per week for 2 weeks, then to one session per week. Proteinuria improved (from 16 to 2 g/d). He continued with one PP a week Seven years after transplantation the patient voluntarily interrupted the PP. Proteinuria and plasma creatinine level increased. He now has nephrotic proteinuria (4.5 g/d) and a plasma creatinine level of 2.1 mg/dL. Recently, he has been tested for the permeability factor, which was positive (0.65).
Patient 3 A 19-year-old woman underwent renal biopsy because of a NS. A diagnosis of minimal change glomerulonephritis was made. She was treated with prednisone and then with cyclophospamide without any responese. A few months later, she underwent a second renal biopsy, which showed a FSGS. A treatment with CsA obtained a partial remission of the NS but was interrupted after 14 weeks because of an increase in plasma creatinine level. In the following years, renal failure continued to progress and the patient had to start chronic hemodalysis in May 1995. On June 1997 she underwent a living donor kidney transplantation from her mother. She was treated with CsA and prednisone. On day 4, the patient had an acute rejection which was treated with three intravenous high-dose metylprednisolone pulses. Plasma creatinine levels rapidly improved from 1.8 to 1.4 mg/dL but
PONTICELLI, CAMPISE, AND TARANTINO proteinuria appeared and progressively increased up to 10 g/d. PP was started and after three sessions proteinuria decreased to 0.26 g/d. PP was interrupted. Six months later, enalapril also was withdrawn because of anemia. At the most recent observation 5 years after transplantation, the patient is without proteinuria. Her plasma creatinine level is 1.4 mg/dL.
DISCUSSION
The recurrence of FSGS after transplantation ranges between 20% and 30%,14,15 but is almost constant in retransplanted patients who lost the previous graft for recurrent FSGS.16 –18 The prognosis is poor for patients with recurrence as half of them lose their allograft within a few months after the diagnosis of recurrence.6,14 Sporadic cases of success have been reported in children with high-dose CsA19 or cyclophosphamide,20 but in most cases pharmacological treatment is of little if any help. The best results have been reported with PP or with immunoadsorption with protein A. The rationale for such a treatment rests on the evidence that patients with recurrence of FSGS have a circulating permeability factor that can be removed by plasma exchange. Moreover, a recent study showed that the injection of a human FSGS factor to normal Sprague-Dawley rats induces proteinuria.21 A review of the literature found remission of proteinuria in 32 of 44 patients with recurrent FSGS. Only the presence of sclerosis at the time of biopsy of the graft predicted treatment failure.22 In most cases, however, the follow-up was short, thus it is difficult to assess the impact of plasma exchange on the long-term outcome. In this article we described three different examples of effectiveness of PP. Case 1, partially reported elsewhere,23 has several peculiar characteristics. As expected, this patient who lost his first graft because of recurrent FSGS, had another recurrence after retransplantation. NS spontaneously disappeared, however, and the patient remained without proteinuria for almost 1 year. Spontaneous remission of nephrotic proteinuria after recurrent FSGS is possible17 but exceptional. At any rate, the patient had a relapse of NS that reverted after intensive PP. He had a relapse of proteinuria a few months later. A new course of PP obtained stable remission. The patient is still without proteinuria after 10 years. The analysis of this case gives several messages: (1) spontaneous remission may occur even in re-recurrent FSGS, (2) although early PP must be recommended in recurrent FSGS, late PP also may obtain remission of NS in some transplant recipients with already established histological lesions on the allograft, and (3) PP also can obtain long-term remission in patients with repeated relapses of NS after transplantation. Case 2 is an example of PP-dependence. This young patient had recurrence of severe proteinuria whenever PP was interrupted. Eventually it was decided to continue PP. Proteinuria maintained in a subnephrotic range and plasma creatinine level remained stable. The voluntary interruption of plasmapheresis after 7 years of treatment led to an overt
PATTERNS OF RESPONSE TO PLASMAPHERESIS
NS and a graft function deterioration. Nevertheless, the transplanted kidney is still working. A few cases of PPdependence have been reported already.8,9,11 Whether or not one should insist on PP in these patients is still unclear. The example of our patient may support the decision of offering a prolonged PP treatment to patients with frequent relapses or who are PP-dependent. Such a strategy may maintain proteinuria within an acceptable range and may help in protecting from graft dysfunction caused by FSGS progression itself. Case 3 represents the most optimistic example of an excellent response to PP. This woman had an onset of nephrotic proteinuria after an early acute rejection. Although graft biopsy was not performed, it is likely that the increase in proteinuria was due to a recurrence of FSGS. In fact, proteinuria continued to increase while plasma creatinine level rapidly improved after a short course of intravenous methylprednisolone pulses. Of interest, she had complete and stable remission of proteinuria after three PP. We cannot exclude a spontaneous remission, although it is very unusual in patients with recurrence. In summary, we have presented three cases of patients with recurrent FSGS who had different responses to PP. The transplant physician should be aware of the potential of such a treatment. Some patients may show an early, complete, and stable response. Other patients become PPdependent. Finally, although there is general agreement that plasma exchange or protein A immunoadsorption should be applied as early as possible, a good response may be obtained even in some cases of late treatment. REFERENCES 1. Hoyer JR, Raij L, Vernier RL, et al: Lancet 2:343, 1972
3071 2. Leuman EP, Briner J, Donckerwolcke RAM, et al: Nephron 25:65, 1980 3. Pinto J, Lacerda G, Cameron JS, et al: Transplantation 32:81, 1981 4. Axelsen RA, Seymur AE, Mathew TH, et al: Clin Nephrol 21:110, 1984 5. Striegel JE, Sibley RK, Fryd DS, et al: Kidney Int 30:S44, 1986 6. Banfi G, Colturi C, Montagnino G, et al: Transplantation 50:594, 1990 7. Savin VJ, Sharma R, Sharma M, et al: N Engl J Med 334:878, 1996 8. Dantal J, Goodfrin Y, Koll R, et al: J Am Soc Nephrol 9:1709, 1998 9. Andresdottir MB, Ajubi N, Croockewit S, et al: Nephrol Dial Transplant 14:2650, 1999 10. Franke D, Zimmering M, Wolfish N, et al: Pediatr Nephrol 14:965, 2000 11. Matalon A, Markowitz GS, Joseph RE, et al: Clin Nephrol 56:271, 2001 12. Bosh T, Wendler T: Ther Apheresis 5:155, 2001 13. Ohta T, Kawaguchi H, Hattori M, et al: Transplantation 71:628, 2001 14. Dantal J, Baatard R, Hourmant M, et al: Transplantation 52:827, 1991 15. Baum MA, Stablein DM, Panzarino VM, et al: Am J Kidney Dis 59:328, 2001 16. Artero M, Biava C, Amend W, et al: Am J Med 92:375, 1992 17. Stephanian E, Matas AJ, Mauer SM, et al: Transplantation 53:755, 1992 18. Dall’Amico R, Ghiggeri G, Carraro M, et al: Am J Kidney Dis 34:1048, 1999 19. Ingulli E, Tejani A: Transplantation 51:401, 1991 20. Cochat P, Kassir A, Colon S, et al: Pediatr Nephrol 7:50, 1993 21. Sharma M, Sharma R, Reddy SR, et al: Transplantation 73:366, 2002 22. Davenport RD: J Clin Apheresis 16:175, 2001 23. Montagnino G, Tarantino A, Banfi G, et al: Transplant Int 13:166, 2000