American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1131-1144 , December 2009

Proteinuria in Kidney Transplant Recipients: Prevalence, Prognosis, and Evidence-Based Management

  • Greg A. Knoll, MD, MSc

      Affiliations

    • Division of Nephrology, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    • Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    • Corresponding Author InformationAddress correspondence to Greg A. Knoll, MD, MSc, Division of Nephrology, The Ottawa Hospital, Riverside Campus, 1967 Riverside Dr, Ottawa, Ontario, Canada K1H 7W9

Received 7 April 2009 ,Accepted 5 June 2009.

References 

  1. Palmer BF. Proteinuria as a therapeutic target in patients with chronic kidney disease. Am J Nephrol. 2007;27:287–293
  2. Sarafidis PA, Bakris GL. Microalbuminuria and chronic kidney disease as risk factors for cardiovascular disease. Nephrol Dial Transplant. 2006;21:2366–2374
  3. Vassalotti JA, Stevens LA, Levey AS. Testing for chronic kidney disease: A position statement from the National Kidney Foundation. Am J Kidney Dis. 2007;50:169–180
  4. Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis. 2007;49:12–26
  5. Fernandez-Fresnedo G, Escallada R, Rodrigo E, et al. The risk of cardiovascular disease associated with proteinuria in renal transplant patients. Transplantation. 2002;73:1345–1348
  6. Rose BD, Post TW. Measurement of urinary protein excretion (UpToDate 17.1). http://www.utdol.comAccessed January 13, 2009
  7. Schaub S, Mayr M, Honger G, et al. Detection of subclinical tubular injury after renal transplantation: Comparison of urine protein analysis with allograft histopathology. Transplantation. 2007;84:104–112
  8. Schaub S, Rush D, Wilkins J, et al. Proteomic-based detection of urine proteins associated with acute renal allograft rejection. J Am Soc Nephrol. 2004;15:219–227
  9. Garg AX, Muirhead N, Knoll G, et al. Proteinuria and reduced kidney function in living kidney donors: A systematic review, meta-analysis, and meta-regression. Kidney Int. 2006;70:1801–1810
  10. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, classification and stratification. Am J Kidney Dis. 2003;39(suppl 1):S1–S266
  11. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67:2089–2100
  12. Steinhauslin F, Wauters JP. Quantitation of proteinuria in kidney transplant patients: Accuracy of the urinary protein/creatinine ratio. Clin Nephrol. 1995;43:110–115
  13. Rodrigo E, Pinera C, Ruiz JC, et al. Quantitation of 24-hour urine protein excretion in kidney transplant patients by the use of protein to creatinine ratio. Transplant Proc. 2003;35:702
  14. Torng S, Rigatto C, Rush DN, Nickerson P, Jeffery JR. The urine protein to creatinine ratio (P/C) as a predictor of 24-hour urine protein excretion in renal transplant patients. Transplantation. 2001;72:1453–1456
  15. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med. 1983;309:1543–1546
  16. First MR, Vaidya PN, Maryniak RK, et al. Proteinuria following transplantation (Correlation with histopathology and outcome). Transplantation. 1984;38:607–612
  17. Yakupoglu U, Baranowska-Daca E, Rosen D, Barrios R, Suki WN, Truong LD. Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study. Kidney Int. 2004;65:2360–2370
  18. Chung J, Park SK, Park JS, Kim SC, Han DJ, Yu E. Glomerulonephritis is the major cause of proteinuria in renal transplant recipients: Histopathologic findings of renal allografts with proteinuria. Clin Transplant. 2000;14:499–504
  19. Fernandez-Fresnedo G, Plaza JJ, Sanchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M. Proteinuria: A new marker of long-term graft and patient survival in kidney transplantation. Nephrol Dial Transplant. 2004;19:47–51
  20. Halimi JM, Laouad I, Buchler M, et al. Early low-grade proteinuria: Causes, short-term evolution and long-term consequences in renal transplantation. Am J Transplant. 2005;5:2281–2288
  21. Karthikeyan V, Karpinski J, Nair RC, Knoll G. The burden of chronic kidney disease in renal transplant recipients. Am J Transplant. 2004;4:262–269
  22. Kim HC, Park SB, Lee SH, Park KK, Park CH, Cho WH. Proteinuria in renal transplant recipients: Incidence, cause, and prognostic importance. Transplant Proc. 1994;26:2134–2135
  23. Park JH, Park JH, Bok HJ, et al. Persistent proteinuria as a prognostic factor for determining long-term graft survival in renal transplant recipients. Transplant Proc. 2000;32:1924
  24. Vathsala A, Verani R, Schoenberg L, et al. Proteinuria in cyclosporine-treated renal transplant recipients. Transplantation. 1990;49:35–41
  25. Amer H, Fidler ME, Myslak M, et al. Proteinuria after kidney transplantation, relationship to allograft histology and survival. Am J Transplant. 2007;7:2748–2756
  26. Sancho A, Gavela E, Avila A, et al. Risk factors and prognosis for proteinuria in renal transplant recipients. Transplant Proc. 2007;39:2145–2147
  27. Ibis A, Altunoglu A, Akgul A, et al. Early onset proteinuria after renal transplantation: A marker for allograft dysfunction. Transplant Proc. 2007;39:938–940
  28. Roodnat JI, Mulder PG, Rischen-Vos J, et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation. 2001;72:438–444
  29. Boulware LE, Jaar BG, Tarver-Carr ME, Brancati FL, Powe NR. Screening for proteinuria in US adults: A cost-effectiveness analysis. JAMA. 2003;290:3101–3114
  30. Akbari A, Hussain N, Karpinski J, Knoll GA. Chronic kidney disease management: Comparison between renal transplant recipients and nontransplant patients with chronic kidney disease. Nephron. 2007;107:c7–c13
  31. Myslak M, Amer H, Morales P, et al. Interpreting post-transplant proteinuria in patients with proteinuria pre-transplant. Am J Transplant. 2006;6:1660–1665
  32. D'Cunha PT, Parasuraman R, Venkat KK. Rapid resolution of proteinuria of native kidney origin following live donor renal transplantation. Am J Transplant. 2005;5:351–355
  33. Laplante L, Beaudry C, Houde M. Early disappearance of proteinuria attributed to the original kidneys after kidney transplantation. Union Med Canada. 1975;104:246–248
  34. Solez K, Colvin RB, Racusen LC, et al. Banff '05 meeting report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN'). Am J Transplant. 2007;7:518–526
  35. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: A meta-analysis of patient-level data. Ann Intern Med. 2001;135:73–87
  36. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860
  37. Fellstrom B, Holdaas H, Jardine AG, et al. Risk factors for reaching renal endpoints in the Assessment of Lescol in Renal Transplantation Trial. Transplantation. 2005;79:205–212
  38. Fontan MP, Rodriguez-Carmona A, Garcia FT, Valdes F. Early proteinuria in renal transplant recipients treated with cyclosporin. Transplantation. 1999;67:561–568
  39. Letavernier E, Legendre C. mToR inhibitors-induced proteinuria: Mechanisms, significance, and management. Transplant Rev. 2008;22:125–130
  40. Ruiz JC, Campistol JM, Sanchez-Fructuoso A, et al. Increase of proteinuria after conversion from calcineurin inhibitor to sirolimus-based treatment in kidney transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant. 2006;21:3252–3257
  41. Boratynska M, Banasik M, Watorek E, et al. Conversion to sirolimus from cyclosporine may induce nephrotic proteinuria and progressive deterioration of renal function in chronic allograft nephropathy patients. Transplant Proc. 2006;38:101–104
  42. Saurina A, Campistol JM, Piera C, et al. Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: Changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transplant. 2006;21:488–493
  43. Bumbea V, Kamar N, Ribes D, et al. Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant. 2005;20:2517–2523
  44. Letavernier E, Pe'raldi MN, Pariente A, Morelon E, Legendre C. Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation. 2005;80:1198–1203
  45. Myers BD, Sibley R, Newton L, et al. The long-term course of cyclosporine-associated chronic nephropathy. Kidney Int. 1988;33:590–600
  46. Ducloux D, Motte G, Billerey C, et al. Cyclosporin withdrawal with concomitant conversion from azathioprine to mycophenolate mofetil in renal transplant recipients with chronic allograft nephropathy: A 2-year follow-up. Transplant Int. 2002;15:387–392
  47. van den Akker JM, Wetzels JF, Hoitsma AJ. Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients. Kidney Int. 2006;70:1355–1357
  48. Diekmann F, Gutierrez-Dalmau A, Lopez S, et al. Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: Comparison of two CNI-free protocols. Nephrol Dial Transplant. 2007;22:2316–2321
  49. Stephany BR, Augustine JJ, Krishnamurthi V, et al. Differences in proteinuria and graft function in de novo sirolimus-based vs. calcineurin inhibitor-based immunosuppression in live donor kidney transplantation. Transplantation. 2006;82:368–374
  50. Straathof-Galema L, Wetzels JF, Dijkman HB, Steenbergen EJ, Hilbrands LB. Sirolimus-associated heavy proteinuria in a renal transplant recipient: Evidence for a tubular mechanism. Am J Transplant. 2006;6:429–433
  51. Mreich E, Coombes JD, Rangan GK. Sirolimus does not reduce receptor-mediated endocytosis of albumin in proximal tubule cells. Transplantation. 2007;83:105–107
  52. Letavernier E, Bruneval P, Mandet C, et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol. 2007;2:326–333
  53. Dittrich E, Schmaldienst S, Soleiman A, Horl WH, Pohanka E. Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transplant Int. 2004;17:215–220
  54. Mainra R, Mulay A, Bell R, et al. Sirolimus use and de novo minimal change nephropathy following renal transplantation. Transplantation. 2005;80:1816
  55. Izzedine H, Brocheriou I, Frances C. Post-transplantation proteinuria and sirolimus. N Engl J Med. 2005;353:2088–2089
  56. Abramowicz D, Hadaya K, Hazzan M, et al. Conversion to sirolimus for chronic renal allograft dysfunction: Risk factors for graft loss and severe side effects. Nephrol Dial Transplant. 2008;23:3727–3729
  57. Franco AF, Martini D, Abensur H, Noronha IL. Proteinuria in transplant patients associated with sirolimus. Transplant Proc. 2007;39:449–452
  58. Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: A 3-year randomized, multicenter, phase III study. Transplantation. 2005;80:244–252
  59. Hor T, Baldwin D. Urinary albumin excretion in patients with diabetes after renal transplantation. Transplant Proc. 2006;38:2879–2882
  60. Halimi JM, Buchler M, Al Najjar A, et al. Urinary albumin excretion and the risk of graft loss and death in proteinuric and non-proteinuric renal transplant recipients. Am J Transplant. 2007;7:618–625
  61. De Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int. 2004;65:2309–2320
  62. Ruggenenti P, Perna A, Remuzzi G GISEN Group. Retarding progression of chronic renal disease: The neglected issue of residual proteinuria. Kidney Int. 2003;63:2254–2261
  63. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456–1462
  64. Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease: The role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: A patient-level meta-analysis. Ann Intern Med. 2003;139:244–252
  65. Vogt L, Waanders F, Boomsma F, De Zeeuw D, Navis G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol. 2008;19:999–1007
  66. Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 2006;70:2116–2223
  67. Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blockade on the progression of diabetic nephropathy in African Americans. Hypertension. 1997;29:744–750
  68. McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G. The effect of pentoxifylline on proteinuria in diabetic kidney disease: A meta-analysis. Am J Kidney Dis. 2008;52:454–463
  69. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, Avoid SI. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–2446
  70. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30–48
  71. Heinze G, Mitterbauer C, Regele H, et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol. 2006;17:889–899
  72. Opelz G, Zeier M, Lau G, Morath C, Dohler B. No improvement of patient or graft survival in transplant recipients treated with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers: A Collaborative Transplant Study Report. J Am Soc Nephrol. 2006;17:3257–3262
  73. Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA. Renin angiotensin system blockade in kidney transplantation: A systematic review of the evidence. Am J Transplant. 2007;7:2350–2360
  74. Philipp T, Legendre C, Geiger H, et al. Study on the Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET-Study). Kidney Blood Press Res. 2004;27:331–332
  75. A Double-Blind, Randomized Placebo-Controlled Study to Evaluate the Renal Protective Effects of Losartan in Patients with Renal Transplants. ClinicalStudyResults.org http://www.clinicalstudyresults.org/home/Accessed May 14, 2009
  76. Campistol JM, Garcia dM, Alarcon A, et al: Angiotensin II receptor blockage in kidney transplantation: Design and Progress of the AALLOGRAFT study. World Transplant Congress Meeting, Boston, MA, July 22-27, 2006 (abstr 510)
  77. Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C, Jeffery J. Congestive heart failure in renal transplant recipients: Risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol. 2002;13:1084–1090
  78. Knoll GA, Cantarovitch M, Cole E, et al. The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation—Study design. Nephrol Dial Transplant. 2008;23:354–358
  79. Biesenbach G, Zazgornik J, Janko O, Hubmann R, Syre G. Effect of mild dietary protein restriction on urinary protein excretion in patients with renal transplant fibrosis. Wien Med Wochenschr. 1996;146:75–78
  80. Salahudeen AK, Hostetter TH, Raatz SK, Rosenberg ME. Effects of dietary protein in patients with chronic renal transplant rejection. Kidney Int. 1992;41:183–190

 Originally published online as doi:10.1053/j.ajkd.2009.06.031 on September 3, 2009.

PII: S0272-6386(09)00970-6

doi: 10.1053/j.ajkd.2009.06.031

American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1131-1144 , December 2009

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