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Proteinuria should be used as a surrogate in CKD

Abstract

Surrogate end points of renal failure are instrumental to the testing of new treatments in patients with chronic kidney disease, the natural history of which is characterized by a slow, asymptomatic decline in renal function. The magnitude of proteinuria is widely recognized as a marker of the severity of glomerulopathy. Population-based studies have identified proteinuria as a predictor of future decline in glomerular filtration rate and of the development of end-stage renal disease. More importantly, a reduction in proteinuria invariably translates into a protection from renal function decline in patients with diabetic and nondiabetic renal disease with overt proteinuria. Thus, proteinuria should be considered a valuable surrogate end point for clinical trials in patients with proteinuric renal diseases.

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Figure 1: Association between proteinuria level, ESRD and rate of GFR decline in patients with nondiabetic chronic nephropathies enrolled in the Ramipril Efficacy In Nephropathy (REIN) study.
Figure 2: Association between reductions in proteinuria and increased proteinuria selectivity.

References

  1. 1

    United States Renal Data System Annual Data Report. United States Renal Data System [online], (2010).

  2. 2

    Ruggenenti, P. & Remuzzi, G. Kidney failure stabilizes after a two-decade increase: impact on global (renal and cardiovascular) health. Clin. J. Am. Soc. Nephrol. 2, 146–150 (2007).

    Article  Google Scholar 

  3. 3

    Cravedi, P., Ruggenenti, P. & Remuzzi, G. Kidney failure stabilizes after an increase over 2 decades. J. Ren. Care 33, 100–104 (2007).

    Article  Google Scholar 

  4. 4

    Piantadosi, S. Clinical Trials: a Methodologic Perspective (John Wiley and Sons, New York, 1997).

    Google Scholar 

  5. 5

    Waller, K. V., Ward, K. M., Mahan, J. D. & Wismatt, D. K. Current concepts in proteinuria. Clin. Chem. 35, 755–765 (1989).

    CAS  PubMed  Google Scholar 

  6. 6

    Kim, M. S. Proteinuria. Clin. Lab. Med. 8, 527–540 (1988).

    CAS  Article  Google Scholar 

  7. 7

    Ruggenenti, P. & Remuzzi, G. Time to abandon microalbuminuria? Kidney Int. 70, 1214–1222 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Gerstein, H. C. et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 286, 421–426 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Wachtell, K. et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann. Intern. Med. 139, 901–906 (2003).

    Article  Google Scholar 

  10. 10

    Adler, A. I. et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 63, 225–232 (2003).

    Article  Google Scholar 

  11. 11

    Lemley, K. V. et al. Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus. J. Am. Soc. Nephrol. 11, 2095–2105 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Bazzi, C., Petrini, C., Rizza, V., Arrigo, G. & D'Amico, G. A modern approach to selectivity of proteinuria and tubulointerstitial damage in nephrotic syndrome. Kidney Int. 58, 1732–1741 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Remuzzi, G., Benigni, A. & Remuzzi, A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J. Clin. Invest. 116, 288–296 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Pavkov, M. E. et al. Early renal function decline in type 2 diabetes. Clin. J. Am. Soc. Nephrol. 7, 78–84 (2012).

    CAS  Article  Google Scholar 

  15. 15

    Ruggenenti, P. & Remuzzi, G. Angiotensin-converting enzyme inhibitor therapy for non-diabetic progressive renal disease. Curr. Opin. Nephrol. Hypertens. 6, 489–495 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Barnes, J. L. & Gorin, Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 79, 944–956 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Zoja, C. et al. Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins. Am. J. Kidney Dis. 26, 934–941 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Drumm, K., Bauer, B., Freudinger, R. & Gekle, M. Albumin induces NF-kappaB expression in human proximal tubule-derived cells (IHKE-1). Cell Physiol. Biochem. 12, 187–196 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Tang, S. et al. Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo. J. Clin. Invest. 111, 515–527 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Abbate, M., Zoja, C. & Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 17, 2974–2984 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Rudnicki, M. et al. Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies. Kidney Int. 71, 325–335 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Johnson, D. W., Saunders, H. J., Baxter, R. C., Field, M. J. & Pollock, C. A. Paracrine stimulation of human renal fibroblasts by proximal tubule cells. Kidney Int. 54, 747–757 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Biancone, L. et al. Alternative pathway activation of complement by cultured human proximal tubular epithelial cells. Kidney Int. 45, 451–460 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Nangaku, M., Pippin, J. & Couser, W. G. Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J. Am. Soc. Nephrol. 10, 2323–2331 (1999).

    CAS  PubMed  Google Scholar 

  25. 25

    Rangan, G. K., Pippin, J. W., Coombes, J. D. & Couser, W. G. C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria. Kidney Int. 67, 492–503 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Iseki, K., Iseki, C., Ikemiya, Y. & Fukiyama, K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int. 49, 800–805 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Ruggenenti, P. et al. Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int. Suppl. 63, S54–S57 (1997).

    CAS  PubMed  Google Scholar 

  28. 28

    Ruggenenti, P., Perna, A., Mosconi, L., Pisoni, R. & Remzzi, G. Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int. 53, 1209–1216 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Peterson, J. C. et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease study. Ann. Intern. Med. 123, 754–762 (1995).

    CAS  Article  Google Scholar 

  30. 30

    Wright, J. T. Jr et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 288, 2421–2431 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Retnakaran, R., Cull, C. A., Thorne, K. I., Adler, A. I. & Holman, R. R. Risk factors for renal dysfunction in type 2 diabetes: U. K. Prospective Diabetes Study 74. Diabetes 55, 1832–1839 (2006).

    CAS  Article  Google Scholar 

  32. 32

    Keane, W. F. et al. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study. Clin. J. Am. Soc. Nephrol. 1, 761–767 (2006).

    Article  Google Scholar 

  33. 33

    Atkins, R. C. et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am. J. Kidney Dis. 45, 281–287 (2005).

    Article  Google Scholar 

  34. 34

    de Zeeuw, D. et al. Renal risk and renoprotection among ethnic groups with type 2 diabetic nephropathy: a post hoc analysis of RENAAL. Kidney Int. 69, 1675–1682 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Remuzzi, G. & Bertani, T. Pathophysiology of progressive nephropathies. N. Engl. J. Med. 339, 1448–1456 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Group, T. G. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349, 1857–1863 (1997).

    Article  Google Scholar 

  37. 37

    Ruggenenti, P., Perna, A. & Remuzzi, G. Retarding progression of chronic renal disease: the neglected issue of residual proteinuria. Kidney Int. 63, 2254–2261 (2003).

    CAS  Article  Google Scholar 

  38. 38

    Bjorck, S., Mulec, H., Johnsen, S. A., Norden, G. & Aurell, M. Renal protective effect of enalapril in diabetic nephropathy. BMJ 304, 339–343 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N. Engl. J. Med. 329, 1456–1462 (1993).

    CAS  Article  Google Scholar 

  40. 40

    Jafar, T. H. et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann. Intern. Med. 135, 73–87 (2001).

    CAS  Article  Google Scholar 

  41. 41

    Ruggenenti, P., Schieppati, A. & Remuzzi, G. Progression, remission, regression of chronic renal diseases. Lancet 357, 1601–1608 (2001).

    CAS  Article  Google Scholar 

  42. 42

    Vegter, S. et al. Sodium Intake, ACE Inhibition, and Progression to ESRD. J. Am. Soc. Nephrol. 23, 165–173 (2012).

    CAS  Article  Google Scholar 

  43. 43

    Campbell, R. et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int. 63, 1094–1103 (2003).

    CAS  Article  Google Scholar 

  44. 44

    Hovind, P. et al. Remission of nephrotic-range albuminuria in type 1 diabetic patients. Diabetes Care 24, 1972–1977 (2001).

    CAS  Article  Google Scholar 

  45. 45

    de Zeeuw, D. et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110, 921–927 (2004).

    CAS  Article  Google Scholar 

  46. 46

    Ruggenenti, P. et al. Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J. Hypertens. 29, 207–216 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Schmieder, R. E. et al. Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J. Am. Soc. Nephrol. 22, 1353–1364 (2011).

    Article  Google Scholar 

  48. 48

    Sandhu, S., Wiebe, N., Fried, L. F. & Tonelli, M. Statins for improving renal outcomes: a meta-analysis. J. Am. Soc. Nephrol. 17, 2006–2016 (2006).

    CAS  Article  Google Scholar 

  49. 49

    Conley, J., Olafsson, A. & Djamali, A. Do statins delay the incidence of ESRD in diabetic patients with moderate CKD? J. Nephrol. 23, 321–327 (2010).

    PubMed  Google Scholar 

  50. 50

    Ruggenenti, P. et al. Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: The ESPLANADE Trial. Clin. J. Am. Soc. Nephrol. 5, 1928–1938 (2010).

    CAS  Article  Google Scholar 

  51. 51

    Zoja, C. et al. How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J. Am. Soc. Nephrol. 13, 2898–2908 (2002).

    CAS  Article  Google Scholar 

  52. 52

    Ruggenenti, P. et al. Role of remission clinics in the longitudinal treatment of CKD. J. Am. Soc. Nephrol. 19, 1213–1224 (2008).

    Article  Google Scholar 

  53. 53

    Ruggenenti, P. et al. Preventing microalbuminuria in type 2 diabetes. N. Engl. J. Med. 351, 1941–1951 (2004).

    CAS  Article  Google Scholar 

  54. 54

    Nielsen, S. E. et al. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril. Diabet. Med. 27, 1144–1150 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Nielsen, S. E. et al. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care 33, 1320–1324 (2010).

    CAS  Article  Google Scholar 

  56. 56

    Nielsen, S. E. et al. Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy. Kidney Int. 79, 1113–1118 (2011).

    CAS  Article  Google Scholar 

  57. 57

    Levey, A. S. et al. Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am. J. Kidney Dis. 54, 205–226 (2009).

    Article  Google Scholar 

  58. 58

    Xie, D., Hou, F. F., Fu, B. L., Zhang, X. & Liang, M. High level of proteinuria during treatment with renin-angiotensin inhibitors is a strong predictor of renal outcome in nondiabetic kidney disease. J. Clin. Pharmacol. 51, 1025–1034 (2011).

    CAS  Article  Google Scholar 

  59. 59

    Lea, J. et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch. Intern. Med. 165, 947–953 (2005).

    Article  Google Scholar 

  60. 60

    de Zeeuw, D. et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 65, 2309–2320 (2004).

    CAS  Article  Google Scholar 

  61. 61

    Hunsicker, L. G. et al. Impact of irbesartan, blood pressure control, and proteinuria on renal outcomes in the Irbesartan Diabetic Nephropathy Trial. Kidney Int. Suppl. 92, S99–S101 (2004).

    CAS  Article  Google Scholar 

  62. 62

    Hellemons, M. E. et al. Initial angiotensin receptor blockade-induced decrease in albuminuria is associated with long-term renal outcome in type 2 diabetic patients with microalbuminuria: a post hoc analysis of the IRMA-2 trial. Diabetes Care 34, 2078–2083 (2011).

    CAS  Article  Google Scholar 

  63. 63

    Holtkamp, F. A. et al. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials. Eur. Heart J. 32, 1493–1499 (2011).

    CAS  Article  Google Scholar 

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The authors contributed equally to all aspects of the manuscript.

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Correspondence to Giuseppe Remuzzi.

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Cravedi, P., Ruggenenti, P. & Remuzzi, G. Proteinuria should be used as a surrogate in CKD. Nat Rev Nephrol 8, 301–306 (2012). https://doi.org/10.1038/nrneph.2012.42

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