Targeting Proteinuria as a Valid Surrogate for Individualized Kidney Protective Therapy

Abstract

Related Article, p. 724 Related Article, p. 724 The presence of protein in the urine is a strong indicator that a patient is likely to experience progressive kidney function decline. A patient with proteinuria, even in the setting of a relatively normal glomerular filtration rate (GFR), has a high chance of showing a steep progressive slope of GFR loss compared to a patient with low or no urinary protein excretion. Importantly, treatment of patients with medications that reduce proteinuria appears to be associated with protection against GFR decline.1Lewis 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. 1993; 329: 1456-1462Crossref PubMed Scopus (4965) Google Scholar, 2Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia).Lancet. 1997; 349 (No authors listed): 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1730) Google Scholar, 3Brenner B.M. Cooper M.E. de Zeeuw D. et al.RENAAL Study Investigators Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6034) Google Scholar, 4Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Collaborative Study Group Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4956) Google Scholar, 5Agodoa L.Y. Appel L. Bakris G.L. Beck G. et al.African American Study of Kidney Disease and Hypertension (AASK) Study Group Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.JAMA. 2001; 285: 2719-2728Crossref PubMed Scopus (849) Google Scholar Therefore, proteinuria has been advocated not only as a renal risk marker, but also as a target for treatment.6De Jong P.E. Navis G. de Zeeuw D. Renoprotective therapy: titration against urinary protein excretion.Lancet. 1999; 354: 352-353Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar That proteinuria is a risk marker for renal outcome, independent of other risk factors, is widely accepted. However, the question of whether proteinuria truly is an independent therapeutic target for reducing progressive kidney function loss remains under debate. Clearly, therapy that reduces proteinuria is associated with renal protection, and, interestingly, the more one lowers proteinuria in an individual patient the better the patient is protected against further kidney function loss and eventual kidney failure.7Rossing P. Hommel E. Smidt U.M. Parving H.H. Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment.Diabetologia. 1994; 37: 511-516Crossref PubMed Scopus (171) Google Scholar, 8Apperloo A.J. de Zeeuw D. de Jong P.E. Short-term antiproteinuric response to antihypertensive treatment predicts long-term GFR decline in patients with non-diabetic renal disease.Kidney Int Suppl. 1994; 45: S174-S178PubMed Google Scholar However, currently used renoprotective therapies were not designed to be antiproteinuric; rather they were developed to address other kidney disease risk factors—most notably hypertension—and the ability of these medications to reduce proteinuria was discovered as a “side effect”. Of all the antihypertensive medications, drugs that intervene in the renin-angiotensin-aldosterone system are best known for their antiproteinuric effect; these include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists, and renin inhibitors.9Taguma Y. Kitamoto Y. Futaki G. et al.Effect of captopril on heavy proteinuria in azotemic diabetics.N Engl J Med. 1985; 313: 1617-1620Crossref PubMed Scopus (387) Google Scholar, 10Gansevoort R.T. de Zeeuw D. de Jong P.E. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system?.Kidney Int. 1994; 45: 861-867Crossref PubMed Scopus (312) Google Scholar, 11van Paassen P. de Zeeuw D. Navis G. de Jong P.E. Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function.Nephrol Dial Transplant. 2000; 15: 637-643Crossref PubMed Scopus (41) Google Scholar, 12Schjoedt K.J. Rossing K. Juhl T.R. Beneficial impact of spironolactone in diabetic nephropathy.Kidney Int. 2005; 68: 2829-2836Crossref PubMed Scopus (190) Google Scholar Several large clinical trials using hard end points that include substantial kidney function decline and development of kidney failure have shown that intervention in the renin-angiotensin system subsequently protects kidney function.1Lewis 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. 1993; 329: 1456-1462Crossref PubMed Scopus (4965) Google Scholar, 2Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia).Lancet. 1997; 349 (No authors listed): 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1730) Google Scholar, 3Brenner B.M. Cooper M.E. de Zeeuw D. et al.RENAAL Study Investigators Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6034) Google Scholar, 4Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Collaborative Study Group Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4956) Google Scholar, 5Agodoa L.Y. Appel L. Bakris G.L. Beck G. et al.African American Study of Kidney Disease and Hypertension (AASK) Study Group Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.JAMA. 2001; 285: 2719-2728Crossref PubMed Scopus (849) Google Scholar Interestingly, this protection was associated with reduction in proteinuria, and, importantly, the reduction in proteinuria observed in the first months of treatment was associated with long-term kidney function protection.13de Zeeuw D. Remuzzi G. Parving H.H. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.Kidney Int. 2004; 65: 2309-2320Crossref PubMed Scopus (792) Google Scholar, 14Lea J. Greene T. Hebert L. 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. 2005; 165: 947-953Crossref PubMed Scopus (251) Google Scholar, 15Atkins R.C. Briganti E.M. Lewis J.B. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy.Am J Kidney Dis. 2005; 45: 281-287Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar These findings are supported by Eijkelkamp et al, who recently showed that the initial antiproteinuric effect of an ARB is associated with kidney protection completely independently from the effect of the ARB on blood pressure. Even in individuals in whom use of an ARB was associated with a rise in blood pressure, ARB use remained renoprotective as long as proteinuria was reduced.16Eijkelkamp W.B. Zhang Z. Remuzzi G. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.J Am Soc Nephrol. 2007; 18: 1540-1546Crossref PubMed Scopus (275) Google Scholar However, since these studies were not prospectively designed to isolate the antiproteinuric renoprotective effect from the antihypertensive renoprotective effect, there is still no hard evidence that proteinuria should be targeted for treatment. For proteinuria to become a target of treatment, one needs to establish that proteinuria is an independent cause of progressive kidney function loss. In addition, one needs to find a therapy that reduces proteinuria without affecting any other risk factor for kidney function decline. In this respect Szeto et al describe a very interesting finding in their article in this issue of AJKD.17Szeto C.-C. Chow K.-M. Kwan Ching-Ha B. et al.Oral Calcitriol for the treatment of persistent proteinuria in immunoglobulin A nephropathy: an uncontrolled trial.Am J Kidney Dis. 2008; 51: 724-731Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar They show that oral calcitriol reduces proteinuria in patients with IgA nephropathy in the absence of a significant change in blood pressure or kidney function. There was a simultaneous reduction in serum transforming growth factor β (TGF-β) levels, correlating with the reduction in proteinuria. Although the study was performed in only 10 patients, this finding may be of marked importance for the future treatment of patients with progressive kidney function loss. The current renoprotective treatment of patients with diabetic and nondiabetic nephropathy has reduced the risk of developing end-stage renal disease (ESRD); however, the residual risk remains high. Although studies using ACE inhibitors and ARBs in individuals at high risk for kidney failure, including the Collaborative Study Group, the Ramipril Efficacy in Nephropathy (REIN) study, the Reduction of End Points in Non–Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study, the Irbesartan Diabetic Nephropathy Trial (IDNT), and the African American Study of Kidney Disease and Hypertension (AASK) have all shown a significant risk reduction in hard kidney outcomes (50% decline in GFR or doubling of serum creatinine, development of ESRD), the remaining absolute risk of these end points in these high-risk individuals remained between 25% and 50% within 3 years.1Lewis 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. 1993; 329: 1456-1462Crossref PubMed Scopus (4965) Google Scholar, 2Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia).Lancet. 1997; 349 (No authors listed): 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1730) Google Scholar, 3Brenner B.M. Cooper M.E. de Zeeuw D. et al.RENAAL Study Investigators Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6034) Google Scholar, 4Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Collaborative Study Group Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4956) Google Scholar, 5Agodoa L.Y. Appel L. Bakris G.L. Beck G. et al.African American Study of Kidney Disease and Hypertension (AASK) Study Group Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.JAMA. 2001; 285: 2719-2728Crossref PubMed Scopus (849) Google Scholar In all of these trials, high blood pressure was the target of treatment, and thus blood pressure control had a marked emphasis in the planned treatment regimens. Most (if not all) methods for blood pressure lowering were used to achieve preestablished blood pressure targets; accordingly, chances of further renal risk reduction by further decrease of blood pressure appear to be slim. On the other hand, proteinuria was never a target in any of these trials, and, when examined, these trials show that the degree of proteinuria reduction was associated with renoprotection. Thus, optimization of the antiproteinuric effect might be a means to obtain further kidney protection. What are the current possibilities to further reduce proteinuria? ACE inhibitors, followed by ARBs, have proven antiproteinuric effects, which are enhanced with dose escalation. Notably, administering ACE inhibitors and ARBs at doses far beyond their blood pressure lowering effect still offers increasing proteinuria reduction.18Schmieder R.E. Klingbeil A.U. Fleischmann E.H. Veelken R. Delles C. Additional antiproteinuric effect of ultrahigh dose candesartan: a double-blind, randomized, prospective study.J Am Soc Nephrol. 2005; 16: 3038-3045Crossref PubMed Scopus (132) Google Scholar, 19Rossing K. Schjoedt K.J. Jensen B.R. Boomsma F. Parving H.H. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.Kidney Int. 2005; 68: 1190-1198Crossref PubMed Scopus (201) Google Scholar Furthermore, the antiproteinuric effect of these medications may be enhanced by adding a diuretic to the medication regimen.20Buter H. Hemmelder M.H. Navis G. de Jong P.E. de Zeeuw D. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide.Nephrol Dial Transplant. 1998; 13: 1682-1685Crossref PubMed Scopus (182) Google Scholar Restriction of dietary sodium intake has a similar effect,21Heeg J.E. de Jong P.E. van der Hem G.K. de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril.Kidney Int. 1989; 36: 272-279Crossref PubMed Scopus (339) Google Scholar and, interestingly, combining low sodium intake and diuretic use with ACE inhibition further reduces proteinuria.22Vogt 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; (doi: 10.1681/ASN.2007060693)PubMed Google Scholar Finally, the combination of an ACE inhibitor and an ARB not only further lowers proteinuria23Jacobsen P.K. Preventing end-stage renal disease in diabetic patients - dual blockade of the renin-angiotensin system (Part II).J Renin Angiotensin Aldosterone Syst. 2005; 6: 55-68Crossref PubMed Scopus (9) Google Scholar but also appears to protect the kidneys in patients with nondiabetic renal disease,24Nakao N. Yoshimura A. Morita H. Takada M. Kayano T. Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial.Lancet. 2003; 361: 117-124Abstract Full Text Full Text PDF PubMed Scopus (972) Google Scholar although the latter study still requires confirmation. Notably, all the measures described above not only improve proteinuria but also reduce blood pressure. Are there any antiproteinuric measures that have no impact on blood pressure? Agarwal et al showed that paracalcitol has an antiproteinuric effect.25Agarwal R. Acharya M. Tian J. Hippensteel R.L. Melnick J.Z. Qiu P. Williams L. Batlle D. Antiproteinuric effect of oral paricalcitol in chronic kidney disease.Kidney Int. 2005; 68: 2823-2828Crossref PubMed Scopus (329) Google Scholar Although this study was not prospectively designed to evaluate proteinuria, it was the first to show a clinical effect of a vitamin D analogue on proteinuria; this has now been confirmed in a prospective study by Szeto et al,17Szeto C.-C. Chow K.-M. Kwan Ching-Ha B. et al.Oral Calcitriol for the treatment of persistent proteinuria in immunoglobulin A nephropathy: an uncontrolled trial.Am J Kidney Dis. 2008; 51: 724-731Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar where the antiproteinuric effect of the vitamin D analog calcitriol was demonstrated in the setting of concurrent ACE inhibitor or ARB treatment. However, as Szeto et al only evaluated 10 individuals in this study, larger studies will need to confirm their finding. The Selective Vitamin D Receptor Activator (Paricalcitol) for Albuminuria Lowering Study (VITAL) is such a larger ongoing study.26Abbott: A Study of Paricalcitol Capsules on Reducing Albuminuria in Type 2 Diabetic Nephropathy Being Treated With Renin-Angiotensin System Inhibitors.http://clinicaltrials.gov/ct2/show/NCT00421733Google Scholar Of note, there are several other antiproteinuric measures that demonstrate no blood pressure lowering effect; these include low-protein diets, nonsteroidal anti-inflammatory drugs like indomethacin, and sulodexide, a glycosaminoglycan that may reduce proteinuria through effects on the glomerular basement membrane. These measures have an antiproteinuric effect by themselves and in conjunction with ACE inhibitor or ARB treatment.27Gansevoort R.T. de Zeeuw D. de Jong P.E. Additive antiproteinuric effect of ACE inhibition and a low-protein diet in human renal disease.Nephrol Dial Transplant. 1995; 10: 497-504PubMed Google Scholar, 28Perico N. Remuzzi A. Sangalli F. Azzollini N. Mister M. Ruggenenti P. Remuzzi G. The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.J Am Soc Nephrol. 1998; 9: 2308-2317PubMed Google Scholar, 29Gambaro G. Kinalska I. Oksa A. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial.J Am Soc Nephrol. 2002; 13: 1615-1625Crossref PubMed Scopus (185) Google Scholar The unanswered question remains: Are any of the above additive measures to lower proteinuria, in particular the ones that have no effect on blood pressure, of substantial use in further lowering the risk of progressive kidney disease? If this is true, we will have a breakthrough in the treatment of renal disease. In fact, if a treatment directed to only lower the proteinuria renders additional kidney protection to currently recommended therapies, this will imply that proteinuria should be a target of treatment for optimal kidney protection. However, there are only limited prospects at this time for trials to demonstrate efficacy of these interventions. Further trials evaluating low-protein diets promise to be interesting; however, a repeat of the Modification of Diet in Renal Disease (MDRD) Study is not expected. Trials using nonsteroidal anti-inflammatory drugs are not expected either, given the adverse effects of this class of medications on kidney function. The first large hard end point study that may give an answer is the Sulodexide Trial in Diabetic Nephropathy.30Lambers Heerspink H.J. Fowler M.J. Volgi J. et al.Collaborative Study GroupRationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.Diabet Med. 2007; 24: 1290-1295Crossref PubMed Scopus (25) Google Scholar However, evidence from Agarwal et al and Szeto et al suggest that it should not be long before somebody will take the initiative to start a large, hard end point trial using a vitamin D analogue. Finally, a major challenge for the future is not only to test which drugs synergize in their antiproteinuric effect, but also to assess the best combination of drugs in individual patients. From treatment of high blood pressure we should have learned that each person has an individual response to different antihypertensive drugs and their combinations. For proteinuria reduction one observes something similar, as not every patient responds equally well to ACE inhibitor or ARB therapy. The response may vary from a nearly 100% fall in proteinuria to a rise in proteinuria, with the average being a 50% decrease.31Bos H. Andersen S. Rossing P. De Zeeuw D. Parving H.H. De Jong P.E. Navis G. Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy.Kidney Int Suppl. 2000; 75: S32-S37Crossref PubMed Scopus (48) Google Scholar The same holds true for non–blood-pressure-lowering antiproteinuric therapies such as a low-protein diet, nonsteroidal anti-inflammatory drugs, and sulodexide. Szeto et al showed that oral calcitriol is similar in this respect; some patients show a rise, some a modest drop, and some a distinct fall in proteinuria. This pattern is supported by Eijkelkamp et al, who showed that the antiproteinuric response variation to ARB treatment differs from the antihypertensive variation as some individuals without a blood pressure response experienced a marked lowering of proteinuria and vice versa.16Eijkelkamp W.B. Zhang Z. Remuzzi G. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.J Am Soc Nephrol. 2007; 18: 1540-1546Crossref PubMed Scopus (275) Google Scholar Given the fact that some individuals show a good antiproteinuric response to a drug whereas others show no effect at all, we must ask if it is possible to turn a nonresponder into a responder? Bos et al showed that a nonresponder to ACE inhibitor therapy remains a nonresponder to ARB therapy.31Bos H. Andersen S. Rossing P. De Zeeuw D. Parving H.H. De Jong P.E. Navis G. Role of patient factors in therapy resistance to antiproteinuric intervention in nondiabetic and diabetic nephropathy.Kidney Int Suppl. 2000; 75: S32-S37Crossref PubMed Scopus (48) Google Scholar However, will a nonresponder to ACE inhibitor or ARB therapy have reduced proteinuria with sulodexide or vitamin D analogues? And what will happen if we combine sulodexide with vitamin D analogs? These are several of the major questions and challenges for the coming decade(s). While it will take some time before we can answer these questions with hard end point studies, if we could come to an understanding that proteinuria, like hypertension, is a valid surrogate for hard kidney outcomes, we will be able to considerably reduce the time before we develop optimal individual renoprotective treatment strategies. Support: None. Financial Disclosure: Dr de Zeeuw serves on the Steering/Executive Committee of clinical trials on paricalcitol (Abbott Laboratories), sulodexide (Keryx Biopharmaceuticals) and aliskiren (Novartis Pharmaceuticals). Oral Calcitriol for the Treatment of Persistent Proteinuria in Immunoglobulin A Nephropathy: An Uncontrolled TrialAmerican Journal of Kidney DiseasesVol. 51Issue 5PreviewLaboratory research and previous retrospective study suggest that vitamin D and its analogues have profound effects on immune system function and glomerular mesangial cell proliferation. We conducted an open-label study to evaluate the antiproteinuric effect of calcitriol on proteinuria in patients with immunoglobulin A (IgA) nephropathy. Full-Text PDF