Individual Titration for Maximal Blockade of the... : Journal of the American Society of Nephrology (original) (raw)
Proteinuria nowadays is looked upon as an important and independent risk factor for progression of renal disease (1,2). Moreover, evidence from large clinical trials has become available, showing that reduction of proteinuria is important for long-term renoprotection (3,4). In addition, it has been noted that both residual proteinuria and the amount of antiproteinuric response are predictive for renal outcome in individual patients (5,6), indicating that residual proteinuria during therapy is a predictor of the individual renal prognosis. Accordingly, maximum reduction of proteinuria has been advocated as a treatment target for individual renal patients, in addition to control of BP (7–9). For optimal renoprotection, therefore, recent data suggest that treatment target for proteinuria should be <1 g/d and likely near zero (7,8).
Intervention in the renin-angiotensin system (RAS) is currently the most effective strategy that combines renoprotection with proteinuria lowering. Roughly, the average antiproteinuric response of RAS blocking agents is 50%—both for angiotensin-converting enzyme inhibitors (ACEi) and for angiotensin II antagonists (AIIA) (10,11). There are several strategies to optimize the response, including dose titration of the RAS intervening agents (12), combining RAS blockade with low-sodium diet or a diuretic (13), and combining the different RAS blocking strategies (14). Indeed, ACEi plus AIIA renders more antiproteinuric effect and also more renoprotection (15). Although each of these measures is studied widely on the group level, until now, no individual data of maximal RAS blockade on proteinuria are available (9). Moreover, it is unknown whether it is possible, in a prospective manner, to obtain the target level of proteinuria <1 g/d by titrating these measures in individual patients. In the present study, our aim was to investigate the antiproteinuric potential of additional up-titration with an ACEi to maximal tolerated dose against a background of a maximal dosed AIIA combined with diuretic therapy in a sodium-restricted setting.
Materials and Methods
Patients and Protocol
Patients were selected from our renal outpatient clinic. All patients gave informed consent and fulfilled the inclusion criterion of a stable proteinuria >1 g/d and <10 g/d while they were still on their previous (nonimmune suppressive) antiproteinuric treatment. Moreover, only patients with BP <140/<90 mmHg, creatinine clearance ≥30 ml/min per 1.73 m2, and age between 18 and 70 yr were included. Patients with cardiovascular disease or diabetes were excluded, as well as frequent users of nonsteroidal anti-inflammatory drugs (NSAID; >2 doses/wk).
The study was designed as a practice-based clinical trial. Patients were treated according to an individual dose titration with ACEi added to a standard treatment of AIIA combined with diuretic therapy. Patients were instructed to take the study medication once daily and to adhere to a dietary sodium restriction of 5 to 7 g/d. Our predefined treatment goal was to reduce proteinuria to <1 g/d. After selection, eligible patients entered the run-in phase in which previous medication was replaced for the highest recommended daily dose irbesartan 300 mg (16) combined with the diuretic hydrochlorothiazide 12.5 mg once daily. In patients who were treated previously with diuretic hydrochlorothiazide or furosemide, the diuretic therapy was continued and solely irbesartan 300 mg was added. Then, patients with proteinuria >1 g/d and serum potassium concentration <5.5 mmol/L entered the phase of dose titration. In this phase, lisinopril was added in increasing daily doses to a maximum of 40 mg. All periods of treatment (run-in and up-titration) lasted at least 6 wk. The treatment protocol was discontinued when the predefined goal of proteinuria <1 g/d was reached or further dose titration was not tolerated because of side effects. Expected side effects were defined as hyperkalemia >5.5 mmol/L, complaints of cough or dizziness, or serious increase of serum creatinine >50%.
Clinical and Laboratory Procedures
BP was measured at every visit under similar conditions, at 1-min intervals by an automatic device (Dinamap), with the patient in supine position. After 15 min of measurements, the mean of the last four readings was used for further analysis. Mean arterial pressure (MAP) was calculated as the sum of one third of the systolic and two thirds of the diastolic BP. Urinary protein was determined using the pyrogallol red-molybdate method. At the end of each period, the day before every visit, patients collected 24-h urine samples to obtain proteinuria. Serum and urinary electrolytes, uric acid, and creatinine were determined using an automated multi-analyzer (SMA-C; Technicon, Tarrytown, NY).
Statistical Analyses
Results are expressed as median and 95% confidence intervals (CI). For each patient, the level of residual proteinuria after treatment with irbesartan combined with hydrochlorothiazide and at the maximal tolerated dose of lisinopril was established. The Wilcoxon signed ranks test was used to test whether paired values from standardized irbesartan 300 mg/diuretic treatment and after treatment with added maximal individual lisinopril dose differed. Differences were considered significant at P < 0.05. On the basis of previous data (14), we calculated that a sample size of n = 6 is needed to detect mean reduction in proteinuria of 40% with expected SD of 28% and with a desired power of 80% and α = 0.05.
Results
Patient Characteristics
Twelve nondiabetic proteinuric patients were selected from our outpatient clinic. Four patients, however, did not enter the study protocol because of dizziness (n = 1) or proteinuria <1 g/d (n = 3) during treatment with irbesartan and diuretic. The remaining eight patients were included for up-titration with lisinopril and completed the treatment protocol. These patients, all of whom were middle-aged and white, had mildly to moderately impaired renal function and had biopsy-proven nondiabetic nephropathy with the exception of one patient, in whom it was not possible to take biopsy because of anatomic abnormalities (horseshoe kidney; Table 1). During up-titration, three patients achieved the maximal daily dose of lisinopril 40 mg, whereas lisinopril 30, 20, and 10 mg was achieved in one, two, and two patients, respectively.
Proteinuria
Off-treatment proteinuria (i.e., without treatment with antihypertensive agents, especially no RAS-intervening agents, or immune suppressive medication) was 5.6 g/d (95% CI, 4.1 to 8.4). Residual proteinuria was 3.2 g/d (95% CI, 1.8 to 5.2) on treatment with the combination irbesartan, diuretic, and low-sodium diet. Additional dose titration with lisinopril to the maximal tolerated dose showed a further proteinuria reduction of 55.6% (95% CI, 16.0 to 73.2) to a residual proteinuria of 1.6 (95% CI, 0.8 to 3.6; P = 0.018 versus irbesartan/diuretic) (Figure 1). Proteinuria to creatinine ratio was also significantly reduced (Table 2). Individual up-titration with lisinopril led to further proteinuria reduction in all patients. No relation between the amount of proteinuria reduction (% change) and the dose of lisinopril could be observed (Table 3).
MAP was 92 mmHg (95% CI, 77 to 111). After up-titration to maximal lisinopril doses, MAP was significantly reduced to 85 mmHg (95% CI, 73 to 109; P = 0.043) (Figure 1). Body weight, serum electrolytes, albumin, and lipids were not affected by lisinopril up-titration (Table 2).
With regard to the predefined treatment goal, two out of eight patients reached proteinuria of <1g/d after the maximal individual dose of lisinopril 10 and 40 mg, respectively (Table 3). Six of eight patients did not reach the target proteinuria: two of six because they had still residual proteinuria (>1g/d) on the highest lisinopril dose and four of six because they experienced side effects that prevented further dose increase of the ACEi (Figure 1).
Side Effects
During up-titration with lisinopril, five of eight patients experienced adverse symptoms: Two patients had hyperkalemia (>5.5 mmol/L), two patients complained of cough, and one patient experienced dizziness and had simultaneously >50% increase of serum creatinine (Table 3). One of these five patients also reached the treatment target. Of note, of those patients who experienced adverse effects, none received the maximal additional dose of lisinopril (40 mg once daily), whereas in those patients in whom up-titration to the maximal lisinopril dose was possible, no side effects were observed.
Discussion
The results of this study show that maximal RAS blockade, entailing individual up-titration of the ACEi lisinopril to maximal tolerated dose in addition to a maximum therapy of the AIIA irbesartan combined with diuretic and dietary sodium restriction, induces a >50% reduction of residual proteinuria in the nondiabetic proteinuric patient. However, this benefit occurs at the expense of a number of adverse events, which clearly limit the feasibility in a considerable proportion of patients to obtain optimal antiproteinuric efficacy with the currently available therapeutic options. Indeed, in only two patients was the treatment target of proteinuria <1 g/d obtained.
The high incidence of adverse events in our study seems to be at variance with the expectation on the basis of studies in the different renal populations (14,15,17,18). Clinical studies in both diabetic and nondiabetic renal patients show that dual RAS blockade led to further proteinuria reduction than with maximal recommended doses of monotherapy (ACEi or AIIA) could be obtained, without leading to extra adverse symptoms (14,17,18). Also, in the large trial with 263 nondiabetic patients of Nakao et al. (15), in which the long-term benefit of dual RAS blockade on hard renal end points was demonstrated, the combination therapy of ACEi and AIIA was very well tolerated and did not lead to extra side effects compared with monotherapy with trandolapril.
To explain the high prevalence of adverse effects in our study, one should take into account that most of the observed adverse symptoms (dizziness, hyperkalemia, serious impairment of renal function) in our study tend to show a dose-dependent relation, i.e., the further the maximization of RAS blockade is obtained, the more adverse effects can be expected. Our treatment schedule was characterized by two distinct measures that contribute to obtain the maximum antiproteinuric effect by a RAS blockade–based regimen. First, in our treatment schedule, patients were individually titrated for maximal proteinuria reduction with additional lisinopril doses on top of a fixed high dose of irbesartan. Although no data are available on the dose-response of irbesartan for proteinuria reduction, it is expected that the maximal recommended dose for BP reduction also renders the maximal antiproteinuric response, as indicated by most titration studies in proteinuric patients with other AIIA, such as losartan and candesartan, in which a flattening of the dose-response curve is seen after treatment with higher doses (11,12,19). By contrast, increasing the ACEi dose seems not to show such recline in the dose-response for proteinuria reduction, indicating that higher doses of ACEi than needed for BP control result in further proteinuria reduction (14). Therefore, we expect that individual up-titration with increasing doses of lisinopril on top of high-dose AIIA leads to further maximization of blockade of the RAS for the individual patient. As a consequence, this results not only in improvement of the antiproteinuric effect but also in high prevalence of side effects. In contrast, in the study of Nakao et al. (15), the doses of both trandolapril and losartan used for proteinuria reduction were not based on observations in individual patients but on group level for both trandolapril and losartan.
Second, the dual RAS blockade was given on top of diuretic therapy and dietary sodium restriction. Data from studies in hypertensive patients but also in proteinuric patients indicate that both low-sodium diet and diuretic therapy can restore the blunted therapy response during RAS intervening therapy (13). In our study, patients were instructed to adhere to a sodium-restricted diet that was only moderately successful, as estimated from their 24-h sodium excretion. Moreover, all patients were treated with a diuretic. Because it is known from hypertensive patients that both measures combined act synergistically on the therapy response for BP during ACEi (20), it can be anticipated that the combination also leads to further improvement of the antiproteinuric response during dual RAS blockade. Therefore, individual titration with ACEi for the optimal antiproteinuric response on top of a treatment that consists of AIIA, diuretic, and dietary low sodium results in more effective blockade of the RAS, as indicated by further optimization of proteinuria reduction and BP response. However, as apparent from our data, this strategy has it limits, and it may not only be so because of the occurrence of side effects.
We previously demonstrated that individual antiproteinuric responsiveness to RAS blockade is an important determinant of the renoprotective efficacy of intervention and that despite proven efficacy at the group level, the renoprotective effect of RAS blockade shows a marked between-patient heterogeneity (5). Therefore, the feasibility of individual titration for proteinuria by optimizing the RAS blockade was explored in this study. However, our present data show that this strategy to overcome individual therapy resistance does not result in abolishment of therapy resistance, which is in accordance with other studies, showing that, despite efficacy at the group level, poor responders still fail to catch up with good responders (21,22).
How could we approach the problem of improving antiproteinuric efficacy for individual patients without enhancing side effects? It would be interesting to explore other non-RAS intervening modes of therapy directed to maximization of reduction of residual proteinuria. First, different studies demonstrated that intervention in the synthesis of prostaglandins by using NSAID has antiproteinuric properties with equal effectiveness as ACEi therapy (23,24). Because of the well-known side effects of nonselective NSAID, it would be of great interest to explore whether the relative new selective COX-2 inhibitors, for which lower rates of side effects are reported, share the antiproteinuric properties of NSAID, as discussed previously (25). This issue is currently under investigation by our group. Until now, limited data suggest that addition of COX-2 inhibitors can overcome therapy resistance during ACEi in membranous glomerulopathy by further reducing residual proteinuria (26). Second, lipid-lowering drugs, statins in particular, may exert a renoprotective effect independent from their lipid-lowering effect. In renal patients and in hypertensive patients, long-term treatment with statins is reported to reduce proteinuria (27,28). Importantly, statin treatment added to ACEi and AIIA was shown to improve proteinuria reduction (28,29). Therefore, statins could play role in renal conditions of relative resistance to intervention with RAS blockade.
In conclusion, individual titration for maximal antiproteinuric efficacy by a RAS blockade–based regimen results in successful reduction of residual proteinuria. However, this benefit occurs at the expense of a number of adverse events. Achievement of proteinuria to lowest levels may probably only be pursued by a multidrug approach, with intervention in other relevant pathways, such as prostaglandins or lipids. Future studies should address optimal dosing schedules and evaluate the eventual benefit in terms of renal risk.
Absolute and percentage change of proteinuria and mean arterial pressure after individual up-titration to maximal tolerated doses with lisinopril on background of irbesartan 300 mg + diuretic treatment in eight nondiabetic proteinuric patients. Dotted line represents the proteinuria treatment target of <1 g/d (*P < 0.05; † P< 0.02).
Patient characteristics at baseline (median and 95% CI or number)a
Median (95% CI) of parameters in eight nondiabetic patients after irbesartan 300 mg diuretic combination and after maximal dose of lisinopril addeda
Individual BP and proteinuria change after the maximal tolerated additional lisinopril dose in eight nondiabetic proteinuric patients on irbesartan 300 mg diuretic combination treatmenta
This study was supported by a grant from Sanofi-Synthe[Combining Acute Accent]labo.
We are greatly indebted to our colleague, Dr. G.D. Laverman, for support in collecting clinical observations, as well as blood and urine samples.
Published online ahead of print. Publication date available at www.jasn.org.
References
1. Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL: 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
2. Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi 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
3. 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. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 349: 1857 –1863, 1997
4. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345 : 861 –869, 2001
5. Apperloo AJ, de Zeeuw D, de Jong PE: Short-term antiproteinuric response to antihypertensive treatment predicts long-term GFR decline in patients with non-diabetic renal disease. Kidney Int Suppl 45 : S174 –S178, 1994
6. Rossing P, Hommel E, Smidt UM, Parving HH: Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 37 : 511 –516, 1994
7. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal diseases. Lancet 357 : 1601 –1608, 2001
8. de Jong PE, Navis G, de Zeeuw D: Renoprotective therapy: Titration against urinary protein excretion. Lancet 354 : 352 –353, 1999
9. Vogt L, Laverman GD, de Zeeuw D, Navis G: The COOPERATE trial. Lancet 361 : 1055 –1056, 2003
10. Gansevoort RT, de Zeeuw D, de Jong PE: Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Kidney Int 45 : 861 –867, 1994
11. Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH: Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 57 : 601 –606, 2000
12. Laverman GD, Henning RH, de Jong PE, Navis G, de Zeeuw D: Optimal antiproteinuric dose of losartan in nondiabetic patients with nephrotic range proteinuria. Am J Kidney Dis 38 : 1381 –1384, 2001
13. Buter H, Hemmelder MH, Navis G, de Jong PE, de Zeeuw D: The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 13 : 1682 –1685, 1998
14. Laverman GD, Navis G, Henning RH, de Jong PE, de Zeeuw D: Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int 62 : 1020 –1025, 2002
15. Nakao 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 361 : 117 –124, 2003
16. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345 : 851 –860, 2001
17. Rossing K, Jacobsen P, Pietraszek L, Parving HH: Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: A randomized double-blind crossover trial. Diabetes Care 26 : 2268 –2274, 2003
18. Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving HH: Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 63 : 1874 –1880, 2003
19. Andersen S, Rossing P, Juhl TR, Deinum J, Parving HH: Optimal dose of losartan for renoprotection in diabetic nephropathy. Nephrol Dial Transplant 17 : 1413 –1418, 2002
20. Wing LM, Arnolda LF, Harvey PJ, Upton J, Molloy D, Gabb GM, Bune AJ, Chalmers JP: Low-dose diuretic and/or dietary sodium restriction when blood pressure is resistant to ACE inhibitor. Blood Press 7 : 299 –307, 1998
21. Bos H, Henning RH, De Boer E, Tiebosch AT, de Jong PE, de Zeeuw D, Navis G: Addition of AT1 blocker fails to overcome resistance to ACE inhibition in adriamycin nephrosis. Kidney Int 61 : 473 –480, 2002
22. Laverman GD, de Zeeuw D, Navis G: Between-patient differences in the renal response to renin-angiotensin system intervention: Clue to optimising renoprotective therapy? J Renin Angiotensin Aldosterone Syst 3 : 205 –213, 2002
23. Heeg JE, de Jong PE, Vriesendorp R, de Zeeuw D: Additive antiproteinuric effect of the NSAID indomethacin and the ACE inhibitor lisinopril. Am J Nephrol 10[Suppl 1] : 94 –97, 1990
24. Garini G, Mazzi A, Buzio C, Mutti A, Allegri L, Savazzi G, Borghetti A: Renal effects of captopril, indomethacin and nifedipine in nephrotic patients after an oral protein load. Nephrol Dial Transplant 11 : 628 –634, 1996
25. Vogt L, Navis G, de Zeeuw D: Renoprotection: A matter of blood pressure reduction or agent-characteristics? J Am Soc Nephrol 13[Suppl 3] : S202 –S207, 2002
26. Costanzi S, Sturniolo A, Fulignati P, Passalacqua S, Staffolani E, D’Alonzo S, Splendiani G: Cyclooxygenase (COX)-2 selective inhibitors + ACE inhibitors: A new protocol in the treatment of heavy proteinuria [Abstract]. Nephrol Dial Transplant 18 : 79 –634, 2003
27. Fried LF, Orchard TJ, Kasiske BL: Effect of lipid reduction on the progression of renal disease: A meta-analysis. Kidney Int 59 : 260 –269, 2001
28. Lee TM, Su SF, Tsai CH: Effect of pravastatin on proteinuria in patients with well-controlled hypertension. Hypertension 40 : 67 –73, 2002
29. Bianchi S, Bigazzi R, Caiazza A, Campese VM: A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 41 : 565 –570, 2003
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