Antiproteinuric effect of add-on paricalcitol in CKD patients under maximal tolerated inhibition of renin-angiotensin system: a prospective observational study

BMC Nephrology

Roberto Minutolo¹  Antonio Gorini²  Domenico Russo³  Giuseppe Conte¹  Luca De Nicola⁴ 

[1] Nephrology Departments at Second University, Napoli, Italia;S. Giovanni Evangelista Hospital, Tivoli, Italy;University Federico II, Napoli, Italia;Cattedra di Nefrologia - Dip. Gerontologia, Geriatria, Mal. Metabolismo, Seconda Università di Napoli, Facoltà di Medicina, Piazza Miraglia, 80131, Napoli, Italia

关键词: Proteinuria;    Chronic kidney disease;    Paricalcitol;    Renin inhibitor;    Angiotensin II receptor blocker;    Angiotensin converting enzyme inhibitor;   

Others  :  1083061
DOI  :  10.1186/1471-2369-13-150

 received in 2012-07-16, accepted in 2012-11-18,  发布年份 2012

【 摘 要 】

Background

Whether paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of Renin-Angiotensin-System (RAS) is poorly studied. We evaluated the antiproteinuric effect of PCT in non-dialysis chronic kidney disease (CKD) patients with proteinuria greater than 0.5 g/24 h persisting despite anti-RAS therapy titrated to minimize proteinuria in the absence of adverse effects.

Methods

Forty-eight CKD patients were studied in the first six months of add-on oral PCT (1 mcg/day) and three months after drug withdrawal.

Results

Males were 87.5%, age 63 ± 14 yrs, systolic/diastolic blood pressure (BP) 143 ± 22/78 ± 11 mmHg, eGFR 29.7 ± 14.5 mL/min/1.73 m², diabetes 40%, and cardiovascular disease 38%. At referral in the center (28 months prior to study baseline), proteinuria was 2.44 (95% CI 1.80-3.04) g/24 h with 6 patients not receiving any anti-RAS and 42 treated with a single agent, at low dosage in most cases. At study baseline, twenty patients were under 2–3 anti-RAS drugs while twenty-eight received 1 agent at full dose and proteinuria resulted to be reduced versus referral to 1.23 g/24 h (95%CI 1.00-1.51). Six months of add-on PCT significantly decreased proteinuria to 0.61 g/24 h (95%CI 0.40-0.93), with levels less than 0.5 g/24 h achieved in 37.5% patients, in the absence of changes of BP and GFR. Proteinuria recovered to basal value after drug withdrawal. The extent of antiproteinuric response to PCT was positively associated with diabetes, eGFR and daily Na excretion (R² = 0.459, P < 0.0001). PTH decreased from 201 (IQR 92–273) to 83 (IQR 50–189) pg/mL.

Conclusions

In CKD patients, add-on PCT induces a significant reduction of proteinuria that is evident despite intensified anti-RAS therapy and larger in the presence of diabetes, higher GFR and unrestricted salt intake.

【 授权许可】

   
2012 De Nicola et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Levey AS, Cattran D, Friedman A, Miller WG, Sedor J, Tuttle K, Kasiske B, Hostetter T: 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 2009, 54:205-226.
• [2]De Nicola L, Chiodini P, Zoccali C, Borrelli S, Cianciaruso B, Di Iorio B, Santoro D, Giancaspro V, Abaterusso C, Gallo C, Conte G, Minutolo R, SIN-TABLE CKD Study Group: Prognosis of CKD patients receiving outpatient nephrology care in Italy. Clin J Am Soc Nephrol 2011, 6:2421-2428.
• [3]Ruggenenti P, Perna A, Remuzzi G, GISEN Group Investigators: Retarding progression of chronic renal disease: the neglected issue of residual proteinuria. Kidney Int 2003, 63:2254-2261.
• [4]de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004, 110:921-927.
• [5]Eijkelkamp WB, Zhang Z, Remuzzi G, Parving HH, Cooper ME, Keane WF, Shahinfar S, Gleim GW, Weir MR, Brenner BM, de Zeeuw D: 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, 18:1540-1546.
• [6]K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease Am J Kidney Dis 2004, 43:S1-S230.
• [7]Müller DN, Luft FC: Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006, 1:221-228.
• [8]Velez JC: The importance of the intrarenal renin-angiotensin system. Nat Clin Pract Nephrol 2009, 5:89-100.
• [9]Wolf G, Ritz E: Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic disease: pathophysiology and indications. Kidney Int 2005, 67:799-812.
• [10]Kunz R, Friedrich C, Wolbers M, Mann JF: Metaanalysis: 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.
• [11]De Nicola L, Zamboli P, Bellizzi V, Stanzione G, Russo D, Nappi F, Minco M, Chiodini P, Conte G, Minutolo R: Antiproteinuric response to add-on aliskiren in proteinuric patients treated with dual blockade of the renin-angiotensin system: a 12-month prospective uncontrolled study. Am J Kidney Dis 2011, 57:961-963.
• [12]Li YC: Renoprotective effects of vitamin D analogs. Kidney Int 2010, 78:134-139.
• [13]Agarwal R: Are vitamin D receptor agonists like angiotensin-converting enzyme inhibitors without side effects? Kidney Int 2010, 77:943-945.
• [14]Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qiu P, Williams L, Batlle D: Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int 2005, 68:2823-2828.
• [15]Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, Light RP, Agarwal R: Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 2008, 52:211-212.
• [16]Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N: Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J KidneyDis 2009, 54:647-652.
• [17]de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D: Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010, 376:1543-1551.
• [18]Cheng J, Zhang W, Zhang X, Li X, Chen J: Efficacy and safety of paricalcitol therapy for chronic kidney disease: a meta-analysis. Clin J Am Soc Nephrol 2012, 7:391-400.
• [19]Bianchi S, Bigazzi R, Campese VM: Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases. Am J Kidney Dis 2010, 55:671-681.
• [20]Ruggenenti P, Perticucci E, Cravedi P, Gambara V, Costantini M, Sharma SK, Perna A, Remuzzi G: Role of remission clinics in the longitudinal treatment of CKD. J Am Soc Nephrol 2008, 19:1213-1224.
• [21]O’Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, Mengden T, Myers M, Padfield P, Palatini P, Parati G, Pickering T, Redon J, Staessen J, Stergiou G, Verdecchia P: European Society of Hypertension Working Group on Blood Pressure Monitoring: European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens 2003, 21:821-848.
• [22]Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, Richart T, Torp-Pedersen C, Lind L, Ibsen H, Imai Y, Staessen JA: International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) Investigators: diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year cardiovascular risk. Circulation 2007, 115:2145-2152.
• [23]Minutolo R, Borrelli S, Scigliano R, Bellizzi V, Chiodini P, Cianciaruso B, Nappi F, Zamboli P, Conte G, De Nicola L: Prevalence and clinical correlates of white coat hypertension in chronic kidney disease. Nephrol Dial Transplant 2007, 22:2217-2223.
• [24]Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC: Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc Natl Acad Sci USA 2008, 105:15896-15901.
• [25]Tan X, Wen X, Liu Y: Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol 2008, 19:1741-1752.
• [26]Deb DK, Sun T, Wong KE, Ning G, Zhang Y, Kong J, Shi H, Chang A, Li YC: Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. Kidney Int 2010, 77:1000-1009.
• [27]Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D: Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 2003, 63:1483-1490.
• [28]Kim MJ, Frankel AH, Donaldson M, et al.: Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int 2011, 80:851-860.
• [29]Liu LJ, Lv JC, Shi SF, Chen YQ, Zhang H, Wang HY: Oral calcitriol for reduction of proteinuria in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis 2012, 59:67-74.
• [30]Burns KD: Angiotensin II, and its receptors in the diabetic kidney. Am J Kidney Dis 2000, 36:449-467.
• [31]Huang XR, Chen WY, Truong LD, Lan HY: Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II–mediated diabetic renal and vascular disease. J Am Soc Nephrol 2003, 14:1738-1747.
• [32]De Nicola L, Minutolo R, Bellizzi V, Zoccali C, Cianciaruso B, Andreucci VE, Fuiano G, Conte G: Achievement of target blood pressure levels in chronic kidney disease: a salty question? Am J Kidney Dis 2004, 43:782-795.
• [33]Cianciaruso B, Bellizzi V, Minutolo R, Tavera A, Capuano A, Conte G, De Nicola L: Salt intake and renal outcome in patients with progressive renal disease. Miner Electrolyte Metab 1998, 24:296-301.
• [34]Slatopolsky E, Cozzolino M, Lu Y, Finch J, Dusso A, Staniforth M, Wein Y, Webster J: Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia. Kidney Int 2003, 63:2020-2027.