Albuminuria Reduction With Renin Angiotensin System Inhibitors in SCA Patients

NCT01195818 | Completed

• 2 other identifiers: P081110AOR09063
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

The prevalence of Sickle Cell Associated Nephropathy (SCAN) is increasing and is a growing concern. Microalbuminuria is detected in the early onset of SCAN. Noteworthy, as in diabetic nephropathy, hyperfiltration seems to be a frequent finding, with, in our series, an overall incidence of 57 % and suggests a pathological links between glomerular hyperpressure and glomerulosclerosis which occurs several years after. Nitric oxide (NO) deficiency and the renin angiotensin system (RAS) are likely to be involved in the glomerular hyperpressure leading to hyperfiltration. Renin angiotensin antagonists are currently given for NEPHROPROTECTION in numerous nephropathy including SCAN despite few available reports. The percentage of decrease of albuminuria or the percentage of responders (ie patient normalizing albuminuria) has never been reported to our knowledge in SCAN patients at the time of hyperfiltration. The focus of our study is therefore to 1) Quantify albuminuria reduction after 6 months RAS treatment (primary end point); 2) Quantify glomerular filtration rate (GFR) reduction after 6 months of RAS treatment, and to test the hypothesis of a beneficial effect of RAS inhibitors on several biomarkers assessing hemolysis, NO inhibition and the endothelial damages (secondary end points). The ultimate aim of our study is to identify relevant (new) biomarkers associated to hyperfiltration and/or albuminuria decrease (/normalization).

Conditions

Sickle Cell Disease

Keywords

Albuminuria, hyperfiltration, RAS inhibitors, ADMA

Outcome Measures

Primary Outcomes (1)

• Comparison of albuminuria/ urinary creatinin ratio before and after a 6 months RAS inhibitor treatment period

  6 months RAS inhibitor treatment period

Secondary Outcomes (2)

• Comparison of albuminuria/ urinary creatinin ratio under RAS inhibitor treatment and after 1 month wash-out period

  1 month wash-out period

• Comparison of glomerular Filtration Rate (51CR EDTA clearance) before and after a 6 months RAS inhibitor treatment period

  6 months RAS inhibitor treatment period

Study Arms (1)

RAS Inhibitors

EXPERIMENTAL

RAS Inhibitors

Drug: RAS Inhibitors

Interventions

RAS Inhibitors DRUG

Clinical trial testing the effect of RAS inhibitors (Ramipril or Irbesartan)on sickle cell disease patients wit hyperfiltration and albuminuria for a six month period followed by one month wash out period. Drug will be given after the first GFR measurement on a daily basis with a full dose given after the first month.

RAS Inhibitors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Homozygous sickle cell disease
• \> 18 years
• Patient with social insurance
• Albuminuria/ urinary creatinin \> 10 mg/mmol creatinin (at 2 different times) and MDRD \> 140 ml/min/1.73m2.
• Written inform consent

You may not qualify if:

• Hemoglobin SC or S-betathalassemia disease
• Patient currently treated with: lithium, aspirin, antihypertensive drugs, non steroid-antiinflammatory drugs.
• Pregnancy
• Woman without contraception
• Transfusion within the last 3 months
• Intolerance to RAS inhibitors
• Treatment with RAS in the last month
• Patient with Congenital galactosemia or a malabsorption of glucose or lactase deficiency
• Treatment with hydroxyurea began or changed in the last 3 months
• Infection with HIV or C hepatitis
• Angio-edema

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Centre de la Drépanocytose, Service de Médecine Interne. Hôpital Tenon, 4 Rue de la Chine

Paris, Paris, 75020, France

Location

Related Publications (24)

• Dharnidharka VR, Dabbagh S, Atiyeh B, Simpson P, Sarnaik S. Prevalence of microalbuminuria in children with sickle cell disease. Pediatr Nephrol. 1998 Aug;12(6):475-8. doi: 10.1007/s004670050491.

  PMID: 9745872 BACKGROUND

• Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006 Aug;17(8):2228-35. doi: 10.1681/ASN.2002010084. Epub 2006 Jul 12.

  PMID: 16837635 BACKGROUND

• Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med. 1992 Apr 2;326(14):910-5. doi: 10.1056/NEJM199204023261402.

  PMID: 1542341 BACKGROUND

• Olson JL, Hostetter TH, Rennke HG, Brenner BM, Venkatachalam MA. Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass. Kidney Int. 1982 Aug;22(2):112-26. doi: 10.1038/ki.1982.143. No abstract available.

  PMID: 6182335 BACKGROUND

• Serjeant GR, Higgs DR, Hambleton IR. Elderly survivors with homozygous sickle cell disease. N Engl J Med. 2007 Feb 8;356(6):642-3. doi: 10.1056/NEJMc066547. No abstract available.

  PMID: 17287491 BACKGROUND

• Manci EA, Culberson DE, Yang YM, Gardner TM, Powell R, Haynes J Jr, Shah AK, Mankad VN; Investigators of the Cooperative Study of Sickle Cell Disease. Causes of death in sickle cell disease: an autopsy study. Br J Haematol. 2003 Oct;123(2):359-65. doi: 10.1046/j.1365-2141.2003.04594.x.

  PMID: 14531921 BACKGROUND

• Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, Johnson C. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991 Oct 15;115(8):614-20. doi: 10.7326/0003-4819-115-8-614.

  PMID: 1892333 BACKGROUND

• Barros FB, Lima CS, Santos AO, Mazo-Ruiz MF, Lima MC, Etchebehere EC, Costa FF, Saad ST, Camargo EE, Ramos CD. 51Cr-EDTA measurements of the glomerular filtration rate in patients with sickle cell anaemia and minor renal damage. Nucl Med Commun. 2006 Dec;27(12):959-62. doi: 10.1097/01.mnm.0000243373.03636.6e.

  PMID: 17088681 BACKGROUND

• Marouf R, Mojiminiyi O, Abdella N, Kortom M, Al Wazzan H. Comparison of renal function markers in Kuwaiti patients with sickle cell disease. J Clin Pathol. 2006 Apr;59(4):345-51. doi: 10.1136/jcp.2005.026799.

  PMID: 16567469 BACKGROUND

• Vedel P, Obel J, Nielsen FS, Bang LE, Svendsen TL, Pedersen OB, Parving HH. Glomerular hyperfiltration in microalbuminuric NIDDM patients. Diabetologia. 1996 Dec;39(12):1584-9. doi: 10.1007/s001250050618.

  PMID: 8960846 BACKGROUND

• Berg UB. Differences in decline in GFR with age between males and females. Reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant. 2006 Sep;21(9):2577-82. doi: 10.1093/ndt/gfl227. Epub 2006 May 23.

  PMID: 16720595 BACKGROUND

• Chiarelli F, Cipollone F, Romano F, Tumini S, Costantini F, di Ricco L, Pomilio M, Pierdomenico SD, Marini M, Cuccurullo F, Mezzetti A. Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria: relation to glomerular hyperfiltration. Diabetes. 2000 Jul;49(7):1258-63. doi: 10.2337/diabetes.49.7.1258.

  PMID: 10909986 BACKGROUND

• Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005 Jul 6;294(1):81-90. doi: 10.1001/jama.294.1.81.

  PMID: 15998894 BACKGROUND

• Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002 Dec;8(12):1383-9. doi: 10.1038/nm1202-799. Epub 2002 Nov 11.

  PMID: 12426562 BACKGROUND

• Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005 Apr 6;293(13):1653-62. doi: 10.1001/jama.293.13.1653.

  PMID: 15811985 BACKGROUND

• Kato GJ, McGowan V, Machado RF, Little JA, Taylor J 6th, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006 Mar 15;107(6):2279-85. doi: 10.1182/blood-2005-06-2373. Epub 2005 Nov 15.

  PMID: 16291595 BACKGROUND

• Landburg PP, Teerlink T, Muskiet FA, Duits AJ, Schnog JJ; CURAMA study group. Plasma concentrations of asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell patients but do not increase further during painful crisis. Am J Hematol. 2008 Jul;83(7):577-9. doi: 10.1002/ajh.21184.

  PMID: 18383318 BACKGROUND

• Loutzenhiser R, Bidani A, Chilton L. Renal myogenic response: kinetic attributes and physiological role. Circ Res. 2002 Jun 28;90(12):1316-24. doi: 10.1161/01.res.0000024262.11534.18.

  PMID: 12089070 BACKGROUND

• Sochett EB, Cherney DZ, Curtis JR, Dekker MG, Scholey JW, Miller JA. Impact of renin angiotensin system modulation on the hyperfiltration state in type 1 diabetes. J Am Soc Nephrol. 2006 Jun;17(6):1703-9. doi: 10.1681/ASN.2005080872. Epub 2006 May 3.

  PMID: 16672313 BACKGROUND

• Aoki RY, Saad ST. Enalapril reduces the albuminuria of patients with sickle cell disease. Am J Med. 1995 May;98(5):432-5. doi: 10.1016/S0002-9343(99)80341-6.

  PMID: 7733120 BACKGROUND

• Foucan L, Bourhis V, Bangou J, Merault L, Etienne-Julan M, Salmi RL. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med. 1998 Apr;104(4):339-42. doi: 10.1016/s0002-9343(98)00056-4.

  PMID: 9576406 BACKGROUND

• Reboldi G, Gentile G, Angeli F, Verdecchia P. Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials. Vasc Health Risk Manag. 2009;5(1):411-27. doi: 10.2147/vhrm.s4235.

  PMID: 19475778 BACKGROUND

• Lionnet F, Arlet JB, Bartolucci P, Habibi A, Ribeil JA, Stankovic K; groupe de recommandations et d'etude de la drepanocytose de l'adulte (GREDA). [Guidelines for management of adult sickle cell disease]. Rev Med Interne. 2009 Sep;30 Suppl 3:S162-223. doi: 10.1016/j.revmed.2009.07.001. Epub 2009 Aug 26. French.

  PMID: 19713011 BACKGROUND

• van Deventer HE, George JA, Paiker JE, Becker PJ, Katz IJ. Estimating glomerular filtration rate in black South Africans by use of the modification of diet in renal disease and Cockcroft-Gault equations. Clin Chem. 2008 Jul;54(7):1197-202. doi: 10.1373/clinchem.2007.099085. Epub 2008 May 16.

  PMID: 18487286 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Albuminuria

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Proteinuria; Urination Disorders; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2010
• First Posted: September 6, 2010
• Study Start: September 1, 2010
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: June 18, 2015

Record last verified: 2015-06

Locations

FR (1)