The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Since publication of their article, no further potential conflict of interest was reported.
1. Tryon RC, White SD, Bannasch DL. Homozygosity mapping

4. Schwarze U, Pyott S, Russell D, Sussman M, Harris C, Byers

approach identifies a missense mutation in equine cyclophilin B (PPIB) associated with HERDA in the American Quarter Horse. Genomics 2007;90:93-102. 2. Rycyzyn MA, Reilly SC, OMalley K, Clevenger CV. Role of cyclophilin B in prolactin signal transduction and nuclear retro translocation. Mol Endocrinol 2000;14:1175-86. 3. van Dijk FS, Nesbitt IM, Zwikstra EH, et al. PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 2009; 85:521-7.

PH. Mutations in PPIB, which encodes a prolyl cis-trans isomerase (cyclophilin B), in recessive forms of osteogenesis imperfecta (OI). In: Program and abstracts of the 59th Annual Meeting of the American Society of Human Genetics, Honolulu, October 20-24, 2009:73. abstract. (Accessed April 29, 2010, at http://www .ashg.org/2009meeting/pdf/platforms_4up.pdf.) 5. Van Dijk FS, Pals G, Van Rijn RR, Nikkels PG, Cobben JM. Classification of osteogenesis imperfecta revisited. Eur J Med Genet 2010;53:1-5. 6. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101-16.

Stage IV Chronic Kidney Disease

To the Editor: In the review of stage IV chronic kidney disease by Abboud and Henrich (Jan. 7 issue),1 there is an omission that, as a practicing physician and kidney-transplant recipient, I would like to point out. The authors suggest that patients be informed about methods of renal-replacement therapy and specify that upper-extremity veins should be protected in case vascular access is needed for hemodialysis. However, the authors should also have suggested that appropriate patients be encouraged to identify live kidney donors early on, in order to plan for possible transplantation before or shortly after the onset of end-stage renal disease. The selection and evaluation of a suitable kidney donor, related or not, can take many months. Patients who have identified a donor who is willing but who is ABO-incompatible or crossmatch-incompatible may be eligible for exchange programs or desensitization, but these arrangements take even longer. The best chance for timely implementation is active discussion while the patient is in stage IV chronic kidney disease. Roberta M. Falke, M.D.
Harvard Vanguard Medical Associates Boston, MA rfalke@rcn.com No potential conflict of interest relevant to this letter was reported.
1. Abboud H, Henrich WL. Stage IV chronic kidney disease.

ered preferred antihypertensive agents for patients with stage IV chronic kidney disease who have a minimal degree of proteinuria. For patients with proteinuria, reduction of urinary protein to approximately 500 mg per day appears to be beneficial. An ACE inhibitor or ARB at modest doses does not typically achieve this goal. Thus, the prescription of an ACE inhibitor or an ARB itself does not define optimal treatment for chronic kidney disease. Clinical experience1 and trial data2 suggest that targeted reduction of proteinuria, by increasing the dose of an ACE inhibitor or ARB or (arguably) by adding medications, slows the progression of renal disease. In the Renoprotection of Optimal Antiproteinuric Doses (ROAD) trial,2 a strategy of increasing the dose of benazepril or losartan to achieve optimal antiproteinuric effects, as compared with conventional dosing, reduced the incidence of the doubling of serum creatinine, endstage renal disease, or death over the course of a median 3.7-year follow-up. In other studies, high doses of lisinopril (80 mg per day)3 or candesartan (128 mg per day)4 have been shown to reduce proteinuria more than do standard doses. Sheldon Hirsch, M.D.
Mercy Hospital Chicago, IL shelman100@aol.com No potential conflict of interest relevant to this letter was reported.
1. Ruggenenti P, Schieppati A, Remuzzi G. Progression, re-

N Engl J Med 2010;362:56-65.

To the Editor: The evidence that angiotensinconvertingenzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) preserve renal function is limited to patients with a high degree of proteinuria. Given the risk of hyperkalemia, ACE inhibitors and ARBs should not be consid1942

mission, regression of chronic renal diseases. Lancet 2001;357: 1601-8. 2. Hou FF, Xie D, Zhang X, et al. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol 2007;18:1889-98. 3. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid

n engl j med 362;20 nejm.org may 20, 2010

The New England Journal of Medicine Downloaded from nejm.org on April 2, 2014. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

correspondence
antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009;20:2641-50. 4. Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximal dose of candesartan in proteinuric renal disease. J Am Soc Nephrol 2009;20:893-900.

The Authors Reply: We are in complete agreement with the suggestions in Falkes letter. Kidney transplantation remains the treatment of choice for most patients with end-stage renal disease, including and especially patients with diabetic kidney disease. Patients with stage IV chronic kidney disease or renal disease that has progressed almost to end-stage disease should undergo counseling and education about the available methods to treat end-stage renal disease. This should include encouragement to identify live kidney donors when appropriate. For patients who opt to receive a transplant from a live kidney donor, evaluation of both the donor and the recipient should be performed at least 6 months before the predicted need for renal-replacement therapy. William L. Henrich, M.D. Kidney transplantation offers the best outcome, Hanna E. Abboud, M.D. especially when it is performed before hemodialyUniversity of Texas Health Science Center at San Antonio sis is initiated.1 San Antonio, TX We thank Hirsch for his comments. The reno- henrich@uthscsa.edu protective benefits of ACE inhibitors or ARBs are Since publication of their article, the authors report no further not seen in patients with chronic kidney disease potential conflict of interest. who do not have diabetes or proteinuria.2 Since cardiovascular disease is the most common cause 1. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outof complications and death among patients with comes: a paired donor kidney analysis. Transplantation 2002; chronic kidney disease, particularly when they 74:1377-81. also have diabetes, ACE inhibitors or ARBs 2. Kent DM, Jafar TH, Hayward RA, et al. Progression risk, urinary protein excretion, and treatment effects of angiotensinshould be considered for the treatment of hyper- converting enzyme inhibitors in nondiabetic kidney disease. tension in these patients. The propensity for J Am Soc Nephrol 2007;18:1959-65. hyperkalemia increases with declining glomeru- 3. Eijkelkamp WB, Zhang Z, Remuzzi G, et al. Albuminuria is a target for renoprotective therapy independent from blood preslar filtration rate, and therefore these agents sure in patients with type 2 diabetic nephropathy: post hoc should be used with caution in patients with analysis from the Reduction of Endpoints in NIDDM with the advanced chronic kidney disease, with or with- Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol 2007;18:1540-6. out proteinuria. 4. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progresTreatment of hypertension and the reduction sion and regression of renal lesions of chronic nephropathies of proteinuria to maximize renoprotection should and diabetes. J Clin Invest 2006;116:288-96. 5. Berl T. Maximizing inhibition of the renin-angiotensin system also be the goal of therapy with ACE inhibitors with high doses of converting enzyme inhibitors or angiotensin or ARBs. However, doses sufficient to lower receptor blockers. Nephrol Dial Transplant 2008;23:2443-7.

blood pressure to target levels may not reduce proteinuria optimally, and residual proteinuria is a risk factor for progression.3 Evidence suggests that more effective blockade of the reninangiotensin system, rather than simply more effective blood-pressure control, confers maximal renoprotection.4 Some, but not all, studies show that doses of ACE inhibitors or ARBs above the maximum recommended doses achieve a greater reduction in proteinuria than do conventional doses in patients with chronic kidney disease both those with diabetes and those without diabetes.5 Alternatively, a combination of conventional doses of an ACE inhibitor and an ARB may achieve similar benefits,5 although randomized trials are lacking to compare treatment with an ACE inhibitor or ARB at doses that are higher than the maximum recommended doses with treatment that consists of a combination of these two agents at conventional doses.

Case 2-2010: A Man with Abdominal and Flank Pain

To the Editor: Isselbacher et al. (Jan. 21 issue)1 report the case of a 47-year-old Latin-American immigrant with Chagas cardiomyopathy and a left ventricular apical aneurysm with thrombus who had abdominal and flank pain because of a renal embolism. In addition to providing anticoagulation therapy, the authors considered using a trypanocidal drug and decided to administer
1943

n engl j med 362;20 nejm.org may 20, 2010

The New England Journal of Medicine Downloaded from nejm.org on April 2, 2014. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.