JASN Express. Published on November 14, 2007 as doi: 10.1681/ASN.2007101073

EDITORIALS www.jasn.org

Towards the Incidence of significant but small percentage of patients who undergo develop mild, transient elevations in serum cre- Acute Phosphate Nephropathy atinine related to . In this study, the mean rise in serum among patients with AKI was only 0.41 Glen S. Markowitz,* Jai Radhakrishnan,† and mg/dl and no data on reversibility were available. In contrast, Vivette D. D’Agati* among the 21 cases of APhN we previously reported, the *Department of Pathology and †Department of Medicine, Ne- mean increase in serum creatinine was 2.9 mg/dl (mean base- phrology Division, Columbia University, College of Physicians & line, 1.0 mg/dl; mean peak, 3.9 mg/dl).2 The renal insuffi- Surgeons, New York, New York ciency was largely irreversible, with 4 patients progressing to J Am Soc Nephrol 18: 3020–3022, 2007. end-stage renal disease and a mean final creatinine of 2.4 doi: 10.1681/ASN.2007101073 mg/dl in the remaining 17 patients.2 When Brunelli et al. re-examined their data using a stricter definition of AKI that In 2003, Desmeules et al.1 reported a 71-yr-old female who de- requires a 1 mg/dl increase in serum creatinine, the number veloped acute renal failure after the use of an oral sodium phos- of patients with AKI declined from 116 to only 3.8 Thus, their phate (OSP) solution as bowel purgative before colonoscopy. study design is biased toward detection of relatively small Renal revealed tubular injury and abundant tubular cal- increments in serum creatinine that are not likely to repre- cium phosphate deposits, suggesting a pathophysiological link sent APhN. Although the incidence of APhN remains un- between phosphate ingestion and the pattern of renal injury. known, it is likely to be relatively low and quite possibly Ͻ1in The authors proposed the term acute phosphate nephropathy 1000, making a study of Ͻ1500 patients exposed to OSP un- (APhN). We subsequently reported 21 cases of APhN,2 and ad- derpowered to detect APhN. ditional case reports have followed.3–6 APhN most commonly In this same issue of JASN, Hurst et al.9 report a larger, occurs in older white females, particularly those with history of observational, retrospective cohort study on 9799 patients and receiving therapy with renin-angiotensin in- over the age of 50 yr who underwent outpatient colonoscopy. hibitors. It is estimated that approximately 14 million screening Patients were identified through the electronic medical are performed each year in the United States,7 yet records of Department of Defense beneficiaries in the Wash- the incidence of APhN remains unknown. ington, DC area. This study applied a more appropriate, Two large, observational, retrospective studies8,9 in this stricter definition of AKI of Ն50% increase in serum creati- issue of JASN aim to define that incidence and identify risk nine from baseline levels over the 12 mo after colonoscopy. factors. The article by Brunelli et al.8 is a retrospective, case- Among the cohort, 65.6% of patients received an OSP pur- control study of patients undergoing outpatient colonoscopy gative. A total of 114 patients (1.16%) developed AKI, includ- at three University of Pennsylvania Health System affiliates. It ing 1.29% of the patients who received OSP and 0.92% of the compares patients who subsequently developed acute kidney patients who received (PEG). By univar- injury (AKI) to those who maintained normal renal function. iate analysis, no association between OSP and AKI was iden- AKI was defined by either a 25% or a 0.5-mg/dl increase in tified because the PEG group included high-risk patients who serum creatinine over the 6 mo after colonoscopy. Using were significantly older and had a higher incidence of diabe- these criteria, 141 of 2237 patients (6.3%) had AKI. Complete tes mellitus, hypertension, atherosclerotic cardiovascular dis- data were available for 116 of the subjects, who were then ease, heart failure, chronic , therapy, compared with 349 controls. Risk factors for the develop- and use of renin-angiotensin inhibitors (all P Ͻ 0.05). When ment of AKI included female gender, heart failure, and di- multiple logistic regression models were applied to adjust for uretic use. An association between OSP and AKI could only covariates and suspected risk factors, OSP emerged as the be demonstrated in patients who were simultaneously receiv- strongest risk factor for the development of AKI after ing inhibitors of the renin-angiotensin system. colonoscopy (odds ratio 2.35; P Ͻ 0.001).9 When the authors The study by Brunelli et al.8 is limited by the small sample applied a more stringent definition for AKI that required size and the permissive definition of AKI. It is likely that a doubling of serum creatinine, multiple logistic regressions revealed an even stronger association between OSP use and AKI (odds ratio 3.52; P ϭ 0.03). Follow-up data were pro- Published online ahead of print. Publication date available at www.jasn.org. vided on 99 of the 114 patients with AKI, and only 16 patients Correspondence: Dr Glen S. Markowitz, Department of Pathology, Columbia (16%) returned to baseline creatinine levels. For the 99 pa- University, College of Physicians & Surgeons, 630 West 168th Street, VC14- 224, New York, NY 10032. Phone: 212-305-7460; Fax: 212-342-5380; E-mail: tients with AKI, the mean precolonoscopy, postcolonoscopy, [email protected] and follow-up creatinine values were 0.98, 1.78, and 1.38 mg/ Copyright © 2007 by the American Society of dl, respectively. We commend the authors on their excellent

J Am Soc Nephrol 18: 3020–3022, 2007 ISSN : 1046-6673/1812-3020 3017 EDITORIALS www.jasn.org study and agree with their conclusion that PEG purgatives are DISCLOSURES preferable in older patients and in patients with comorbidities. G.S.M. and J.R. are consultants for Salix Pharmaceuticals. We live in an era of informed consent and evidence- based medicine. The two studies in this issue of JASN sug- gest that at least 50% of patients undergoing screening colonoscopy receive an OSP purgative. Extrapolating from REFERENCES the 14 million screening colonoscopies performed annually in the United States, at least 7 million individuals each year 1. Desmeules S, Gergeron MJ, Isenring P: Acute phosphate nephropathy are exposed to an agent that can cause APhN. Hypotheti- and renal failure. N Engl J Med 349: 1006–1007, 2003 cally, if the incidence of APhN falls somewhere between 1 in 2. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD: Acute phos- phate nephropathy following oral sodium phosphate bowel purgative: 1000 and 1 in 5000, then the number of new cases of APhN An underrecognized cause of chronic renal failure. J Am Soc Nephrol occurring annually would be in the range of 1400 to 7000. 16: 3389–3396, 2005 Based on the paper by Hurst et al.,9 these numbers may be 3. Gonlusen G, Akgun H, Ertan A, Olivero J, Truong L: Renal failure and underestimates of the true incidence. Clearly, additional associated with oral sodium phosphate bowel prospective studies are needed to more precisely determine cleansing. Arch Patholo Lab Med 130: 101–106, 2006 4. Manley P, Somerfield J, Simpson I, Barber A, Zwi J: Bilateral uraemic the incidence of APhN so that physicians and patients can optic neuritis complicating acute nephrocalcinosis. Nephrol Dial make informed decisions regarding the choice of bowel Transplant 21: 2957–2958, 2006 purgative. 5. Aasebo W, Scott H, Ganss R: Kidney taken before and after Multiple recent steps have been taken to curtail the inci- sodium phosphate bowel cleansing. Nephrol Dial Transplant 22: 920– dence of APhN. Heightened physician awareness followed the 922, 2006 6. Beyea A, Block C, Schned A: Acute phosphate nephropathy following alert issued by the United States Food and Drug Administra- oral sodium phosphate solution to cleanse the bowel for colonoscopy. tion in May 2006 about the potential for OSP products to cause Am J Kidn Dis 50: 151–154, 2007 acute renal failure and APhN.10 This warning was added to a 7. Seeff LC, Richards TB, Shapiro JA, Nadel MR, Manninen DL, Given LS, consensus document on bowel preparation issued jointly by Dong FB, Winges LD, McKenna MT: How many endoscopies are per- the American Society of Colon and Rectal Surgeons, the Amer- formed for colorectal cancer screening? Results from the CDC’s survey of endoscopic capacity. Gastroenterol 127: 1670–1677, 2004 ican Society of Gastrointestinal Endoscopy, and the Society of 8. Brunelli SM, Lewis JD, Gupta M, Latif SM, Weiner MG, Feldman HI: American Gastrointestinal and Endoscopic Surgeons.11 Hope- Risk of kidney injury following oral phosphosoda bowel preparations. fully this will lead to increased awareness of the risk factors for J Am Soc Nephrol 18: 3199–3205, 2007 APhN and more judicious, individualized selection of bowel 9. Hurst FP, Bohen EM, Osgard EM, Oliver DK, Das NP, Gao SW, Abbott purgatives. KC: Association of oral sodium phosphate purgative use with . J Am Soc Nephrol 18: 3192–3198, 2007 Based on our understanding of the pathophysiology of 10. Oral Sodium Phosphate (OSP) Products for Bowel Cleansing: FDA APhN, recent changes in dosing and hydration should have a Alert [5/2006]. www.fda.gov/cder/drug/infopage/osp_solution. Ac- positive impact. A new generation of OSP solution and tablets cessed October 1, 2007. are now being marketed in which the phosphate content has 11. Wexner S, Beck D, Baron T, Fanelli RD, Hyman N, Shen BS, Wasco been reduced by 16.7% and 20%, respectively. Greater empha- KE: A consensus document on bowel preparation before colonos- copy: Prepared by Task Force from the American Society of Colon sis has been placed on the importance of adequate hydration and Rectal Surgeons (ASCRS), the American Society for Gastroin- before, during, and after colonoscopy, with current recom- testinal Endoscopy (ASGE), and the Society of American Gastroin- mendations increased to a minimum of 72 ounces of clear testinal and Endoscopic Surgeons (SAGES). Surg Endosc 20: 1147– liquids to accompany a regimen of 45 and 30 ml of OSP. Future 1161, 2006 recommendations may include increasing the interval between OSP administrations, avoidance of anesthesia regimens that require no oral intake for 4 to 6 h, alternative dosing in females, See the related articles, “Risk of Kidney Injury Following Oral Phosphosoda and dose reduction or avoidance in the elderly and in patients Bowel Preparations,” on pages 3199–3205, and “Association of Oral Sodium with significant comorbidities. Phosphate Purgative Use with Acute Kidney Injury,” on pages 3192–3198.

3018 Journal of the American Society of Nephrology J Am Soc Nephrol 18: , 2007