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Home , Acute kidney injury, Nephrotic syndrome, Phosphate nephropathy

In-Depth Review

Adverse Renal and Metabolic Effects Associated with Oral Phosphate Bowel Preparation

Eliot C. Heher,* Samuel O. Thier,*† Helmut Rennke,‡ and Benjamin D. Humphreys§ *Department of , Division of , Massachusetts General Hospital, Boston, Massachusetts; †Department of Medicine and Healthcare Policy, Harvard Medical School, Boston, Massachusetts; ‡Renal Pathology and §Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts

Colorectal can be prevented by the removal of adenomatous polyps during screening , but adequate bowel preparation is required. Oral sodium phosphate (OSP), an effective bowel purgative, is available over the counter and requires a substantially lower volume than -based preparative agents. Accumulating reports implicate OSP in disturbances as well as (AKI) in a syndrome termed (a form of ). Despite published case reports and case series, the actual incidence, risk factors, and natural history of phosphate nephropathy remain largely undefined. Several recent observational studies have provided new information on these important issues while supporting a link between OSP and acute phosphate nephropathy as well as the development of chronic in elderly patients, many of whom had a normal serum at the time of OSP ingestion. This review summarizes current knowledge about the renal complications of OSP, risk factors for its development, and the pathophysiology of acute and chronic kidney damage in nephrocalcinosis. Clin J Am Soc Nephrol 3: 1494–1503, 2008. doi: 10.2215/CJN.02040408

pproximately 14 million are performed known as Nu-Lytely, formulated without the unpalatable in- in the United States yearly for colon cancer screening, gredient sodium sulfate, became available in 1990 (9). Recent A and efforts to increase screening rates have included formulations have combined half-dose Nu-Lytely (2 L rather endorsements by celebrities (1,2). The diagnostic accuracy and than 4 L) with Bisacodyl tablets (called Half-Lytely). cost-effectiveness of colonoscopy are closely related to the qual- Despite the effectiveness and relative safety of PEG-ELS, many ity of the colon preparation, and yet methods to safely, effec- patients complain about the taste and the large volume they must tively, quickly, comfortably, and affordably prepare the colon drink. The search for alternatives to standard PEG-ELS preps led remain elusive (3). In clinical trials, nearly 75% of subjects back to oral sodium phosphate (OSP) preparations, which have undergoing bowel preparation report adverse events, most existed for many years. In early studies comparing the two ap- commonly abdominal distention, , , abdominal proaches, patients and colonoscopists preferred OSP (10–12). A pain, and dizziness (4). recent meta-analysis concluded that OSP preps result in better Methods of bowel preparation have evolved from the tradi- bowel cleansing, perhaps because patients are more likely to com- tional approach of dietary restriction and , which al- plete them (13). An industry-sponsored study that compared OSP though effective, are time-consuming and uncomfortable (5). tablets with PEG-ELS ϩ bisacodyl concluded that OSP is more An early preparative agent was , but it results in the efficacious and better tolerated (4). production of methane, hydrogen, and other flammable gases Like lactulose and milk of magnesia (magnesium hydroxide), and has been associated with fatal colonic explosions during OSP preparations are osmotic purgatives that obligate polypectomy and electrocautery (6,7). Large volumes of saline excretion into the intestinal lumen to maintain its isotonicity or balanced electrolyte lavage solutions are also effective, but with plasma (in contrast to the kidney, the proximal small their use results in significant net fluid and electrolyte absorp- intestine does not create or maintain an osmotic gradient be- tion. A significant advance occurred when Davis et al. at Baylor tween the luminal and side) (14). The retention of water University substituted nonabsorbable sodium sulfate in place in the bowel lumen results in peristalsis and colonic evacuation of sodium chloride and added polyethylene glycol for osmotic (15). It is the high sodium and phosphate content of OSP preps, effect (8). They called this iso-osmolar, nonabsorbable solution which render them hyperosmolar. Each 45-ml dose of Fleet’s “GoLytely,” although it is more generally known as polyethyl- Phospho-soda contains5gofsodium and 17.8 g of phosphate, ene-glycol electrolyte lavage solution (PEG-ELS) (8). A version yielding a solution with an osmolarity of 16,622 mOsm/L (748 mOsm/45 ml) (14). The amount of elemental phosphorus in

Published online ahead of print. Publication date available at www.cjasn.org. two 45-ml doses is approximately 11.5 g, a substantial load compared with the typical daily dietary intake of 1 to 1.5 g (16). Correspondence: Eliot C. Heher, MD, Massachusetts General Hospital, GRB 1003, 55 Fruit Street, Boston, MA 02114. Phone: 617-584-0359; Fax: 617-724-1122; E-mail: Two OSP tablet preparations are also approved for use: Visicol, [email protected] which is similar in content to Fleet’s Phospho-soda, and Osmo-

Copyright © 2008 by the American Society of Nephrology ISSN: 1555-9041/305–1494 Clin J Am Soc Nephrol 3: 1494–1503, 2008 Oral Sodium Phosphate Solution and Kidney Injury 1495

Prep, which contains approximately 20% less phosphate than Visicol (15). All OSP preparations lead to both sodium and phosphate absorption. If phosphate absorption did not occur, a 100-ml dose would obligate 4.1 L of stool (17).

Metabolic Disturbances Associated with Bowel Preparation: a “Forgotten Menace?” Metabolic disturbances, including , hy- pocalcemia, , , , and anion-gap , have been reported in association with OSP preps, sometimes accompanied by volume depletion and AKI typically attributed to tubular injury (16,18–20). Be- cause 1 to 1.8 L of hypotonic fluid is lost after the use of a 45-ml dose of OSP solution, , volume depletion, and hy- pernatremia are not uncommon (17,21,22). Osmotic resulting from the high concentration of intratubular phosphate Figure 1. Clinical course observed in a 74-yr-old who received may contribute to the volume depletion (23). Central pontine 90 ml of oral sodium phosphate solution before colonoscopy. myelinolysis has been reported in a patient whose sodium rose (36) Reproduced by permission, © Georg Thieme Verlag KG. to 180 mMol/L after an OSP prep (24). In contrast, when excess water is retained during bowel preparation, severe hyponatremia and its associated complica- tions can occur (25,26). Two deaths from hyponatremia have Kidney Injury after OSP Bowel Preps: been reported in patients with end-stage renal disease who Studies More recent attention has been directed to the possibility that received PEG-ELS, which has also resulted in hyponatremic in some patients the deposition of -phosphate crystals seizures in patients with normal renal function (26,27). In these after OSP administration may result in AKI. In a 2003 letter to cases, the affected patients consumed significant quantities of the New England Journal of Medicine, Desmeules et al. reported a hypotonic fluids in addition to the PEG-ELS prep. The nonos- 71-yr-old whose creatinine rose from 1.0 to 4.5 mg/dl in a motic release of antidiuretic , possibly as a result of 10-wk period after the use of a OSP solution administered nausea and stress, appears common during colonoscopy and before colonoscopy (47). Analysis of the kidney biopsy speci- likely impairs the ability to excrete free water (28). Patients with men by light microscopy, scanning electron microscopy, and significant (CKD) may on rare occasion x-ray microanalysis confirmed the presence of intratubular cal- experience a significant increase in plasma volume after PEG- cium-phosphate deposits in the form of hydroxyapatite. Kidney ELS and decompensated may result (29,30). function remained abnormal one year later. The authors called Hyperphosphatemia after OSP ingestion routinely occurs the patient’s condition “phosphate nephropathy.” even in individuals with normal renal function, with one study In 2004, Markowitz et al. at Columbia University extended this reporting a rise in the mean serum phosphate from 3.7 to 7.3 report by describing 5 patients who developed AKI after OSP mg/dl (10,31,32). In another study, calcium-phosphate prod- preps, all of whom had distal tubular injury and calcium-phos- ucts exceeding 65 were observed in more than one third of phate deposits demonstrated on kidney biopsy (48). Subse- normal volunteers (21). Severe hyperphosphatemia compli- quently, the same group reviewed 7349 kidney and iden- cated by and have been reported in those tified an additional 16 patients who appeared to have phosphate with both abnormal and normal renal function (Figure 1) (33– nephropathy associated with OSP (49). The mean age of the 21 37). Older patients, those with abnormal gut motility (which total patients identified by Markowitz et al. was 64, and at baseline enhances phosphate absorption) and those who have received 17 of them had good renal function (mean creatinine Ͻ1.2 mg/dl). repeated doses of OSP, have experienced particularly severe Two thirds (14 of 21) were receiving angiotensin-converting en- electrolyte disturbances and deaths (38–41). Enemas that con- zyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) at tain phosphate can also result in severe hyperphosphatemia the time of OSP administration, and several were on nonsteroidal and AKI as well as other complications (42,43). anti-inflammatory or . Many of them were left with Some authorities recognized the risk of electrolyte disturbances CKD: at follow-up roughly 17 mo after OSP exposure, the mean from OSP early on and counseled against their use, particularly in serum creatinine was 2.4, and 4 of 21 were dependent. patients with comorbid conditions such as kidney, , or heart Additional biopsy-proven reports of phosphate nephropathy disease (44,45). The first FDA review of the safety of OSP occurred have appeared, including one in which a patient had two kidney in 2001 and resulted in a report urging physician awareness and biopsies, the first of which showed membranous nephropathy and recommending of in high-risk patients the second performed two months after the first, after an OSP (46). In the face of ongoing reports of metabolic complications, one prep, which showed membranous nephropathy plus de novo cal- group termed OSP “a forgotten menace” (36). cium-phosphate deposits not present on the first biopsy (50–53). 1496 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1494–1503, 2008

Another patient with biopsy-proven phosphate nephropathy after found a statistically significant decline in GFR 6 months after OSP presented with acute visual loss from uremic optic neurop- OSP exposure (58,59). ACE and ARB use and mellitus athy (54). were again identified as risk factors. Like the Hurst et al. study discussed earlier (56), this study also appears to identify a Kidney Injury after OSP: Observational subset of patients who do not develop clinically manifest AKI Studies but nonetheless end up with CKD as a result of the exposure. Although dramatic, the biopsy-based case series of Markow- Of note, the control group included patients who had not itz et al. (48,49) and others leave unanswered important ques- received colonoscopy as well as patients who had not devel- tions about the mechanisms by which OSP might result in oped renal failure after colonoscopy. Selecting a control group phosphate nephropathy and do not address the risk of this by excluding patients with the outcome of interest will inevi- in a population of patients who receive OSP. tably bias a study toward a positive result. Recently, several observational studies of patients with pre- In conclusion, two of these four observational studies sup- served renal function who underwent bowel preparation have port an association between OSP and kidney injury and two do appeared and have reached conflicting conclusions about OSP not. The reasons for these different results may lie in study and the risk of kidney injury (55–58). methodologies, including the different definitions of kidney Using a U.S. Department of Defense data system, Hurst et al. injury as well as the interval after colonoscopy at which the studied 9799 patients who underwent colonoscopy and identi- renal function was assessed. Selection of patients from different fied 114 who had a Ͼ50% increase in baseline creatinine after eras may have also influenced the results: whereas Hurst et al. the procedure (56). After adjustment for confounders in a mul- (56) studied colonoscopy procedures conducted from 2002 tivariate analysis, the use of OSP was associated with increased through 2006, Brunelli et al. (55) assessed procedures from 2004 risk of renal failure (odds ratio ϭ 2.35). This association became and 2005, many of which were performed coincident with or stronger when the authors limited their analysis to patients after the Markowitz et al. report (48), which might have biased with more severe kidney injury (defined as a doubling of serum providers against OSP. In each of these studies, patients who creatinine). Older age was an independent risk factor for kid- receive PEG-ELS appear at baseline to be at higher risk for ney injury from OSP. At follow-up an average of 8 months after kidney injury than patients who receive OSP, reflecting the the colonoscopy, the mean creatinine among the group with widespread (although not universal) awareness among provid- kidney injury (1.38) was below the peak value (1.78) but re- ers concerning the potential risk of OSP; thus, residual con- mained substantially above the preprocedure value (0.98), sup- founding or bias if present would skew the results in favor of porting the hypothesis that OSP causes CKD in addition to OSP safety. Clearly, further studies are required to precisely AKI. In the same issue, Brunelli et al. reported a case-control determine the incidence of both AKI and CKD after OSP prep- study using data from a cohort of 2237 patients who underwent aration. Randomized trials could eliminate the problem of re- colonoscopy at hospitals associated with the University of sidual confounding but would be limited to low-risk patients, Pennsylvania (55). Using a definition of kidney injury that was which might not reflect the patients exposed to OSP in actual somewhat less restrictive than that of Hurst et al. (56), the clinical practice. Studies that report 6- to 12-month follow-up of authors identified 116 patients with kidney injury after colonos- patients who develop metabolic complications after PEG-ELS copy but were unable to find any association with OSP use. are also absent from the literature. Further work is also re- Patients who received OSP preps and were taking ACE inhib- quired to define how and when CKD can complicate OSP in the itors or angiotensin receptor blockers did appear to be at in- absence of AKI, which will require stricter definition of the two creased risk for kidney injury compared with those who were entities. As discussed below, different pathophysiologic pro- not. cesses might explain these different clinical presentations. Investigators from the Degge Group, a safety consulting firm based in Arlington, VA, working with collaborators and Mechanism of Kidney Injury from OSP: data from the Henry Ford Health System and grant support Nephrocalcinosis from the C.B. Fleet Company, studied 2352 patients with base- As is typical in clinical nephrology, the AKI associated with line normal renal function who underwent colonoscopy with OSP is likely multifactorial. Advanced age and ACE/ARB use OSP or PEG-ELS preparation and had creatinine determina- have been identified in both case series and population studies tions within 6 months of the procedure; 3.8% of OSP recipients as risk factors. Additional putative risk factors, which have not and 3.3% of PEG-ELS recipients developed kidney injury, de- been rigorously defined, are shown in Table 1 and include fined by a reduction in estimated glomerular filtration rate acute or CKD or the presence of a kidney transplant, excessive (GFR) to Ͻ60 ml/min. The adjusted odds ratio for GFR decline or repeated dosing, retention of OSP resulting from poor bowel was 1.14 in the OSP group relative to PEG-ELS, but this differ- motility or colitis, female gender, true or effective volume de- ence was not statistically significant (confidence interval, 0.55 to pletion from congestive heart failure or , a history of 2.39). The authors concluded that the risk of renal impairment or diabetes, and , lithium, or nonsteroidal is similar with both preparations. anti-inflammatory drug use (31,33,49,60). Although these fac- Khurana et al., who had previously reported a series of 12 tors are familiar to nephrologists as risks for prerenal cases of clinically diagnosed cases of phosphate nephropathy, and acute tubular injury, a unique aspect of kidney injury subsequently reported a retrospective case-control study and associated with OSP is the deposition of calcium-phosphate Clin J Am Soc Nephrol 3: 1494–1503, 2008 Oral Sodium Phosphate Solution and Kidney Injury 1497

Table 1. Putative risk factors for phosphate gent, whereas calcium oxalate crystals are birefringent upon nephropathy examination under polarized light. Hypercalciuria is a well- established risk factor for calcium crystal deposition, but Preexisting acute or chronic kidney disease or a nephrocalcinosis can occur in the setting of normal calcium kidney transplant excretion, particularly in the presence of primary or secondary Advanced age hyperoxaluria (63). Patients with primary hyperoxaluria over- Female gender produce oxalate due to inherited enzyme defects and develop Hypertension or diabetes mellitus severe nephrocalcinosis and nephrolithiasis (64). Secondary hy- True or effective volume depletion peroxaluria in patients with inflammatory bowel disease or Abnormal bowel motility malabsorption is also a common cause of nephrocalcinosis and Angiotensin-converting enzyme inhibitors, may on occasion be associated with atherosclerosis due to angiotensin receptor blockers, diuretic, lithium or calcium-oxalate deposition in the vasculature. Recently, calci- nonsteroidal anti-inflammatory drug use um-oxalate nephropathy has been reported in a patient taking Excessive/repeated dosing of oral sodium phosphate , an over-the-counter medication that inhibits intestinal lipid metabolism and results in secondary hyperoxaluria (65). crystals, also known as nephrocalcinosis. It seems likely that Ethylene glycol is metabolized to oxalate and can also result in mineral deposition is less reversible than the typical lesion of kidney injury due to calcium-oxalate deposition. and thus might predispose patients to the CKD observed by Markowitz et al. (48) and others. Nephrocalcinosis is a tubulointerstitial nephropathy that either reflects a primary pathophysiologic process or results from severe tissue injury of any cause, so-called “dystrophic” . In mild cases, plain x-rays may reveal nephrocalcinosis as small deposits of calcium salts in the calyces, resembling “pictures of the night sky” (61). Although CT scanning is the most sensitive im- aging technique to detect nephrocalcinosis, severe cortical calcifi- cations detected by kidneys, , and bladder (KUB) plain film weeks or months after an ischemic kidney injury indicate renal cortical necrosis and is associated with nonrecovery of renal func- tion (62). In cases of hyperparathyroidism, calcium salts are typi- cally found along medullary tubular basement membranes, as concretions within tubules, and in the interstitium (62). The calci- um-phosphate deposits seen after OSP are found primarily in the tubular lumens and the cytoplasm of tubular epithelial cells, with rare interstitial deposits as well (48). Paradoxically, many patients with nephrocalcinosis detected radiographically may have mini- mally impaired renal function, whereas nephrocalcinosis seen in association with OSP use, which can only be detected by kidney biopsy, may be associated with acute and CKD. Nephrocalcinosis may be diagnosed incidentally or may present like any tubulointerstitial nephropathy, with low-grade (Ͻ1 g/d), a bland sediment, or an unex- plained rise in the serum creatinine. The patient may have a history of nephrolithiasis or . Hypercalcemia and Figure 2. Renal pathology in nephrocalcinosis. (A) Hematoxylin hypercalciuria associated with hyperparathyroidism or malig- and eosin-stained biopsy from a patient with phosphate ne- nancy are the most common causes, whereas granulomatous phropathy. Note the evidence of acute tubular injury with disease, immobilization, or intoxication may on oc- simplified epithelial cell brush borders and necrotic luminal cell casion be implicated. Through a variety of mechanisms, distal debris. (B) von Kossa stain of the same biopsy specimen reveals may cause nephrocalcinosis, although abundant intraluminal calcium crystals. (C) Hematoxylin and nephrocalcinosis itself may cause distal acidification defects, eosin-stained from a patient with and inflammatory bowel disease. (D) On polarized light, thus confusing the association. Particularly in children, medul- the calcium oxalate crystals from the same section are positively lary sponge kidney and nephrocalcinosis may coexist. birefringent. (E) Hematoxylin and eosin-stained section from a Nephrocalcinosis occurs when calcium precipitates in con- patient with advanced with bony metastases and junction with either oxalate or phosphate. The phosphates in hypercalcemia. Note the thickening of tubular basement mem- calcium-phosphate deposits are detected in paraffin sections by branes. (F) von Kossa stain from the same biopsy reveals typical the von Kossa stain (Figure 2). This stain does not detect pure findings in metastatic calcification with punctate and linear calcium oxalates. Calcium phosphate crystals are not birefrin- tubular basement calcium phosphate crystals. 1498 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1494–1503, 2008

In many cases, the initial event in the development of both phate supplementation (and calcitriol) commonly develop nephrocalcinosis and nephrolithiasis may be the formation of nephrocalcinosis. Verge et al. described 19 of 24 XLH patients calcium-phosphate deposits in the thin limb of Henle, called “Ran- with nephrocalcinosis detected by ultrasound and successfully dall’s plaques,” which form largely due to supersaturation of correlated the grade of nephrocalcinosis with the mean dose of calcium and phosphate in that portion of the tubule (66,67). When exogenous phosphate (82). Three children with XLH reported these plaques rupture into the urinary space, they serve as a nidus by Alon et al. had kidney biopsies, which demonstrated calcium for calcium-oxalate crystallization, and nephrocalcinosis results phosphate deposition by von Kossa staining (83). Stickler and when the urothelium overgrows and encapsulates the crystals Morgenstern described two XLH patients who developed end- (63,68). The observation that most calcium-oxalate stones contain stage renal disease as a result of nephrocalcinosis (84). Hyper- some calcium-phosphate supports this mechanism (61,66). calciuria induced by calcitriol may also have contributed to the Throughout much of the kidney tubule, calcium and phosphate development of nephrocalcinosis in these patients. exist in an “unstable compromise” of ionic supersaturation that is Recently, Patel et al. at Baylor reported that urinary calcium maintained by inhibitors, such as citrate, Tamm-Horsfall protein, excretion declined dramatically in five normal subjects who and pyrophosphate (69). Once calcium-phosphate crystals form, received OSP (23). The authors conclude that their findings are urinary crystals of any type can promote crystal growth, which consistent with calcium-phosphate precipitation within the kid- explains why treatment of hyperuricemia with allopurinol can ney, an effect similar to that seen in the other settings of prevent calcium stone formation (70). Despite these mechanistic exogenous phosphate administration described above. similarities, clinical experience shows that some patients with The is a well-described cause of AKI, nephrolithiasis have no nephrocalcinosis whereas other patients which usually results from the endogenous release of display the opposite pattern. but can also result from phosphate release with subsequent The deposition of calcium oxalate and calcium phosphate can crystal deposition in the renal tubules (85). Boles et al. reported be viewed within the broader context of renal crystal deposi- a series of 34 patients with calcium-phosphate deposition asso- tion. Under even normal conditions, the progressive concentra- ciated with the tumor lysis syndrome, including the case of a tion of urine through the removal of water and the extremes of 15-yr-old boy with acute leukemia who developed dialysis urinary pH can create an environment conducive to crystal dependent AKI (86). Although alkalinization of the urine is formation (66). Uric acid and cystine crystals form most readily often recommended to prevent uric acid deposition in the in an acid urine, whereas alkaline conditions favor calcium- setting of tumor lysis, this therapy may increase the risk of phosphate crystals. In contrast, calcium oxalate crystal forma- calcium-phosphate deposition, which occurs more readily at an tion is pH independent. Medications that are concentrated in alkaline pH. The maintenance of a high flow of urine at a the urine can precipitate and contribute to kidney injury. Well- neutral pH may be the best approach to avoid either form of recognized offenders include acyclovir, foscarnet, methotrex- crystal deposition during tumor cell lysis. ate, the sulfonamides, and indinavir (71). Recently, the deposi- Animal studies support the notion that hyperphosphaturia, tion in kidney and other tissues of the cation gadolinium in independent of hypercalciuria, can result in nephrocalcinosis association with phosphate and other anions has been impli- and kidney injury. In a mouse model of XLH, animals treated cated in the pathogenesis of nephrogenic systemic fibrosis (72). with phosphate and vitamin D develop nephrocalcinosis. Gadolinium deposits are basophilic on hematoxylin and eosin Ritskes-Hoitinga et al. also described nephrocalcinosis in rats staining and may be confused with nephrocalcinosis (73). fed a high phosphate , an effect that was attenuated by parathyroidectomy and hypermagnesiuria, which may inhibit Hyperphosphaturia and Kidney Injury calcium-phosphate crystal deposition (87,88). Alternative Just as nephrocalcinosis can result from hyperoxaluria and the mechanisms of kidney injury have also been suggested by subsequent deposition of calcium-oxalate crystals, hyperphos- animal studies. Using a rat model, Zager has shown that hy- phatemia and hyperphosphaturia can cause nephrocalcinosis and perphosphatemia potentiates kidney injury by inducing prox- AKI through the deposition of calcium-phosphate crystals. This imal tubular vacuolization and capillary collapse, without evi- phenomenon, which has been described in diverse clinical settings dent nephrocalcinosis (89). as well as in animal models of hyperphosphaturia, lends support to the hypothesis that phosphaturia after OSP administration un- Mechanism of Kidney Injury from OSP: derlies the development of phosphate nephropathy. Possible Role of the Immune System In the 1930s and again in the 1960s, the use of phosphate to By contrast, the pathophysiology of CKD after OSP admin- treat symptomatic hypercalcemia of varying causes was com- istration is unknown and speculative. Despite the absence of plicated by metastatic and AKI (74–78). Extraskel- experimental evidence, insight may be gained from other crys- etal calcifications were occasionally demonstrated on plain x- tal-induced inflammatory and fibrotic diseases such as calcium rays and slit-lamp examination (79). Clinical investigations crystal arthropathy, gout and nephrogenic systemic fibrosis confirmed that phosphate administration lowered serum cal- (NSF). Increasing experimental data implicates the innate im- cium primarily through Ca-Pi deposition (80,81). mune system in mediating the pro-inflammatory actions of In another example of exogenous phosphate therapy driving tissue crystal deposition. Pattern recognition receptors, such as calcium-phosphate deposition in the kidney, patients with X- the Toll-like receptor (TLR), mediate monosodium urate mono- linked hypophosphatemic rickets (XLH) treated with phos- hydrate-dependent nitric oxide and IL-1␤ release from chon- Clin J Am Soc Nephrol 3: 1494–1503, 2008 Oral Sodium Phosphate Solution and Kidney Injury 1499 drocytes and macrophages, respectively. Given the ability of nephropathy may affect as many as 1400 to 7000 Americans specific TLRs to recognize calcium crystals and the expression each year, prospectively collected data defining the true inci- of a variety of TLRs in the adult kidney, we speculate that dence of phosphate nephropathy are needed (100). Such data intraluminal calcium-phosphate crystal formation after OSP would also provide better information concerning putative risk leads to recognition by specific epithelial TLRs with activation factors, such as hypertension, diabetes, female gender, and of the innate immune response (90,91). Persistence of these renin-angiotensin blockade. The role of OSP-induced kidney crystals could result in chronic with extracellular injury in the development CKD, in the absence of diagnosed matrix deposition and interstitial fibrosis (92). Clearly, the cel- AKI, needs investigation, as does the role of parathyroid hor- lular and molecular mechanisms of OSPS-mediated renal fibro- mone and vitamin D status as potential risk factors (101). sis require investigation. An intriguing correlation between hyperphosphatemia, crystal Conclusion deposition, and tissue fibrosis has been suggested in the patho- Adequate bowel preparation is mandatory for colorectal can- genesis of nephrogenic systemic fibrosis (72). Gadolinium-based cer screening, and clinicians selecting bowel-cleansing agents contrast exposure is strongly implicated in the development of must consider the potential metabolic consequences of OSP and NSF, and patients developing this debilitating condition have PEG-ELS use. Although the ethical imperative to “do no harm” ϩ Gd3 tissue deposition (93). Excess serum phosphate may bind and the large and growing number of colonoscopies performed ϩ ϩ free Gd3 with subsequent tissue deposition. Gd3 -phosphate each year compel physicians to favor bowel purgatives that complexes can be demonstrated in tissues of patients with NSF pass a very high standard of safety, the renal risks posed by (72). The subsequent process of Gd3ϩ-crystal-induced fibrosis OSP raised in this article need not change clinical practice in may be similar to that evoked by calcium phosphate crystals, with low-risk patients. Table 2 summarizes our suggested absolute phagocytosis of crystals into resident phagocytes (or perhaps ep- ithelial cells) mediated by pattern recognition receptors, ultimately activating the innate immune response and causing a chronic inflammatory and pro-fibrotic process. Table 2. Suggested contraindications to oral sodium phosphate administration A Lower Dose Product and Remaining Absolute contraindications Questions Estimated glomerular filtration rate Ͻ60 In response to the reports of phosphate nephropathy as well ml/min as warnings from government agencies concerning the use of Significant kidney disease with preserved OSP, the largest manufacturer of OSP products, the C.B. Fleet GFR (e.g., ) Company, discontinued the sale of the 90-ml OSP preparation Preexisting hyperphosphatemia of any cause (45 ml ϩ 45 ml) and substituted a 75-ml dose product (45 ml ϩ Clinically significant congestive heart failure 30 ml), which reportedly has equal efficacy (94–96). Recom- or cardiomyopathy mendations from the company continue to emphasize the im- Clinically significant cirrhosis and/or portance of separating the two doses by an interval approach- , as detailed on ing 12 h and of maintaining adequate hydration before, during, package label including obstruction, and after OSP bowel preparation (97). megacolon, perforation, ileus, inflammatory Although lower-dose OSP preparations appear to cause more bowel disease modest elevations in serum phosphate, it is unknown whether Hypersensitivity to the ingredients they are safer than standard dose preparations. Similarly, it Relative contraindications unknown whether optimal oral hydration can replace OSP- Age Ͻ18 or Ͼ60 to 70 or clinically significant associated losses while maintaining normal electrolyte levels debilitation and preventing phosphate nephropathy. Recommendations for Use of diuretics, angiotensin-converting volume repletion with OSP preps vary from 0.7 to 2.2 L (Fleet enzyme inhibitors, angiotensin receptor currently recommends a “minimum” of 72 oz), but the optimal blockers, or nonsteroidal anti-inflammatory amount may exceed 3.7 L (98,99). Even carefully selected pa- drugs, especially if in combination tients who were given explicit instructions for oral hydration Dehydration or risk for dehydration (e.g., and were studied in the setting of a clinical trial lost an average nausea, vomiting, , low salt diet, of 2.3 lbs of body weight after sodium phosphate bowel prep, inability to take adequate oral fluids). although weight loss has also been observed with the combi- Uncorrected electrolyte abnormalities nation of PEG-ELS ϩ bisacodyl (4,94). In addition, the benefits Cardiac disease as detailed on package of increased water intake need to be balanced against the risk of labeling, including recent MI, prolonged QT hyponatremia (23,25,26). It is also unknown whether water is interval, or drugs that prolong interval, adequate for oral hydration or whether electrolyte-containing , unstable angina. oral rehydration solutions would be safer (97). Pregnancy or nursing a child, as per package Other significant gaps exist in our knowledge of OSP-asso- labeling. ciated kidney injury. Although some estimate that phosphate 1500 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1494–1503, 2008 and relative contraindications for OSP prescription. Multiple 7. 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