Correspondence University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA

Email lienhoward@gmail.com

Introduction

Routine screening for colon and rectal cancer after the age of 50 by use of colonoscopy has been one of the most successful public health projects worldwide. As a result of improvements in colonoscopy technology, bowel preparation is now the least tolerable part of the procedure, so gastroenterologists have been searching for more tolerable, efficient, and economic ways to cleanse the bowel. At present, oral sodium phosphate (OSP) solution is favored.¹ The initially reported adverse effects of this agent were unremarkable, particularly in patients with normal kidney and gastrointestinal function.² However, the attractive safety profile of OSP has been questioned recently following a series of cases of OSP-induced acute and irreversible renal failure.³ This disease has been named acute phosphate nephropathy (APN)^{3, 4} because renal biopsy uniformly revealed nephrocalcinosis. These and subsequently reported cases of APN^{5, 6} raised such concern that the FDA issued a warning about the use of OSP in patients with chronic kidney disease (CKD) or major cardiovascular comorbidities. Several retrospective studies have been performed in order to facilitate a better understanding of APN. Unfortunately, the results of these studies are quite differing, adding to the controversy over the safety of OSP. This uncertainty about the toxicity of OSP clearly increases the anxiety of those who are scheduled to undergo elective colonoscopy and their physicians, and the lack of clear instructions regarding the use of OSP for bowel preparation further increases the level of uneasiness. The purpose of this Review is to provide a nephrologist's perspective on the pathogenesis, risk factors, and prevention of APN, based on the current literature.

Patterns of acute kidney injury induced by oral sodium phosphate

Two patterns of OSP-induced acute kidney injury (AKI) can be distinguished: early symptomatic, and late insidious (Table 1).⁵ The former presents as an acute illness that manifests as changes in mental status, tetany, or cardiovascular collapse, usually within hours of bowel preparation. Patients have marked hyperphosphatemia (4.5–19.4 mmol/l) and hypocalcemia (1.0–1.7 mmol/l) and require urgent fluid resuscitation, rapid correction of electrolyte abnormalities, and even hemodialysis. Outcomes vary—some patients show excellent recovery of renal function, while others develop CKD or die soon after the onset of symptoms. The second pattern of AKI is insidious onset of renal failure days or months after colonoscopy.³ At the time of diagnosis, serum phosphorus and calcium levels are normal or near normal unless APN is detected within 3 days of bowel preparation.⁷ None of these patients recover their renal function completely and some even progress to end-stage renal disease. The major difference in bowel preparation between these two groups of patients is that those with early symptomatic AKI received a much higher phosphate load than the standard dose.^{2, 5, 8} Their symptoms are mainly related to hypocalcemia, and, if managed promptly and aggressively, recovery of renal function is possible. In patients whose presentation is insidious, the opportunity to remove renal calcium phosphate precipitates is often missed, and CKD develops.

Table 1 Patterns of acute kidney injury after bowel preparation with oral sodium phosphate solution for colonoscopy.

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Acute phosphate nephropathy after standard dose of oral sodium phosphate

A review of the literature reveals potential risk factors for APN in patients with normal or near-normal baseline renal function who received the standard dose of OSP^{4, 5, 6, 7, 9, 10, 11} (Table 2). Of these 27 cases, 20 are from the largest series by Markowitz et al.⁷ One patient from this series was excluded because of excessive phosphate load. Overall, the male to female ratio in the entire cohort is 1:4, and the mean age is 65 years. Elderly females seem to be particularly susceptible to APN, probably because they have reduced renal capacity to handle a phosphate load, and their smaller body mass makes them more sensitive to fluid loss. Renal biopsy was performed in 24 patients and revealed diffuse nephrocalcinosis with interstitial inflammation in all cases. At the end of follow-up, the mean serum creatinine level, excluding that of three patients with end-stage renal disease, was 194 mol/l (range 80–301 mol/l). The time between colonoscopy and diagnosis of APN varied widely, which simply reflects the silent nature of renal failure. At the end of follow-up, the serum creatinine levels of three patients who were diagnosed with APN 1 day after colonoscopy (115 mol/l, 221 mol/l, and 239 mol/l) were not much different from those of patients who were diagnosed later than this.

Table 2 Reports of acute phosphate nephropathy after standard dose of oral sodium phosphate in patients with normal or near-normal kidney function.

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Of the 27 patients, 19 had hypertension, 16 were taking an angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 5 were on diuretics. These comorbidities and medications tend to be associated with volume depletion and reduced glomerular filtration rate (GFR), both of which increase the risk and severity of APN. The next two most common conditions associated with APN were diabetes (6 patients) and colitis (4 patients). Most patients with diabetes were taking an ACEI or an ARB; in addition, uncontrolled diabetes can lead to volume depletion and hypercalciuria,¹² thus increasing the risk of calcium phosphate precipitation. Colitis can slow bowel transit and thereby enhance phosphate absorption in the intestines.

Incidence of and risk factors for acute phosphate nephropathy

During the past year or so, five retrospective publications have reported the incidence of APN in similarly defined populations of patients who underwent colonoscopy for bowel cancer screening.^{13, 14, 15, 16, 17} Patients in whom serum creatinine levels were measured before and 6–12 months after the procedure were selected for analysis (Table 3). Except for one study, patients with a serum creatinine level greater than 133 mol/l before colonoscopy were excluded. However, since most patients were 50 years or older, many with stage 3 CKD were included. The causes of renal failure were carefully evaluated by chart review in only one study.¹⁶

Table 3 Retrospective studies of renal failure associated with bowel preparation with oral sodium phosphate solution.

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As shown in Table 3, the relative risk of AKI associated with use of OSP rather than of polyethylene glycol is significantly higher in only one of four studies.¹³ In the most recent study,¹⁷ the control group comprised comorbidity-matched patients who did not undergo colonoscopy. OSP administration was associated with an average GFR loss of 6 ml/min/1.73 m² and 8 ml/min/1.73 m² at 6 and 12 months after colonoscopy, respectively, compared with no loss of GFR at 6 months and a loss of only 1.3 ml/min/1.73 m² at 12 months in the control group. Hurst et al.¹³ also demonstrated incomplete recovery of renal function after bowel preparation: the mean serum creatinine level before colonoscopy, after colonoscopy (mean 126 days), and at the end of follow-up (mean 269 days after onset), was 87 mol/l, 157 mol/l, and 122 mol/l, respectively. This increase in serum creatinine level reflects a GFR loss of 20–30 ml/min/1.73 m². In an era of growing CKD awareness, such a loss in GFR is clearly unacceptable.

Risk factor analyses of these studies also have several limitations, and there are very few consistent findings.^{13, 14, 15, 16, 17} Lower baseline GFR, use of ACEIs or ARBs, and older age seem to be the most probable risk factors for APN after OSP use; other candidates are congestive heart failure, NSAID use, hypertension, diabetes, and diuretic use. Sex does not seem to be a major risk factor for APN, according to the results of two studies. The overall inconsistencies in the findings of the studies could be due to variations in the criteria used to diagnose AKI, other causes of kidney failure during the 6 or 12 months after colonoscopy, and factors that directly affect the risk of APN, such as volume depletion during bowel preparation (which were not assessed).

These retrospective studies did not identify any patients with severe renal failure or requiring dialysis (as described in the original report by Markowitz et al.³), but the results indicate that the incidence of AKI after taking OSP is in the range of 1–4%. This rate is comparable to that of contrast nephropathy in nondiabetic, nonazotemic patients (0.6–2%).¹⁸ Of note, AKI was not reported in several prospective safety and efficacy studies of OSP, in which serum creatinine level was measured at the time of colonoscopy.² As with contrast nephropathy, it is possible that detection of AKI requires assessment of serum creatinine 48–72 h after OSP administration.

Electrolyte abnormalities after use of oral sodium phosphate

Besides renal failure, use of OSP has been associated with a variety of electrolyte abnormalities (Box 1).

Pathogenesis of acute phosphate nephropathy

APN after OSP use is a direct consequence of the acute phosphate load, which rapidly raises serum phosphate level, thereby stimulating PTH release²⁵ and reducing the synthesis of 1,25-dihydroxyvitamin D.²⁹ The high serum PTH and phosphorus levels cause endosomal retrieval of the type IIa sodium–phosphate cotransporter from the apical membrane of the proximal tubular cells, thus inhibiting phosphate reabsorption. The low serum 1,25-dihydroxyvitamin D levels also reduce phosphate absorption in the intestines. These two mechanisms eventually drive the serum phosphate level back to normal. Fibroblast growth factor-23, the newly identified phosphatonin, probably does not have any major role in phosphorus homeostasis after an acute phosphate load. Infusion of potassium phosphate does not affect serum fibroblast growth factor-23 level in humans, even though it doubles serum phosphate level.³⁰

The standard dose of OSP contains 11.5 g of phosphorus, which is seven times the average daily dietary phosphorus intake. About 57% of the dose is excreted in feces, 15% in urine, and 28% is retained in the body for 24 h.³¹ DiPalma et al. reported the time course of changes in serum and urinary phosphorus and calcium levels after standard doses of OSP in healthy volunteers aged 21–41 years (Figure 1).²⁵ The changes in serum calcium and phosphorus levels are as expected and both parameters return to the normal range within 24 h. The urinary findings are more dramatic and show a longer-lasting effect. The urine phosphorus level increases after the first and second doses to fourfold and eightfold of the baseline level, respectively, and remains elevated at 24 h. The total amount of phosphate excreted in the urine after the second dose is threefold to fourfold that excreted after the first dose. These results suggest that the second dose of OSP is particularly dangerous because renal reabsorption of phosphate is fully inhibited at the time of dosing, and thus the urinary concentration of phosphate remains elevated for a prolonged period.

Figure 1 Time course of changes in serum and urinary phosphorus and calcium concentrations after standard doses of oral sodium phosphate.

Arrows indicate the two doses given at 0 h and 12 h. The data are averaged from seven healthy volunteers studied by DiPalma et al. (3 men and 4 women; age range 21–41 years).²⁵

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Urinary calcium level increases initially after OSP administration, probably because the accompanying sodium load suppresses calcium reabsorption in the proximal tubule.²⁵ Subsequently, however, the urinary calcium level becomes very low because of the decreased filtered calcium load, increased calcium reabsorption (as a result of high PTH levels), and calcium phosphate precipitation in the distal tubule. On the basis of data from phosphate-loaded and PTH-treated rats, Asplin et al.³² predicted that the tubular fluid in the loop of Henle is supersaturated with respect to calcium and phosphate ions after OSP administration, resulting in production of a solid-phase material—probably immature apatite. The calcium phosphate crystals can flow downstream, bind to epithelial cells, and undergo internalization, triggering inflammatory reactions and cellular damage.^{33, 34} In patients with APN, calcifications are mainly observed in the distal tubules and collecting ducts and have a predominant intraluminal and intracytoplasmic distribution.⁷

If intratubular calcification is inevitable even in the normal kidney, why is the incidence of APN not higher? One explanation is that only small portions of the renal tubules are damaged in the majority of patients, and such damage is difficult to detect or tends to be ignored. When urine is concentrated, the urinary level of calcium–phosphate product rises exponentially, which increases the risk of calcification. Excessive fluid loss should, therefore, be avoided during bowel preparation. Unfortunately, however, the average weight loss during bowel preparation is 0.9–1.4 kg.^{24, 26}

Recommendations to minimize the renal risks of oral sodium phosphate

Conclusions

The incidence of AKI after bowel preparation with OSP is 1–4% in the general population, indicating that OSP is as nephrotoxic as intravenous contrast media. In addition, OSP is associated with clinically relevant electrolyte abnormalities, including hypokalemia, hyperphosphatemia, and hypocalcemia, particularly in elderly patients. Severe hyperphosphaturia occurs after the second dose of OSP, as a result of the high PTH levels induced by the first dose. Calcium phosphate precipitation is likely to occur even in the normal kidney. Until safer bowel preparation agents are available, use of OSP in older patients and in those with risk factors for APN should be avoided. If OSP is used, ensuring adequate fluid intake, delaying and reducing the second dose of OSP, or replacing the second dose with that of another agent, might reduce the risk of renal injury. Colonoscopy centers should consider incorporating intravenous hydration and a renal function panel into the procedure.

Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Acute renal failure