http://www.kidney-international.

org & 2009 International Society of Nephrology

the renal consult

Acute phosphate nephropathy

Alexander K. Rocuts1, Sushrut S. Waikar1, Mariam P. Alexander1,2, Helmut G. Rennke2 and Ajay K. Singh1
1 2

Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA and Department of Pathology, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA

CASE PRESENTATION

A 60-year-old white Latino female with a clinical diagnosis of diabetes mellitus (diagnosed in 1993) and hypertension was referred to the chronic kidney disease clinic at Brigham and Womens Hospital for the evaluation of acute kidney injury; serum creatinine had increased from a baseline of 0.9 to 1.5 mg/dl in a 11-week period. She was asymptomatic at the time of presentation. Her past medical history included a total abdominal hysterectomy with bilateral salpingo oophorectomy and upper vaginectomy for high-grade squamous intraepithelial lesion of the cervix, 11 weeks prior to presentation. Three weeks prior to presentation (8 weeks after surgery) and within a week of each other, she was evaluated for two consecutive episodes of acute onset of chest pain with pulmonary edema in the setting of severe hypertension. Both episodes had blood pressures in excess of 190200 mm Hg systolic that resolved with intravenous diuretics. Cardiovascular workup revealed no evidence of ischemic heart disease. Additionally, renal evaluation included magnetic resonance angiography with and without gadolinium, which did not reveal renal artery stenosis. However, serum creatinine peaked at 1.9 mg/dl immediately after surgical procedure and remained elevated at 1.5 mg/dl throughout the course of her current presentation (corresponding to a glomerular filtration rate of 33 ml/min per 1.73m2, estimated by the modification in diet in renal disease III (MDRD 3) equation). At presentation, medications included amlodipine, furosemide, metoprolol, lisinopril, atorvastatin, insulin glargine, cyanocobalamin, acetylsalicylic acid, and naproxen. The patient had no prior exposure to radiocontrast agents. Physical examination revealed an overweight women weighing 207 lbs with a blood pressure of 142/60 mm Hg and a heart rate of 60 beats per

minute. The rest of the examination was unremarkable. Her laboratory data is summarized in Table 1. A postoperative kidney ultrasound showed no hydronephrosis. The etiology of the acute kidney injury was unclear. Progressive diabetic nephropathy exacerbated by other contributory factors, such as exposure to lisinopril, acetylsalicylic acid, or naproxen, was regarded as the most plausible explanation. Despite discontinuation of these medications, kidney function did not improve; it worsened in a 4-week period after presentation. Hence, a kidney biopsy was performed.

KIDNEY BIOPSY

Correspondence: Ajay K. Singh, Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA. E-mail: asingh@partners.org Kidney International (2009) 75, 987991; doi:10.1038/ki.2008.293; published online 25 June 2008 Received 18 October 2007; revised 4 February 2008; accepted 12 February 2008; published online 25 June 2008
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A total of nine glomeruli were in the core. The predominant feature observed on light microscopy was a multifocal deposition of calcium phosphate within the tubules (basophilic, rounded concretions), in the interstitium, and focally along tubular basement membranes (Figure 1a). The deposits of calcium were non-birefringent under polarized light and were best visualized in the sections stained with von Kossa stain (Figure 1b). Degenerative changes of the tubular epithelium were focally noted with attening of the epithelium. Tubular necrosis was not seen. An associated focally dense lymphocyte-rich mixed inammatory inltrate in the interstitium was also noted without interstitial edema. Tubulitis was not present. Moderate tubular atrophy and interstitial brosis affecting 30% of the parenchyma were also observed. All of the glomeruli present in the sample were hypertrophic and showed marked mesangial sclerosis with the formation of distinctive acellular nodules (Figure 1c). Globally sclerotic glomeruli were not observed. On Periodic acid-Schiff and Jones methenamine silver stains, the peripheral capillary loops showed thickened walls and frequent double contours. Rare craters were also seen. There was mild arteriosclerosis. Arterioles exhibited moderate sclerosis of the vessel walls with accumulation of hyaline material. On immunouorescence microscopy, no signicant immune deposits were observed in the glomeruli. Electron microscopy examination yielded no additional diagnostic information, but conrmed the tubular degenerative changes observed on light microscopy.
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AK Rocuts et al.: Acute phosphate nephropathy

CLINICAL DIAGNOSIS

Acute kidney injury from acute phosphate nephropathy and diabetic nodular glomerulosclerosis.
CLINICAL FOLLOW-UP

On subsequent visits, a more detailed evaluation of the patients history revealed exposure to oral sodium phospho-soda
Table 1 | Laboratory parameters at presentation
Investigation Complete blood count White blood cells Hemoglobin Platelets Serum chemistry Sodium Potassium Chloride Calcium Phosphate Creatinine Total CO2 Other chemistry PTH Glucose Urinalysis pH Specific gravity Blood Protein Serum electrophoresis Value 4.27 k/ml 9.6 g/dl 260 k/ml 139 mmol/l 4.5 mmol/l 103 mmol/l 9.1 mg/dl 3.8 mg/dl 1.5 mg/dl 27 mmol/l 108.1 pg/ml 178 mg/dl Reference value 410 k/ml 11.516.4 g/dl 150450 k/ml 136142 mmol/l 3.55 mmol/l 98108 mmol/l 8.810.5 mg/dl 2.45.0 mg/dl 0.71.3 mg/dl 2332 mmol/l 1180 pg/ml 54118 mg/dl

(OSPS), also known as Fleet Phospho-soda (C.B. Fleet, Lynchburg, VA, USA), 1 day before gynecological surgery (11 weeks prior to presentation). Blood pressure was last noted as 127/50 mm Hg. Kidney function has not returned to baseline (serum creatinine of 1.9 mg per 100 ml with an estimated glomerular ltration rate of 30 ml/min per 1.73m2 by MDRD 3 equation) 5 months after sodium phospho-soda exposure. The most recent albumin-to-creatinine ratio is 513 mg albumin per gram of creatinine. Laboratory data of the patient at the baseline and after OSPS exposure are summarized in Figure 2.
DISCUSSION

6 1.011 1+ 2+ No abnormal electrophoretic pattern noted

4.58.0 1.0031.035 0 0

Acute phosphate nephropathy is an unusual cause of acute kidney injury. It is most frequently reported in elderly patients, particularly among women, following exposure to the bowel-cleansing preparation, OSPS. Acute phosphate nephropathy is a diagnosis that tends to be overlooked, as OSPS is not widely recognized as a precipitating cause of acute kidney injury. We present a patient with an underlying history of diabetes and hypertension with acute kidney injury that was initially attributed to the progression of diabetic nephropathy, but on kidney biopsy was diagnosed as acute phosphate nephropathy secondary to OSPS exposure. OSPS preparations are used as part of a bowel-cleansing regimen; they prepare the colon for X-ray or endoscopic examination as well as for surgery.14 OSPS preparations emerged in 1990 as better alternatives to standard bowel preparations and were regarded as very safe and effective solutions for adequate mucosal visualization.1 However, as their use continued to grow, case reports of serious electrolyte disturbances (including some fatal outcomes) appeared in

Figure 1 | Renal biopsy findings in acute phospho-nephropathy. (a) Coarse basophilic, rounded deposits of calcium phosphate are present within the lumina of tubules (hematoxylineosin, high-power field, original magnification 40). (b) The widespread multifocal nature of the intratubular calciumphosphate deposits is best illustrated with the von Kossa stain (von Kossa stain, high-power field, original magnification 60). (c) Glomeruli displaying mesangial sclerosis with the formation of distinctive acellular nodules (periodic acid-Schiff stain, high-power field, original magnification 40).
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the renal consult

80 9.2 70 68 8.2 9 9.5 9.5 9.2

10 9 8 Total urine protein-to-creatinine ratio (g/g), calcium (mg / dl) and phosphate (mg/dl)

60 Estimated GFR (ml/min/1.73m2)

7 50 6 40 38 33 30 2.7 20 2.6 1.47 10 0.96 1 0.91 0 Baseline 0 Postop 2 3 4 5 Time from SPS Exposure (months) Estimated GFR (ml/min/1.73m2) Phosphate (mg/dl) Calcium (mg/dl) Proteinuria (g/g) 2 3.7 27 4.8 4.1 26 4.1 4 26 3 5

Figure 2 | Acute phosphate nephropathy progression after OSPS exposure. Graph shows the trends of estimated glomerular filtration rate, serum calcium and phosphate, and total urine protein-to-creatinine ratio at baseline and up to 5 months after exposure to OSPS. The arrow marks the time when the patient was exposed to OSPS.

the literature; they are associated with severe electrolyte abnormalities (hyperphosphatemia, hypernatremia, hypokalemia, hypocalcemia, and hypomagnesemia), metabolic acidosis, acute kidney injury, and death when higher than the recommended doses are used.5,6 The pathophysiology and histologic lesion underlying acute kidney injury from OSPS were unrecognized until the publication of a letter by Desmeules et al.7 in the New England Journal of Medicine in 2003. The term acute phosphate nephropathy was used to describe a syndrome observed in a 71-year-old woman whose creatinine increased from 1.0 to 4.5 mg per 100 ml over a 10week period after administration of the recommended doses of OSPS.7 Since then, there have been several cases in the literature of biopsy-proven acute phosphate nephropathy secondary to OSPS exposure.712 The potential for OSPS to cause acute kidney injury and electrolyte disturbances led some authors to advise against their use in patients with kidney, cardiac, or liver disease.11 The US Food and Drug Administration (FDA) in 2001, and Health Canada in 2002, reviewed the safety of OSPS and issued a report urging greater physician awareness.5,13 However, after the report by Desmeules et al., Markowitz et al. performed a detailed study of 21 cases of acute kidney injury after OSPS administration. Subsequently, in May 2006, the FDA issued an alert noting the association between OSPS preparations and acute phosphate nephropathy. The FDA
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published a scientic background paper advising against the use of these preparations in patients with kidney disease, impaired renal function, dehydration, or uncorrected electrolyte abnormalities.12 Multiple media reports have appeared on the subject and the consumer advocacy group Public Citizen has added OSPS preparations to its worse pills website.11 Recently, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society of American Gastrointestinal and Endoscopic Surgeons published an addendum to their consensus statement warning on the association of OSPS and phosphate nephropathy.1,14 However, these reports may have underestimated the actual number of patients who develop acute phosphate nephropathy since only the original cases of Desmules et al.7 and Markowitz et al.9 have been published.
PREDISPOSING FACTORS FOR ACUTE PHOSPHATE NEPHROPATHY

OSPS-induced acute kidney injury appears to be rare. Predisposing conditions have not been elucidated in their entirety. Contraindications to the use of OSPS include electrolyte disorders, impaired kidney function, and renal failure.12 Pathophysiologic factors thought to predispose patients to acute phosphate nephropathy include inadequate hydration, volume depletion and excessive OSPS dosing.12 Additionally, factors that are common in patients with acute
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AK Rocuts et al.: Acute phosphate nephropathy

phosphate nephropathy include female gender (this could perhaps be related to the greater degree of volume depletion caused by OSPS in the smaller body mass of elderly women9,15,16), older age, history of hypertension, diabetes, hyperparathyroidism and the use of angiotensin converting enzyme inhibitors. Angiotensin receptor blockers, diuretics, or non-steroidal anti-inammatory drugs, exacerbate volume depletion, particularly in older patients.9
CLINICAL PRESENTATION

There appears to be two distinct clinical patterns of acute kidney injury after OSPS administration.8
Early-onset acute phosphate nephropathy

An acute pattern of presentation is present when acute kidney injury is noted as part of a systemic syndrome after OSPS exposure. These patients present with severe electrolytic abnormalities (hypocalcemia and hyperphosphatemia) with acute neurological symptoms, such as confusion, tetany and/ or lethargy, loss of consciousness, severe diarrhea, cardiac arrest, or delay in awakening after anesthesia. Their calciumphosphate product usually increases to X100 mg/dl but then returns to normal baseline values after exposure to OSPS; conservative treatment, including phosphate-binding resins and calcium gluconate, are recommended for the hypercalcemia and hyperphosphatemia. Gonlusen et al.8 reviewed the presentation of 11 patients and observed a fatal outcome in 27% of these individuals. Of those who survived, renal function returned to baseline in 56% and/or improved in 22% of the patients. The cause of acute kidney injury was not denitively diagnosed, as kidney biopsies were not performed consistently.8,11
Insidious onset acute phosphate nephropathy

especially in patients with even a mild degree of existing renal damage.16,21 Thus, it seems that in patients presenting acutely, marked hyperphosphatemia may be directly tubulotoxic.8 Indeed, Gonlusen et al.8 have observed acute tubular cell injury in tubules with calciumphosphate deposition, but have also reported the presence of tubular injury even without concurrent calciumphosphate deposition. Rapid correction of hypocalcemia/hyperphosphatemia in patients of this group may help prevent chronic injury and account for the partial reversibility of renal function in most cases. Although it is possible that the insidious form of acute phosphate nephropathy has a different pathogenetic mechanism, this has not been demonstrated denitively. It is likely that in the patients who progress to chronic kidney disease after exposure to OSPS, calciumphosphate deposits causes long-lasting tubular damage and subsequent brosis, and nephron loss and brosis.11
MANAGEMENT OF ACUTE PHOSPHATE NEPHROPATHY

In recent reports, an insidious form of OSPS-induced kidney injury has been described. This syndrome is frequently detected as an incidental nding (such as in the patient reported herein) or presents with nonspecic symptoms including malaise, nausea, or vomiting weeks to months after OSPS exposure. Patients have normal electrolytes, a bland urine sediment, and modest or minimal levels of proteinuria.9 At follow-up, the majority of these patients develop chronic kidney disease with a mean serum creatinine of 2.3 mg/dl.7,8,10,17 Some patients progress to end-stage renal disease requiring hemodialysis.
PATHOGENESIS OF ACUTE PHOSPHATE NEPHROPATHY

The pathogenesis of acute kidney injury following OSPS remains obscure, and is most likely multifactorial.11 Animal studies (in rats), in which phosphate is infused via the intraperitoneal route or feeding with a high-phosphorus diet, demonstrate proximal tubular injury after 1 day, and phosphate nephropathy in the kidney by the third day.18,19 Among humans, up to 20% of the phosphate in the OSPS is reabsorbed,20 and a moderate increase in the dose of phosphate absorption can cause severe hyperphosphatemia,
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The management of acute phosphate nephropathy has two important dimensionsacute management and prevention. In those subjects who present with early-onset acute phosphate nephropathy, the diagnosis is suggested if there is a history of OSPS exposure, and associated laboratory abnormalities are present. In these patients, treatment targeted at the hyperphosphatemia and hypercalcemia are key.16 In those who present with an insidious course and with nonspecic symptoms, renal biopsy is important for diagnosis because the phosphate and calcium levels are usually normal at the time of presentation. Preventing acute phosphate nephropathy is also very important. The awareness of acute phosphate nephropathy secondary to OSPS cannot be overemphasized. There exists no clear cutoff glomerular ltration rate or serum creatinine that contraindicates the administration of OSPS. Indeed, both Markowitz et al. and Gonlusen et al. have observed acute phosphate nephropathy in most subjects with normal baseline creatinine values. It is thus imperative to avoid OSPS in patients with predisposing risk factorselderly age, comorbidities, such as diabetes mellitus and hypertension, and patients on concomitant medications, such as angiotensinconverting enzyme inhibitors, non-steroidal anti-inammatory drugs, and diuretics. The patient we have presented here underscores the importance of being alert to the syndrome of acute phosphate nephropathy in patients with a normal serum creatinine but with other risk factors. Although our patient had a serum creatinine in the normal range at 0.9 mg per 100 ml, she was in an older age group, had diabetes mellitus and hypertension, and was being treated with an angiotensinconverting enzyme inhibitors and non-steroidal anti-inammatory drugs. The patients long-standing diabetes may have increased her risk of developing an ileus in her postoperative course. If a considerable amount of the OSPS is absorbed in normal subjects,20 and a moderate increase in phosphate absorption may be sufcient to cause severe
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the renal consult

Fleet Phospho-Soda Warning

REFERENCES
1. Wexner SD, Beck DE, Baron TH et al. A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc 2006; 20: 11471160. Huynh T, Vanner S, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia. Am J Gastroenterol 1995; 90: 104107. Pineau B, Paskett E, Chen G et al. Virtual colonoscopy using oral contrast compared with colonoscopy for the detection of patients with colorectal polyps. Gastroenterology 2003; 125: 304310. Zmora O, Pikarsky AJ, Wexner SD. Bowel preparation for colorectal surgery. Dis Colon Rectum 2001; 44: 15371549. Curran M, Plosker GL. Oral sodium phosphate solution. Drugs 2004; 64: 16971714. Vukasin P, Weston LA, Beart RW. Oral Fleet Phospho-Soda laxative-induced hyperphosphatemia and hypocalcemic tetany in an adult: report of a case. Dis Colon Rectum 1997; 40: 497499. Desmeules S, Bergeron MJ, Isenring P. Acute phosphate nephropathy and renal failure. N Eng J Med 2003; 349: 10061007. Gonlusen G, Akgun H, Ertan A et al. Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing. Arch Pathol Lab Med 2006; 130: 101106. Markowitz GS, Stokes MB, Radhakrishnan J et al. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an under recognized cause of chronic renal failure. J Am Soc Nephrol 2005; 16: 33893396. Markowitz GS, Nasr SH, Klein P et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004; 35: 675684. Heher E, Rennke H, Humphreys B. Nephrocalcinosis, oral sodium phosphate solution, and phosphate nephropathy. Nephrology Rounds 2007; 2: 2; http://www.nephrologyrounds.org. Center for Drug Evaluation Research. U.S. Food and Drug Administration. Oral Sodium Phosphate (OSP) Products for Bowel Cleansing. US Government Printing Office: Washington, DC, 2006. Schwetz BA. From the Food and Drug Administration. JAMA 2001; 286: 2660. Wexner SD, Beck DE, Baron TH; et al. A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc 2006; 20: 1161. Wechsler A, Schneider R, Sapojnikov M et al. Bowel cleansing in patients with chronic renal failurean often overlooked hazard. Nephrol Dial Transplant 2006; 21: 11331134. Patel V, Emmett M, Santa Ana CA et al. Pathogenesis of nephrocalcinosis after sodium phosphate catharsis to prepare for colonoscopy: intestinal phosphate absorption and its effect on urine mineral and electrolyte excretion. Hum Pathol 2007; 38: 193194. Markowitz GS, Whelan J, DAgati VD. Renal failure following bowel cleansing with a sodium phosphate purgative. Nephrol Dial Transplant 2005; 20: 850851. Haase P. The development of nephrocalcinosis in the rat following injections of neutral sodium phosphate. J Anat 1975; 119: 1937. Matsuzaki H, Uehara M, Suzuki K et al. High phosphorus diet rapidly induces nephrocalcinosis and proximal tubular injury in rats. J Nutr Sci Vitaminol 1997; 43: 627641. Sweetman SC (ed). Martindale: The Complete Drug Reference. Pharmaceutical Press: London, UK, 2004. Aaseb W, Scott H, Ganss R. Kidney biopsies taken before and after oral sodium phosphate bowel cleansing. Nephrol Dial Transplant 2007; 22: 920922.

Renal failure from acute phosphate nephropathy is a rare but serious adverse event associated with oral sodium phosphate bowel cleansing, Fleet enemas and oral Fleet Phospho-Soda should be avoided in patients with acute renal failure, chronic kidney disease, advanced age, dehydration, and uncorrected electrolyte abnormalities.

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Figure 3 | Fleet Phospho-soda warning in the hospital clinical information system.

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hyperphosphatemia, it is reasonable to assume that a prolonged intestinal transit period in our patient may have predisposed her to acute phosphate nephropathy. Her kidney biopsy also revealed arteriolar and arterial sclerosis, both features known to pre-dispose to acute kidney injury after OSPS administration.9 The other important point that our patient illustrates is the value of performing a kidney biopsy in patients with diabetic kidney disease who develop worsening kidney function for no apparent reason. In view of her nonspecic symptoms and normal laboratory parameters, it was not possible to diagnose acute phosphate nephropathy on clinical data alone; however, kidney biopsy made this diagnosis possible. After this case came to our attention, the Brigham and Womens Hospital, at our request, implemented a warning in its clinical information system so that each time OSPS is prescribed in any of its pharmacological preparations, physicians are required to weigh its risks and benets (Figure 3). We believe that these types of alerts are important in avoiding this eminently preventable syndrome.
CONCLUSION

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Both patients and health-care professionals should be vigilant of acute kidney injury following the use of OSPS. Although this agent is widely used as part of a colorectal-cleansing preparation because of its efcacy, tolerability, and cost compared with other available regimens, its use will most likely fall due to the increased number of cases of acute phosphate nephropathy that continue to be reported in the literature. Although acute phosphate nephropathy has been recognized as a result of OSPS use, it is a diagnosis that may be overlooked by nephrologists and by other specialists. The adverse effects of phosphate-based preparations may still be underestimated because there is no clear serum creatinine or glomerular ltration rate cutoff that permits their safe application.
ACKNOWLEDGMENTS

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Special thanks to Dr Bharati Mittal and Dr Sikander Surana for their helpful insights.

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