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Home , Hydronephrosis, Phosphate nephropathy

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provided by Elsevier - Publisher Connector http://www.kidney-international.org the renal consult & 2009 International Society of

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

1Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA and 2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

minute. The rest of the examination was unremarkable. CASE PRESENTATION HerlaboratorydataissummarizedinTable1. A 60-year-old white Latino female with a clinical diagnosis A postoperative ultrasound showed no of mellitus (diagnosed in 1993) and . was referred to the chronic clinic at The etiology of the was unclear. Brigham and Women’s Hospital for the evaluation of acute Progressive exacerbated by other kidney injury; serum had increased from a contributory factors, such as exposure to lisinopril, baseline of 0.9 to 1.5 mg/dl in a 11-week period. She was acetylsalicylic acid, or naproxen, was regarded as the most asymptomatic at the time of presentation. Her past plausible explanation. Despite discontinuation of these medical history included a total abdominal hysterectomy medications, kidney function did not improve; it worsened with bilateral salpingo oophorectomy and upper in a 4-week period after presentation. Hence, a kidney vaginectomy for high-grade squamous intraepithelial was performed. 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. KIDNEY BIOPSY Both episodes had blood pressures in excess of A total of nine glomeruli were in the core. The predominant 190–200 mm Hg systolic that resolved with intravenous feature observed on light microscopy was a multifocal . Cardiovascular workup revealed no evidence of deposition of phosphate within the tubules ischemic heart disease. Additionally, renal evaluation (basophilic, rounded concretions), in the interstitium, and included magnetic resonance angiography with and focally along tubular basement membranes (Figure 1a). The without gadolinium, which did not reveal renal artery deposits of calcium were non-birefringent under polarized . However, serum creatinine peaked at 1.9 mg/dl light and were best visualized in the sections stained with immediately after surgical procedure and remained von Kossa stain (Figure 1b). Degenerative changes of the elevated at 1.5 mg/dl throughout the course of her current tubular epithelium were focally noted with flattening of presentation (corresponding to a glomerular filtration rate 2 the epithelium. Tubular necrosis was not seen. An associated of 33 ml/min per 1.73m , estimated by the modification in focally dense lymphocyte-rich mixed inflammatory infiltrate diet in renal disease III (MDRD 3) equation). At in the interstitium was also noted without interstitial presentation, medications included amlodipine, edema. Tubulitis was not present. Moderate tubular atrophy furosemide, metoprolol, lisinopril, atorvastatin, insulin and interstitial fibrosis affecting 30% of the parenchyma glargine, cyanocobalamin, acetylsalicylic acid, and were also observed. All of the glomeruli present in the naproxen. The patient had no prior exposure to sample were hypertrophic and showed marked mesangial radiocontrast agents. Physical examination revealed an sclerosis with the formation of distinctive acellular nodules overweight women weighing 207 lbs with a blood (Figure 1c). Globally sclerotic glomeruli were not observed. pressure of 142/60 mm Hg and a heart rate of 60 beats per 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 Correspondence: Ajay K. Singh, Renal Division, Department of Medicine, was mild arteriosclerosis. Arterioles exhibited moderate Brigham and Women’s Hospital, Harvard Medical School, Boston, sclerosis of the vessel walls with accumulation of hyaline Massachusetts, USA. E-mail: [email protected] material. On immunofluorescence microscopy, no significant Kidney International (2009) 75, 987–991; doi:10.1038/ki.2008.293; immune deposits were observed in the glomeruli. Electron published online 25 June 2008 microscopy examination yielded no additional diagnostic Received 18 October 2007; revised 4 February 2008; accepted 12 information, but confirmed the tubular degenerative changes February 2008; published online 25 June 2008 observed on light microscopy.

Kidney International (2009) 75, 987–991 987 the renal consult AK Rocuts et al.: Acute phosphate nephropathy

CLINICAL DIAGNOSIS (OSPS), also known as Fleet Phospho-soda (C.B. Fleet, Acute kidney injury from acute phosphate nephropathy and Lynchburg, VA, USA), 1 day before gynecological surgery diabetic nodular . (11 weeks prior to presentation). Blood pressure was last noted as 127/50 mm Hg. Kidney function has not returned to CLINICAL FOLLOW-UP baseline (serum creatinine of 1.9 mg per 100 ml with an On subsequent visits, a more detailed evaluation of the patient’s estimated glomerular filtration rate of 30 ml/min per 1.73m2 history revealed exposure to oral sodium phospho-soda by MDRD 3 equation) 5 months after sodium phospho-soda exposure. The most recent albumin-to-creatinine ratio is Table 1 | Laboratory parameters at presentation 513 mg albumin per gram of creatinine. Laboratory data of Investigation Value Reference value the patient at the baseline and after OSPS exposure are summarized in Figure 2. Complete blood count White blood cells 4.27 k/ml4–10k/ml Hemoglobin 9.6 g/dl 11.5–16.4g/dl DISCUSSION Platelets 260 k/ml 150–450k/ml Acute phosphate nephropathy is an unusual cause of acute kidney injury. It is most frequently reported in elderly Serum chemistry Sodium 139 mmol/l 136–142mmol/l patients, particularly among women, following exposure to Potassium 4.5 mmol/l 3.5–5mmol/l the bowel-cleansing preparation, OSPS. Acute phosphate Chloride 103 mmol/l 98–108mmol/l nephropathy is a diagnosis that tends to be overlooked, as Calcium 9.1 mg/dl 8.8–10.5mg/dl Phosphate 3.8 mg/dl 2.4–5.0mg/dl OSPS is not widely recognized as a precipitating cause of Creatinine 1.5 mg/dl 0.7–1.3mg/dl acute kidney injury. We present a patient with an underlying Total CO2 27 mmol/l 23–32mmol/l history of diabetes and hypertension with acute kidney injury Other chemistry that was initially attributed to the progression of diabetic PTH 108.1 pg/ml 11–80pg/ml nephropathy, but on kidney biopsy was diagnosed as acute Glucose 178 mg/dl 54–118mg/dl phosphate nephropathy secondary to OSPS exposure. OSPS preparations are used as part of a bowel-cleansing Urinalysis pH 6 4.5–8.0 regimen; they prepare the colon for X-ray or endoscopic 1–4 Specific gravity 1.011 1.003–1.035 examination as well as for surgery. OSPS preparations Blood 1+ 0 emerged in 1990 as better alternatives to standard bowel Protein 2+ 0 preparations and were regarded as very safe and effective 1 Serum electrophoresis No abnormal solutions for adequate mucosal visualization. However, as electrophoretic their use continued to grow, case reports of serious electrolyte pattern noted disturbances (including some fatal outcomes) appeared in

ab

c

Figure 1 | findings in acute phospho-nephropathy. (a) Coarse basophilic, rounded deposits of calcium phosphate are present within the lumina of tubules (hematoxylin–eosin, high-power field, original magnification  40). (b) The widespread multifocal nature of the intratubular calcium–phosphate 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).

988 Kidney International (2009) 75, 987–991 AK Rocuts et al.: Acute phosphate nephropathy the renal consult

80 10

9.2 9.5 9.5 9.2 9 70 9 68 8 60 8.2 ) 2 7

50 6

38 4.8 40 5 33 4.1 4.1 4 30 26 26 3.7 2.7 3

Estimated GFR (ml/min/1.73m 27

20 2.6 Total urine protein-to-creatinine ratio

1.47 2 (g/g), calcium (mg/dl) and phosphate (mg/dl) 10 0.96 1 0.91

0 0 Baseline Postop 2 3 4 5 Time from SPS Exposure (months)

Estimated GFR (ml/min/1.73m2) Calcium (mg/dl) Phosphate (mg/dl) (g/g)

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 published a scientific background paper advising against the abnormalities (, , hypoka- use of these preparations in patients with kidney disease, lemia, , and hypomagnesemia), metabolic impaired renal function, , or uncorrected elec- acidosis, acute kidney injury, and death when higher than trolyte abnormalities.12 Multiple media reports have ap- the recommended doses are used.5,6 The pathophysiology peared on the subject and the consumer advocacy group and histologic lesion underlying acute kidney injury from Public Citizen has added OSPS preparations to its ‘worse OSPS were unrecognized until the publication of a letter by pills’ website.11 Recently, the American Society for Gastro- Desmeules et al.7 in the New England Journal of Medicine in intestinal Endoscopy (ASGE) and the Society of American 2003. The term acute phosphate nephropathy was used to Gastrointestinal and Endoscopic Surgeons published an describe a syndrome observed in a 71-year-old woman whose addendum to their consensus statement warning on the creatinine increased from 1.0 to 4.5 mg per 100 ml over a 10- association of OSPS and phosphate nephropathy.1,14 How- week period after administration of the recommended doses ever, these reports may have underestimated the actual of OSPS.7 Since then, there have been several cases in the number of patients who develop acute phosphate nephro- literature of biopsy-proven acute phosphate nephropathy pathy since only the original cases of Desmules et al.7 and secondary to OSPS exposure.7–12 Markowitz et al.9 have been published. The potential for OSPS to cause acute kidney injury and electrolyte disturbances led some authors to advise against PREDISPOSING FACTORS FOR ACUTE PHOSPHATE their use in patients with kidney, cardiac, or liver disease.11 NEPHROPATHY The US Food and Drug Administration (FDA) in 2001, and OSPS-induced acute kidney injury appears to be rare. Health Canada in 2002, reviewed the safety of OSPS and Predisposing conditions have not been elucidated in their issued a report urging greater physician awareness.5,13 entirety. Contraindications to the use of OSPS include However, after the report by Desmeules et al., Markowitz electrolyte disorders, impaired kidney function, and renal et al. performed a detailed study of 21 cases of acute .12 Pathophysiologic factors thought to predispose injury after OSPS administration. Subsequently, in May 2006, patients to acute phosphate nephropathy include inadequate the FDA issued an alert noting the association between OSPS hydration, volume depletion and excessive OSPS dosing.12 preparations and acute phosphate nephropathy. The FDA Additionally, factors that are common in patients with acute

Kidney International (2009) 75, 987–991 989 the renal consult AK Rocuts et al.: Acute phosphate nephropathy

phosphate nephropathy include female gender (this could especially in patients with even a mild degree of existing renal perhaps be related to the greater degree of volume depletion damage.16,21 Thus, it seems that in patients presenting caused by OSPS in the smaller body mass of elderly acutely, marked hyperphosphatemia may be directly tubulo- women9,15,16), older age, history of hypertension, diabetes, toxic.8 Indeed, Gonlusen et al.8 have observed acute tubular hyperparathyroidism and the use of angiotensin converting cell injury in tubules with calcium–phosphate deposition, but enzyme inhibitors. Angiotensin receptor blockers, diuretics, have also reported the presence of tubular injury even or non-steroidal anti-inflammatory drugs, exacerbate volume without concurrent calcium–phosphate deposition. Rapid depletion, particularly in older patients.9 correction of hypocalcemia/hyperphosphatemia in patients of this group may help prevent chronic injury and account for CLINICAL PRESENTATION the partial reversibility of renal function in most cases. There appears to be two distinct clinical patterns of acute Although it is possible that the insidious form of acute kidney injury after OSPS administration.8 phosphate nephropathy has a different pathogenetic mechan- ism, this has not been demonstrated definitively. It is likely Early-onset acute phosphate nephropathy that in the patients who progress to An acute pattern of presentation is present when acute kidney after exposure to OSPS, calcium–phosphate deposits causes injury is noted as part of a systemic syndrome after OSPS long-lasting tubular damage and subsequent fibrosis, and 11 exposure. These patients present with severe electrolytic loss and fibrosis. abnormalities (hypocalcemia and hyperphosphatemia) with acute neurological symptoms, such as confusion, tetany and/ MANAGEMENT OF ACUTE PHOSPHATE NEPHROPATHY or lethargy, loss of consciousness, severe , cardiac The management of acute phosphate nephropathy has two arrest, or delay in awakening after anesthesia. Their important dimensions—acute management and prevention. calcium–phosphate product usually increases to X100 mg/dl In those subjects who present with early-onset acute but then returns to normal baseline values after exposure to phosphate nephropathy, the diagnosis is suggested if there OSPS; conservative treatment, including phosphate-binding is a history of OSPS exposure, and associated laboratory resins and calcium gluconate, are recommended for the abnormalities are present. In these patients, treatment hypercalcemia and hyperphosphatemia. Gonlusen et al.8 targeted at the hyperphosphatemia and hypercalcemia are 16 reviewed the presentation of 11 patients and observed a fatal key. In those who present with an insidious course and with outcome in 27% of these individuals. Of those who survived, nonspecific symptoms, renal biopsy is important for renal function returned to baseline in 56% and/or improved diagnosis because the phosphate and calcium levels are in 22% of the patients. The cause of acute kidney injury was usually normal at the time of presentation. not definitively diagnosed, as kidney were not Preventing acute phosphate nephropathy is also very performed consistently.8,11 important. The awareness of acute phosphate nephropathy secondary to OSPS cannot be overemphasized. There exists Insidious onset acute phosphate nephropathy no clear cutoff glomerular filtration rate or serum creatinine In recent reports, an insidious form of OSPS-induced kidney that contraindicates the administration of OSPS. Indeed, injury has been described. This syndrome is frequently both Markowitz et al. and Gonlusen et al. have observed detected as an incidental finding (such as in the patient acute phosphate nephropathy in most subjects with normal reported herein) or presents with nonspecific symptoms baseline creatinine values. It is thus imperative to avoid OSPS including malaise, nausea, or weeks to months after in patients with predisposing risk factors—elderly age, co- OSPS exposure. Patients have normal electrolytes, a bland morbidities, such as diabetes mellitus and hypertension, and urine sediment, and modest or minimal levels of proteinur- patients on concomitant medications, such as angiotensin- ia.9 At follow-up, the majority of these patients develop converting enzyme inhibitors, non-steroidal anti-inflamma- chronic kidney disease with a mean serum creatinine of tory drugs, and diuretics. 2.3 mg/dl.7,8,10,17 Some patients progress to end-stage renal The patient we have presented here underscores the disease requiring . importance of being alert to the syndrome of acute phosphate nephropathy in patients with a normal serum PATHOGENESIS OF ACUTE PHOSPHATE NEPHROPATHY creatinine but with other risk factors. Although our patient The pathogenesis of acute kidney injury following OSPS had a serum creatinine in the ‘normal range’ at 0.9 mg per remains obscure, and is most likely multifactorial.11 Animal 100 ml, she was in an older age group, had diabetes mellitus studies (in rats), in which phosphate is infused via the and hypertension, and was being treated with an angiotensin- intraperitoneal route or feeding with a high-phosphorus diet, converting enzyme inhibitors and non-steroidal anti-inflam- demonstrate proximal tubular injury after 1 day, and matory drugs. The patient’s long-standing diabetes may phosphate nephropathy in the kidney by the third day.18,19 have increased her risk of developing an ileus in her Among humans, up to 20% of the phosphate in the OSPS is postoperative course. If a considerable amount of the OSPS reabsorbed,20 and a moderate increase in the dose of is absorbed in normal subjects,20 and a moderate increase in phosphate absorption can cause severe hyperphosphatemia, phosphate absorption may be sufficient to cause severe

990 Kidney International (2009) 75, 987–991 AK Rocuts et al.: Acute phosphate nephropathy the renal consult

Fleet Phospho-Soda Warning REFERENCES 1. Wexner SD, Beck DE, Baron TH et al. A consensus document on bowel Renal failure from acute phosphate nephropathy is a rare but serious adverse event associated with oral sodium phosphate bowel cleansing, preparation before : prepared by a task force from the Fleet and oral Fleet Phospho-Soda should be avoided in patients American Society of Colon and Rectal Surgeons (ASCRS), the American with acute renal failure, chronic kidney disease, advanced age, dehydration, and uncorrected electrolyte abnormalities. Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc 2006; 20: 1147–1160. 2. Huynh T, Vanner S, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or . Am J Gastroenterol 1995; 90: Figure 3 | Fleet Phospho-soda warning in the hospital clinical 104–107. information system. 3. Pineau B, Paskett E, Chen G et al. Virtual colonoscopy using oral contrast compared with colonoscopy for the detection of patients with colorectal polyps. 2003; 125: 304–310. 4. Zmora O, Pikarsky AJ, Wexner SD. Bowel preparation for colorectal surgery. Dis Colon 2001; 44: 1537–1549. hyperphosphatemia, it is reasonable to assume that a 5. Curran M, Plosker GL. Oral sodium phosphate solution. Drugs 2004; 64: prolonged intestinal transit period in our patient may have 1697–1714. predisposed her to acute phosphate nephropathy. Her kidney 6. Vukasin P, Weston LA, Beart RW. Oral Fleet Phospho-Soda laxative-induced hyperphosphatemia and hypocalcemic tetany in biopsy also revealed arteriolar and arterial sclerosis, both an adult: report of a case. Dis Colon Rectum 1997; 40: 497–499. features known to pre-dispose to acute kidney injury after 7. Desmeules S, Bergeron MJ, Isenring P. Acute phosphate nephropathy and 9 renal failure. N Eng J Med 2003; 349: 1006–1007. OSPS administration. The other important point that our 8. Gonlusen G, Akgun H, Ertan A et al. Renal failure and patient illustrates is the value of performing a kidney biopsy in associated with oral sodium phosphate bowel cleansing. Arch Pathol Lab patients with diabetic kidney disease who develop worsening Med 2006; 130: 101–106. 9. Markowitz GS, Stokes MB, Radhakrishnan J et al. Acute phosphate kidney function for no apparent reason. In view of her nephropathy following oral sodium phosphate bowel purgative: an nonspecific symptoms and normal laboratory parameters, it under recognized cause of chronic renal failure. J Am Soc Nephrol 2005; was not possible to diagnose acute phosphate nephropathy on 16: 3389–3396. 10. Markowitz GS, Nasr SH, Klein P et al. Renal failure due to acute clinical data alone; however, kidney biopsy made this diagnosis nephrocalcinosis following oral sodium phosphate bowel cleansing. possible. After this case came to our attention, the Brigham and Hum Pathol 2004; 35: 675–684. Women’s Hospital, at our request, implemented a warning in 11. Heher E, Rennke H, Humphreys B. Nephrocalcinosis, oral sodium phosphate solution, and phosphate nephropathy. Nephrology Rounds its clinical information system so that each time OSPS is 2007; 2: 2; http://www.nephrologyrounds.org. prescribed in any of its pharmacological preparations, physi- 12. Center for Drug Evaluation Research. U.S. Food and Drug Administration. Oral Sodium Phosphate (OSP) Products for Bowel Cleansing.US cians are required to weigh its risks and benefits (Figure 3). Government Printing Office: Washington, DC, 2006. We believe that these types of alerts are important in avoiding 13. Schwetz BA. From the Food and Drug Administration. JAMA 2001; 286: this eminently preventable syndrome. 2660. 14. Wexner SD, Beck DE, Baron TH; et al. A consensus document on bowel preparation before colonoscopy: prepared by a task force from the CONCLUSION American Society of Colon and Rectal Surgeons (ASCRS), the American Both patients and health-care professionals should be vigilant of Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc acute kidney injury following the use of OSPS. Although this 2006; 20: 1161. agent is widely used as part of a colorectal-cleansing preparation 15. Wechsler A, Schneider R, Sapojnikov M et al. Bowel cleansing in patients because of its efficacy, tolerability, and cost compared with with chronic renal failure—an often overlooked hazard. Nephrol Dial Transplant 2006; 21: 1133–1134. other available regimens, its use will most likely fall due to the 16. Patel V, Emmett M, Santa Ana CA et al. Pathogenesis of nephrocalcinosis increased number of cases of acute phosphate nephropathy that after sodium phosphate catharsis to prepare for colonoscopy: intestinal phosphate absorption and its effect on urine mineral and electrolyte continue to be reported in the literature. Although acute excretion. Hum Pathol 2007; 38: 193–194. phosphate nephropathy has been recognized as a result of OSPS 17. Markowitz GS, Whelan J, D’Agati VD. Renal failure following bowel use, it is a diagnosis that may be overlooked by nephrologists cleansing with a sodium phosphate purgative. Nephrol Dial Transplant 2005; 20: 850–851. and by other specialists. The adverse effects of phosphate-based 18. Haase P. The development of nephrocalcinosis in the rat following preparations may still be underestimated because there is no injections of neutral sodium phosphate. J Anat 1975; 119: 19–37. clear serum creatinine or glomerular filtration rate cutoff that 19. Matsuzaki H, Uehara M, Suzuki K et al. High phosphorus diet rapidly induces nephrocalcinosis and proximal tubular injury in rats. J Nutr Sci permits their safe application. Vitaminol 1997; 43: 627–641. 20. Sweetman SC (ed). Martindale: The Complete Drug Reference. Pharmaceutical Press: London, UK, 2004. ACKNOWLEDGMENTS 21. Aasebø W, Scott H, Ganss R. Kidney biopsies taken before and after oral Special thanks to Dr Bharati Mittal and Dr Sikander Surana for their sodium phosphate bowel cleansing. Nephrol Dial Transplant 2007; 22: helpful insights. 920–922.

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