Eckstein, Jens

Eugster, Thomas

Gürke, Lorenz

Mayr, Michael

Pargger, Hans

Pechula, Martina

Savic, Spasenija

Steiger, Jürg

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Interesting CaseExtensive calcifications induced by hyperphosphataemia caused byphosphate-based enema in a patient after kidney transplantationJens Eckstein1, Spasenija Savic2, Thomas Eugster3, Hans Pargger4, Lorenz Gu¨rke3,Martina Pechula1, Ju¨rg Steiger1 and Michael Mayr11Division of Transplantation Immunology and Nephrology, 2Institute for Pathology, 3Division of Vascular andTransplantation Surgery and 4Division of Operative Critical Care, Department of Anesthesia, University Hospital Basel,Basel, SwitzerlandKeywords: dystrophic calcification;hyperphosphataemia; kidney transplantation;phosphate-based enema; phosphate intoxication;visceral calcificationsIntroductionThe use of phosphate-based enemas as a laxative is stillstandard practice in clinical medicine. Absorption ofphosphate with consecutive hyperphosphataemia andhypocalcaemia is a serious adverse event which isespecially dangerous in patients with renal insuffi-ciency and impaired bowel movement. Despite severalreports including cases of death, the seriousness of thissituation appears to be underestimated in clinicalpractice [1,2].We report a case of severe hyperphosphataemiaafter kidney transplantation induced by phosphate-containing enemas resulting in fatal calcifications.Case reportA 64-year-old woman with end-stage renal failure dueto analgesic nephropathy had been on chronicperitoneal dialysis for 18 months. Several years ago,gastrectomy, oesophagojejunostomy and splenectomywere performed because of a perforated gastriculcer. Secondary hyperparathyroidism was treated bycalcium-containing phosphate binders and calcitriol.During the course of peritoneal dialysis, intact para-thyroid hormone levels were decreased from 804 pg/mlto 82 pg/ml. The calcium–phosphate molar productwas never higher than 56.5mg2/dl2 (4.5mmol2/l2).Besides dialysis with disturbed calcium phosphatebalance, hypertension and a history of smoking existedas cardiovascular risk factors. However, the patient’smedical history was free from ischaemic vascularevents. Dobutamine stress echocardiography revealedno cardiac ischaemia, and duplex sonography showedno stenosis of the pelvic vessels. The patient received akidney graft from a marginal donor with a history ofhypertension and a prolonged warm ischaemia time.The renal artery of the graft was arteriosclerotic. Theoperative procedure was uneventful and no severe orprolonged episode of hypotension occurred. However,colouration of the graft from livid to rosy wasdecelerated. The index biopsy revealed signs ofmoderate arteriolar hyalinosis and interstitial fibrosis.The induction immunosuppression consisted of basi-liximab (20mg i.v. on days 0 and 4) combined withmethylprednisolone (1000, 500 and 250mg on days 0, 1and 2–4, respectively), ciclosporin from day 4 on(dosage adapted to serum drug levels from 250 to350 mg/l), mycophenolate mofetil (1000mg orally twicea day), and prednisone (125mg/day from day 5 withtapering to 20mg). Due to primary non-function,haemodialysis was started on day 1. Duplex ultrasoundshowed a normal arterial flow and an accelerated flowof the renal vein in the area of crossing the renal artery.On the same day, a phosphate-based enema wasadministered to stimulate bowel activity. During thefollowing night, severe hyperphosphataemia of17.1mg/dl (5.55mmol/l) developed, with a concomi-tant fall in serum calcium from 9.96mg/dl to 8.63mg/dl (2.48–2.15mmol/l) and a calcium–phosphate molarproduct of 147mg2/dl2 (12mmol2/l2). The episode ofhyperphosphataemia was accompanied by hypotension(blood pressure 93/55mmHg) and liver enzymesincreased dramatically: aspartate aminotransferase6666U/l, alanine aminotransferase 2096U/l andlactate dehydrogenase of 6804U/l (Figure 1). Duplexsonography of the kidney showed the same patternas the day before. Computed tomography of theCorrespondence and offprint requests to: Michael Mayr, MD,Division of Transplantation Immunology and Nephrology,University Hospital Basel, Petersgraben 4, 4031 Basel,Switzerland. Email: mmayr@uhbs.chNephrol Dial Transplant (2006) 21: 2013–2016doi:10.1093/ndt/gfl284Advance Access publication 30 May 2006 The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.orgabdomen revealed extensive lesions in the livercompatible with ischaemic or drug-induced tissuedamage. Further, generalized atherosclerosis, includingthe mesenteric vessels, was seen. Mycophenolatemofetil was stopped, as a potential causative agent ofdrug-induced liver failure. Immediately, an additionalhaemodialysis was performed to remove phosphate.After dialysis, phosphate levels decreased andremained in a range from 3.46 to 8.48mg/dl (1.12–2.74mmol/l). The liver enzymes returned to normallevels within 7 days. Nevertheless, the patient’scondition continued to deteriorate and she becamedelirious. The abdomen remained distended withoutany signs of bowel activity. During the weekend (onday 6), unaware of the severe hyperphosphataemia onday 2, two more phosphate-containing enemas wereinstilled. Again, an increase of the serum phosphateto 13.25mg/dl (4.28mmol/l) and a decrease in serumcalcium from 9.4mg/dl to 8.0mg/dl (2.34–1.99mmol/l)with a calcium–phosphate molar product of 106mg2/dl2(8.5mmol2/l2) was observed. The general conditionof the patient worsened and the kidney graft remainednon-functioning. On day 9, explorative surgeryrevealed a dark blue kidney and a transplant nephrect-omy was performed. Histologically, thrombosis ofthe renal vein and a partial thrombosis of the arterywere found. The completely necrotic organ showedmassive nephrocalcinosis. After graft nephrectomy, thepatient’s condition improved only slightly. However,on day 15 the patient suffered from feculent vomiting.Laparotomy revealed a necrotic colon and pancreas.Hemicolectomy, cholecystectomy and peripancreaticnecrosectomy were performed. Thirteen days later,despite repeated second-look operations with debride-ments and broad-spectrum antibiotics, the patientdeveloped septic shock and died of multiple organfailure.The histology of the colon, rectum and gall bladderrevealed severe calcifications of small and medium-sized arteries and veins and regions of superficial andtransmural necrosis with calcifications. Intimal pro-liferation, endovascular fibrosis and thrombosis of thevessels were not found. In the liver, an infarct of 8 cmwith parenchymal calcifications and multiple haemo-rrhagic infarcts (up to 4 4 8 cm) were present. Theperipheral and central veins within the infarcted areasrevealed subacute thromboses. The pancreas presenteda pattern of subacute pancreatitis and subacute,partly organized thromboses of small peripancreaticveins. In conclusion, severe dystrophic calcifications inliver, colon, rectum, gall bladder and the kidney graftin a patient with pre-existing generalized athero- andarteriolosclerosis were diagnosed. Brain, lung and skinshowed no calcifications at all.DiscussionSince the clinical trial of Vanner et al. [3] in 1990,sodium phosphate preparations have been widelyprescribed as a safe and well-tolerated colonic cleans-ing agent. They are, however, not recommended forFig. 1. Course of disease, x-axis: days after transplantation, y-axis: phosphate mg/dl (black triangle; asterisk: phosphate after first dialysissession), calcium mg/dl (open triangle), aspartate aminotransferase U/l 1000 (open circle). NOTE: To convert serum phosphate in milligramper decilitre to millimole per litre, multiply by 0.323; serum calcium in milligram per decilitre to millimole per litre, multiply by 0.250.2014 J. Eckstein et al.patients with impaired renal function. In cases ofrenal insufficiency, the development of severe, life-threatening hyperphosphataemia with concomitanthypocalcaemia has been described. This observationis documented in several case series. Fass et al. [1]summarized 28 cases. The patients were between4 months and 81 years old. All of them received aphosphate-based cathartic, most of them rectally. Theadministered doses varied between 65 and 690ml(mostly Fleet Phospo-Soda containing 15.4 g elementalphosphate per 120ml). The observed increase in serumphosphate varied between 4.3mg/dl (1.38mmol/l) and67mg/dl (21.6mmol/l). Pre-disposing factors forhyperphosphataemia in adults were chronic constipa-tion, ileus, excessive enema use and renal insufficiency.In five cases the outcome was poor, including braindamage, cardiac arrest, coma and death in twocases [1]. The reported mortality rate in cases ofsevere hyperphosphataemia due to phosphate admin-istration (rectally and orally) is about 33% (four of 12patients) [4]. Recently, Markowitz et al. [5] reported 21cases of acute renal failure following oral sodiumphosphate bowel cleansing. The most distinctivefinding in all cases was abundant calcium phosphatedeposits in distal tubules and collecting ducts. Themean baseline creatinine was 1.0mg/dl [range 0.6–1.7mg/dl (53–150 mmol/l)]. The renal outcome waspoor, all patients developed chronic renal insufficiencywith a mean serum creatinine of 2.4mg/dl [range1.3–3.4mg/dL (115–300 mmol/l)] and four of themrequired chronic haemodialysis.Under normal conditions, up to 20% of thephosphate in enemas is resorbed [6]. On day 1 aftertransplantation, our patient received Practo-Clyss120ml containing 2.9 g disodium hydrogenphosphate(20.3mmol) and 14.8 g sodium dihydrogenphosphate(122.8mmol). The volume of phosphate distribution isnot fixed and depends greatly on cellular and boneuptake. Therefore, only a simple calculation is neededto show that a moderate increase in phosphate absorp-tion may be sufficient to cause severe hyperphos-phataemia, especially if the renal excretion ofphosphate is disturbed. In our patient, assuming anextracellular volume of 12 litre, only about 53mmol ofphosphate had to be absorbed to increase the serumphosphate from 3.3mg/dl (1.06mmol/l) to 17.1mg/dl(5.55mmol/l) as observed on day 1.Hebert et al. [7] showed that the administeredphosphate lowers serum calcium by physiochemicalprecipitation of CaHPO4 as its solubility product isexceeded. In three of their patients, even calciumdeposits could be radiologically explored in the vein inwhich phosphate was infused [7]. Otherwise, as shownalready in 1932 by Albright et al. [8], phosphateadministered to hypercalcaemic patients might result insoft tissue calcification. Clinically, it is very importantat which site the CaHPO4 precipitation occurs.As discussed by Floege et al. [9], the differentpathogenetic pathways of vascular, valvular, organand soft tissue calcifications in uraemic patients arecomplex. Besides passive precipitation, due to anexcessive calcium phosphate product, active cellularprocesses, systemic or local deficiency of inhibitoryfactors to prevent precipitation and the local milieumay be important factors in the different pathogenesisof calcifications [9]. Haldimann et al. [10] studied theeffect of Practo-Clyss 120ml in two volunteers withrenal insufficiency. Similar to our patient, one of themwas a patient with non-functioning graft and bowelmotility 2 days after renal transplantation [10]. As withour case, they saw an increase of serum phosphate witha decrease of serum calcium, strongly suggestingCaHPO4 precipitation. However, in our patient, theincautious administration resulted in a catastrophe.The hyperphosphataemia was accompanied by hypo-tension and, given the pre-existing mesenteric athero-and arteriolosclerosis, led to ischaemia in visceralorgans. Subsequently, phosphate overload and a highserum calcium phosphate product caused severedystrophic calcifications. Especially, the sharp anddramatic increase in liver enzymes and the liver infarctswith calcifications may have been caused by hypoper-fusion with subsequent dystrophic calcifications.The same mechanism of hypoperfusion and ischaemiamay explain the extended calcifications in the pre-damaged graft of a marginal donor.This is, to our knowledge, the first published caseproven by autopsy, in which enema-induced hyper-phosphataemia led to disseminated dystrophic calcifi-cations in virtually all visceral organs. Despite twohaemodialysis sessions within 12 h to eliminate thephosphate, the process of calcification could not bereversed.To know more about the use of phosphate-basedbowel preps in the post-operative period of kidneytransplantation, we performed a survey in 70 centres inthe Eurotransplant area and in Swisstransplant. Theresponse rate was 50% (35 centres). In 16 centres(46%), phosphate-containing enemas are never used.In 8 centres (23%), phosphate-containing preps are notused in the immediate post-transplantation period.Seven of them restrict the use of phosphate-containingpreps to a functioning graft, whereas the proposedcut-off defining a functioning graft (expressed byserum creatinine or creatinine clearance) varies widely[serum creatinine less than 300mmol/l to 150mmol/l(3.4–1.6mg/dl); creatinine clearance more than20–40ml/min]. In 11 centres (31%), phosphate-basedenemas are prescribed in the post-operative period, ofwhich 10 centres (28%) use it without restriction forfunctioning grafts and one centre limits its use tonormal serum phosphate levels. In summary, nearlyone-third of the centres which replied, use phosphate-based preps without restriction to functioning graft.The following conclusions can be drawn. First,the potential seriousness of the adverse effects ofphosphate-based preps may still be underestimated,especially in the early post-operative period in kidneytransplantation. Second, there exists no clear creatininecut-off which permits the safe application ofphosphate-based preps. It should be noted that in theafore-mentioned study of Markowitz et al. [5] most ofExtensive calcifications induced by phosphate-based enemas 2015the patients had a baseline serum creatinine within thenormal range.In conclusion, it is hazardous to administerphosphate-based enemas in patients with renal insuffi-ciency, especially in patients with a risk of increasedretention due to atonic bowel or faecal impaction.In the early post-operative period of kidney transplan-tation, the administration of phosphate-based enemasis contraindicated.Acknowledgements. The authors thank Michael J. Mihatsch(Institute for Pathology) for the helpful discussion.Conflict of interest statement. None declared.References1. Fass R, Do S, Hixson LJ. Fatal hyperphosphatemia followingFleet Phospo-Soda in a patient with colonic ileus. Am JGastroenterol 1993; 88: 929–9322. Korzets A, Dicker D, Chaimoff C, Zevin D. Life-threateninghyperphosphatemia and hypocalcemic tetany following the use offleet enemas. J Am Geriatr Soc 1992; 40: 620–6213. Vanner SJ, MacDonald PH, Paterson WG et al. A randomizedprospective trial comparing oral sodium phosphate withstandard polyethylene glycol-based lavage solution (Golytely)in the preparation of patients for colonoscopy. Am JGastroenterol 1990; 85: 422–4274. Fine A, Patterson J. Severe hyperphosphatemia followingphosphate administration for bowel preparation in patientswith renal failure: two cases and a review of the literature. Am JKidney Dis 1997; 29: 103–1055. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD.Acute phosphate nephropathy following oral sodium phosphatebowel purgative: an underrecognized cause of chronic renalfailure. J Am Soc Nephrol 2005; 16: 3389–33966. Martindale the complete drug reference. Parmaceutical press,London, UK, 2004.7. Hebert LA, Lemann J, Jr, Petersen JR, Lennon EJ. Studies ofthe mechanism by which phosphate infusion lowers serumcalcium concentration. J Clin Invest 1966; 45: 1886–18948. Albright F, Bauer W, Claflin D, Cockrill JR. Studies inparathyroid physiology.III.The effect of phosphate ingestion inclinical hyperparathyroidism. J Clin Invest 1932; 11: 4119. Floege J. When man turns to stone: extraosseous calcification inuremic patients. Kidney Int 2004; 65: 2447–246210. Haldimann B, Vogt K. Hyperphosphatemia and tetanyfollowing phosphate enema. Schweiz Med Wochenschr 1983;113: 1231–1233Received for publication: 2.12.04Accepted in revised form: 25.4.062016 J. Eckstein et al.

Extensive calcifications induced by hyperphosphataemia caused by phosphate-based enema in a patient after kidney transplantation

Extensive calcifications induced by hyperphosphataemia caused by phosphate-based enema in a patient after kidney transplantation

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