Acute Renal Failure in a Patient with Crohn’s Disease

by Vincent M. Brandenburg, MD (1)
Marie-Luise Berres, MD (2)

Department of Nephrology (1),
Department of Gastroenterology (2)
University Hospital Aachen,
Germany

Corresponding author:

Vincent M. Brandenburg, MD
Department of Nephrology & Clinical Immunology
University Hospital Aachen
Pauwelsstraße 30
D-52057 Aachen
Germany

Phone: 0049 – 241 – 8036072
FAX: 0049 – 241 – 8082446

Email: Vincent.Brandenburg@post.rwth-aachen.de

Case Vignette:
A 50-year old woman was admitted to our hospital with acute renal failure.

Serum creatinine levels had been normal 6,5 months ago, calculated GFR was 65 ml/min at that time. In her late twenties Crohn’s disease had been diagnosed. In the past few years the patient has developed chronic relapsing disease. At the time of admission she had been treated with 20 mg prednisolone per day for 2 months (monotherapy). Eight days before admission the patient started preparing for colonoscopy with 2 bottles of Fleet® Phospho-soda. Colonoscopy was scheduled due to increasing abdominal pain and the re-onset of diarrhea. The examination revealed signs of acute exacerbation. Four days before admission she started feeling generalized malaise and discomfort. Two days later she noticed mild ankle edema. On the day of admission she experienced tetany (left carpopedal spasm). She was on a normal Western diet.

Question 1) - What are the possible causes of acute kidney injury or chronic kidney disease in a patient with Crohn’s disease? (Only ONE answer is correct)
>	a) Administration of 5-aminosalicylic acid.
>	b) Renal amyloidosis.
>	c) Dehydration, infection, septicemia in severe courses.
>	d) Phosphate overload following oral sodium phosphate bowel cleansing.
>	e) All of the above.
<% if Answer1 = RightAnswer1 then Response.Write " Answer to question n. 1 is right! " else Response.Write " Answer to question n. 1 is wrong! " Response.Write " The right answer is the checked one! " end if %> The administration of 5-aminosalicylic acid may be associated with the development of interstitial nephritis in patients with colitis (1). Rash, fever, eosinophilia, and eosinophiluria are typical signs several days or weeks after the administration of a causative drug. However, the present patient had not received mesalazine or sulfasalazine and signs of hypersensitivity reactions were absent. In long-lasting, chronic relapsing Crohn’s disease systemic amyloidosis may develop based on the chronic inflammatory state (SAA-amyloidosis) (2). Of course, severe or fatal bursts of the disease may end up with acute kidney injury due to dehydration, infection and septicemia. The administration of oral sodium phosphate bowel cleansing (oral sodium phosphosoda, OPS) is an increasingly recognized cause for acute hyperphosphatemia with several potentially fatal sequelae (please refer to question 2) (3,4). Acute kidney failure may be among them. In the outpatient setting, it is clearly recommended to use oral sodium phosphate bowel cleansing only with high amounts of oral fluid intake. National drug safety guidelines recommend the intake of additional 1700 ml of clear liquid / water during the last 24 hrs prior to colonoscopy, if bowel preparation with two bottles of Fleet® Phospho-soda is scheduled. Each 45 ml bottle of Fleet® Phospho-soda contains 24.4g Natriumdihydrogenphosphat-2H2O and 10.8 g Natriummonohydrogenphosphat-12H2O. OPS contain about approximately six times the average daily phosphate intake (5). <% newID = 2 else newID = 11 %>

Question 2) - Which of the following findings supports the hypothesis that phosphate intoxication might be the cause of the acute renal failure in the present patient? (Only ONE answer is correct)
>	a) 0.15 g proteinuria per day
>	b) Blood pressure 175/95 mmHg
>	c) Absence of eosinophilia
>	d) Hypocalcemia with tetany
>	e) Nephrocalcinosis
>	f) Negative findings for ANCA and ANA
>	g) Absence of dysmorphic erythrocytes and casts in the urinary sediment
>	h) All of the above
<% if Answer2 = RightAnswer2 then Response.Write " Answer to question n. 2 is right! " else Response.Write " Answer to question n. 2 is wrong! " end if %> The correct answer is h): All of the above-mentioned findings support the presumed diagnosis of acute kidney injury due to Fleet phospho-soda ingestion. Renal amyloidosis typically presents with large proteinuria (>> 1.0 g/day) and potentially overt nephrotic syndrome. Blood pressure is typically low in amyloidotic renal disease. Eosinophilia und eosinophiluria may be diagnostic for interstitial nephritis. The findings of the present patient therefore did not support renal amyloidal or interstitial nephritis. In contrast, severe hyperphosphatemia and pronounced hypocalcemia are typical for phosphate intoxication and consecutive acute renal failure. While tetany due to hypocalcemia is rarely seen in chronic renal failure patients, it is a typical finding in patients with acute phosphate overload. Proteinuria is mild (< 600mg/day in (4)). A combination of phosphate intoxication and a volume-depleted state (diarrhea) may be the most accurate explanation for the development of the renal failure in the case vignette. A relative hypokalemia is also a common finding in patients treated with OPS (6). ACE-inhibitors are accused of aggravating the risk of acute renal failure related to OPS (4,5). It appears advisable to pause ACE-inhibitors or ARB if possible or to switch to polyethylene glycol based purgatives. Female gender is another risk factor (4). Renal failure was oliguric in the present patient (800ml/day). In the present case hypocalcemia was probably aggravated by a severe vitamin D deficiency (calcidiol 7µg/L at presentation), that was interpreted as a consequence of Crohn’s disease. The QTc time was 490 msec. We started i.v. calcium substitution and signs of tetany rapidly resolved. Due to worsening of renal failure we initiated hemodialysis treatment on day 2 and performed 3 sessions until day 4. Renal ultrasound showed nephrocalcinosis with normal kidney size. Hyperphosphatemia –related findings in patients after oral sodium phosphate bowel cleansing may present in two particular patterns (7): Acute hydroelectrolytic abnormalities with lethargy, seizure, confusion, tetany hours or days after OPS administration or a more prolonged course where renal failure after days to weeks with nephrocalcinosis is the predominant finding. <% newID = 3 else newID = 22 %>

Question 3) - Which of the following statements concerning phosphate metabolism is NOT true? (Only ONE answer is correct)
>	a) Mean daily oral intake of phosphate is about 1500mg in western countries.
>	b) A group of sodium-phosphate-cotransporters regulates intestinal uptake, as well as renal excretion of phosphate.
>	c) PTH, calcitriol, and the “phosphatonins” are main regulators of phosphate metabolism.
>	d) The phosphatonins increase renal phosphate absorption.
<% if Answer3 = RightAnswer3 then Response.Write " Answer to question n. 3 is right! " else Response.Write " Answer to question n. 3 is wrong! " end if %> The correct answer is d): The phosphatonins including FGF23 decrease (not increase) the renal phosphate absorption and lead to hypophosphatemia and renal phosphate wasting. Disease conditions, in which the biological action of phosphatonins in increased (increased synthesis, reduced degradation) are characterized by renal phosphate wasting and osteomalacia (8). <% newID = 4 else newID = 33 %>

The clinical course of our patient was satisfactory. Renal function recovered to normal urinary output within four days. S-creatinine levels slowly decreased and were normal 3 months later. This complete remission is exceptional: In a large case series 4/21 patients developed ESRD and the remaining 17/21 recovered but all exhibited CKD after a mean of 17 months of follow-up.



Nephrocalcinosis was no longer detectable on ultrasonography three months later.
A recent case control study could not prove an increase in the risk of developing renal failure in patients prepared for endoscopy with OPS (5). However, renal failure was defined as an increase in S-creatinine within 6 months after endoscopy. Our case report highlights the fact that even severe renal failure requiring dialysis may resolve completely and that within 3 months S-creatinine levels may decrease to normal levels. Therefore, a prospective short-term plus long-term follow-up study is required in order to assess the true dimension of the problem.

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Question 4) - What is incorrect? Hyperphosphatemia may be caused by ... (Only ONE answer is correct)
>	a) oral intake of dietary phosphate in patients with normal renal function.
>	b) concomitant Vitamin D therapy.
>	c) ketoacidosis.
>	d) inadequate parenteral nutrition.
>	e) chemotherapy / tumor-lysis syndrome.
>	f) hemolytic anemia.
>	g) rhabdomyolysis.
>	h) laboratory errors in patients with multiple myeloma.
<% if Answer4 = RightAnswer4 then Response.Write " Answer to question n. 4 is right! " else Response.Write " Answer to question n. 4 is wrong! " Response.Write " The right answer is the checked one! " end if %> Hyperphosphatemia is an every-day finding in patients with renal failure or CKD. In contrast, in patients with normal renal function, the renal excretory mechanisms of phosphate are effective and prevent the development of overt hyperphosphatemia. The mechanism is reducing the amount of phosphate reabsorption in the proximal tubular cells. Interestingly, there is an gastrointestinal-kidney regulatory axis by which high amounts of nutritional phosphate in the gut increase renal phosphate excretion already before absorption into the circulation has occurred (9). Therefore, overt hyperphosphatemia by increased oral intake virtually never develops in patients with normal renal function. In the present case mild renal insufficiency has most likely contributed to the development of the syndrome. There is a rare cause for hyperphosphatemia in patients with plasmocytoma: Serum phosphate may be spuriously elevated due to interactions between colorimetric assays for phosphate measurements and the high concentration of paraproteins (10). <% newID = 5 else newID = 44 %>