Introduction
For most American Society of Nephrology (ASN) Kidney Week attendees, case-based clinical nephrology talks are one of the most exciting venues. The Nephrology Quiz and Questionnaire (NQQ) is the essence of clinical nephrology and represents what drew all of us into the field of nephrology. This year’s NQQ in surprisingly temperate Chicago, with full-house attendance, was no exception. The expert discussants prepared vignettes of puzzling cases, which illustrated some topical, challenging, or controversial aspect of the diagnosis or management of key clinical areas of nephrology. These eight interesting cases were presented and eloquently discussed by our four expert ASN faculty. Subsequently, each discussant prepared a manuscript summarizing his or her case discussions, which serves as the main text of this article. (Mark A. Perazella and Michael Choi, Comoderators)
Case
A 35-year-old woman who underwent a kidney–pancreas transplant for ESRD secondary to diabetic nephropathy 7 years ago presented with 2 months of diarrhea. Diabetic complications before transplant included retinopathy, nephropathy, mild autonomic neuropathy, and gastroparesis. She also had hypertension and chronic headaches.
Initial immunotherapy included induction with thymoglobulin and intravenous high-dose methylprednisolone followed by maintenance therapy with prednisone (dose tapered to 5 mg by 3 months), tacrolimus (maintenance at 8–10 ng/ml), and mycophenolate mofetil (MMF; 1000 mg twice daily). She was positive for cytomegalovirus (CMV) and Epstein–Barr virus IgG before transplant and received 3 months of CMV prophylaxis with valganciclovir.
Because of early issues with nausea and epigastric distress, her MMF dosage was changed to from 1000 mg twice daily to 500 mg four times daily, with relief of symptoms. Her baseline serum creatinine was 1.1–1.3 mg/dl, and her tacrolimus level was 7–8 ng/ml. Blood glucose and lipase levels, laboratory tests used to monitor her pancreas transplant, remained normal and she remained off insulin therapy.
Two months before her current presentation, she began having loose bowel movements with no other symptoms of pain, nausea, vomiting, fever, or chills. There was no travel history nor had she taken any new medications. No family members had similar symptoms. Her stool samples were negative for bacterial pathogens, Giardia, Clostridia difficile toxin, norovirus, and adenovirus. Because of her persistent diarrhea, a computed tomography scan with oral contrast was performed and the results were normal. Further reduction in MMF dosage to 500 mg twice daily did not improve her diarrhea. Currently, she has five to six loose bowel movements per day and has lost 10 lbs.
Her current medications are prednisone 5 mg daily; tacrolimus 3 mg twice daily; MMF 500 mg twice daily; telmisartan/hydrochlorothiazide 40/25 mg daily; famotidine 20 mg daily; rosuvastatin 10 mg Monday, Wednesday, and Friday; and aspirin 81 mg daily.
She was afebrile and had a 10-mm orthostatic drop in systolic BP. Her physical examination was otherwise normal, including a nontender abdomen.
Laboratory data revealed a slight elevation in creatinine (from 1.5 to 1.2 mg/dl), thought to be because of volume contraction. Her bicarbonate (18 mEq/L) and potassium (3.5 mEq/L) levels were depressed and her tacrolimus levels elevated from baseline (from 7 to 13 ng/dl), as expected with diarrhea. Her white blood cell count was 4.4 cells/mm3, hemoglobin was 12 g/dl, and hematocrit was 37%. A colonoscopy is planned.
Question 1
On the Basis of the Clinical and Laboratory Data, Which Is the Most Likely Explanation for Her Diarrhea?
Diabetic enteropathy
Mycophenolate toxicity
CMV colitis
Lymphoma
Discussion
The correct answer is “B,” mycophenolate toxicity. Diarrhea in long-term recipients of kidney or kidney–pancreas transplants can be because of infectious causes, drug causes, malignancy, and metabolic causes, such as diabetic enteropathy (Table 1). Common infectious causes include CMV colitis, Clostridium difficile colitis, and norovirus infections, as well as bacterial, parasitic, and fungal organisms (1,2). Drug causes are also common, with mycophenolic acid (MPA) being the most common. Malignancy and metabolic causes must also be considered. It is critical to have a reliable laboratory to identify not only common pathogens but also viruses, especially norovirus, which is common and may be severe and not self-limited in organ recipients (3).
Common causes of diarrhea in a long-term recipient of kidney or kidney–pancreas transplant
In this patient, tests for viral, bacterial, and parasitic pathogens and C. difficile toxin were negative. Although CMV colitis can occur at any time after transplant, it is more common in the early (1–2 years) post-transplant period and in patients who are seronegative receiving a seropositive CMV kidney (unlike this patient), and it would be unusual to persist for 2 months without fever and leukopenia (4). Lymphoma is always a possibility but the absence of abdominal pain or findings on computed tomography scan make this diagnosis less likely. Diabetic enteropathy is not usually associated with significant weight loss and would be unusual in a recipient with no previous enteropathy symptoms, who is now 7 years post-transplant.
Subsequent blood tests (CMV and Epstein–Barr virus PCR) and lactate dehydrogenase provided more evidence against CMV and lymphoma as etiologies. A colonoscopy is performed and the results are negative.
Question 2
Which Is the Best Treatment for This Patient?
Start loperamide
Lower mycophenolate dose
Discontinue mycophenolate and maintain on tacrolimus and prednisone
Switch mycophenolate to azathioprine
Discussion
The correct answer is “D,” switch from mycophenolate to azathioprine. Starting loperamide would not get at the proximal cause. Further reduction in MMF dosage (to 250 mg twice daily) or stopping it without adding azathioprine could leave her underimmunosuppressed, especially as a recipient of a pancreas transplant. Discontinuing MMF when a 50% reduction in drug dose does not yield resolution, and substituting azathioprine is the approach recommended in a recent review of severe diarrhea in recipients of kidney transplant (1). This was done and within weeks her diarrhea had subsided. Within a month, she gained back much of the weight she had lost.
MPA is an antimetabolite that reversibly inhibits the inosine monophosphate dehydrogenase pathway needed for purine synthesis. Activated B and T lymphocytes depend on this pathway for de novo synthesis of purine nucleotides because they lack a salvage pathway for this process. Thus, MPA is ideal for inhibiting lymphocyte proliferation. Because it is poorly absorbed, MPA is available as two prodrugs, MMF (Cellcept) and mycophenolate sodium (Myfortic). Both drugs are converted to MPA to exert their biologic effect. For the remainder of this discussion, we will use the term MPA instead of MMF or mycophenolate sodium. MPA has largely replaced azathioprine in the prevention of rejection in most United States transplant centers and is recommended as the antimetabolite of choice in Kidney Disease Improving Global Outcomes Guidelines (5). It is also used to treat lupus nephritis, membranous glomerulopathy, psoriasis, and autoimmune disorders. Although it has been demonstrated to reduce rejections more than azathioprine in cyclosporine-treated transplant recipients, it causes more gastrointestinal symptoms, including diarrhea (6).
Most diarrhea with MPA occurs early after transplant (7) and may respond to a reduction in dose. Tacrolimus can also cause diarrhea but MPA is a more common culprit. Caution must be exercised when reducing or discontinuing MPA dose, as this has been associated with rejection and decreased allograft survival (8).
The incidence of severe diarrhea occurring later, after the initial period of MPA introduction, and associated with significant weight loss and malabsorption may be a distinct entity. Patients have been reported as presenting with diarrhea, weight loss, and malabsorption and subsequently, villous atrophy of the small bowel is demonstrated with duodenal biopsy or capsule endoscopy (9,10). Other patients have been reported with colitis found on colonoscopy and pathology demonstrating lesions similar to Crohn disease, graft versus host disease, or ischemic lesions (11–13). Cases have been most commonly described in recipients of kidney transplant but have also been reported in other solid organ transplants (13), as well as patients with autoimmune disease. Although the mechanism of these lesions is not completely understood, the presence of crypt atrophy, abscesses, and apoptosis in the lesions has led to the hypothesis that apoptotic cell death may be a pathogenic factor in the mucosal injury (12). Whether this is because of direct drug toxicity or an immune effect is not clear. It is also not clear whether this mechanism of intestinal epithelial cell injury plays any role in diarrhea observed when MPA is initially introduced, and which often responds to a dose reduction.
Many patients with reported cases of severe diarrhea and malabsorption have described the need for drug discontinuation to relieve symptoms (9,14). This is why it is important to recognize the entity of MPA colitis or small intestinal villous atrophy as an entity. It has been speculated that that some of the previously described cases of this entity could be undiagnosed norovirus infection (1), but further study is needed to determine whether this is true. This was not the case with our patient, as norovirus was not detected. There does not seem to be a correlation between MPA blood level and diarrhea (15). Although a few case reports have described improvement by switching to enteric-coated MPA (10), one would not expect this result to be common as the effects of MMF and enteric-coated mycophenolate in the small intestine and colon are similar.
In summary, when severe diarrhea occurs in a recipient of a kidney or kidney–pancreas transplant, the most common infectious causes must first be excluded (1–3,13). Viruses, especially norovirus, need to be looked for, as this infection is becoming increasingly appreciated as a cause of severe, chronic diarrhea, requiring a reduction or change in immunosuppression to achieve resolution (1,3). Colonoscopy with biopsies should always be performed when an initial evaluation is negative, to look for colitis and to exclude CMV colitis and lymphoma. CMV gastrointestinal involvement may occur in the absence of CMV viremia. When infectious causes are excluded with reliable testing, one needs to consider the entity of MPA-induced colitis or small intestinal villous atrophy. The diarrhea and associated malabsorption in such cases often requires complete discontinuation of the drug, with the substitution of azathioprine in most patients to reduce the risk of rejection.
Disclosures
None.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
- Copyright © 2017 by the American Society of Nephrology