4. A 56-year-old CKD 5 received a kidney transplant from his wife with a 122 mismatch and no DSAs. He is on triple immunosuppression (cyclosporine 150 mg BD, Mycophenolate Mofetil 1gm BD and prednisolone 10 mg OD). His baseline S Cr is 123 µmol/L. He suffers from gouty arthritis with infrequent flare up (one attack/year). He is currently on allopurinol 100 mg BD. One month after transplantation, his started to develop watery diarrhoea (4 times daily). Stool culture and colonoscopy are normal
- What is your management plan?
IV hydration, check for causes of post TX diarrhea such as:
CMV, rotavirus, norvovirus, C. difficil, cryptosporidium, giardia , E.Coli and other infections
Drugs: MMF, tacrolimus, sirolimus, PPIs
others: PTLD, Colon cancer, IBD
Monitoring CNI level
Specific treatment based on etiology such as: Metronidazole for giardiosis
IVI ,good hydration , FU KFT , Do CNI trough level , decrease dose of MMF by 25% , CMV PCR , exclude causes of infectious diarrhea.
Diarrhea post transplant may be due to infectious causes or non-infectious causes
infectious due to CMV, Clostridium difficile colitis and Norovirus
NON infectious secondary to drugs as MMF
lab studies : C.Diff toxin CMV PCR, stool culture ( enteric pathogen . faecal lactoferrin and stool ova, cysts and parasites
discontinue non essential drugs
colonscopy with biopsies
25% to 50% MMF dose reduction
CNI dose adjustment
C Diff : Metronidazole or vancomycin
CMV : Ganciclovir
Enquire further history. Travel history , dietary history, high risk behavior history.
Clinical examinations : Look for other systemic manifestation of CMV infection, Tuberculosis. Features of CNI toxicity.
Investigations:
Full blood count, electrolytes, Renal Profile, Liver function test. Uric acid. Infective markers CRP. Blood and stool culture. Urine microscopy.
TDM for CSA. TB screening.
Management plan
Admit to isolation room.
IV hydration as per clinical status.
Antimicrobial if evidence of infective diarrhea.
Valganciclovir if evidence of CMV infection.
Sick day advice for chronic oral steroid. change oral prednisolone to IV hydrocortisone 50mg TDS.
Dose adjustment for allopurinol according to e GFR.
Adjustment of immunosuppressants base on local guidelines. I would consider switching CSA to Tacrolimus. Reduction of MMF dose.
Low purine diet.
causes like:
1- drugs related to MMF or CsA so drug level needed
2- infection either bacteria or viral or protozoa
CMV is important to exclude as he is one-month post-transplant.
stool for examination and culture or PCR for viral causes
CBC, CRP, URIC Acid level
may need colonoscopy with biopsies
I will change CsA to Tac
change MMF to myfortic
last choice;
if he does not improve
azathioprine in 50% low usual dose can be given with close monitoring of WBCs
because a combination of Azathioprine with allopurinol carries a high risk of severe bone marrow suppression which is serious toxicity
Allopurinol is a CYP3A inhibitor, hence affecting CNI and MMF metabolism.
Managing such patient will include:
Early diarrhoea post-renal transplant (within first 3 months) is common and is hazardous to the patient life and graft survival because he is usually heavily immunosuppressed in this early period, so it is important to take as serious as possible.
Firstly: ensure proper clinical assessment and examination ABC pathway, think about potential possible causes especially opportunistic infection like bacteria (E.coli, C.dificle, C.jejuni), Viral (CMV, other gastroenteritis viruses), Parasitic.
Secondly; IS drugs like MMF, Tacrolimus, m.TOR inhibitors, Laxatives, Colchicine.
Others like graft VS host disease, IBD, GIT malignancy, and DM.
Maintain well hydration, keep an eye on electrolytes and correct if disturbed.
Monitor vital signs, UOP, input/output chart, daily body weight, stool chart, daily renal function tests and electrolytes.
Routine blood investigations like FBC, LFT, CRP, electrolytes blood sugar.
Monitor IS drug level especially CNI which usually be high with diarrhoea.
Investigations for the above-mentioned DD especially virology (CMV) and stool analysis and culture and C.difficle and other pathogens.
Hold MMF, it can be switched to Mycophenolic acid sodium (less GIT upset) or it can be switched to Azathioprine (however in this patient you should take care as he is on Allopurinol.
Management is to modified according to the results of above requested investigations
This is a common scenario in our practice.
A detailed history is important, it can help in diagonsi and complications of this chronic diarrhea. So ask about presence of fever is significant.
Good examinatin and assess the degree of patient hydration with the vital signs to decide indications for admission.
Other investigations like cyclosporin level, CBC, LFT, renal function test, stool analysis and even CT abdomen might be needed.
If infections, malignancy and lymphoproliferative disease are excluded we need to consider immunosuppressive drugs as causing diarrhea mainly MMF or Tac.
So reduce MMF dose, if not improved we can stop it and substitute with MPS.
Immuran can not be used instead of MMF unless allopurinol is stopped because of drug interaction
What is your management plan 1- adequate history taking ( fever , other non immune supresive medication, ..)
2- examination to assess the degree of dehydration ….
3- investigation ( case by case directed , GSE , STOOL FOR CULTURE AND SENSITIVITY, OTHER VARIABLE CAUSE ,
Keep in mind that cause of diarhea in kidney transplant is variable
1- non immune suppressive drug induced .
2- infectious cause
A -viral CMV (common) norovirus , rota virus ,adeno virus EBV (PTLPD ) .
B- bacterial cause – clostridia defficile , compylobacter , salmonella . ……
C- mycobacterial
D- Fungal – candida , a spergelosis ….
E- Protozoal giardiasis , amebiasis ..
3-immune suppressive drug induced ( MMF –commonly , EC MF- to lesser extent , cyclosporine .tacrolimus , sirolimus ..
In this patient
First to exclude non immune supresive drug cause which can be easly dealt with ( to stop it )
Later on to exclude infectious cause and treat accordingly
Lastly to modify the immune suppressive medication .
the common cause is MMF , splitting the dose in not beneficial , changing MMF to EC MFA usually is not successful but it can be tried . changing to azathioprine is contraindicated in this patient as there is sever drug drug interaction with allopurinol which may cause sever bone marrow suppression .
decreasing the dose to 1 gram or stop (with steroid dose increasing ) and restart with smaller dose is beneficial .
reference :
Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Curr Opin Nephrol Hypertens. 2017 Nov;26(6):484-493. doi: 10.1097/MNH.0000000000000368. PMID: 28863048.
full history and examination
Hospital admission
Good hydration with fluid chart
full investigations and correction of electrolyte imbalance .
Cyclosporin level ( trough and peak levels )
infection panel including viral , bacterial , protozoal causes of diarrhea ( CMV , PK , C.Difficille , giardiasis and cryptosporidium )
check uric acid level and stop allopurinol and start febuxostat if indicated
Stop any non immunosuppressive medication which may cause diarrhea such as ( PPI , H2 antagonist and oral hypoglycemic medications )
In case of dairrhoea one month post transplant, we need to explore infectious and noninfectious underlying causes like immunsuppression therapy like MMF, CNI; Tacrolimus ,cyclosporine .Diarrhoea could affect drug level of tac and cyclosporine ;drug level should be checked. Infective colitis causes like bacterial , viral ; rotavirus , adenovirus , CMV, fungal and protozoal cryptosporidiosis and C. difficile infection. Stool culture and parasitology testing and viral genome molecular testing are indicated . Tissue biopsy could be needed for CMV diagnosis.
Other drugs like PPI and magnesium supplementation can cause diarrhoea.
It could be favorable to switch from cyclosprine to tacrolimus with shift to mycophenolic sodium improve dairrhea . Azathioprine combination with allopurinol is associated with sever bone marrow suppression, hence should be avoided.
References:
Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Curr Opin Nephrol Hypertens. 2017 Nov;26(6):484-493.
Mazzali M. Uric acid and transplantation. Semin Nephrol. 2005 Jan;25(1):50-5. doi: 10.1016/j.semnephrol.2004.
4-Kanbay M, Akcay A, Huddam B, Usluogullari CA, Arat Z, Ozdemir FN, Haberal M. Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients. Transplant Proc. 2005 Sep;37(7):3119-20.
Management Plan:
Presence or Absence of Fever would be an important clue.
Ref: Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Curr Opin Nephrol Hypertens. 2017 Nov;26(6):484-493. doi: 10.1097/MNH.0000000000000368. PMID: 28863048.
Diarrhea is mainly due to CNI and MMF
Where diarrhea may cause CNI level disturbance which should be monitored regularly
And correct dehydration and electrolyte disturbance if present
CMV PCR and stool culture
Stopping MMF and immuran may be considered
Gout is common in cyclosporine regimens. this patient has arthritis despite prensiolone so we need to shift to tacroliömus (preferably), watery diarrhea can bee due to many reasons but itself causes uric acid increase to we to need hydration. adding colchicine low dose (not to exacerbate diarrhea), transiently lowering the dose of MMF..
Post transplant diarrhoea : more than 3 loose stools per day.
Malabsorptiin work up in case of chronic diarrhoea
Stopping allopurinol and giving febuxostat
First line microbiological investigations and may be CMV PCR
Optimization of immunosuppression:
Dose reduction of MMF or switching to EC-MPS if no response, withdraw and azathioprine to initiate to avoid inadequate immunosoppression .
General measures eg. hydration, hygiene
Post transplant diarrhoea decrease the quality of life, decreases graft survival and increases tac toxicity.
1.first look for nonimmunosuppressive drug like
allopurinol may cause diarrhoea, hence may
be changed to febuxostat.
2.treat dehydration and sent for stool re me
with pcr test of
viralpathogen(adeno,noro,cmv..)Giardia,
campylobacter,clostridium Difficle toxin and
treat for the same.
3.reduce dose of mmf 25%,not working change
to ec mmf,still not working change to tac and
special stance for cyclosporine and tac level
because during diarrhoea cyclosporine level
level decreases causing rejection and tac level
Increases causing tac toxicity.
4.If after all this endeavour diarrhoea still
persist then colonoscopy guided colonic
biopsy will tell the any other pathology like i
inflammatory bowel disease ,malabsorption
syndrome, malignancy,tb and though rare
very early ptld,cmv colitis.
first patient should be resuccitated with iv fluids to prevent dehydration ,thenstop any non immunesupressive medication that can cause diarrhoea as ppi oral antidiabetic drugs, allopurinol also could be acause of diarhoea by direct effect or drug combination with other immunesuppressive medications,
second test blood for cmv pcr bk virus and stool for bacterial or protozoeal cultures plus c defficille, giardiasis.
as mentioned above that stool and clonoscopy is normal:
so The cause may be drug-induced diarrhoea, especially with MMF, can be shifted to MMF-sodium enteric coated tablets. Adjustment of immunosuppressants to be considered and CNI dose adjustment. With note not to change MMF to azathioprine because the patient had gout and he is taking Allopurinol which has drug-drug reaction.
reply to dr ahmed halawa
CNI level increases during diarrheal episodes due to reduced transit time in gut and impaired cyt 450 enzyme activity. So CNI level should be measured during diarrhea to readjust the the dose of cni.
In the beginning we should check & correct any volume and electrolyte loss , then perform a microbiologic workup for diarrhea ( besides stool culture already done ) including microscopic stool exam , stool PCR , toxin testing
Review of medications that might be the cause of diarrhea like antibiotics , PPIs , avoiding or temporarily holding any agent that might cause further kidney harm like RAS blockers or NSAIDs ( which both classes can add to the harmful effect of CNI on glomerular filteration ) . also to consider MMF dose reduction , splitting the daily dose to tds or qds , or even to switch to the EC MPA ( Myyfortic ).
given the history of gout flares , it is better to consider switching cyclosporin to tacrolimus .
Management Plan:
Meticulous history regarding the frequency, consistency, fever, abd. Pain , vomiting , tenesmus , recurrence , blood in stool , worms in stool , drug history ( Colchicine ?) and assessment of the volemic status .
Cyclosporine trough level and peak level ( revision of the past recent levels as well and correlate, may be helpful ) .
MMF level
Stool culture
Serum electrolytes – if severe diarrhea
Fluid resuscitation oral (better) or parenteral
Anti-diarrheal if infection excluded
Treatment of the cause
Management Plan:
Algorithm for post-transplant diarrhoea
***Post-Transplant diarrhoea may lead to serious complications in form of dehydration electrolytes imbalances and affect trough level of immunosuppressive drugs which further leads to graft dysfunction decrease kidney function and increased mortality.
***The causes of diarrhoea post-transplant may be infectious or non-infectious or related to adverse reactions of some immunosuppressive drugs as MMF .
***Infections may be bacterial e.g : E.Coli and C.difficiles , viral e.g CMV , rotavirus and adenoviruses , parasitic or fungal.
>>>Mangement plan :
– Switch from cyclosporine to tacrolimus.
-Shift from MMF to enteric coated one .
– The use of Azathioprine with allopurinol must be avoided as leads to bone marrow suppression .
– Good hydration with intravenous fluids .
-PCR- Based screening for enteric organisms .
References
1. Scallan, E., et al., Foodborne illness acquired in the United States–unspecified agents. Emerg Infect Dis, 2011. 17(1): p. 16-22.
2. Ekberg, H., et al., Increased prevalence of gastrointestinal symptoms associated with impaired quality of life in renal transplant recipients. Transplantation, 2007. 83(3): p. 282-9.
3. Ekberg, H., et al., Clinicians underestimate gastrointestinal symptoms and overestimate quality of life in renal transplant recipients: a multinational survey of nephrologists. Transplantation, 2007. 84(8): p. 1052-4.
4. Gil-Vernet, S., et al., Gastrointestinal complications in renal transplant recipients: MITOS study. Transplant Proc, 2007. 39(7): p. 2190-3.
5. Herrero, J.I., et al., Gastrointestinal complications in liver transplant recipients: MITOS study. Transplant Proc, 2007. 39(7): p. 2311-3.
6. Jokinen, J.J., et al., Association between gastrointestinal symptoms and health- related quality of life after heart transplantation. J Heart Lung Transplant, 2010. 29(12): p. 1388-94.
7. Krones, E. and C. Hogenauer, Diarrhea in the immunocompromised patient. Gastroenterol Clin North Am, 2012. 41(3): p. 677-701.
Reports suggest that the plasma concentration of cyclosporine may be increased during concomitant treatment with allopurinol, however cyclosporine is not involved in diarrhea.
Of the immunosuppressants used, Mycophenolate Mofetil is widely mentioned in the literature as related to diarrhea. Its dosage is necessary whenever used, especially when the patient has diarrhea, nausea, vomiting and fatigue. Depending on the result, the dosage should be reduced or even suspended.
Diarrhea is a common complication after renal transplantation. It can change immunosuppressant level ( Tac level increased during diarrhea due to decreasing of intestinal P- glycoprotein enzyme activity) necessitate monitoring drug level, also it can increase hospitalization with subsequent graft loss & increased mortality. Diarrhea can be caused by:
At first the patient should be well hydrated with full screen of infection including stool exam & serological test to exclude Cl. difficile, CMV, & norovirus or other infectious agents. If infectious cause s are excluded, the most common cause of diarrhea may be due to using of MMF. Because the recipient had high mismatch with his donor it is risky to change MMF to AZA while he is using allopurinol, but we may decrease the dose of MMF with close monitoring of renal function or other sign of rejection & observe the patient status, if diarrhea not stopped MMF may should be stopped & reintroduced at lower dose after improvement of diarrhea.
References:
Management
Resuscitation in the form of fluid and maintaining electrolyte balance.
The diarrhoea can be related to increase drug levels or infective aetiologies ,so monitoring of drug levels, Stool culture for viruses(CMV,Cryptosporidosis,enteroviruses)bacteria(Salmonella,E.coli,), CMV PCR DNA (BLOOD), PCR for nova virus, Stool for C Diff toxin followed by Colonoscopy if required.
In immunosuppression, the dose of MMF can be split into multiple dosing or reduced to half or discontinued if no response. Monitor Tacrolimus levels and can be switched to Cyslosporin as Tac levels increase during diarrhea due to large variation in bioavailability because of intestinal metabolism and active secretion into lumen by P-glycoprotein .However ,azathioprine cannot be used instead of MMF because of its interaction with allopurinol.
REFERENCES:
1- Maes, B., Hadaya, K., De Moor, B., Cambier, P., Peeters, P., De Meester, J., Donck, J., Sennesael, J. and Squifflet, J.-P. Severe Diarrhea in Renal Transplant Patients: Results of the DIDACT Study. American Journal of Transplantation, 2006;6: 1466-1472.
2- Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Current Opinion in Nephrology and Hypertension. 2017 ,Nov 1;26(6):484-93.
3- Asano T, Nishimoto K, Hayakawa M. Increased tacrolimus trough levels in association with severe diarrhea, a case report. Transplantation Proceedings. 2004 Sep;36(7):2096-7
I would start vigorous hydration to replace the losses caused by diarrhea. I would start the investigation of the for possible causes :
1) Immunosuppression medications(MMF&CNI toxicity)
2)Infections( viral,bacterial,&protozoal)
Further, plan of management depends on the cause.
Dear All
None of you mentioned monitoring the CNI level. Why does it need monitoring?
Dear Dr Ahmed,
CNI level will be affected in cases of diarrhea (whatever the underlying cause of diarrhea) due to the effect on the pharmacokinetics of the CNI.
In the gut, the CNIs are repeatedly taken up and transported out of intestinal enterocytes by P-gp, allowing for reuptake and repeated exposure to CYP3A4/5, leading to significant pre-systemic metabolism. Because of this, these agents can exhibit relatively poor bioavailability (1). Therefore, inflammation of the bowel wall associated with diarrhea can lead to impaired enteric metabolism of CNI, leading to elevated serum concentration with an increased risk of CNI toxicity.
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
The drug levels of CNI depend on intestinal absorption, which is variable with respect to ethnicity, food intake and diarrhea. Diarrhea affects the activity of Cytochrome P450 enzymes leading to variable drug levels, especially with tacrolimus. Hence it is important to measure CNI levels frequently during diarrhea.
References
1) Issa N, Kukla A, Ibrahim HN. Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am J Nephrol. 2013;37(6):602-12. doi: 10.1159/000351648. Epub 2013 Jun 18. PMID: 23796509.
2) Lemahieu W, Maes B, Verbeke K, Rutgeerts P, Geboes K, Vanrenterghem Y. Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea. Am J Transplant. 2005 Jun;5(6):1383-91. doi: 10.1111/j.1600-6143.2005.00844.x. PMID: 15888045.
3) Maes BD, Lemahieu W, Kuypers D, Evenepoel P, Coosemans W, Pirenne J, Vanrenterghem YF. Differential effect of diarrhea on FK506 versus cyclosporine A trough levels and resultant prevention of allograft rejection in renal transplant recipients. Am J Transplant. 2002 Nov;2(10):989-92. doi: 10.1034/j.1600-6143.2002.21018.x. PMID: 12484345.
Diarrhea affected on CNI pharmacokinetics especially Tacrolimus which increasing its level due to loos of intestinal enterocytes which led to loss of exporter capacity of tacrolimus (1).
we should be aware of the potential raised in tacrolimus trough level during diarrheas’ in post organ transplant patients. Therapeutic drug monitoring (TDM) should be performed to prevent tacrolimus toxicity.(2).
1-T Asano 1, K Nishimoto, M Hayakawa
Increased tacrolimus trough levels in association with severe diarrhea, a case report(2004 Sep;36(7):2096-7. doi: 10.1016/j.transproceed.2004.06.026).2-Tan See Teng, MBBS, Koon Boon Yoong, MSURG
Effect of diarrhoea on Tacrolimus trough level in a post liver transplant patient.
Med J Malaysia.2020 Nov;75(6):734-735
Pharmacokinetic study suggested that the increase of Tac exposure in patients with diarrhea could be due to an increased oral bioavailability of Tac. Blood levels of Tac were maximally elevated during the absorption phase of Tac, between 90 and 360 min after intake with consequent elevations of dose-normalized AUC and Cmax, whereas the kinetic parameters Tmax and,especially, T1/2did not differ compared to diarrhea-freecontrols suggesting that increase of Tac assimilation, rather than the alternative explanation for the increased exposure, a decrease of Tac elimination
Intestinal PGP activity is impaired in patients with persistent diarrhea compared to diarrhea-free controls and healthy volunteers. This is in agreement with the relative distribution of CYP3A4 and PGP along the gastrointestinal tract. The more proximal localization of intestinal CYP3A4 could explain its preserved activity, since diarrhea appeared to cause moreextensive mucosal damage in the distal intestinal tract.
Shortening of oro-anal transit time in patients with diarrhea is expected to lead to a shortened residence time and hence diminished drug absorption. However, the opposite was noticed.
references
Lemahieu et al- Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea
What is your management plan?
causes are :
1-Infectious
Bacterial- clostridium difficile diarrhoea
Viral – CMV, Norovirus
2-Medications
Mycophenolate mofetil (MMF)
General management
1-Good hydration with IV fluid.
2-Monitoring of the vital signs, urine output, and graft function.
3-PCR-based screening for enteric pathogens.
4-consider stopping non-immunosuppressive medications that can cause diarrhea.
5-Switch from MMF to EC-MPS
6-monitor CNI blood level
Although it is well known that diarrhea results in decreased trough levels of cyclosporine, this is not true for tacrolimus as its level will increase during diarrhea. Tacrolimus shows large variability in bioavailability after oral administration, both due to intestinal metabolism by cytochrome P450 (CYP3A4) and active secretion from enterocyte into intestinal lumen by P-glycoprotein. During diarrhea, the epithelial cells of the intestine may be destroyed, abrogating P-glycoproteins, thereby increasing the levels of tacrolimus. It is recommended to monitor trough levels of tacrolimus during severe diarrhea of any nature to prevent tacrolimus-related complications.
References:
The main route of elimination of CNI is fecal , fecal elimination constitute around 92.3 percent, so obviosly diarrhia can decrease the level of CNI.
On the other hand, case reports found mush increase in tacrolimus level during diarrhia and this was explained by the damage of enterocytes that contain P- glycoprotein responsible for active secretion of tacrolimus into the intestinal lumen. (1)
So it is mandatory to measure CNI level during diarrhia episodes.
Referances
1- T Asano et al. Increased tacrolimus trough levels in association with severe diarrhea, a case report. Transplant Proc. 2004 Sep
CNI level increases during diarrheal episodes due to reduced transit time in gut and impaired cyt 450 enzyme activity. So CNI level should be measured during diarrhea and doses need to be reduced to prevent toxicity
This patient has 5/6 mismatch and should have been on higher immunosuppression dosage. The diarrhoea can be related to higher drug dosage or infective aetiologies like CMV . C Diff. Norvirus, Giardia etc.
The patient will require resuscitation in the form of fluid and maintaining electrolyte balance. Monitoring of drug levels, Stool culture for C Diff, Blood CMV PCR, PCR for nova virus, C Diff toxin check.
As regards immunosuppressin the dose of MMF can be decreased or discontinued. Monitor Tacrolimus levels and can be switched to Cyslosporin. Aothioprim use can be risky due to interaction with allopurinol.
References.
P. Frei et al.Lessons from a transplant patient with diarrhea, cryptosporidial infection, and possible mycophenolate mofetil-associated colitis. Transpl infect dis. 2011 Aug;13(4):416-8
DT Kenedy et al. Azathioprine and allopurinol: the price of an avoidable drug interaction. Ann. Pharmacother. 996 Sep;30(9):951-4
At first, I would start vigorous hydration to replace the losses caused by diarrhea. I would start the investigation of the probable causes described below
Immunosuppressive Drugs
Infectious diseases
In this situation, I would do the investigation as follows:
– Collect of viral panel and for Clostridoidis difficile by PCR method in feces
– Collect of toxins A and B for Clostridioidis difficile
– Culture for opportunistic germs in feces
– Reduce the dose of MMF or discontinue if there is no improvement
– Measure Tacrolimus values and evaluate the switch to Cyclosporine
– I would not use Azathioprim due to the risk of interaction with allopurinol and its consequences
for this patient I will:
1- check all nonimmunosuppressive medications he is on . if any one is suspected to cause diarrhea , then iwill consider changing it( anti-arrhythmics, antibiotics, anti-hypertensives, diuretics, anti-diabetic medication, laxatives, proton-pump inhibitors, protease inhibitors )
2- revise stool culture and check for the possibilities of acid-fast bacteria (Mycobacterium complex), parasites , fungi (including but not limited to Candida spp., and Clostridium difficile toxin
3- check the viral causes (adenovirus, enterovirus, rotavirus and cytomegalovirus )
4- check for bacterial overgrowth through 14C-glycocholic acid or d-xylose breath tests,
5- empirical anti-diarrheal drugs, supplemental bacteria (e.g. Lactobacillus casei Shirota) or diets (including lactose-free diets) which resulted in remission of diarrhea in 11 out of 28 patients in DIDACT study
5- if after the above tests no cause was identified , then I would reduce by 50% or even stop Mycophenolate Mofetil. According to DIDACT Study, remission rates were 65% for MMF, 100% for cyclosporine ,42% for tacrolimus and 60% for steroids (1).
If despite all the above measures the diarrhea persist, it could be then due to side effects of allopuranol . if I stop allopuranol , then I would consider changing cyclosporine into tacrolimus, as the former is associated with high serum uric acid, to keep the patient on dual therapy. (2)This will increase the risk of rejection since his mismatch was 1-2-2. Hence I would keep him on close follow up.
1- Maes, B., Hadaya, K., De Moor, B., Cambier, P., Peeters, P., De Meester, J., Donck, J., Sennesael, J. and Squifflet, J.-P. (2006), Severe Diarrhea in Renal Transplant Patients: Results of the DIDACT Study. American Journal of Transplantation, 6: 1466-1472
2- Mazzali M. Uric acid and transplantation. Semin Nephrol. 2005 Jan;25(1):50-5. doi: 10.1016/j.semnephrol.2004.09.008. PMID: 15660335.
What is your management plan?
From this vignette the differential diagnosis for the diarrhoea in a recent transplant patient includes
Infectious
Bacterial- clostridium difficile diarrhoea
Viral – CMV, Norovirus
Medications
Mycophenolate mofetil (MMF)
In this patient since cultures were normal, I will make the assumption that c difficile is excluded and norovirus.
Since he was only recently transplanted, the most likely cause of the diarrhoea is likely MMF.
In terms of management
General management
History and examination to exclude other causes of diarrhoea like IBD, IBS etc
Examination- Assess level of dehydration and exclude signs of systemic infection.
Based on findings on examination- decide on mode of rehydration, most likely home oral fluids but if severely dehydrated will need iv fluids inpatient.
Stop mycophenolate, take blood for Tacrolimus level ensure that patients trough level is within acceptable level. Continue prednisolone. Considerations for immunosuppression;
1. You could start Azathioprine but due to drug interactions with allopurinol, the allopurinol will have to be stopped and an alternative treatment for gout sought.
2. The second option would be to try another formulation of mycophenolate; Enteric-coated mycophenolate sodium (Langone AJ et al, Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicentre, double-blind, randomized study. Transplantation. 2011).
3. The third option would be to restart MMf at a lower dose of 500mg once a day and gradually increase dose as tolerated.
My preferred option would to switch to the enteric coated mycophenolic sodium at 750mg bd, and if this fails then consider switch to azathioprine after stopping the allopurinol.
Chronic diarrhea after kidney transplantation is common. The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs. However, this patient had acute diarrhea that started a month post-transplant.
Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF. MMF and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in post-transplant diarrhea. Generally, dose reduction is followed by the decrease or the disappearance of diarrhea.
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage. Sirolimus causes self-limiting diarrhea in 14–42% of treated patients.
On the other hand, Diarrhea can be commonly infectious and the microbes usually responsible are CMV and C. difficile, but the literature describes a wide range of organisms in solid organ transplant (SOT) recipients.
Chronic norovirus infection has only recently emerged as one of the leading infectious causes (approximately 17–26% ) of severe post-transplant diarrhea in kidney transplant recipients
CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality. The most common target organ is the gastrointestinal tract, causing CMV gastrointestinal disease.
Noninfectious diarrhea is not uncommon among renal transplant recipients and has been reported to increase the risk of graft loss and mortality.
Management:
· Hydration
· Monitor drugs levels.
· Stool analysis and culture.
· The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia, via CMV PCR. Tissue biopsy through colonoscopy might be helpful. Patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir. Intravenous GCV is often used if there is a concern for inadequate absorption of oral valGCV (e.g. in patients with vomiting and diarrhea) or early in the treatment of proven CMV colitis.
· The gold standard for C. difficile detection is the cell-based cytotoxicity assay. However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR tests.
· If all negative, consider MMF dose reduction or to switch to mycophenolic acid.
Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Current Opinion in Nephrology and Hypertension. 2017 Nov 1;26(6):484-93.
Viral infection(cmv) should be ruled out.
MMF is most likely cause.
Adequate hydration.
Change MMF to EC.MMF if not effective.
Stop Azathioprine with reduction of50%
of Allopurinol dose. Monitor of WBC
carefully.
Everolimus may be considered.
Some case STUDIES reports respondes of MMF induced colitis to SINGLE dose of influximab with reintroduction of small dose of ECMP.OTHER REPORTS octreotide.
Potential etiology
Drug side effect of MMF, allopurinol
Infection; CMV, parasitic
Management plan:
– Good hydration and better to do fluid chart even if as out-patient to compensate fluid loss accurately
– Monitor electrolytes
– Monitor renal function
– Change MMF to mycophenolate mofetil (enteric coated preparation)
– Reduce the dose of allopurinol or use alternative
– Check for CMV and if positive needs treatment
The risk of having post transplant Diarrhoea is higher due to several interplaying factors including a generslized immunosuppressed status, and exposure to multiple medications including broad spectrum antibiotics. Therefore causes of post transplant diarrhoea are infections, immunosuppressive drugs, antibiotics and other drugs. Its important to resolve this problem as its associated with potentially life threatening consequences, such as loss of the graft.
Infectious causes are into virological including CMV infection rotavirus, adenovirus and Norovirus as the most common. Protozoal etiology where Entamoeba histolytica is the commonest as per a study from India. Less commonly Giardia, Strongloides, Cryptodporidium and microsporidia. Bacterial etiology involve E. Coli, Klebdiella,shigella and Clostridium difficile. The current neuclic acid detecting multiplex PCR is sensitive and more accurate than the conventional cultivation procedures. The non infectious causes are related to immunosuppressants, particularly Mycophenolate medicines.
Therefore after excluding infectious causes, I think we need to reduce the dose of MMF as its dose dependent, and Would suggest convertion to Tacrolimus with optimization of trough level to 7_8 ng/ml to ensure better coverage while minimizing the MMF. In the extreme cases withdrawal of MMF is warranted.
Reference s:
1)Mycophenolate induced Diarrhoea. Ashwunikumar Aiyangar, Prashant Rajput, Bharat V Shah. J Assoc Physicians India.
2) Diarrhoea in Renal transplant recipients_Reteospective Observational study from a center in South India. Jyothipriya Jyothindrakumar et al. Indian Journal of Transplantation. 2021
3)Causes and management of post renal transplant Diarrhoea.. By HS shin. Curr. Opin. Nephrol Hypertens. 2017
Diarrhea post renal transplant can be either due to infectious causes, or due to non-infectious causes.
The management will involve supportive treatment and specific treatment.
Supportive treatment:
1) Fluid and electrolyte management: To prevent dehydration and AKI
2) Nutrition
Specific treatment: As per etiology of diarrhea.
For this, we need to evaluate the cause of diarrhea.
History:
History of induction therapy use
History of any rejection
Any other medication use, especially use of colchicine for acute gout flare or metformin for glycemic control.
Lab evaluation:
CNI drug levels
Stool routine and culture, specifically for cryptosporidium, any ova or cyst
Stool for C. difficle.
Blood CMV PCR quantitative.
Stool PCR for giardia, campylobacter and viruses like norovirus
Specific Treatment:
1) Treat infectious cause as per diagnosis.
2) If no infectious cause:
Change MMF to enteric coated formulations.
If no response, decrease dose to 360 mg twice a day.
If still no response, change to Azathioprine, but keep a watch on blood counts including total leukocyte count.
Use of allopurinol with azathiprine should be avoided due to increased myelosuppression.
This is a patient with 5/6 mismatch, hence the level of immunosuppression should not go down in this early post-transplant period. Cyclosporine can be converted to Tacrolimus.
References:
1) Aulagnon F, Scemla A, DeWolf S, Legendre C, Zuber J. Diarrhea after kidney transplantation: a new look at a frequent symptom. Transplantation. 2014 Oct 27;98(8):806-16. doi: 10.1097/TP.0000000000000335. PMID: 25073040.
2) Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Curr Opin Nephrol Hypertens. 2017 Nov;26(6):484-493. doi: 10.1097/MNH.0000000000000368. PMID: 28863048.
3) Tiwari V, Anand Y, Gupta A, Divyaveer S, Bhargava V, Malik M, Gupta A, Bhalla AK, Rana DS. Etiological Spectrum of Infective Diarrhea in Renal Transplant Patient by Stool PCR: An Indian Perspective. Indian J Nephrol. 2021 May-Jun;31(3):245-253. doi: 10.4103/ijn.IJN_169_20. Epub 2021 Feb 16. PMID: 34376938; PMCID: PMC8330656.
Management plan
Posttransplantation diarrhea is a serious condition as may be complicated with dehydration , prerenal AKI , electrolytes disturbance and fluctuating IS trough levels.
Diarrhea has several causes including
1- Infectiuos causes
a- Bacterial; cl . difficile, E coli
b- Viral: CMV, Rota and adenovirus.
c- Parasitic
2- Non infectious causes as
a- I S drug side effect specially MMF.
b- Other drugs as PPI , antibiotics
c- PTLD
d- Malabsorption .
Management of the patient
1- Assess volume status and electrolytes with correction of any abnormalities .
2- Specific management directed to the underlying cause , in this pt negative stool culture can exclude bacterial and parasitic infection and normal colonoscopy can exclude GIT invasive CVM infection , so his diarrhea is most probably caused by MMF , we can start with decreasing or temporary stop MMF and re assess the patient response .
-Rrehydration and maintain euvolemic state is cornerstone to avoid prerenal acute kidney injury in transplanted kidney.
-Start full investigation focus on
CMV PCR to exclude CMV VIRUS
pre transplant Epstein bar virus state (think about post transplant lymph proliferative disorder ).
-Infection screen for rare and opportunistic infection
(fungal ,protozoal and TB).
IF NO DIAGNOSIS :
-Perform upper OGD to exclude infection (giariasis ,Hpylori,fungal) or diagnosis of hidden malignancy .
IF WE NOT REACH DIAGNOSIS :
Think about drug side effect
MMF .allopurinol ,steroid , cyclosporine all can cause diarrhoea but most common
with MMF
so need to stop allopurinol first then try to manipulate other drug and last one MMF
Diarrhoea related to MMF usually not respond to dose splitting or change from one MMF to other (cellcept to myfortic ) but well respond to dose reduction or replace it .
IMPORTANT MASSAGE
diarrhoea post transplant first to think about drug side effect but we should last to deal with it after exclude all causes so as not to miss important treatable cause and expose patient to risk of rejection with unnecessary stop or change important drug .
The patient has severe diarrhea – more than 4 episodes a day. The problem started post transplant.
However, there can be can be various causes for diarrhea post transplant. It can be infection, dietary problems, diarrhea-causing concomitant medications. Correct diagnosis of the cause of severe diarrhoea protects graft survival.
GI infections – bacterial, fungal, viral, dyspepsia, diarrhea are common in transplant recipients. Diarrhea can cause increase in serum creatinine and fluctuating immunosuppressive drug levels.
MANAGEMENT PLAN :
NON-IMMUNOSUPPRESSIVE DRUG ADAPTATION
The first step would be to stop the allopurinol administered to this patient or taper it to see if the diarrhea episodes become less frequent or stop.
MICROBIOLOGICAL STOOL EXAMINATION
SCREENING FOR VIRUS
Screen for viral agents such as adenovirus, enterovirus, rotavirus, CMV (CMV PCR). If CMV positive, then biopsy specimen can be taken from upper or lower GI tract for histology and immunoperoxidase staining.
EXCLUDING BACTERIAL OVERGROWTH
If there is no remission of diarrhea with the above steps then bacterial overgrowth can be excluded by C glycolic acid or D xylose breath tests if available. If results came back positive then appropriate antibiotics can be given to the patient and followed up.
EMPIRICAL TREATMENT
Patient can be given anti-diarrhea drugs, supplemental bacterial Lactobacillus, diet adjustment with more fibre and patient re-evaluated in four days.
IMMUNOSUPPRESSIVE DRUGS ADAPTATION
Make sure patient is hydrated up to accepted level because of risk of dehydration. Diarrhea complications can be temporary graft dysfunction and metabolic acidosis.
REFERENCES:
Diarrhea can impair renal graft function as a result of dehydration and weight loss. The most common causes of posttransplant diarrhea are infections and immunosuppressive drug-related causes.
1. IV fluids and determine the impact of non-immunosuppressive diarrhea-inducing drugs. If any drug caused the diarrhea was found and considered safe to be withdrawn, the drug should be stopped, or replaced.
2. A microbiological stool examination: The stool examination included cultures for pathogenic bacteria like Shigella spp., Salmonella spp., E. coli, Campylobacter spp. Stains and cultures for acid-fast bacteria (Mycobacterium complex), examinations for ova and parasites, assays for fungi, and an assay for Clostridium difficile toxin.
3. Screens for viruses like adenovirus, enterovirus, and CMV. If a positive CMV case was identified or suspected, then a biopsy specimen takes from the upper and/or lower GI tract for histology and immunoperoxidase staining.
4. If no diagnosis or remission from diarrhea was obtained following step 3,
bacterial overgrowth must exclude by the 14C-glycocholic acid or d-xylose breath tests. If the test was positive, then the patient treats with relevant antibiotic therapy. The patient must be followed up 1–2 weeks later to determine whether such treatment had been successful.
5. If diarrhea had still not resolved, the patient needs adaption of his immunosuppressive(MMF). Patient reevaluates after 1–2 weeks to determine the effect of the change.
6. If diarrhea persists, a colonoscopy with mucosal biopsies take for histological examination. If lesions were found, appropriate therapy initiates and the patient reevaluate within 1–2 weeks.
7. If diarrhea had still not resolved, empirical treatment with anti-diarrheal drugs, or diets (including lactose-free diets) was allowed. The patient reevaluates within 1–2 weeks after this step.
-Roos-Weil D, Ambert-Balay K, Lanternier F, et al. Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea. Transplantation 2011; 92: 61.
– B. Maes,K. Hadaya,B. De Moor,P. Cambier,P. Peeters,J. De Meester,J. Donck,J. Sennesael,J-P. Squifflet. Severe Diarrhea in Renal Transplant Patients: Results of the DIDACT Study.American Journal of transplantation.First published: 29 March 2006
The patient has more than 3 times diarrhoea
I would like to workout for malabsorption workout first with 1st line microbiological stool study
• Stool cultures for pathogenic bacteria
• Stool examination for parasites and fungi
• C. difficile toxin assay
• Test for rota virus, adenovirus and norovirus
Then, plasma CMV PCR
If all these workout turn out to be negative,I would like to send for multiplex PCR testing for
• Campylobacter species
• Enteropathogenic and enterotoxigenic E.coli, shigella, salmonella , yersinia, cryptosporidium, enterocytozoon bienseusi
Adaptation of IS drug regime
-MMF dose reduction or switch to EC-MMF or switch to AZA if more than 50% reduction in MMF
but,
-Switching MPA to AZA is usually avoided due to reports showed reduced graft survival with AZA as compared to MMF, although some studies showed short term benefit
-Allopurinol combines with AZA will lead to increasing level of 6-mercaptopurine which may lead to blood dyscrasias and bone marrow suppression
so i would avoid using AZA, better to use EC-MPA
if doesn’t work,
-CNI withdrawal, switch to mTORI ( might benefit in norovirus)
If still persist , Breath test (14C-glycocholic acid or D-xy lose)-to look for small intestine bacterial overgrowth
references
Florence Aulagnon et al: Diarrhoea after kidney transplantation: A new look at frequent symptom
Thank you for mentioning the possible risk of combining AZA and allopurinol
Most likely drug induced diarrhea like cellcept. first of all stop cellcept to another drug like imuran 75mg or myfortic 750mg and fluid resuscitation correct electrolytes disturbance
blood sample for CMV igM, IgG
regular input / output chart to avoid dehydration
Post transplant diarrhea is a common complication in the first year post transplant and may lead to dehydration, medication toxicity and graft rejection.
management include defining the cause of diarrhea, appropriate and targeted therapy and maintaining proper hydration.
characteristics of diarrhea may help:
fever may indicate viral cause as CMV or invasive bacterial cause as campylobacter.
non-bloody watery diarrhea may indicate viral infection or drug induced diarrhea
history of recent antibiotic intake (most important risk factor for clostridium difficile infection)
stool examination for ova and parasites
testing stool for Clostridium difficile
CMV PCR to assess viral load
test for viral pathogens by PCR if diarrhea is still persistent and no cause detected
Fluid replacement, oral rehydration is preferred in mild and moderate cases while severe dehydration and hypovolemic shock requires IV rehydration
All medications should be reviewed and unnecessary non-immunosuppressive agents should be stopped
treatment of concurrent infection, antimicrobial drug is determined according to identified agent:
Clostridium difficile: metronidazole or oral vancomycin in severe and persistent cases
CMV: oral valganciclovir
if no cause is detected, reduction of the dose of MMF or shifting MMF to EC-MPA may lead to remission.
reduction of immunosuppression should be considered cautiously as may result in graft loss
empiric antidiarrheal medication and probiotic if all tests are negative and infectious causes are excluded.
Aulagnon F, Scemla A, DeWolf S, Legendre C, Zuber J. Diarrhea after kidney transplantation: a new look at a frequent symptom. Transplantation. 2014;98(8):806‐816.
Angarone M, Snydman DR, AST ID Community of Practice. Diagnosis and management of diarrhea in solid‐organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical Transplantation. 2019 Sep;33(9):e13550.
Van Gelder T, Hesselink DA. Mycophenolate revisited. Transpl Int 2015; 28:508–515.
Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Current Opinion in Nephrology and Hypertension. 2017 Nov 1;26(6):484-93.
What is your management plan?
1- regular follow-up of fluid intake and urine output to maintain adequate hydration and prevention of volume depletion.
2- regular check-up of renal chemistry for several days to ensure no pre-renal azotemia.
3- changing Mycophenolate Mofetil to Mycophenolate sodium ( Myfortic ) as 720 mg bid or 360 mg /6 hours …. sometime this regimen is satisfactory for managing drug related diarrhea.
4- holding Cellcept for few days can be considered in refractory cases. then starting Myfortic at lower doses as 360 mg tid or even bid with gradual increment.
Diarrhea in an organ transplant recipient may result in significant morbidity including dehydration, increased toxicity of medications, and rejection.
Transplant recipients are affected by a wide range of etiologies of diarrhea
-Most common causes being infections like Clostridioides difficile infection, cytomegalovirus, and norovirus.
Other bacterial, and parasitic infections.
-Non infectious causes including medication toxicity, inflammatory bowel disease, post-transplant lymphoproliferative disease, and malignancy .
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Management of diarrhea:
Is directed at the cause of the diarrhea
Clinical history
Examination
Investigation
Fluid replacement
Antibiotics for infection
Diarrhea is common among transplant recipients and is associated with mycophenolate and tacrolimus. Adjustments in doses or conversion to alternative agents may be required. However some develop severe diarrhea after tolerating these medications initially.
https://journals.lww.com › fulltext
Dear All
Can we switch MMF to azathioprine in this case?
Azathyoprin with high uric ucid necessiating management may not be a good choice here because of myelosupprezion risk incase of combinattion ..
It could be wise to lower or stop MMF trasiently then starting with lower dise .. keeping in mind ther dehydration and prerenal azotemia are also reasons for high uric acid ( notmal beforr dehydration; lowered with hydration: can be monitired as marker for couples of days. Withholding MMF and increasing steroid a little bit in addition to hydration wih prevent gouty arthritis attack
..
Taking in consideration that the patient has infrequent flares of gouty arthritis, the hyperurecimic effect of azathioprine, and the possible gastrointestinal effects of MMF, patient can be switched to azathioprine with caution, along with discontinuation of allopurinol( or febuxostat) with closed monitoring of the uric acid level and low uric acid diet.
To note that azathioprine significantly suppress purine synthesis and increase uric acid production.
better to aviod such combinations
I agree with my colleagues that the combination of Azathioprine with allopurinol (or even Febuxostat) is risky and better to be avoided. A suggested approach is to reduce the dose of Azathioprine by 50% and follow up the WBCs count. However, even with this approach still, there is high risk of severe leukopenia necessitating discontinuation of Azathioprine (1).
Suppose the clinician expected the patient to suffer from GIT side effects of Mycophenolate Mofetil. In that case, it is worse for a trial to switch to the enteric-coated mycophenolic acid formulation (e.g., Myfortic). Some studies showed improved GIT symptoms after changing the formulation (1).
References:
1) Karen Hardinger, Daniel C Brennan. Kidney transplantation in adults: Maintenance immunosuppressive therapy. © 2022 UpToDate. (Accessed on 20 March 2022).
We should keep in mind that the patient is high immunological risk as he is 5 out of 6 mismatch and still in 1st month post KTX, so better to know data about his induction therapy and if MMF is not tolerated so for , better also to shift cyclosporine to Tacrolimus.(to avoid risk of rejection),
If MMF shifted to azathioprine so F/U CBC.
Also febuxostat interact with azathioprine.
• Switching MPA to AZA is usually avoided due to reports showed reduced graft survival with AZA as compared to MMF, although some studies showed short term benefit
• Allopurinol combines with AZA will lead to increasing level of 6-mercaptopurine which may lead to blood dyscrasias and bone marrow suppression
canot because of
1- drug drug interaction.
2-MMF based regimen inferior to old immuran based regimen regarding graft survival but still last option if diarrhoea proved to be MMF RELATED and not response to dose reduction
Certain points should be considered before answering this question:
-the patient is early post transplant & a high risk, and so AZA is less effectve than MMF in preventic acute rejectio.
-The possible interaction with allopurinol.though he as only infrequent attachs of gouty arthritis.
-So if the exhaustive workup doe not reveal any other possible cause of his diarrhea, I would first manipulate and adjusst the dose and dosaging of MMF
-IF this did not help the diarrhea, then I would, cautiously & considering the a/m points, consider shifting to AZA.with cautious adjusment of the dose
-screenin tes for xanthine oxidase inhibitor(IF AVAILABLE)
Yes with reduction of dose of allopurinol to 50% and following up for leukopenia.
Reduce aza dose to 50%.
The Mechanism and Drug Interaction – Allopurinol and Azathioprine and Risk of Bone Marrow Suppression
Summary:
While not commonly used together for the treatment of various chronic conditions, the concomitant use of allopurinol and azathioprine has been used to improve outcomes in pediatric and adult patients with inflammatory bowel disease, prevention of rejection in organ transplantation, and reducing thiopurine-induced hepatotoxicity. Coadministration of these medications did require dose reductions and extra monitoring for life threatening reductions in WBC.Allopurinol inhibits the enzyme xanthine oxidase (XO), which is one of 3 enzymes responsible for inactivating 6-mercaptopurine (active form of azathioprine). It may also have effects on TPMT activity as one study showed a reduction in methylated metabolites with the combination. Due to this inhibition, 6-mercaptopurine is shunted down to form metabolites that are incorporated into the DNA resulting in a reduction in WBC replication/activation, as well as inhibition of the activity of Rac1 GTP which stimulates apoptosis of WBCs.The coadministration of allopurinol and azathioprine (especially if doses are not reduced) can therefore result in life-threatening reductions in WBCs and should only be done by clinicians with specific expertise.
Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers: Jon D. Herrington, PharmD, BCPS, BCOP
Expert Contributor: Paul A. Blaker, PhD, MRCP
Last Reviewed: January 2017
Diarrhea is one of the most common and annoying complain most of patient suffer post transplantation
How to manage
1st history taking..most important questions to ask like upper GIT manifestation, frequency, consistency ,any new drugs and tenesmus
Bacterial infection and food poison usually cause gastroenteritis and need antibiotics
Viral infection mostly cause secretory diarrhea only without upper GIT manifestation
Protozoa usually cause tenesmus and usually response to metronidazole
Drugs simply this patient has gouty so maybe someone prescribe colchicine for him
2-examination
I should check the vital signs like bp, temperature,pulse,RR
Sever diarrhea can cause sever hypovolemia and this is very important to decide if this patient need to be admitted in the hospital or just need home hydration
Infection mostly associated with fever
3-investigations
CNI trough level
Dividing the dose of MMF or shifting to mycophonelate sodium can help
Some viral panel PCR like CMV and ROTA
STOOL culture
Stool osmolar gap
Serum electrolytes
Upto colonoscopy and biopsy in sever cases
The plan of management which will be fluid resuscitation either oral or parentral regarding the severity and evaluation of patient volume status and the ability to take oral fluids until diagnosis and treatment of the cause.
Reference
lorence Aulagnon 1, Anne Scemla, Susan DeWolf, Christophe Legendre, Julien Zuber. Diarrhea after kidney transplantation: a new look at a frequent symptom.
Transplantation. 2014 Oct 27;98(8):806-16.
Will you check for viral gastroenteritis first?
Will you check for C Def toxins?
Both are separate tests from stool culture. Colonoscopy could be normal in both conditions if the disease is mild.
sure , i will
thanks for remind me professor halawa
You are the only one who paid attention to the CNI level. Well done
Diarrhea is one of the most frequent post-transplant complications and may result in discontinuity of immuno- suppressive therapy. Usually supported by bacterial, viral and parasitic causes, the onset can also be determined by drugs used in the post-transplantation period.
The incidence of diarrheal episodes is 12.6%, with 41.5% of cases related to infectious episodes and 34% correlated to drugs. The average period of onset of diarrhoea was about 10 months after transplantation (2–12 years).
Furthermore, while 12% of the episodes occurred in the first month, 22% were diagnosed around 1–6 months post-transplant and 66% in the late period (after 6 months).
The picture is going with drug-induced diarrhoea. As the patient has poor matching :
i will start by rehydration of the patient
I will check the cyclosprine level(high level can cause diarrhoea)
I will start by dividing the dose of MMF 4 times per day, If no response, I will reduce the dose of the MMF by 50%.If no response, I will shift to EC-MPS.
If diarrhea perisistant, I will shift the patient to azathioprine( one third of the recommended dose to avoid profound leukopenia).
stoping the antimetabolites after one month of transplanation will increase the risk of rejection.
Altıparmak MR, Trablus S, Pamuk ÖN, Apaydın S, Sarıyar M, Öztürk R, et al. Diarrhoea following renal transplantation. Clin Transplant. 2002;16(3):212–6.
Will you check for viral gastroenteritis first?
Will you check for C Def toxins?
Both are separate tests from stool culture. Colonoscopy could be normal in both conditions if the disease is mild.
Yes, I will send for Clostridium difficile, Campylobacter jejuni, Salmonella spp. CMV, HSV, Epstein-Barr virus.
. I thought they sent and the result is negative.