This case discusses a renal transplant recipient with a history of familial Mediterranean fever who presented with persistent fever, diarrhea, abdominal pain, and neurological symptoms. Initial workup ruled out infection as a cause. The patient's symptoms correlated with higher cyclosporine levels. Literature suggests there may be a pharmacokinetic interaction between cyclosporine and colchicine that increases free drug concentrations, potentially leading to toxicity. Reducing the cyclosporine dose addressed the patient's symptoms.

1. Ayman Refaie,MD
Chief, Nephrology & Transplantation Unit
Urology & Nephrology Center
Mansoura University

2. Monday, July 15, 2019 GCP Aurangabad. 2

3. Monday, July 15, 2019 GCP Aurangabad. 3

4. Keeping the gift

5. Successful renal transplant
Not Only Normal S. Creatinine
• Quality of life
• Other comorbidities
• Graft survival
• Graft loss

6. Management of a renal transplant: The art
Keeping the balance

7. Immunosuppressive protocols
I. Induction therapy
II. Maintenance immunosuppression
Proper Tailoring

8. Induction Therapy: The proper choice
Depleting Non-Depleting

9. Maintenance Immunosuppression: The
proper choice

10. Low-risk & Pediatrics
• Baxiliximab induction
• Tacrolimus + MMF (steroid-free)
Moderate-risk
• Basiliximab induction
• Steroid + Tacrolimus + MMF
High-risk
• Thymoglobulin induction
• Steroid + Tacrolimus + MMF
Choice of the immunosuppression protocol

11. Low-risk & Pediatrics
• Baxiliximab induction
• Tacrolimus + MMF (steroid-free)
Moderate-risk
• Basiliximab induction
• Steroid + Tacrolimus + MMF
High-risk
• Thymoglobulin induction
• Steroid + Tacrolimus + MMF
Immunosuppression protocol

12. Low-risk & Pediartics
• Baxiliximab induction
• Tacrolimus + MMF (steroid-free)
Moderate-risk
• Basiliximab induction
• Steroid + Tacrolimus + MMF
High-risk
• Thymoglobulin induction
• Steroid + Tacrolimus + MMF
Immunosuppression protocol

13. Low-risk & Pediatrics
• Baxiliximab induction
• Tacrolimus + MMF (steroid-free)
Moderate-risk
• Basiliximab induction
• Steroid + Tacrolimus + MMF
High-risk
• Thymoglobulin induction
• Steroid + Tacrolimus + MMF
Immunosuppression protocol

14. Graft Loss
The nightmare
for both
the patient and his physician

15. Death
56%
Chronic
rejection
21%
Noncompliance
13%
Other
6%
Recurrence
4% Cause of death2
USRDS 1st kidney transplants 1995–2003
(excluding 30% unknown)
Cause of graft loss*1
*beyond the first year after transplantation
Cardiovascular disease
43.5%
Infection
26.3%
Malignancy
10.7%
Other
19.4%
What is the most common cause of graft
loss in kidney transplant recipients
beyond the first year after
transplantation?
Graft Loss

16. Riella et al. Transplantation Reviews 31 (2017) 1–9
Causes of chronic allograft injury

17. Chronic allograft injury:
non-immunologic causes
• CNIs nephrotoxicity
• BK-Nephropathy
• Hypertension
• Dyslipidemia
• Diabetes
• Donor factors
Riella et al. Transplantation Reviews 31 (2017) 1–9

18. Keeping the balance
• Part I: Over immunosuppression
• Part II: Under immunosuppression

19. Keeping the balance
• Part I: Over immunosuppression

20. Part I: over immunosuppression
Three case scenarios
• Infection
• Malignancy
• Serious interaction

21. Each case …..
 A case scenario
 Review of literature
 A message

22. Case # 1

23. The recipient
A 50-year-old female dermatologist.
ESRD (ADPKD)
HD for 2 years.

24. The donor
24-year-old.
Same blood group.
HLA, DR – 50%.
PRA 0%

25. Immunosuppression ( July, 2005)
Induction: Basiliximab
Maintenance: - Steroids
- Tacrolimus (0.015 mg/kg,
trough level 4-8 ng/ml)
- MMF (1.5 gm/day)

26. 3rd Post operative day
Deterioration of graft function
Graft biopsy
Acute rejection II A
- positive C4d
- negative DSA
C4d: positive

27. Anti rejection
Pulses of methyl prednisilone
Rituximab (375 mg/m2)
Plasma exchanges
Partial response: improvement of urinary output, serum
creatinine, and Doppler indices.

28. 10th Post operative day
Shock
Graft rupture possibly due to the severity of rejection and
associated weakening point of biopsy.
Exploration and evacuation of a peri-graft hematoma.
The graft was preserved
A biopsy was taken, revealed acute rejection II A.

29. 14th Post operative day
Oliguria
Tacrolimus, stopped
Prednisolone (10 mg/day), MMF (1.5 g/day)
Plasma exchange: continued
Supportive hemodialysis

30. 22nd Post operative day
Graft function started to recover, clinical and laboratory
Addition of small dose of tacrolimus.
Discharge, 2 weeks later (day 36).

31. One week after discharge
Fever
Frontal headache
left-sided proptosis
CT & MRI
Left ethimoidal sinusitis (thick mucosa)

32. One week after discharge
Drainage of the ethimoidal sinus.
Repeated sinus debridement
Histopathology of the
necrotic tissue
Mucormycosis hyphae

33. Critical Decision

34. Critical Decision
Recent kidney transplant
Serious rhino-cerebral fungal infection (mucormycosis)
On immuosuppression (steroid-TAC-MMF)
S. Creatinine ~ 3 mg/dL

35. Critical Decision
To save the patient’s life on the expense of the graft
Liposomal form of amphotericin B (4mg/kg day), 1 month.
Withdraw TAC & MMF and Maintaine only on low-dose
prednisone (5 mg/day).
Supportive dialysis when indicated.

36. One month later
Sinus: free (clinically, radiologically, repeated sinus
biopsies)

37. One month later
Sinus: free (clinically, radiologically, repeated sinus
biopsies)
Graft biopsy: acute rejection II A

38. One month later
Dilemma ???

39. One month later
Dilemma ???
Group decision and patient counseling

40. One month later
Dilemma ???
Group decision and patient counseling
Increase the dose of steroids (10 mg/day).
Add sirolimus (5 mg/day, trough level 7-10 ng/ml).
Close monitoring.

41. Two weeks later
Gradual increase of urine output
Dialysis-independent
Gradual drop of s. creatinine

42. Within two months
Sinus: free
Serum creatinine: 1.4 mg/dl
Maintained on:
- Steroid (10 mg/day)
- Sirolimus (3 mg/day).

43. Literature Review (2007)
Only 11 cases of mucormycosis in renal allograft
recipients were reported.
In all cases, the prognosis was poor and the story ended
with either death of the patient or removal of the graft.

44. We reported, for the first time, a unique case of rhino-cerebral
mucormycosis in a renal allotransplant recipient where both the
patient and the graft could be saved.
Urology and Nephrology Centre, Mansoura University, Mansoura, Egypt

45. 45

46. 46

47. 47

49. Mucormycosis
It is caused by fungi of order mucorales and genera rhizopus.
These fungi are found in decaying vegetative and organic
matter.
The usual infection route is inhalation of the spores, but
certain procedures such as intravenous cannulation and
bladder catheterization are often the cause of infection.

50. Mucormycosis
They have minimal intrinsic pathogenicity, but can cause
grave and often fatal infections in renal allograft
recipients.
They are angio-invasive, can cause thrombosis of the
small and large arteries, infarction, and organ necrosis.

51. Mucormycosis
Diagnosis requires the demonstration of broad, non-
septated, right-angle branching fungal hyphae in the
biopsy specimen.
.

52. Mucormycosis
Diagnosis requires the demonstration of broad, non-
septated, right-angle branching fungal hyphae in the
biopsy specimen.
The prognosis of rhino-cerebral form is poor, with an
overall mortality of up to 50% and residual defects in
70% of survivors.

53. Mucormycosis
Liposomal amphotericin B has been introduced in an
effort to reduce side effects, as they allow the
administration of high doses with less nephrotoxicity.

54. Mucormycosis
Liposomal amphotericin B has been introduced in an
effort to reduce side effects, as they allow the
administration of high doses with less nephrotoxicity.
The optimum duration of amphotericin B therapy is
unknown, but it is recommended that it be maintained
until the disease is clinically and radiologically resolved.

55. Message (Case # 1)
 Mucormycosis in a renal allograft recipient is an extremely
rare but potentially lethal complication.
 Aggressive antirejection therapy is a risk factor for the
development of this unfavorable outcome.
 Early diagnosis, antifungal therapy and early surgery in order
to avoid complications and progression to Rhino-orbital-
cerebral mucormycosis (ROCM) , which has a high morbidity
and mortality rate, with devastating consequences.

56. Case # 2

57. Case # 2
A 23-year-old male patient.
ESRD.
HD for 3 years.

58. The donor
Father.
50-year-old.
Same blood group.
HLA, DR – 50%.

59. Immunosuppression ( Oct. 2003)
Induction: Basiliximab
Maintenance: - Steroids
- Cyclosporine A
- Azathioprine

60. Post operative course
Post-operative course was uneventful
Discharge (2 wks) - S.cr 1.1 mg/dl
- Cr.Cl 89 ml/min
As rejection free recipient

61. One year protocol biopsy
CAI (mild degree)

62. Modification of immunosuppression
One year protocol biopsy
Chronic allograft nephropathy
CsA low window
Switch from AZA to MMF

63. Two years post tx
Bl.Pr. 70/40.
Hematemsis.
Melena.
Jaundice.
Enlarged inguinal LN.
Multiple skin lesions (? Kaposi sarcoma).

64. Laboratory investigations
S.cr 2.6 mg/dl
HB 8.2 gm/dl “basal 11 gm/dl”
Bilirubin 7.2 mg/dl “mainly direct”
Proth. conc. 58 %
ALT 82 IU/L
AST 78 IU/L

65. The Skin
Kaposi sarcoma

66. Skin biopsy
Kaposi sarcoma

67. Gastroscopy
Ulcerations.
Pigmented nodules.
Biopsy.

68. Gastric biopsy
Kaposi sarcoma

69. Chest CT
Multiple lower zone patches

70. MRI abdomen
Liver: irregular contour, heterogeneous pattern

71. Treatment Plan
Correction of shock ( Blood Tx, hemostatics, etc…
Gradual tapering of steroids.
Withdrawal of MMF.
Switch from CsA to Sirolimus.

72. Follow up Plan
Graft function.
Sirolimus level.
Gastroscopy every 3 months.
Chest CT every 3 months.

73. The Skin
Normal skin

74. Follow up Chest CT
Marked reduction of pulmonary nodules

75. Follow up MRI abdomen
Irregular contour, heterogeneous pattern No definite focal lesions

76. Castroscopy
Mild gastritis and no focal lesions

77. Gastric biopsy
Gastric mucosa, no residual lesion

78. Chest CT (one year)
FREE Chest CT

79. Laboratory investigations
 Serum creatinine is 1.4 mg/dl
 Creatinine clearance 100 ml/min
 Silrolimus level is 7.8 ng/ml

80. Immunosuppression
 Steroid: 7.5 mg / day
 Sirolimus 7 mg /day

81. Successful Rescue
Combined visceral and cutaneous kaposi sarcoma in
renal transplant recipient on CNI & MMF.
Withdrawal of MMF
Switch from CsA to Sirolimus.
Improvement of both types.
Preserved graft function for 10 years.

83. Kaposi Sarcoma
The incidence of Kaposi’s sarcoma among recipients of
solid organs is about 500 times the rate in the general
population, suggesting a role for immunosuppression in
its development.
The clinical presentation of Kaposi’s sarcoma in
transplant recipients is often limited to the skin, although
visceral lesions have been described.

84. Kaposi Sarcoma
Traditionally, treatment of transplant-related Kaposi’s
sarcoma consisted mainly of reduction or cessation of
immunosuppression.
This approach was associated with remission rates of
32% to 60%. However, these approaches are associated
with deterioration of renal function in approximately 65%
of patients.

85. Message (Case # 2)
Sirolimus should be included in the standard
treatment for Kaposi’s sarcoma after
transplantation, to permit remission of the
sarcoma (both cutaneous and visceral) while
preserving the renal function.

86. Case # 3

87. The recipient
A 28-year-old female patient.
Two renal allografts
France (1989), cadaveric donor
Cairo (1997) Living unrelated donor
Original kidney disease FMF-amyloidosis

88. Immunosuppression
• Steroids: 17.5 mg/day
• Cyclosporine A: 75mg / 12 h
+ Colchicine: 1 mg/day

89. June, 2000 (UNC)
Persistent pyrexia, diarrhea and abdominal pain.
Musculoskeletal pains: particularly affecting the shoulder
girdle and.
Hospitalization elsewhere for 3 weeks, where she
developed in addition generalized seizure with proximal
motor weakness in the left upper limb due to grade III left
fasciobrachial monoparesis.
She received empirical courses of antibiotics and
physiotherapy, with little response.

90. Laboratory investigations
S.cr 1.6 mg/dl
Na 138 mM / l
K 3.7 mM / l
Ca 9.3 mg /dl
Po4 3.4 mg /dl
Uric a 8.1 mg /dl
Cholesterol 152 mg /dl
Sugar 72 mg /dl
Urinalysis Free
CsA trough level 185 ng/ml
Bilirubin 0.4 mg/dl
Albumin 3.1 g /dl
ALT 61 IU/L
AST 88 IU/L
Alk phos 73 IU/L
Hb 9 gm/dl
Hct 26.6 %
WBCs 5500
Normal coagulation profile

91. Further investigations
?

92. Viral Profile
HBV: Negative
CMV: Negative
HIV: Negative
HCV (RNA): Positive

93. Laboratory investigations
Urine Culture (repeated): Sterile
Blood Culture (repeated): Sterile
Stool Culture (Shigella & salmonella): Negative
Widal test: Negative
Tests for brucellosis: Negative
Tests for toxoplasmosis: Negative
Malaria Film: Negative
Screening tests for vasculitis and collagen diseases: Negative

94. Laboratory investigations
LDH: 717 IU/L
CPK: 129 IU/L

95. Radiological investigations
Chest X-ray: Free
Abdominal US: Free
Doppler US: Normal graft indices
Echocardiography: Normal valves, no vegetations
Colonoscopy: Normal colonic mucosa

96. Discussion
• All cultures and serology, negative
• Radiologic and endoscopic examination, negative
• Infectious etiology is mostly ruled out

97. Discussion
• Symptoms were more intense when CsA level > 150
ng/ml …..
• Therefore, the issue of poor tolerance to CsA in FMF
amyloidotic kidney transplant recipients receiving
colchicine was raised……

98. Literature (Cohen et al.,1989 )
Both CsA and colchicine
have a large apparent
volume of distribution,
indicating that they are
highly bound to either fat or
tissue sites, and both are
found in high concentrations
in the same organs, thus
raising the possibility of
pharmacokinetic interaction
with increased free
concentration of one or both
drugs.

99. Literature (Siegal et al.,1987 )
GIT symptoms usually occur at the end of the 2nd or beginning of the
3rd week after transplantation, a time where CsA concentration might
reach a toxic levels..

100. Literature (Kuncl et al.,1987 )
A syndrome of neromyopathy
related to colchicine therapy has
been described and characterized
by generalised muscle weakness,
elevated CPK, diffuse myositic
pattern on EMG and non
inflammatory vacuolar changes
on muscle biopsy.

101. Literature (Choi et al.,1999 )

102. Management
• Cyclosporine was replaced by Tacrolimus (dose; 0.15
mg/kg aiming foe trough level 5-10 ng/ml ( ?????).
• Response: cessation of diarrhea and disappearance of
fever 2 days post conversion.

103. Management
• Persistence of muscle pains…..
• Cessation of colchicine
• Response: the neuromyopathic symptoms disappeared
gradually over 2 months …..

104. Interestingly
• The patient reported that she experienced the same
scenario (fever, abdominal pain and diarrhea) for 3
months in the early postoperative period following her
first transplant in France, in 1989.

105. importance of this case: twofold
1. The importance of careful monitoring of CsA levels in
patients receiving both colchicine and CsA.
2. Tacrolimus could replace CsA in such patients.

107. Transplantation for Renal Amyloidosis
The outcomes of renal tx in patients
with amyloidosis was controversial
•Pasternack
•3-year survival
•Patients with amyloidosis 51%
•Patients with glomerulonephritis 79%
Pasternack A et al. Transplantation 1986; 42:598

109. Transplantation for Renal Amyloidosis
( Mansoura Experience )

110. Transplantation for Renal Amyloidosis
( Mansoura Experience )
 Outcome of kidney transplantation in patients with ESRD caused by renal amyloidosis is
comparable with results of patients with ESRD caused by primary glomerulonephritis.
 Maintenance colchicine treatment prevents recurrence of FMF symptoms after transplantation.
 CsA may induce GIT side effects in FMF-amyloidotic patients maintained on colchicine
therapy. These side effects could be easily controlled by reduction of CsA dose.

111. Transplantation for Renal Amyloidosis
( Mansoura Experience )

112. Transplantation for Renal Amyloidosis
( Mansoura Experience )

114. 8 Years Later .…..
Impact of Amyloidosis on kidney
transplantation: A long term study
Thesis in General Medicine
Mansoura Faculty of Medicine.
By: Ali Mohamed Sherif Ali
(2000)

115. Transplantation for Renal Amyloidosis
( Mansoura Experience )

116. Transplantation for Renal Amyloidosis
( Mansoura Experience )
The long-term outcome of live donor kidney transplantation in
patients with ESRD secondary to amyloidosis is similar to results
in transplant recipients with ESRD from other causes.

117. Transplantation for Renal Amyloidosis
( Mansoura Experience )

118. Transplantation for Renal Amyloidosis
( Mansoura Experience )
EMG-evidenced neuromyopathy is more liable to occur in long term live-donor FMF
amyloidotic kidney transplant recipients than in the other non-amyloidotics
recipients even with no clinical manifestations or high CPK levels.

119. • GIT symptoms are more frequent in FMF recipients
receiving CsA which could be easily controlled by
reduction of CsA dose or switch to tacrolimus.
• Neuromyopathic manifestations are more liable to
occur among FMF-amyloidotic recipients receiving CsA
& colchicine.
Message (Case # 3)

120. • Many kidney transplant patients are seen in general
medical practice
• Follow up of transplant patient is an art (cumulative
Experience)
• Always work with a transplant center and a nephrologist
who is well trained in immunosuppression management
• When in doubt, ask for help!
Take Home Message

121. My advise
for further
reading

122. Nephrology & Transplantation Unit
Mansoura Urology & Nephrology Center
Thank You