This case discusses a patient who underwent a living related kidney transplant and subsequently developed increased creatinine levels and CMV viremia. Further workup revealed an enhancing nodule in the patient's native right kidney. The patient underwent surgery where a 3x3cm solid mass was removed from the right lower pole of the native kidney. A review of literature on renal cell carcinoma after kidney transplantation showed it can develop through transmission from donor, de novo occurrence in recipient, or recurrence in recipient. Immunosuppression places transplant patients at higher risk for developing various cancers.

1. Kidney Transplantation
Conference
Maj. Chaken Maniyan M.D.
Division of Nephrology, Department of Medicine
Phramongkutklao Hospital
28.2.2017

2. Case Profile
§ESRD (วินิจฉัย 2543) on
§ CAPD x 3 yr (multiple infected CAPD) à remove TK catheter
§ then shift to hemodialysis via left AVF for 7 yr
§ S/P LRKT (27 ก.ค. 2559)
§Hypertension/ Dyslipidemia
§Tertiary hyperparathyroidism s/p total parathyroidectomy
§SVD (CAG : 40% LAD stenosis , No PCI)
§History of gut obstruction s/p lysis adhesion with blood transfusion 2546
§HbE trait

3. Case Profile
§ESRD S/P LRKT (27 กรกฎาคม 2559)
§Donor (ลูกสาว) HLA mismatch 0-1-1 PRA 0%
§DSA –HLA class II positive , flow cytometry : negative
§Pre-Condition with Plasmapheresis and methylprednisolone
§Induction : Basilliximab, tacrolimus , MMF
§ Intraoperative bleeding approx. 2 L
§No Delay graft function , No allograft rejection
§Scr before D/C 1.8 mg/dL

4. Infectious Profile
DONOR RECIPIENT
AntiHIV Negative Negative
AntiHCV Negative Negative
HBsAg/AntiHBs Negative/Positive Negative/Positive
Anti-CMV IgG +ve
IgM -ve
IgG +ve
IgM +ve
(borderline)
Anti-HSV IgG +ve
IgM –ve
IgG +ve
IgM –ve
Anti-EBV IgG +ve
IgM –ve
IgG +ve
IgM –ve

5. Chief Complaint
§ มาตรวจตามนัด แล้วพบว่ามี creatinine เพิ่มสูงขึ้น.
(post operative day 70)

6. Present illness
§ 6 ตุลาคม 2559 (post-operation day 70)
§มาตรวจตามนัด อาการทั่วไปปกติ มีอ่อนเพลียเล็กน้อย
ไม่มีไข้ ปัสสาวะออกประมาณ 3-3.5 ลิตรต่อวัน ดื่มน้ำได้
ประมาณ 3 ลิตรต่อวัน ไม่มีถ่ายเหลว ไม่มีมือสั่น
§ Work up lab เบื้องต้น SCr 1.8 à 2.1 mg/dL

7. Present illness
§รับประทานยาสม่ำเสมอ ไม่ขาดยา
§ปฏิเสธ NSAIDs , ยาสมุนไพร , ยาต้ม , ยาลูกกลอน
§No alcohol, smoking

8. Drugs Preparation Dose/Frequency
Tacrolimus (Prograf) 1 mg 3 x 2 Oral pc (8.00, 20.00)
Tacrolimus (Prograf) 0.5 mg 1 x 2 Oral pc (8.00, 20.00)
MMF (Cellcept) 250 mg 3 x 2 Oral pc (9.00, 21.00)
Prednisolone 5 mg 4 x 1 Oral pc
Cotrimoxazole 400/80 mg 1 x 1 Oral pc
Vitamin D 2 20,000 units 1 capsule Oral จ พ ศ
Aspirin 81 mg 1x1 o pc
Atorvastatin 40 mg ½ x 1 oral hs
CaCo3 1,500 mg 1 x 2 Oral AC
10% MgCl2 10 ml bid
Current medication

9. Physical Examination
§V/S: BP 120/70 mmHg, P 90 /min, RR 20, T 37 C, BW 76 kg BMI 26.2 kg/m2
§GA: A middle-aged Thai male, alert
§HEENT: mildly paled conjunctivae, anicteric sclera, no gum hypertrophy
§LN: not palpable
§Heart: Normal S1, S2 , no murmur
§Lungs: normal breath sound, no adventitious sound
§Abdomen: normoactive bowel sound, soft, no tenderness, no guarding
§Extremities: no edema, no tremor both hands
§Neuro: no weakness, intact pinprick test, BBK dorsiflexion, DTR 2+ all

10. Physical Examination
§V/S: BP 120/70 mmHg, P 90 /min, RR 20, T 37 C, BW 76 kg BMI 26.2 kg/m2
§GA: A middle-aged Thai male, alert
§HEENT: mildly paled conjunctivae, anicteric sclera, no gum hypertrophy
§LN: not palpable
§Heart: Normal S1, S2 , no murmur
§Lungs: normal breath sound, no adventitious sound
§Abdomen: normoactive bowel sound, soft, no tenderness, no guarding
§Extremities: no edema, no tremor both hands
§Neuro: no weakness, intact pinprick test, BBK dorsiflexion, DTR 2+ all

11. Laboratory results
§ CBC: Hb 9.3 g/dL, Hct 29.4 %, MCV 73.3 fl, RDW 20%
WBC 6,200 N 82 %, L 11%, M 5%, E 1%, Plt 242,000
§FPG 100 mg/dL, Chol/Trig 137/250, LDL-c 62 mg/dL
§BUN/Cr: 23.3/2.1 mg/dL (baseline Scr =1.8 mg/dL)
§Na 136, K 4.57, Cl 101.3 , HCO3 20.5 mEq/L, Albumin 3.6 AG 14.2
§Ca 9.2, PO4 3.3, Mg1.9
§U/A: pH 6.5, 1.010, RBC 0-1. WBC 0-1, protein-neg, sq epithelial few
§CXR : WNL

12. CMV viral load
Date CMV VL (copies/ml)
26/7 Undetectable
11/8 Undetectable
17/8 Undetectable
29/8 147
8/9 891
14/9 2,610
19/9 4,050
6/10 2,619 -à ganciclovir 7 days
13/10 1,845
19/10 603
27/10 Undetectable
10/11 Undetectable
8/12 Undetectable
5/1/2017 Undetectable

13. Problem list
§Azotemia in post LRKT d70
§History of Recipient CMV IgM positive
§Hypertension
§Dyslipidemia
§Tertiary hyperparathyroidism s/p total
parathyroidectomy
§SVD

14. What is differential diagnosis and
further investigation

15. CMV viral load
Date CMV VL (copies/ml)
26/7 Undetectable
11/8 Undetectable
17/8 Undetectable
29/8 147
8/9 891
14/9 2,610
19/9 4,050
6/10**** 2,619

16. BK viral load
Date BK VL (copies/ml)
11/8/2016 Undetectable
6/10/2016 Undetectable

17. Prograf level (ng/ml)
Date Prograf level (ng/ml)
25/8/2016 10.2
29/8/2016 >8.6
8/9/2016 10.8
14/9/2016 15.7
19/9/2016 19.7
22/9/2016 (previous OPD visit ) 9.9
6/10/2016 (current) > 30

18. Plan of management
§Ganciclovir (2.5 mg/kg/d) 175 mg IV OD
§↓ immunosuppressive drugs
§Prednisolone (5) 3 x 1 o pc
§Cellcept (250) 2x2 o pc (0900, 2100)
§Prograf (1) 1x2 o pc (0800, 2000)
§Prograf (0.5) 1x2 o pc (0800, 2000)
§Monitor CMV viral load weekly
§NSS 60 mL/hr
§Monitor prograf level q 24-48 hr
§ F/U BUN, Cr daily

19. BUN/CR level
Date BUN Cr
6/10/2016 23 2.1
7/10/2016 21 1.9
8/10/2016 19 1.6

20. Progression D3 after hospitalization
§ มีอาการปวดจุกท้องใต้ลิ้นปี่ Pain score 10/10 คลื่นไส้ อาเจียน > 10 ครั้ง ได้ omeprazole 40 mg ,
metoclopramide 10 mg IV , tramol 50 mg IV อาการไม่ดีขึ้น
§PE : V/S BT 37.7 C BP 90/60 RR 22/m PR 106/m
§HEENT: mildly paled conjunctivae , anicteric sclerae
§H/L : unremarkable
§Abd : Moderate tenderness at epigastrium and LUQ, normoactive bowel sound,
guarding positive , no rebound tenderness
§Murphy’s sign negative
§Shifting dullness positive , fluid thrill positive

21. Problem list
§New onset of peritonitis in post LRKT
§CMV viremia
§CNI toxicity

22. What is differential diagnosis and
further investigation

23. Laboratory results
§CBC: Hb 10.5 g/dL, Hct 30.3%, MCV 74.3 fl, RDW 20%
§WBC 13500 N 92% band 5%, L 1%, M 1%, E 1%, Plt 253,000
§BUN/Cr: 24.3/2.3 mg/dL
§Na 132.5 , K 5.16, Cl 102.3 , HCO3 15.3 mEq/L, Albumin 3.6 AG 14.2
§LFT : Alb 3.4 AST 13 ALT 17 ALP TB 0.5 DB 0. 2 Amylase 37 lipase 26
§Ascites : WBC 300 , PMN 72 % mono 28 % RBC 20,000
§ G/S : No organism seen

24. Plain film acute abdomen

25. § ย ้ายไป ICU 2
§ NSS load 300 ml , Levophed (1:25) 5 ud/m
§ Septic W/U : Abdominal tapping (send for cell
count/ diff , G/S, C/S), H/C , U/C
§ Empiraical ATB Tazocin 4.5 gm iv q 6 hr
§ Continue : ganciclovir 175 mg iv q 24 hr
§ Consult surgery due to sign of peritonitis , r/o bowel
perforation

26. CT whole abdomen emergency :
§Multifocal beak point of obstruction at proximal jejunum without extraluminal compression or soft tissue
mass, upstream jejunal dilatation and wall thickening.
§No pneumoperitoneum is seen.
§Large amount of ascites at perihepatic. subhepatic. inter bowel loops, paracolic gutter and pelvic cavity
§Liver reveals normal in size, shape without gross space taking lesion. No dilatation of CBD or IHD.
§The gallbladder, pancreas, spleen and both adrenal glands are unremarkable.
§The transplant kidney at right sided pelvic cavity is normal in size & shape with good excretion.
§The native kidneys are small in size with several bilateral renal cortical cysts, size up to 2 cm at lower pole
of left kidney.
§No excretory function of both native kidneys are seen.
§1. 6 -cm enhancing nodule at lower pole of right kidney.
§No hydronephrosis is observed in both kidneys
§Urinary bladder is partially distend without definite mass or stone.
§No significant sized intraabdominal lymph node is seen

28. Enhancing nodule Rt. Lower pole of native kidney

29. Enhancing nodule Rt. Lower pole of native kidney

30. Progression
Set OR for lysis adhesion band and appendectomy
After surgery:
◦ Tail off norepinephrine ได้
◦ ปวดท้องลดลง , step diet ได้ตามปกติ
◦ Consult urosurgery evaluate enhancing nodule Rt.Kidney
◦ Set OR for Open radical Right native nephrectomy

31. What is differential diagnosis of
enhancing nodule /
further management

32. Progression
Consult urosurgery evaluate enhancing nodule Rt.Kidney
◦ Set OR for Open radical Right native nephrectomy

35. Operative Note
Incision: Right subcortical incision
Finding :confined solid mass size 3x3 cm at Right lower
pole kidney with multiple renal cyst at upper pole
No immediate complication
EBL = 200 ml
JD No 10 was placed within retroperitoneal space

37. Previous US KUB
สค. 2554: Bilateral renal paranchymal disease with multiple cyst
, no stone , mild hydronephrosis , thickening bladder wall
มิย 2555: Bilateral renal paranchymal disease with multiple
cortical cyst
พย. 2556: Both kidney increased echotexture and cystic change
, multiple scattered calyceal stones in both kidneys (0.6-0.8 cm)
No hydronephrosis
มค. 2559 : Decreased size both kidney (LK 6.5 cm , RK 6.4 cm),
multiple small cortical cyst (< 2 cm in size )

38. Review :
renal cell carcinoma
after kidney transplantation

39. Common malignancies after KT
Engels EA, et al. JAMA 306: 1891–1901, 2011

40. Standardized incidence ratio (SIR) of cancer
after KT , compared general and with ESRD
Kasiske, et al , American Journal of Transplantation, Vol. 4, No. 6, (June 2004), pp. (905-913).

41. Oncogenic viruses
Epstein–Barr virus Lymphoma
Human herpes virus 8 Kaposi’s sarcoma Lymphoma
Human papillomaviruses
(HPV)
Cervical cancer
Penile cancer
Vulvar cancer
HPV 58 Bowen’s disease
HPV 16, 20 Skin cancer
Tonsillar cancer
Hepatitis B and C viruses Hepatocellular carcinoma
Nephrol Dial Transplant (2007) 22 [Suppl 1]: i4–i10

42. Etiology of Increased Risk of
Cancer in Transplant Patients
§Impaired immune surveillance
§Oncogenic viruses
§Chronic antigenic stimulation and immune regulation
§Environmental factors
§Direct neoplastic action of immunosuppressive drugs
Peter J.Morris, Stuart, Kidney transplantation: principles and practice 6th edition

43. Mechanisms of developing malignancy
§Develop in three different ways:
§Transmission of malignancy from donor
§De novo occurrence in recipient
§Recurrent malignancy in recipient
Peter J.Morris, Stuart, Kidney transplantation: principles and practice 6th edition

44. Transmission of Cancer from the Donor
§ Melanoma : most common transferred from
a donor to recipient
§Post-transplant lymphoproliferative disorder
(PTLD) in a recipient may be a direct result of
viral transmission from the donor.
Peter J.Morris, Stuart, Kidney transplantation: principles and practice 6th edition

45. De novo occurrence in recipient
§ Foreign allograft antigens in a recipient may
be important in cancer causation.
§Chronic lymphoid stimulation results in a high
incidence of malignant lymphomas

46. Direct Neoplastic Action of
Immunosuppressive Drugs
§ Calcineurin Inhibitors (Cyclosporine and
Tacrolimus)
§Inhibitors of Mammalian Target of Rapamycin
§Corticosteroids
§Azathioprine
§Mycophenolate Mofetil
§Lymphocyte-Depleting Agents

47. Calcineurin inhibitors
§Production of TGF-beta (potent inhibitor of IL-
2–stimulated T-cell proliferation
§Induce invasive nontransformed cells in
association with morphologic change
§increase in proangiogenic effect due to
elevated expression of VEGF
Guba M,et al . Transplantation 2004; 77:1777.

48. Azathioprine
§ Disrupts the synthesis of DNA and RNA, causing
immunosuppression by interfering with
lymphocyte proliferation
§Azathioprine is associated with an
§increased risk of lymphomas
§increased risk of a wide range of solid
neoplasms,
§squamous cell carcinomas,
§urinary bladder tumors
§breast carcinomas
§brain tumors
Guba M,et al . Transplantation 2004; 77:1777.

49. Guba M,et al . Transplantation 2004; 77:1777.

50. Mammalian target of rapamycin inhibitor
(mTORi)
§Suppresses growth and proliferation of tumors in various animal
models
§mTORi complex with FK binding protein complex (FKBP-12),
binding with high affinity to mammalian target of rapamycin
(mTOR).
§Inhibit mTOR, down-regulating p70S6 kinase activity and
subsequent translation of specific mRNAs required for cell-cycle
progression from the G1 to S phase.
§Possible mechanisms of actions include inhibition of p70 S6K
interleukin-10 (IL-10, decreasing tumor cell Jak/STATs activity),
and cyclins (blocking cell cycle activity).
Guba M,et al . Transplantation 2004; 77:1777.

51. Guba M,et al . Transplantation 2004; 77:1777.

52. mTORi associated malignancy:
registry analysis
§ Retrospective SRTR database analysis including 33,249 kidney
transplant recipients from 1996-2001 receiving maintenance IS of:
§– SRL/EVL
– SRL/EVL + CNI (CsA or tac) – CNI
§+ any combination of MMF, AZA, prednisone
Kauffman et al. Transplantation 2005;80: 883–

53. CNI withdrawal from mTORi
based regimen: RMR study
§ 430 kidney recipients receiving SRL (5-15 ng/ml) + CsA (150-
400ng/ml) + prednisone randomized at 3 months to:
§– Continue treatment (n=215)
– Withdraw CsA, SRL trough 20-30 ng/ml (n=215)
Alberto J . et al JASN 17: 581–589, 2006

54. RCC after kidney transplantation

55. Epidemiology
§Incidence of RCC in native kidney varies 0.3- 14.6%
§Risk of developing RCC in native kidneys of KTRs
§H/D vintage > 5 yrs
§Acquired cystic kidney disease
§Male gender
§African-American
§Recipients aged>65 years
§Longer pretransplant dialysis interval
§Microscopic haematuria
Goh A et al , . Am J Transplant 2011; 11: 86-92.

56. Risk factors
§Smoking :
§Hypertension
§Diabetes mellitus
§Obesity
§Occupational exposure :
§ Toxic compounds, such as
cadmium, asbestos, and
petroleum by-products
§ May be associated with
mutations in genes associated
with the pathogenesis of RCC,
von Hippel-Lindau tumor
suppressor gene
§Acquired cystic disease of the
kidney :
§ 30 times greater in dialysis
patients with acquired polycystic
disease
§ develops after at least 8 to 10
years of dialysis
§ male-to-female ratio 7:1
§ large cysts→ increased risk for
malignant transformation
§Analgesic abuse nephropathy
§Genetic factors
§Polycystic kidney disease
§Cytotoxic chemotherapy
§Chronic hepatitis C infection

57. Nature of RCC after KT
§ Majority are asymptomatic
§ Incidental finding in other indication for
other disease
§US of native kidney detect tumor at early
stage in 80% and CT pick up rates close to
100%
§Malignancy generally develops after at least
8 to 10 years of dialysis, although a shorter
interval can be seen

58. Pathogenesis of RCC after KT
§ Nephron loss à compensatory hypertrophy
§ Activation of proto-oncogenes
§ Release of growth factors (suepidermal and
hepatocyte growth factors)
§Over a prolonged period of time, can lead to
tubular hyperplasia and cyst formation
malignant transformation

59. NCCN Guidelines Staging Kidney Cancer

64. §

65. Reduction of immunosuppression
§We suggest consideration be given to reducing
immunosuppressive medications for KTRs with cancer.
(2C)
§Important factors for consideration include (Not
Graded):
§Stage of cancer at diagnosis
§Likelihood of cancer exacerbation by
immunosuppression
§20.2: For patients with Kaposi sarcoma, we suggest
using mTORi along with a reduction in overall
immunosuppression. (2C)
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice
guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(Suppl 3): S1–S157.