7-2 TransplantationCase-Based Discussion

Tadashi Sofue, MD, PhD

Division of Nephrology and Dialysis, Department of Internal Medicine, Kagawa University Hospital

The 58th JSN 2015/6/4@NagoyaAPSN Continuing Medical Education Course 2015

Division of Nephrology and Dialysis, Department of CardioRenal and CerebroVascular Medicine,

Faculty of Medicine.

Statement of Disclosure

• The author does not have any financial conflict of interest regarding the material in this presentation.

Patient： 35-year-old MalePast History：Type-2 Diabetes (from 15 years old)

Diabetic retinopathyFamily History：Older sister: DM Mother: DMPresent illness• 15 y.o. Diagnosed with diabetes and hypertension (No treatment)• 25 y.o. Treatment with sulfonylurea • 30 y.o. Kidney dysfunction with nephrotic syndrome• 34 y.o. Initiation of hemodialysis (HD) • 35 y.o. He consulted our hospital for the purpose of a living-donor

kidney transplantation from his father.

Case Presentation

Status before KT

StatusHeight：165 cm Body weight：72 kg BMI: 26.5Blood pressure： 162/87 mmHg Heart rate：60/minLung: clear, no rale. Heart: regular, no murmurAbdomen: soft and flatLeg edema: none, left forearm: AVF

Patient backgroundOccupational history: sake dealer (drank two cans of beer/day)Smoking history： 20×15 years (stopped smoking before KT)

Medication:Candesartan 8 mg 1 tab/dayAmlodipine 5 mg 2 tab/dayDoxazosin 2 mg 1 tab/dayLansoprazole 15 mg 1 tab/day

Laboratory Data before KTGGTP 15 U/L

CHE 222 U/L

WBC 5,690 /μL

RBC 386 104/μL

Hb 11.0 g/dL

Ht 34.1 %

Plt 24.0 104/μL

CRP 0.11 mg/dL

TP 7.0 g/dL

Alb 3.7 g/dL

BUN 57.8 mg/dL

Cr 12.84 mg/dL

Na 140 mEq /L

K 5.3 mEq /L

Cl 99 mEq /L

Ca 9.4 mg/dL

IP 7.6 mg/dL

T-bil 0.3 mg/dL

GOT 3 U/L

GPT 9 U/L

ALP 229 U/L

LDH 144 U/L

C3 70 mg/dL

C4 27 mg/dL

CH50 31.6

ANA 40 fold

IgA 218 mg/dL

IgG 1,237 mg/dL

IgM 88 mg/dL

iPTH 152 pg/mL

β2MG 24.7 mg/L

HbA1c (NGSP) 6.7 %

Examination before KT

• CT: no malignancy• Gastrointestinal endoscopy: n.p.• Colorectal endoscopy: n.p.• HCV-ab, HBV-ag: negative

Left ventricular hypertrophyEjection fraction: 49%,

Wall motion: diffuse, mild hypokinesis

Sinus rhythm

ECGCTR = 44%

Chest Xp

Echo cardiography

Myocardial Ischemia?

Father (72 years old)• Height: 168 cm Body weight: 72 kg BMI: 25.5• Smoking: 10/day × 50 years• Past history: hypertension• Medication:

Carvedilol 20 mg 1 tab/dayAmlodipine 5 mg 1 tab/ day

• Blood pressure：128/70 mmHg• Kidney function：Cr 0.77 mg/dL eGFR 75.7 mL/min/1.73 m2

• Urinary protein (dipstick): negative• Urinary occult blood (dipstick): negative• Urinary albumin excretion (UAE)：16.7 mg/gCr

Donor Examination (1)

• Gastrointestinal endoscopy: atrophic gastritis• Immunochemical fecal occult blood test: negative• ECG：within normal range• UCG：EF 73%, no asynergy• HCV-ab, HBV-ab: negative

Enhanced 3D-CT

Donor Examination (2)

99mTc-MAG3 scintigraphy

Split kidney function: right/left=48/52 No abnormality of renal artery or vein

Immunological Condition Histocompatibility test

CDC XM ： T(−) Bw (−) Bc (−)Flow XM ： T(−) B(−)Flow PRA ： class I (+) class II (−)HLA mismatch： 3/6

Blood-type Incompatible (B+ → O+) Recipient anti-B IgG 64-foldRecipient anti-B IgM 64-fold

Type-2 diabetes Possibility of myocardial ischemia Marginal donor with hypertension ABO-incompatible KT

Problems Associated with this Case

Indication or contraindication for LDKT?

Sørensen VR, et al. Diabetologia 2007;50(5):922-9

KT for diabetic patients markedly improves survival rates.

Transplantation for Diabetic Patients

Transplant with diabetes

Waiting list with diabetes

Non-candidates with diabetes

Factors aggravating BS control• CNI • PSL• Weight gain

Diabetic patients are not contraindicated for KT

Diabetic patients with ESRD

Although a positive myocardial perfusion study is predictive of CAD (more than 70%), a poor negative predicted value (64.6%) was reported in cases of ESRD with DM.

Negative

Myocardial perfusion scintigraphy (Recipient)

Possibility of Myocardial Ischemia (1)

Welsh RC, et al. Transplantation 2011;91(2):213-8

Myocardial perfusion imaging and degree of coronary artery stenosis

CAD>70%

Negative

CAG

Wall motion: intact, EF 68%

LVG

Possibility of Myocardial Ischemia (2)

Overall, he showed a low risk of cardiovascular events in the peri-operative period.

No apparent stenosis was observed in his coronary artery.

To prevent acute antibody-mediated rejection caused by anti-blood-type antigen, we treat recipients before ABO-incompatibleKT by antibody removal therapy (plasma exchange and double-filtration plasmapheresis) and inhibition of antibody production.

Plasmapheresis for ABO-incompatible KT

Age > 70 years oldeGFR <80 (>70) mL/min

HypertensionTwo anti-hypertensive drugs

UAE<30 mg/gCr

Marginal Donor (living-kT)

Acceptable as a living-donor?

This donor candidate had many marginal factors

Living-donor Criteria in the World and Japan

Amsterdam forum Marginal criteria in JapanAge ≦65 ≦80Kidney function(mL/min/1.73 m2) eGFR≧80 eGFR≧70

BMI ≦35 kg/m2 ≦32 kg/m2

Hypertension ≦140/80 mmHgwith less than 1 drug(age>50, UAE≦30 )

≦140/80 mmHg with no drugor ≦130/80 mmHg

with less than 2 drugs + UAE≦30 mg/gCr

Proteinuria ≦300 mg/day ≦150 mg/day or UAE≦30 mg/gCrDiabetes Excluded HbA1c≦6.5% + UAE≦30 mg/gCr

Amsterdam Forum; Delmonico F, Transplantation. 2005;79(6 Suppl):S53-66Donor criteria for living-donor kidney transplantation in Japan 2014

Age: 72 years oldeGFR: 76 mL/min/1.73 m2

HypertensionTwo anti-hypertensive drugs

UAE: 17 mg/gCr

Acceptable as living marginal donor

Our donor candidate

Pre-transplant lifestyle modifying is also important

Hypertension and the degree of albuminuria did not affect thedonor kidney function after donation.

Recipients of hypertensive donors with high-normal albuminuriashowed lower eGFR than other recipients.

Living-donor KT from Hypertensive Donors with High-normal Albuminuria (15-30 mg/gCr)

Sofue T, et al. Transplantation 2014; 97(1):104-110

YES(in Japan)

Problems before KT

Type-2 diabetes Suspected myocardial ischemia ABO incompatible Marginal donor (Hypertension, eGFR)

Indication for LDKT?

Kidn

ey T

rans

plan

tatio

n

Day -7 Day 7

Clinical Course (1)S-

Cr (m

g/dL

)

10

Basiliximab

TxDay -5 Day 14

5

Prolonged-release Tacrolimus: Trough 8-10 ng/mLMMF (mg) 1,000 2,000 1,500

500250

125

80 40 20mPSL (mg)

HDHDHDHD

Day -2

PEDFPPDFPPRituximab 200 mg

×64

×32

×16 ×16

×8

×4Anti-B IgG titer

Donor Nephrectomy

Laparoscopy with hand assist

Left kidney

Urologist

Recipient Operation

Donor renal artery

Recipient internal iliac artery

Donor renal vein

Recipient common iliac vein

First-catch urine

Donor ureter

Donor kidneyAfter perfusion

Preimplantation (0 h) biopsy

at bench

1.30

Kidn

ey T

rans

plan

tatio

n

Day -7 Day 7

Clinical Course (2)S-

Cr (m

g/dL

)

10

Basiliximab

TxDay -5 Day 14

5

Prolonged-release Tacrolimus: Trough 8-10 ng/mLMMF (㎎) 1,000 2,000 1,500

500250

125

80 40 20mPSL (mg)

HDHDHDHD

Day -2

PEDFPPDFPPRituximab 200 mg

×64

×32

×16 ×16

×8

×4

×4

×8

×16

Anti-B IgG titer

no acute antibody-mediated allograft rejection was observed

C3

Pathological diagnosis：Fibrous intimal thickening

Global glomerular sclerosis 4/20No IgA deposition

Preimplantation Allograft Biopsy

3 years

Clinical Course (3)

1 year

1,000 mg

mPSL 2 mg

MMF 1,500 mg

S-Cr

(mg/

dL)

1

2

1 month

Recipient

UP (−) (−) (++)

3 years6 months

S-Cr

(mg/

dL)

1

2

pre

Dona

tion

Donor

1 year

2 years

(+)

2 years

0.77

1.21

1.151.151.10 1.12

6 months

1.301.18

1.41

1.28 1.18

(−)

HbA1c (%)

7.57.8

7.37.0 7.0

OB (−) (−) (+)(−) (++)

UP (−) (−) (−)(−)(−)(−)

4 mg

Prolonged-release Tacrolimus: Trough (ng/mL) 4~6

Lifestyle modifying (stop smoking, reduce Na intake)

Episode Allograft Biopsy

Indication for episode allograft biopsy• 30% increase in Cr from baseline• Urinary protein > 0.5 g/gCr• Appearance of occult blood in the urine

Possible causes of urinary abnormality in this case Chronic antibody-mediated rejection CNI toxicity Recurrent diabetic nephropathy De novo (or unknown-origin) glomerulonephritis

KDIGO Transplant Work Group, Am J Transplant. 2009; 9 Suppl 3: S33-37.

Causes of Proteinuria after KT

Modified from Sun Q, et al. PLoS One. 2012;7(5):e36654

n=98, from China

Banff score:t0,i1,g0,v0,ci2,ct2,cg0,cv0,ah3,aah1,mm3,ptc0No acute rejection, severe IF/TA Arteriolar hyaline thickening (due to diabetes?)No CNI toxicity

Results of Allograft Biopsy (1)

AUC study: Tac-ER AUC0-24 94.2 ng h/mL

Results of Allograft Biopsy (2)

Post-transplant IgA nephropathyMesangial expansion + IgA deposition in the mesangial domainwith tuft necrosis (no crescent formation)We could not diagnose de novo or recurrent IgA nephropathy, because he did not undergo kidney biopsy before KT.

How can we treat this case?

IgA

Kawamura T, et al. Nephrol Dial Transplant. 2014;29(8):1546-53

Tonsillectomy with steroid pulse therapy reduced proteinuria in cases of IgA nephropathy involving the native kidney.

Treatment for IgA Nephropathy in Native Kidney

From Japan

Treatment for Recurrent IgA Nephropathy

Tonsillectomy alone, without steroid pulse therapy, reducedproteinuria in patients with recurrent IgA nephropathy.

An effect of ARB on the improvement of graft survival wasnot evident.

Modified from Kennoki T, et al. Transplantation. 2009;88:935-941 Courtney AE, et al. Nephrol Dial Transplant. 2006;21(12):3550-4.

NS

Insulin

3 years

Clinical Course (4)

1 year

1,000 mgProlonged-release Tacrolimus: Trough (ng/mL) 4~6

mPSL 2 mg

MMF 1,500 mg

S-Cr

(mg/

dL)

1

2

1 month

Recipient

UP (−) (−) (++)2 years

(+)

6 months

1.301.18

1.41

1.28 1.18

(−)

HbA1c (%)

7.57.8

7.37.0 7.0

OB (−) (−) (+)(−) (++)

7.8Rb

(+)(+)

1.35

Tonsillectomy

4 mg PSL 20 mgmPSL 1,000 mg

Tonsillectomy + steroid pulse therapy reduced urinary abnormality, although his blood glucose was aggravated.

Summary

Our case shows that:Diabetes, ABO incompatibility, and marginal donor are

not contraindications for living-donor kidney transplantation.

Allograft biopsy is needed to diagnose the causes ofpost-transplant urinary abnormality.

Participation of a nephrologist is needed to prolonggraft survival.