effects of simultaneous kp transplantation vs kd single in type 2 diabetics: seven years follow-up

Effects of Simultaneous Kidney-Pancreas and Kidney Alone Transplantation on Diabetic

Enteropathy: a 7-year Follow-up Study

Università Vita-Salute San Raffaele

Scuola di Specializzazione Chirurgia dell’Apparato DigerenteDirettore Prof. Carlo Staudacher

Diploma di Specializzazione del Dott.: Francesco LUPARINI matr. 001443

Background• DEFINITION: All gastrointestinal disorders associated with hyperglycaemia• EPIDEMIOLOGY: Ranging from 20-76%

Janatuinen (1993) Scan J Gastroenterol; Bytzer (2001) Arch Intern Med. ;Feldman (1983) Ann Intern Med; Maleki (2000) Arch Intern Med

• ETIOLOGY: Autonomic Neuropathy and Vasculopathy. Bjornsson (1994) Scand J. Gastroenterol ; Koch (1999) Dig Dis Sci

• SYMPTOMS: • Upper GI: Early satiety; Nausea; Vomiting; Heartburn ; Dysphagia;

Gastroparesis. • Lower GI: Constipation; Abdominal Pain; Diarrhea; Fecal incontinence.

• DIAGNOSIS IMAGING: Esophageal Manometry; Electrogastrography; Gastric Emptying Scintigraphy; Anorectal Manometry; Defecography; Electromiography

• THERAPY: only symptomatic and poorly effective

Francesco Luparini MD

Aims of the Study

1) To evaluate the effects of Kidney-Pancreas Transplantation (KP) or Kidney Alone (KD) through:

- Laboratory/Blood Pressure values

- Specimen of rectal mucosa

- Gastrointestinal symptoms/fecal incontinence

2) To correlate biochemical,functional and microscopic data in Kidney-Pancreas or Kidney transplantation toward Diabetic Enteropathy


Patients

• Patients: Type 1 Diabetic undergoing renal substitutive therapy

• Observation Period: 06/2000 – 06/2010

• Follow-up: 7 years (mean)


Methods

Evaluation during Recovery:Haematic samples for biochemical, metabolic values and

plasma sample for Ghrelin Elisa assay

Interview-based Questionnaire consisting of 15 items (GSRS;

Rating Scale for Gastrointestinal Symptoms) Svedlund (1988) Dig Dis Sci

Anorectal Manometry

Rectal mucosa biopsies for optical and electronic microscopy


Patients’ Characteristics IBaseline

KD (n=20)Age (yrs)* 43.4±7.0

Duration of Diabetes (yrs) 31.3±12.7

HbA1c (%) 8.5±1.6

Gender (male/female) 13/7

Time of Dialysis (months) 43.8±25.9

Laser-treated Retinopathy (%) 61%

Kidney Warm Ischemia (min) 45.2±21.3

Kidney Cold Ischemia (h) 7.6±9.5

BMI 23.7±3.1

Creatinine (mg/dl) 8.7±2.5eGFR (ml/min/1.73m2) 7.0±2.4

yrs= years ; Hb1Ac=Glycated hemoglobin; min= minutes BMI= body mass index; * p= 0.004

KP (n=26) Age (yrs)* 37.3±3.7

Duration of Diabetes (yrs) 27.6 ±6.2

HbA1c (%) 8.3±1.7

Gender (male/female) 17/9

Time of Dialysis (months) 53.4±30.2

Laser-treated Retinopathy (%) 72%

Kidney Warm Ischemia (min) 40.0±19.6

Kidney Cold Ischemia (h) 7.0±4.6

BMI 22.9±2.3

Creatinine (mg/dl) 8.4±2.6 eGFR (ml/min/1.73m2) 7.9±2.9


Patients’ Characteristics IIBaseline

KD (n=20)

BUN (mg/dl) 147.1±51.8

Uric Acid (mg/dl) 6.7±1.5

EIR (UI/die) 39.1±17.2

Systolic BP 146.3±18.7

Diastolic BP 82.8±8.5

TG (mg/dl) 191.7±119.2

Chol (mg/dl) 198.4±50.3

LDL (mg/dl) 109.7±37.1

HDL (mg/dl) 47.9±12.1

KP (n=26)

BUN (mg/dl) 142.0±44.0Uric Acid (mg/dl) 6.9±1.3EIR (UI/die) 37.4±11.0

Systolic BP 143.5±12.9

Diastolic BP 83.7±8.3

TG (mg/dl) 162.5±92.7

Chol (mg/dl) 201.0±45.7

LDL (mg/dl) 116.3±40.3

HDL (mg/dl) 48.1±14.4

eGFR= glomerular filtration rate; BUN= blood urea nitrogen; EIR= exogen insulin requirement; UI= international unit; BP= blood pressure; TG= Tryglicerids; Chol= cholesterol; LDL= low density lipoprotein; HDL= high density lipoprotein


Biochemistry

Basal 2 yrs 7 yrs (n=20) (n=15) (n=8)

Basal 2 yrs 7 yrs (n=26) (n=25) (n=22)

KP KD*

*

* p<0.01 vs. all

* p<0.01 vs. all


Biochemistry

Basal 2 yrs 7 yrs (n=20) (n=14) (n=12)

Basal 2 yrs 7 yrs (n=26) (n=26) (n=23)

KP KD*

*

*

*

* p<0.01 vs. all * p<0.01 vs. all

* p<0.01 vs. all * p<0.01 vs. all


Biochemistry

Basal 2 yrs 7 yrs (n=24) (n=24) (n=22)

Basal 2 yrs 7 yrs (n=17) (n=16) (n=9)

KP KDp=0.03

p<0.01


Biochemistry

Basal 2 yrs 7 yrs (n=22) (n=22) (n=20)

Basal 2 yrs 7 yrs (n=17) (n=17) (n=10)

KP KD


Biochemistry

Basal 2 yrs 7 yrs (n=11) (n=7) (n=2)

Basal 2 yrs 7 yrs (n=10) (n=6) (n=2)

KP KD

p= 0.02 p< 0.001

p= 0.01 p< 0.001


Blood pressure

Basal 2 yrs 7 yrs (n=25) (n=25) (n=22)

Basal 2 yrs 7 yrs (n=17) (n=16) (n=9)

KP KD

* p<0.01 vs. all

* p<0.01 vs. all

*

*


GSRS questionnaireKP KD

Basal 2 yrs 7 yrs (n: 18) (pts:13) (pts:10)

Basal 2 yrs 7 yrs (pts: 10) (pts:8) (pts:4)

p=0.03


GSRS questionnaireKD



KP


GSRS questionnaireKP KD




Anorectal Manometry


KD


KP

p=0.06

Normal value: 55-120 mmHgCorsetti, Passeretti (2009) Colorectal Disease


Anorectal Manometry


KP KD


p=0.01

Normal value: 160-370 mmHgCorsetti, Passeretti (2009) Colorectal Disease


Anorectal ManometryKP KD



Normal value: <100 mlCorsetti, Passeretti (2009) Colorectal Disease


Anorectal ManometryKP



KD

p=0.01

Normal value: 100-180 mlCorsetti, Passeretti (2009) Colorectal Disease


H&E

KP pre-tx

KP 2 years

KP 7 years

KD pre-tx

KD 2 years

KD 7 years

CD31 S100 Serotonin Glycentin PYY Somatostatin

Original magnification 20x

Pathology


PathologyKP KD


Control

Pre-tx

2 years

7 years

Pre-tx

2 years

7 years

Original magnification 40x

Pathology: Ki67KP KD


Pathology: Crypt of Lieberkühn

KP KD

p <0.01

p <0.01p <0.05


Pre-Tx

EM: Endothelium and Vases

Pre-Tx

KP KD

2 years 2 years

7 years 7 years

Control


EM: Endothelial Cells

p < 0.05

KP KD


EM: Endothelial CellsKP KD


EM: Mucosal Nerves

Pre-Tx Pre-Tx

KDKP

2 years 2 years

7 years 7 years

Control


EM: Mucosal Nerves KP KD

p <0.01 p <0.05

* * * p <0.05

p <0.01

p <0.05


EM: Schwann Cells

Pre-Tx Pre-Tx

KP KD

2 years 2 years

7 years 7 years

Control


EM: Schwann CellsKP KD


Overview IMPROVE STABLE WORSEN

Biochemical

Ghrelin KP- KD

Glycemia KP KD

Creat. & Uremia KP-KD

TG KP KD

ClinicalB. Pressure KP KD

Abd. Pain KP KD

Diarrhoea KP-KD

Microscopy

Immunohist. KP-KD

Ki-67 KP KD

Endothelium KP-KD

Nerves Vesicles KP KD

Schwann KP-KD

AnorectalManometry

Resting KP KD

Contraction KP KD

Reflex KP KD

Urgency KP KD

KP

KP

KP

KPFrancesco Luparini MD

Conclusions

KP tx, but not KD, improves diabetic enteropathy

• Effect on Biochemistry: improves glycemic and TG profile

• Effect on Symptoms: reduces abdominal pain

• Effect on Manometry: stabilises continence

• Effect on Ultrastructures: improves mitosis, nerves vesicles, endothelial and Schwann cells

Further studies are requested to confirm our observation in larger pool of kidney–pancreas recipients


effects of simultaneous kp transplantation vs kd single in type 2 diabetics: seven years follow-up

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