Enteropatia Diabetica nel Trapianto Rene-Pancreas vs Rene Singolo: follow-up di 7 anni

1. Università Vita-Salute San Raffaele
Effects of Simultaneous Kidney-Pancreas and
Kidney Alone Transplantation on Diabetic
Enteropathy: a 7-year Follow-up Study
Scuola di Specializzazione Chirurgia dell’Apparato Digerente
Direttore Prof. Carlo Staudacher
Diploma di Specializzazione del Dott.:
Francesco LUPARINI
matr. 001443

2. 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

3. 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
Francesco Luparini MD

4. Patients
• Patients: Type 1 Diabetic undergoing renal
substitutive therapy
• Observation Period: 06/2000 – 06/2010
• Follow-up: 7 years (mean)
Francesco Luparini MD

5. 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
Francesco Luparini MD

6. Patients’ Characteristics I
Baseline
KP (n=26) KD (n=20)
Age (yrs)* 37.3±3.7 Age (yrs)* 43.4±7.0
Duration of Diabetes (yrs) 27.6 ±6.2 Duration of Diabetes (yrs) 31.3±12.7
HbA1c (%) 8.3±1.7 HbA1c (%) 8.5±1.6
Gender (male/female) 17/9 Gender (male/female) 13/7
Time of Dialysis (months) 53.4±30.2 Time of Dialysis (months) 43.8±25.9
Laser-treated Retinopathy (%) 72% Laser-treated Retinopathy (%) 61%
Kidney Warm Ischemia (min) 40.0±19.6 Kidney Warm Ischemia (min) 45.2±21.3
Kidney Cold Ischemia (h) 7.0±4.6 Kidney Cold Ischemia (h) 7.6±9.5
BMI 22.9±2.3 BMI 23.7±3.1
Creatinine (mg/dl) 8.4±2.6 Creatinine (mg/dl) 8.7±2.5
eGFR (ml/min/1.73m2) 7.9±2.9 eGFR (ml/min/1.73m2) 7.0±2.4
yrs= years ; Hb1Ac=Glycated hemoglobin; min= minutes
BMI= body mass index; * p= 0.004 Francesco Luparini MD

7. Patients’ Characteristics II
Baseline
KP (n=26) KD (n=20)
BUN (mg/dl) 142.0±44.0 BUN (mg/dl) 147.1±51.8
Uric Acid (mg/dl) 6.9±1.3 Uric Acid (mg/dl) 6.7±1.5
EIR (UI/die) 37.4±11.0 EIR (UI/die) 39.1±17.2
Systolic BP 143.5±12.9 Systolic BP 146.3±18.7
Diastolic BP 83.7±8.3 Diastolic BP 82.8±8.5
TG (mg/dl) 162.5±92.7 TG (mg/dl) 191.7±119.2
Chol (mg/dl) 201.0±45.7 Chol (mg/dl) 198.4±50.3
LDL (mg/dl) 116.3±40.3 LDL (mg/dl) 109.7±37.1
HDL (mg/dl) 48.1±14.4 HDL (mg/dl) 47.9±12.1
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
Francesco Luparini MD

8. Biochemistry
KP KD
*
* p<0.01 vs. all
*
* p<0.01 vs. all
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n=26) (n=25) (n=22) Francesco Luparini MD (n=20) (n=15) (n=8)

9. Biochemistry
KP KD
* *
* p<0.01 vs. all * p<0.01 vs. all
* *
* p<0.01 vs. all * p<0.01 vs. all
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n=26) (n=26) (n=23) (n=20) (n=14) (n=12)
Francesco Luparini MD

10. Biochemistry
KP KD
p=0.03
p<0.01
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n=24) (n=24) (n=22) Francesco Luparini MD(n=17) (n=16) (n=9)

11. Biochemistry
KP KD
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n=22) (n=22) (n=20) Francesco Luparini MD (n=17) (n=17) (n=10)

12. Biochemistry
KP KD
p= 0.02 p< 0.001
p= 0.01 p< 0.001
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n=11) (n=7) (n=2) (n=10) (n=6) (n=2)
Francesco Luparini MD

13. Blood pressure
KP KD
*
* p<0.01 vs. all
*
* p<0.01 vs. all
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n=25) (n=25) (n=22) (n=17) (n=16) (n=9)
Francesco Luparini MD

14. GSRS questionnaire
KP KD
p=0.03
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD

15. GSRS questionnaire
KP KD
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD

16. GSRS questionnaire
KP KD
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD

17. Anorectal Manometry
KP KD
p=0.06
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD Normal value: 55-120 mmHg
Corsetti, Passeretti (2009) Colorectal Disease

18. Anorectal Manometry
KP KD
p=0.01
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD Normal value: 160-370 mmHg
Corsetti, Passeretti (2009) Colorectal Disease

19. Anorectal Manometry
KP KD
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD Normal value: <100 ml
Corsetti, Passeretti (2009) Colorectal Disease

20. Anorectal Manometry
KP KD
p=0.01
Basal 2 yrs 7 yrs Basal 2 yrs 7 yrs
(n: 18) (pts:13) (pts:10) (pts: 10) (pts:8) (pts:4)
Francesco Luparini MD Normal value: 100-180 ml
Corsetti, Passeretti (2009) Colorectal Disease

21. Pathology
H&E CD31 S100 Serotonin Glycentin PYY Somatostatin
KP pre-tx
KP 2 years
KP 7 years
KD pre-tx
KD 2 years
KD 7 years
Original magnification 20x
Francesco Luparini MD

22. Pathology
KP KD
Francesco Luparini MD

23. Pathology
KP KD
Francesco Luparini MD

24. KP KD
Pathology: Ki67
Pre-tx Pre-tx
2 years 2 years
Control
Original magnification 40x
7 years Luparini MD
Francesco
7 years

25. Pathology: Crypt of Lieberkühn
KP KD
p <0.01
p <0.01
p <0.05
Francesco Luparini MD

26. KP KD
EM:
Endothelium and Vases
Pre-Tx Pre-Tx
2 years 2 years
Control
7 years
Francesco Luparini MD
7 years

27. EM: Endothelial Cells
KP KD
p < 0.05
Francesco Luparini MD

28. EM: Endothelial Cells
KP KD
Francesco Luparini MD

29. KP KD
EM:
Mucosal Nerves
Pre-Tx Pre-Tx
2 years 2 years
Control
7 years Luparini MD
Francesco
7 years

30. EM: Mucosal Nerves
KP KD
p <0.01 p <0.05
* * * p <0.05
p <0.01
p <0.05
Francesco Luparini MD

31. KP KD
EM:
Schwann Cells
Pre-Tx Pre-Tx
2 years 2 years
Control
Francesco Luparini MD
7 years 7 years

32. EM: Schwann Cells
KP KD
Francesco Luparini MD

33. Overview IMPROVE STABLE WORSEN
Ghrelin KP- KD
Glycemia KP KD
Biochemical
Creat. & Uremia KP
KP-KD
TG KP KD
B. Pressure KP KD
Clinical Abd. Pain
Diarrhoea
KP KP KD
KP-KD
Immunohist. KP-KD
Ki-67 KP KD
Microscopy Endothelium KP-KD
Nerves Vesicles KP KP KD
Schwann KP-KD
Resting KP KD
Anorectal Contraction KP KD
Manometry Reflex
KPKP
KP
KD
KD
Urgency
Francesco Luparini MD

34. 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
Francesco Luparini MD