Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy.

AIMS/HYPOTHESIS: The glucosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA1c. We hypothesised that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys. METHODS: This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30-65 years old, with a BMI of 25-35 kg/m2 and stable body weight (±2 kg) over the preceding 3 months, and HbA1c <42 mmol/mol (6.0%). Participants had undergone renal transplant with and without removal of native kidneys and were on a stable dose of immunosuppressive medications. Participants received a single dose of dapagliflozin 10 mg or placebo on two separate days, at a 5- to 14-day interval, according to randomisation performed by our hospital pharmacy, which provided dapagliflozin and matching placebo, packaged in bulk bottles that were sequentially numbered. Both participants and investigators were blinded to group assignment. RESULTS: Twenty non-diabetic renal transplant patients (ten with residual native kidneys, ten with bilateral nephrectomy) participated in the study. Dapagliflozin induced greater glucosuria in individuals with residual native kidneys vs nephrectomised individuals (8.6 ± 1.1 vs 5.5 ± 0.5 g/6 h; p = 0.02; data not shown). During the 6 h study period, plasma glucose decreased only slightly and similarly in both groups, with no difference compared with placebo (data not shown). Following administration of placebo, there was a progressive time-related decline in EGP that was similar in both nephrectomised individuals and individuals with residual native kidneys. Following dapagliflozin administration, EGP declined in both groups, but the differences between the decrement in EGP with dapagliflozin and placebo in the group with bilateral nephrectomy (Δ = 1.11 ± 0.72 µmol min-1 kg-1) was significantly lower (p = 0.03) than in the residual native kidney group (Δ = 2.56 ± 0.33 µmol min-1 kg-1). In the population treated with dapagliflozin, urinary glucose excretion was correlated with EGP (r = 0.34, p < 0.05). Plasma insulin, C-peptide, glucagon, prehepatic insulin:glucagon ratio, lactate, alanine and pyruvate concentrations were similar following placebo and dapagliflozin treatment. ß-Hydroxybutyrate increased with dapagliflozin treatment in the residual native kidney group, while a small increase was observed only at 360 min in the nephrectomy group. Plasma adrenaline (epinephrine) did not change after dapagliflozin and placebo treatment in either group. Following dapagliflozin administration, plasma noradrenaline (norepinephrine) increased slightly in the residual native kidney group and decreased in the nephrectomy group. CONCLUSIONS/INTERPRETATION: In nephrectomised individuals, the hepatic compensatory response to acute SGLT2 inhibitor-induced glucosuria was attenuated, as compared with individuals with residual native kidneys, suggesting that SGLT2 inhibitor-mediated stimulation of hepatic glucose production via efferent renal nerves occurs in an attempt to compensate for the urinary glucose loss (i.e. a renal-hepatic axis). TRIAL REGISTRATION: ClinicalTrials.gov NCT03168295 FUNDING: This protocol was supported by Qatar National Research Fund (QNRF) Award No. NPRP 8-311-3-062 and NIH grant DK024092-38. Graphical abstract.

A technique for retroperitoneal pancreas transplantation with portal-enteric drainage.

BACKGROUND: Pancreas transplantation (PTx) with portal-enteric drainage (PED) has been associated with difficulties in respect to arterial anastomosis and graft accessibility for percutaneous biopsy. We describe a new technique that circumvents these difficulties. METHODS: Between April 2001 and April 2004, a total of 113 recipients were scheduled for PTx with PED. The superior mesenteric vein was approached from the right retroperitoneal aspect instead of from the anterior transmesenteric route. The pancreas graft was eventually placed in the right retroperitoneal space, being covered by the ascending colon and its mesentery. RESULTS: One hundred ten (97.3%) PTx were performed as planned. Systemic venous effluent was preferred in three patients because of incidental diagnosis of liver cirrhosis during surgery (n=1) and severe obesity (body mass index>35 kg/m2) (n=2). The Y iliac artery graft was kept as short as possible, and arterial anastomosis was always performed with ease. After a mean follow-up period of 21.2+/-19.9 months, the relaparotomy rate was 13.6%. No patient died after repeat surgery, and none required multiple relaparotomies. Overall, 10 grafts were lost because of acute rejection (n=3), chronic rejection (n=2), venous thrombosis (n=2), recipient death (n=2), and late (6-month) arterial thrombosis (n=1). One-year patient and graft survival were 98.1% and 90.7%, respectively. CONCLUSIONS: Our data confirm that PTx with PED is not associated with an increased risk. The technique described has distinctive technical advantages and should be included in the repertoire of PTx.

Pregnancy after renal transplantation in Italian patients: focus on fetal outcome.

BACKGROUND: In the last few years advances in surgical techniques and immunosuppression have improved not only survival, but also quality of life in organ transplanted patients. Hence, the number of women of child-bearing age who decide to have a child--which means resuming a normal life--has increased. This multicenter retrospective study describes pregnancies after kidney transplantation and is the first such survey in Italy. METHODS: We analyzed the outcomes from 56 pregnancies in 42 kidney transplant recipients from data collected in questionnaires, hospital records, and phone interviews. All recipients were maintained on cyclosporine (CsA), azathioprine (AZA), corticosteroids or tacrolimus (FK506) before and during pregnancy. RESULTS: The average time from transplantation to childbirth was 62 months (range 12 to 180). Complications arose during pregnancy in 16 out of 36 term pregnancies (44.4%). Four transplant rejections (11.8%) were documented, two of them irreversible. Thirty-six infants were born, and 20 abortions reported (35.7%). Of these 36 babies, 16 (44.4%) were born at term, and 20 (55.6%) before term. Thirty-three Cesarean sections were performed (91.7%). Among the 20 pre-term babies, 11 can be grouped as follows: 5 low-birth-weight (LBW) (13.9%), 4 very low-birthweight (VLBW) (8.3%) and 2 extremely very low-birth-weight (EVLBW) (5.6%). The children were followed up for periods ranging from 2 months to 13 years. CONCLUSIONS: In kidney transplant recipients who became pregnant the incidence of spontaneous abortion and preterm delivery was increased. Newborns delivered to these patients had low birth weight, but no congenital defects were noted and their development was normal.

Outcome of pregnancy after organ transplantation: a retrospective survey in Italy.

The number of women who decide to have a child after organ transplantation has increased. We determined the outcomes of 67 pregnancies of women who had undergone kidney, liver or heart transplantation. All recipients had been maintained on immunosuppressive therapy before and during pregnancy. Pregnancy complications at term were observed in 17 out of 67 women (25%), hypertension being the most frequent complication (16.17%). Two transplant rejections were reported. Sixty-eight infants were delivered (including one pair of twins); five women had two pregnancies at term. Twenty-eight miscarriages (29.2%) were recorded. Of these 68 babies (including the pair of twins), 40 (58.8%) were born at term and 28 (41.2%) before term. The babies were followed-up for 2 months to 13 years. According to our previous experience, our study shows that patients who have undergone organ transplantation can give birth to healthy infants as long as they are monitored accurately during pregnancy.