Diabetic Renal Transplant Patients Research Articles

Efficacy and safety of insulin degludec in renal transplant recipients with pre-existing diabetes

IntroductionGlycemic control is important in renal transplant receptions with diabetes. In the early post-transplant period, recovering renal function and concomitant steroids and immunosuppressants increase the risk of dysglycemia which adversely impacts allograft and patient survival. We evaluated the short-term efficacy and safety of insulin degludec in diabetic renal transplant patients in early post-transplant period in outpatient settings. Materials and methodsA real world prospective observational study in 61 diabetes patients with ESRD who underwent renal transplant and were followed up for three months at Endocrinology OPD post discharge, as per routine clinical practice. All patients received standard and individualized treatment with insulin degludec. The primary outcome was change in glycosylated hemoglobin (HbA1c) and the secondary outcomes included changes in fasting (FPG)and post-prandial plasma glucose (PPPG) levels and body weight. Safety assessments included reports of hypoglycemia and changes in serum levels of creatinine and tacrolimus. ResultsMean age and duration of diabetes of the participants were 53.17 ± 8.77 years and 14.55 ± 5.71 years, respectively. During follow up, there were significant reductions in mean HbA1c (8.11 ± 1.94% to 6.96 ± 1.33%) and FPG (220.61 ± 79.42 mg/dL to 120.00 ± 37.80 mg/dL) and PPPG (303.97 ± 105.90 mg/dL to 164.25 ± 51.10 mg/dL) levels. A total of 43 patients (70.49%) achieved HbA1c target of <7%. Serum levels of creatinine and tacrolimus also reduced significantly during follow up. No significant reductions in body weight. Nocturnal hypoglycemia was reported in five patients and no patients reported severe hypoglycemia. ConclusionInsulin degludec was effective and safe in long standing diabetes patients undergoing renal transplant. Insulin degludec was well tolerated and was effective in lowering FPG, PPPG and HbA1C in early post-transplant OPD settings.

Outcomes of SGLT2 Inhibitors Use in Diabetic Renal Transplant Patients

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are newly introduced hypoglycemic drugs that work by inhibiting glucose reabsorption at proximal renal tubules. The use of SGLT2 inhibitors in nontransplant diabetic patients with or without cardiovascular disease has well-established efficacy and safety. The risks of renal graft dysfunction and urinary tract infections might be the limiting factors for their use in renal transplant patients. Data regarding the safety and long-term efficacy of SGLT2 inhibitors use in diabetic renal transplant patients is scanty. The aim of the study is to report our experience with use of SGLT2 inhibitors in 8 diabetic renal transplant patients supported by literature review. Eight diabetic renal transplant patients were recruited from Tawam hospital during the period between June 2016 and January 2019. Demographic, clinical, and laboratory data were collected and analyzed. Adding SGLT2 resulted in significant decrease in hemoglobin A1c and body mass index after 12 months of treatment. There was significant negative correlation between the duration of treatment with SGLT2 and hemoglobin A1c. Diabetic renal transplant patients with stable kidney function had better glycemic control with use of SGLT2 inhibitors. There was no deterioration of kidney function and risk of recurrent urinary tract infection was low.

MON-170 OUTCOMES OF SGLT2 INHIBITORS USE IN DIABETIC RENAL TRANSPLANT PATIENTS- SINGLE CENTER EXPERIENCE

New-onset diabetes after transplantation (NODAT) is common among renal transplant patients. The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-transplant diabetic patients with cardiovascular (CV) disease has well established efficacy and safety. It has long term renal protective effects in patients with impaired kidney function. Data regarding the safety and long term efficacy of SGLT2 inhibitors use in diabetic renal transplant patients is lacking. We report our experience with use of SGLT2 inhibitors in diabetic renal transplant patients. A retrospective chart review study was conducted at our institution over 2 years from 6 /2016 until 10/2018. We included all diabetic transplant patients who were started on SGLT2 inhibitors. Demographic, clinical and laboratory data were collected and analyzed using descriptive analysis. Complications related to use of SGLT2 inhibitors were monitored. a total of 8 renal transplant patients were included, two patients (25%), had long standing diabetes mellitus type 2 and six patients (75%) had post-transplant diabetes (NODAT). The majority were males (75%), with mean age of 56.8 years. The co-morbid conditions in our cohort were hypertension (7 [87.5 %]), dyslipidemia (7 [87.5%]), history of urinary tract infection (2 [25%]) and obesity ( body mass index ) BMI > 30 (4 [50%]). Median years from transplantation were 9.6 years and all patients had transplant from living unrelated donors, with stable allograft function (eGFR >60). The immunosuppressant medications used were tacrolimus (62.5%), cyclosporine (37.5%), prednisolone (100%), and mycophenolate (62.5%), mycophenolic acid (37.5%) and all patients were maintained on triple therapy regime. The median baseline HbA1c was 9.3 and hypoglycemic medications used including; metformin (37.5%), gliclazide modified release (62.5%), DPP4 inhibitors (37.5%), insulin (37.5%), and dulaglutide 1.5 mg q wk (37.5%). SGLT2 inhibitors (empagliflozin (6), dapagliflozin (2)) were added for diabetic transplant patients for better glycemic control that was noted with minor reduction of HbA1c at 3 and 6 months in some patients. The renal graft functions were stable with use of SGLT2 inhibitors without any acute kidney injury event and there was minor reduction of weight. Incidence of acute urinary tract infections were low (1) and no reported fungal infections. The two patients who had previous history of UTI did not experience recurrent episodes, except one patient developed one episode of UTI after 1 year of SGLT2 use. SGLT2 inhibitors were well tolerated. diabetic renal transplant patients with stable kidney function and CKD stage I or II (eGFR>60), had slightly better glycemic control with use of SGLT2 inhibitors. There was no deterioration of kidney function and risk of recurrent UTI was low. Further studies are needed to explore the long term safety and efficacy of SGLT2 inhibitors in diabetic renal transplant patients.

Renal transplantation: Assessment of "at risk" diabetic foot and recommendations for mitigation.

We conducted a prospective study (between November 2013 and January 2015) to identify "foot at risk" in the diabetic renal transplant patients at a Tertiary Care Hospital in India. Patients (151) were divided into three groups: diabetic transplant recipients (n = 42), new onset diabetes after transplantation (NODAT) (n = 59), and controls (nondiabetic renal transplant recipients) (n = 50). Foot neuropathy and vasculopathy were assessed by standard methods. Patients with "at risk" feet were given foot care advice. Of the 151 patients, 144 patients were male and seven were female with a male:female ratio of 20:1. Peripheral neuropathy was present among 42.9% of diabetic transplant patients, 35.6% of NODAT patients, and 12% of control patients. Vasculopathy was present in 28.6% of diabetic transplant patients, 23.7% of NODAT patients, and 2% of control patients. On multivariate analysis, patient's age, mean time interval since transplantation, and HbA1c levels were significantly associated with neuropathy, whereas the duration of diabetes and vibration perception threshold was associated with vasculopathy. After undergoing renal transplantation, a significant number of diabetic and NODAT patients has their "feet at risk" who in future may develop full-blown lesions of the diabetic foot. Proper advice to patients and information to the treating doctor helps to mitigate the risk.

Efficacy and safety of enteric‐coated mycophenolate sodium in renal transplant patients with diabetes mellitus: post hoc analyses from three clinical trials

To examine the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) in renal transplant patients with diabetes mellitus, six- and 12-month data from three clinical trials with EC-MPS (Studies B301, B302, and myPROMS) were analyzed post hoc. Studies B301 (de novo patients) and B302 (maintenance patients) followed a randomized double-blind design whereas myPROMS was an open-label study in de novo and maintenance renal transplant patients in which all patients received EC-MPS as part of their immunosuppressive regimen. In studies B301 and B302, diabetic patients were compared against mycophenolate mofetil (MMF, CellCept), the reference drug. For myPROMS, data from diabetic and non-diabetic patients were compared. In total, 246 diabetic patients receiving EC-MPS were analyzed. In study B301, the efficacy failure rate [biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up] in diabetics at 12 months was 17.6% (EC-MPS) vs. 26.2% (MMF), and of BPAR alone 14.7% vs. 19.0% (both n.s.). In de novo patients from myPROMS, the treatment failure rate was similar in diabetic (20.3%) and non-diabetic patients (27.1%), as was the incidence of BPAR (17.7% vs. 23.1%, both n.s.). The overall incidence, severity and pattern of AEs were comparable between EC-MPS and MMF in de novo patients. This was supported by the safety results assessed in maintenance patients (B302) indicating no increased safety risk with the use of EC-MPS in the diabetic patient population, if compared with MMF. Likewise, apart from a higher incidence of severe/serious infections in diabetics, the safety profile of EC-MPS was not different to non-diabetics in myPROMS. In conclusion, preliminary data suggest that EC-MPS in combination with cyclosporine (+/- steroids) can be used efficiently and safely for the prophylaxis of organ rejection in diabetic renal transplant patients. Moreover, diabetic patients can apparently be safely converted from MMF to EC-MPS. More data from prospective studies are needed to fully judge the efficacy and safety profile of EC-MPS in the diabetic transplant population.

Mycophenolic Acid in Diabetic Renal Transplant Recipients

Limited sampling strategies may be useful in optimizing therapeutic drug monitoring of mycophenolic acid (MPA). Their use, however, may be limited by several patient factors, including comorbidity. In this study the pharmacokinetics of MPA in diabetic and nondiabetic renal transplant recipients were compared, and it was evaluated whether a limited sampling strategy developed and validated for nondiabetic patients can also be used in diabetic patients. The pharmacokinetics of MPA were analyzed on days 7 and 11 after transplantation in 136 renal transplant patients, among whom 7 patients had diabetes. All patients received cyclosporine and corticosteroids as maintenance immunosuppressive therapy. A limited sampling strategy [AUC (mg x h/L) = 7.182 + 4.607 C0 + 0.998 C0.67 + 2.149 C2] was developed and validated for nondiabetic patients and was subsequently tested for its usefulness in diabetic patients. Diabetic renal transplant patients did not have significantly different dose-normalized MPA area under concentration-time curve (AUC), MPA clearance, or MPA maximum concentration (Cmax). However, in diabetic patients Tmax (time of Cmax, 1.59 hours) was higher than for nondiabetic patients (0.67 hours) on day 11 (P = 0.04). The developed and validated limited sampling strategy performed acceptably, estimating MPA AUC in nondiabetic patients with a mean bias of 0.2 mg x h/L (95% confidence interval from -1.3 to 1.6 mg x h/L). Applying the limited sampling strategy in diabetic patients revealed a mean bias of -1.5 (-5.7, 2.7 mg x h/L). In conclusion, although diabetic renal transplant patients exhibit increased Tmax, this does not affect the accuracy of the limited sampling strategy.

Posttransplant bone disease

Even after a successful kidney transplantation with good kidney function, many renal transplant patients have disabling skeletal symptoms. Approximately 7% to 10% of renal transplant patients may experience a fracture, mainly of the cancellous bones but also of the vertebrae. The fracture frequency is even higher in female renal transplant patients and much higher still in diabetic renal transplant patients. Furthermore, approximately 60% of renal transplant patients have a significant reduction of the bone mineral content and bone mineral density, which is mainly manifest in the vertebrae and the hips. The etiology of posttransplant bone disease is multifactorial, depending on the pretransplant skeletal condition of the patient, on the immunosuppressive therapy given after transplantation, on posttransplant hormonal disturbances, and on the glomerular filtration rate that is obtained after transplantation. Bone biopsy studies have revealed alterations of bone remodeling that reflect a decrease in bone formation despite a continuing bone resorption. Prophylaxis and treatment of the posttransplant bone disease should take into consideration the numerous pathogenetic factors involved, which might vary significantly from patient to patient. As such, a “simple” and easy-to-manage protocol to be provided to all posttransplant patients has yet to be created.

Management of Hyperhomocysteinemia

Hyperhomocysteinemia is an established risk factor for cardiovascular disease. The modification of traditional cardiovascular risk factors has resulted in better morbidity and mortality outcomes, so the treatment of hyperhomocysteinemia is explored for a similar benefit. Vitamin B(6), vitamin B(12) and folate, as co-factors in the metabolism of homosyteine, are used in the treatment of hyperhomocysteinemia. Betaine, a methyl-donor in a separate homocysteine metabolism pathway, is also used to treat hyperhomocysteinemia. These supplements have been used in various doses and combinations for different periods of time, with favorable outcomes. There is still no concensus whether hyperhomocysteinemia can be treated with folic acid alone, or in combination with vitamin B(6) and vitamin B(12). The dose of the supplements required to normalize fasting homocysteine remains to be determined, especially in diabetic nephropathy, hemodialysis and renal transplant patients. The benefits from lowering homocysteine levels have mainly been demonstrated in surrogate cardiovascular outcomes. The treatment of hyperhomocysteinemia cannot be firmly advocated until there are trials that demonstrate a beneficial clinical endpoint. In patients who have cardiovascular disease in the absence of more established risk factors, investigation and treatment of hyperhomocysteinemia should be considered.

Cyclosporine trough levels in diabetic and nondiabetic renal transplant patients

Cyclosporine trough levels in diabetic and nondiabetic renal transplant patients

Clinical aspects and perspectives in islet xenotransplantation.

In 1990-1993, eight diabetic renal transplant patients had porcine fetal islets injected intraportally at Huddinge Hospital in Stockholm. Four of the patients had evidence of xenograft function reflected in the excretion of small amounts of porcine C-peptide. Two patients had the porcine fetal islets placed under the capsule of a simultaneously transplanted kidney. In one of these patients, a graft biopsy specimen taken 3 weeks after transplantation revealed morphologically intact epithelial cells staining positively for insulin and glucagon. The insulin production was in all instances insufficient to affect the patient's insulin requirements. All patients formed specific xenoantibodies (mostly anti-Gal); presumably, most of the xenoislets were destroyed by rejection. On follow-up studies carried out 6-8 years after xenotransplantation, most patients still had higher-than-pretransplant levels of xenoantibodies. There was no evidence of transmission of porcine endogeneous retroviruses to the patients. All patients expressed a positive attitude toward the use of animal tissue for treatment of disease, and none of the patients regretted participating in the trial. Cell transplantation is leading the way at present for clinical xenotransplantation. The finding that complement inhibition protects intraportally injected porcine islets from an injurious incompatibility reaction holds promise for future clinical application. A similar protective effect might be achievable with the use of islets from transgenic pigs expressing human complement receptors.

Xenoislet transplantation: experimental and clinical aspects.

Ten diabetic renal transplant patients had porcine fetal islet-like cell clusters (ICC) injected intraportally or placed under the kidney capsule. In some patients, temporary graft survival was achieved, as evidenced by the urinary excretion of small amounts of porcine C-peptide (4 patients) and the identification of some intact insulin-staining cells in a biopsy specimen (1 patient). Glucose metabolism remained unaffected. To improve the results, better islets and better immunosuppressive protocols are required. We found that, while fetal porcine ICC produced insulin only after several weeks, adult islets gave immediate insulin production. The search for an optimal immunosuppression was conducted in the pig-to-rat islet transplant model. A clear inhibitory effect on the xenograft rejection was observed when using some of the new drugs. The best results were achieved with a triple drug regimen consisting of cyclosporine, mycophenolate mofetil and leflunomide.

LONG-TERM OUTCOMES IN DIABETICS FOLLOWING CADAVERIC RENAL TRANSPLANTATION

568 Diabetes mellitus accounts for 20% of renal transplants annually. We retrospectively analyzed the long-term outcomes of 308 diabetic cadaveric renal transplant patients transplanted between 1984-1994 to determine the incidence of vascular and musculoskeletal complications. Three separate eras (1984-1987, 1988-1990, 1991-1994) were analyzed because of changing immunosuppressive strategies. The length of follow-up varied from 3 to 13 years. 10 year data for patient survival in Type I vs Type II diabetics was 48% vs 20% (p=0.0001). Similarly, graft survival was 35% vs 8% (p=0.0001). Trends in the more recent years included an older age at transplantation(p<0.001), more patients with Type II DM (p<0.0001), increased pre-transplant coronary artery disease (CAD) screening (p<0.0001), a higher rate of revascularization prior to transplant (p<0.0001) and more cerebrovascular disease (p=0.014). Post-transplant, there were higher rates of peripheral vascular disease in patients transplanted in 1990-1994 (p=0.003). There was no difference in the incidence of cardiovascular, cerebrovascular or musculoskeletal events in the post-transplant period in the three eras. However, 10 years post-transplantation, 44% had cardiac disease, 46% had peripheral vascular disease and 38% had amputations. Pre-transplant cardiac disease appeared to result in poorer post-transplant survival course (p=0.07). Type II diabetics with CAD had a worse outcome(p=0.02). 173 graft failures occurred; the most common causes being death with a functioning graft (51%), chronic rejection (19%), and acute rejection(13%). The most common cause of death was coronary artery disease (29%), followed by infection (16%). In conclusion, recipients with Type II DM have a higher rate of pre-transplant cardiovascular risk factors and hence a not unexpected poorer outcome primarily due to death from CAD. This study emphasizes the importance of aggressive screening for cardiac disease pre-transplant. There is also a suggestion that a very active pancreas-kidney transplant program at this center has added to the changing demographics in this population.

LONG-TERM OUTCOMES IN DIABETICS FOLLOWING CADAVERIC RENAL TRANSPLANTATION

568 Diabetes mellitus accounts for 20% of renal transplants annually. We retrospectively analyzed the long-term outcomes of 308 diabetic cadaveric renal transplant patients transplanted between 1984-1994 to determine the incidence of vascular and musculoskeletal complications. Three separate eras (1984-1987, 1988-1990, 1991-1994) were analyzed because of changing immunosuppressive strategies. The length of follow-up varied from 3 to 13 years. 10 year data for patient survival in Type I vs Type II diabetics was 48% vs 20% (p=0.0001). Similarly, graft survival was 35% vs 8% (p=0.0001). Trends in the more recent years included an older age at transplantation (p<0.001), more patients with Type II DM (p<0.0001), increased pre-transplant coronary artery disease (CAD) screening (p<0.0001), a higher rate of revascularization prior to transplant (p<0.0001) and more cerebrovascular disease (p=0.014). Post-transplant, there were higher rates of peripheral vascular disease in patients transplanted in 1990-1994 (p=0.003). There was no difference in the incidence of cardiovascular, cerebrovascular or musculoskeletal events in the post-transplant period in the three eras. However, 10 years post-transplantation, 44% had cardiac disease, 46% had peripheral vascular disease and 38% had amputations. Pre-transplant cardiac disease appeared to result in poorer post-transplant survival course (p=0.07). Type II diabetics with CAD had a worse outcome(p=0.02). 173 graft failures occurred; the most common causes being death with a functioning graft (51%), chronic rejection (19%), and acute rejection (13%). The most common cause of death was coronary artery disease (29%), followed by infection (16%). In conclusion, recipients with Type II DM have a higher rate of pretransplant cardiovascular risk factors and hence a not unexpected poorer outcome primarily due to death from CAD. This study emphasizes the importance of aggressive screening for cardiac disease pre-transplant. There is also a suggestion that a very active pancreas-kidney transplant program at this center had added to the changing demographics in this population.

Reduction of Gangrene and Amputations in Diabetic Renal Transplant Patients: the Role of a Special Foot Clinic

This 4-year prospective study investigated the reasons for high levels of gangrene and major amputation in diabetic renal transplant patients and whether regular multidisciplinary foot care could reduce morbidity. All foot lesions were documented and investigated in 50 diabetic patients, mean age 49.2 +/- 11.0 (SD) years, duration of diabetes 25.3 +/- 9.0 years, time since renal transplantation 60.2 +/- 35.1 months, who attended a special foot clinic monthly for education, vascular and neurological assessment, podiatry and footwear. Foot lesions included: neuropathic ulcers, ischaemic ulcers, traumatic lesions, Charcot's arthropathy, pathological fracture. Treatment included antibiotics, podiatry, footwear, and angioplasty or distal bypass where appropriate. Only 13 patients were deemed ischaemic but peripheral neuropathy was a very common finding (mean VPT 24.8 +/- 12.9 V). Gangrene and major amputations showed a decrease on previous years and healing times for lesions were similar to those previously reported in diabetic patients without renal transplants. The majority of foot lesions, both in soft tissue and bone, were related to neuropathy and trauma and responded well to optimal foot care within the renal unit. Gangrene and major amputations were usually preventable.

The nasogastric tube syndrome

The nasogastric tube can produce sudden, life-threatening bilateral vocal cord paralysis and is often an unrecognized cause of this clinical entity. The pathophysiologic mechanism is thought to be paresis of the posterior cricoarytenoid muscles secondary to ulceration and infection over the posterior lamina of the cricoid. Since our initial report of this entity in 1981, several cases have been photo-documented. Study of whole organ sections of an involved larynx have demonstrated the histopathology. Diabetic renal transplant patients appear to be particularly susceptible to the condition, due to prolonged gastroparesis and requirement for nasogastric tube drainage. Esophagoscopy should be performed promptly in these patients when pharyngodynia, hoarseness, or evolving stridor present in the postoperative period.