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![Modifiable risk factors:
SIROLIMUS
USRDS database : > 20,000 primary KT recipients receiving sirolimus
or CNI (CsA or Tac) or both in various combination therapies with an
antimetabolite [MMF or AZA]
Johnston et aL,
patients treated with sirolimus in combination with a CNI (CsA or
Tac) had the highest incidence of NODAT.
(Sir + Tac) combination therapy: hazard ratio of 1.9 for developing
NODAT compared with those receiving (Tac + MMF/AZA)
sirolimus was associated with an increased risk for NODAT
independent of any effect of tacrolimus.](https://image.slidesharecdn.com/nodat-170620020643/75/Nodat-16-2048.jpg)
![P: patients undergoing renal transplantation
I: 3-day postrenal transplant group treated with intensive
iv insulin [blood glucose (BG) 70–110 mg/dl] or a control
group treated with sc insulin (BG 70–180mg/dl)
O: primary endpoint: delayed graft function. Secondary
endpoints: glycemic control, graft survival, and acute
rejection episodes
M: randomized controlled trial
Hermayer et al. Glycemic Control on Renal Transplantation J Clin Endocrinol Metab, December 2012,
97(12):4399–4406](https://image.slidesharecdn.com/nodat-170620020643/75/Nodat-29-2048.jpg)
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Nodat
- 1. MelodyAtienza-Pena, MD The sweetsurrender... Melody Atienza-Peña, MD Glucose control in renal transplant
- 2. Objectives To present acase of post transplant Diabetes Mellitus To review the pharmacology of immunosuppressants that cause glucose dysreguation To discuss the current recommendations on glucose control during and post transplant To Discuss New onset diabetes after transplant, its diagnosis and approach to management
- 3. TAKE OFF CASE PATHOPHYSIOLOGYOF NODAT PHARMACOLOGY OF CALCINEURIN INHIBITORS IMPACT OF HYPERGLYCEMIA IN KIDNEY TRANSPLANTATION MANAGEMENT SUMMARY O U T L I N E INTRODUCTION
- 4. M.M. 47,male, married BMI 28 Worksas policeman Angeles city, Pampanga 30 pack year smoker and an alcoholic drinker Chronic kidney disease secondary to obstructive uropathy s/p kidney transplant LNRD June 17, 2009 4 ABDR MM , 0 DR match, blood type O+, crossmatch negative induction: simulect/ tacrolimus /MMF/ prednisone Immediate graft function discharge Creatinine 1.4 Admitted July 2009 (1 month post KT) due to elevated creatinine at 2.5,proteinuria +2, renal graft biopsy showed suspicious of acute rejection on renal graft biopsy, underwent MPPT pulsing
- 5. M.M. Wt 65kg 7/20/09 (Mg/day) 9/9/09 10/6/0911/6/09 12/2/09 2/5/10 4/6/11 11/23/11 3/19/12 1/10/13 8/23/13 9/23/14 Tacrolim us 6 6 6 6 10 10 Sirolimu s 2 2 2 2 2 HD trough 3.6 1.8 3.7 1.1 4.6 5.4 HD Pred 30 10 10 10 10 10 10 5 5 5 5 HD Crea 1.8 1.6 1.3 1.3 1.3 1.4 1.6 1.6 1.8 2.6 4.5 14 Urine protein +2 +1 +2 +2 +3 +2 +2 +2 +3 +3 FBS 83 146 265 167 210 167 134 174 119 150 262 Hba1c 8.3% 9.7% 10.8% Chole 240 204 194 281 199 339 TAG 336 463 224 353 234 787 Remaks Diamicro n 60mg Simva 40 Tacro to sirolimu s LBM prior Ator/ feno PTCA 3VD Post kt 1mo 2mo 3mo 4mo 6mo 8mo 10mo 1y 5mo 2yrs 9mo 3yrs 7 mos 4yrs 2mos 5 yrs 2mos
- 6. Tissues involved inGlucose Balance Harini A. Chakkera, MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research
- 7. Stress hyperglycemia during theearly post- transplant period is a common phenomenon and can affect up to 70–90 % of patients new-onset diabetes (NODA T) itself can affect around 40 % long term Pre transplant Diabetes Transient post transplant hyperglycemia Medication induced hyperglycemia New onset Diabetes After Transplantation Post transplantation Diabetes Mellitus Rodolfo J. Galindo 1 & Amisha Wallia, Hyperglycemia and Diabetes Mellitus Following Organ Transplantation, Curr Diab Rep (2016) 16:14 DOI 10.1007/s11892-015-0707-1
- 9. Incidence Diabetes is theprimary cause of renal disease in up to 28.4 % of adults on the waiting list for a kidney transplant in 2002, rising to 34.2 % by 2012 NODAT incidence: 24 to 37 % (12–36 months) in kidney transplantation Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 annual data report: kidney. Am J Transplant. 2014;14 Suppl 1:11–44 Rodolfo J. Galindo 1 & Amisha Wallia, Hyperglycemia and Diabetes Mellitus Following Organ Transplantation, Curr Diab Rep (2016) 16:14 DOI 10.1007/s11892-015-0707-1
- 10. PATHOPHYSIOLOGY OF NODAT Steroids insulinresistance increased liver gluconeogenesis decreased insulin secretion Sirolimus islet cell toxicity Harini A. Chakkera, MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research Pancreatic B cell dysfunction
- 11. Phuong-Thu T Pham,et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 12. Non modifiable riskfactors AGE Cosio et al, transplant recipients older than 45 years of age were 2.2 times more likely to develop NODAT than those younger at the time of transplantation (P , 0.0001). USRDS: In 11,000 Medicare beneficiaries who received primary KT 1996 - 2000 Kasiske et al: strong association between older age and NODAT. Compared to a reference range of 18–44 years of age transplant recipients age of 45–59 years= relative risk for NODAT of 1.9 (P = 0.0001) 60 years of age= relative risk of 2.09 (P , 0.0001) Phuong-Thu T Pham, et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 13. Non modifiable riskfactors RACE/ ETHNICITY USRDS : NODAT was more common among African Americans (RR = 1.68, P , 0.0001) and Hispanics (RR = 1.35, P , 0.0001) compared with Caucasians FAMILY HISTORY OF DIABETES The increased prevalence of NODAT associated with a family history of diabetes has been documented across all types of solid organ transplantation. Phuong-Thu T Pham, et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 14. Modifiable risk factors: CORTICOSTEROIDS Midtvedtand colleagues: prednisolone dose reduction from a mean of 16 mg daily (range 10 to 30) to 9 mg daily (range 5 to 12.5) resulted in an average increase in insulin sensitivity index of 24 % complete withdrawal of 5 mg/day of prednisolone did not influence insulin sensitivity significantly. OPTN/SRTR database: retrospective analysis consisting of 25,000 KT recipients January 2004 to December 2006 Luan et al, steroid-free immunosuppression was associated with a significant reduction in the likelihood of developing NODAT compared with steroid-containing regimens cumulative incidence of NODAT within three years post KT 12.3% in steroid-free versus 17.7% in steroid-containing regimens, P , 0.001. Phuong-Thu T Pham, et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 15. Modifiable risk factors: CALCINEURININHIBITOR The DIRECT Study: first multi-center open label, randomized trial assess glucose abnormalities in de novo kidney transplant patients who were randomized to cyclosporine microemulsion- (CSA-ME) or tacrolimus-based immunosuppression. The incidence of NODAT or IFG at 6-month post-transplant was significantly lower in CSA-ME (26%) vs tacrolimus- treated patients (33.6%) P = 0.046 lower proportion of CSA-ME patients with NODAT required hypoglycemic medication or dual therapy with insulin and oral hypoglycemic agents compared with their tacrolimus-treated counterparts. Phuong-Thu T Pham, et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 16. Modifiable risk factors: SIROLIMUS USRDSdatabase : > 20,000 primary KT recipients receiving sirolimus or CNI (CsA or Tac) or both in various combination therapies with an antimetabolite [MMF or AZA] Johnston et aL, patients treated with sirolimus in combination with a CNI (CsA or Tac) had the highest incidence of NODAT. (Sir + Tac) combination therapy: hazard ratio of 1.9 for developing NODAT compared with those receiving (Tac + MMF/AZA) sirolimus was associated with an increased risk for NODAT independent of any effect of tacrolimus.
- 17. Other Risk factorsfor NODAT OBESITY = BMI >30 kg/m2 Hypertriglyceridemia/ hypertension Bayer et al: prevalence of NODAT at 1 year increased with increasing number of metabolic syndrome score P = 0.001 0: 0%, 1: 24%, 2: 29%, 3: 31%, 4: 35%, 5: 74% low-density lipoprotein was independently associated with the development of NODAT HYPOMAGNESEMIA Van Laecke et al: hypomagnesemia during the first-month posttransplantation was associated with the development of NODAT, independent of the immunosuppressive regimen used CMV Hjelmesaeth and colleagues: asymptomatic CMV infection was associated with a 4x increased risk of new-onset diabetes (adjusted RR = 4.00; P = 0.025) CMV-induced release of proinflammatory cytokines may lead to apoptosis and functional disturbances of pancreatic β-cells resulting to decreased insulin release HCV insulin resistance; decreased hepatic glucose uptake and glycogenesis; and direct cytopathic effect of the virus on pancreatic β cells Phuong-Thu T Pham, et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 18. Calcineurin Harini A. Chakkera,et al, Calcineurin Inhibition and New-Onset Diabetes Mellitus After Transplantation, NIH Public Access, 2012
- 19.
- 20. Calcineurin inhibition oninsulin secretion Harini A. Chakkera, MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research
- 21. Calcineurin inhibitors andeffect on adipocytes Harini A. Chakkera, MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research
- 22. Calcineurin inhibitors andeffect on skeletal muscles Harini A. Chakkera, MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research
- 23. Tacrolimus vs. Cyclosporineand Glucose Homeostasis Harini A. Chakkera, MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research
- 24. Harini A. Chakkera,MD, MPH, Calcineurin Inhibitors: Pharmacologic mechanisms impacting both insulin resistance and insulin secretion leading to glucose dysregulation and diabetes mellitus, 2016 Mayo Foundation for Medical Education and Research
- 25. Impact of hyperglycemiaon Kidney Transplantation Early perioperative hyperglycemia in patients without pre transplant DM increased acute rejection episodes at BG > 145 mg/dl increased post-operative infections at BG > 200 mg/dl IFG (>100 mg/dl) or NODA T (FBG > 126 md/dl) was associated with increased risk up to 40 months: coronary artery disease (CAD) peripheral vascular disease (PVD) cerebrovascular accidents (CVA) Rodolfo J. Galindo 1 & Amisha Wallia, Hyperglycemia and Diabetes Mellitus Following Organ Transplantation, Curr Diab Rep (2016) 16:14 DOI 10.1007/s11892-015-0707-1 More rapid DM-related complications in NODAT (mean 500 days) renal (31.3 %) neurologic complications (16.2 %) ketoacidosis (8.1 %) ophthalmic complications (8.3 %) hypoglycemia/shock (7.3 %) peripheral circulatory disorders (4.1 %) hyperosmolarity (3.2 %)
- 26. Impact of NODATon allograft outcomes United Renal Data System data: over 11,000 Medicare beneficiaries who received primary KT from 1996 to 2000 NODAT was associated with: 63% increased risk of graft failure (P , 0.0001) 46% increased risk of death-censored graft failure (P , 0.0001) 87% increased risk of mortality (P , 0.0001) Phuong-Thu T Pham, et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 29. P: patients undergoingrenal transplantation I: 3-day postrenal transplant group treated with intensive iv insulin [blood glucose (BG) 70–110 mg/dl] or a control group treated with sc insulin (BG 70–180mg/dl) O: primary endpoint: delayed graft function. Secondary endpoints: glycemic control, graft survival, and acute rejection episodes M: randomized controlled trial Hermayer et al. Glycemic Control on Renal Transplantation J Clin Endocrinol Metab, December 2012, 97(12):4399–4406
- 31. Glycemic Targets During Hospitalization:AACE and ADA IV infusion for BG ≥ 180 mg/dl target: BG of 140– 180 mg/dl lower targets: 110– 140 mg/dl in selected patients Rodolfo J. Galindo 1 & Amisha Wallia, Hyperglycemia and Diabetes Mellitus Following Organ Transplantation, Curr Diab Rep (2016) 16:14 DOI 10.1007/s11892-015-0707-1 target pre-meal BG: <140 mg/dl random BG: < 180 mg/dl SQ basal-bolus regimen preferred NON CRITICALLY ILLCRITICALLY ILL
- 32. Subcutaneous insulin regimen Baldwin,et al two basal-bolus (glargine-glulisine) insulin- dosing regimens in hospitalized patients with DM and CKD (eGFR < 45) half-dose weight-based insulin regimen (TDD of 0.25 units/kg/day) was associated with 50 % less hypoglycemia (15.8 vs 30 %, p = 0.08) and similar glycemic control Baldwin D, Zander J, Munoz C, et al. A randomized trial of two weight-based doses of insulin glargine and glulisine in hospitalized subjects with type 2 diabetes and renal insufficiency. Diabetes Care. 2012;35:1970–4
- 33. Non insulin agentsin inpatient setting Umpierrez,et al, RCT noncritical ill patients with DM treated with sitagliptin alone or in combination with basal insulin may achieve glycemic targets with minimal hypoglycemia, particularly if admission blood glucose <180 mg/dl the use of oral hypoglycemic agents (OHAs) is not currently recommended for routine inpatient glycemic management Umpierrez GE, Gianchandani R, Smiley D, et al. Safety and efficacy of sitagliptin therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes: a pilot, randomized, controlled study. Diabetes Care. 2013;36:3430–5
- 34. Discharge Recommendations insulin therapyfor patients with immediate post-transplant hyperglycemia with the introduction of OHAs later HbA1c in all inpatients with known diabetes or with hyperglycemia, unless it was performed within the preceeding 2–3 months If the insulin dose discharge: >0.25 units/kg (on stable steroids): BASAL BOLUS INSULIN <0.25 units/ kg: BASAL INSULIN WITH CORRECTIONAL SCALE OR OHA diabetes education is a key for a safe discharge and should start as early as possible Rodolfo J. Galindo 1 & Amisha Wallia, Hyperglycemia and Diabetes Mellitus Following Organ Transplantation, Curr Diab Rep (2016) 16:14 DOI 10.1007/s11892-015-0707-1
- 35. MANAGEMENT NODAT Phuong-Thu T Pham,et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 37. Phuong-Thu T Pham,et al, New onset diabetes after transplantation (NODAT): an overview, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 175–186
- 38. Comorbid conditions DYSLIPIDEMIA Pravastatin andfluvastatin are used preferentially in transplant patients with dyslipidemia Sirolimus and glucocorticoids are associated with hypertriglyceridemia that may require treatment with fibrates, fish oil can be used as an alternative BLOOD PRESSURE The National Kidney Foundation: blood pressure control be maintained at below 130/80 mm Hg in renal transplant recipients ACE INHIBITORS AND ARBS are associated with decreases in GFR and hyperkalemia and should be used with caution in renal transplant recipients James T. Lane and Samuel Dagogo-Jack,Approach to the Patient with New-Onset Diabetes after Transplant (NODAT), J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
- 39. Comorbid conditions MICROALBUMINEMIA ominous findingthat is associated with glomerular injury and systemic inflammation from diverse causes no longer merely a marker of diabetic nephrop-athy predictor of renal al-lograft loss and increased mortality HYPERURICEMIA associated with cardiovascular disease, inflammation, insulin resistance, and decreased renal graft survival Herna ´ndez-Molina et al: recommended that interventions be targeted at patients with the highest pretransplant uric acid levels who are also receiving cyclosporine James T. Lane and Samuel Dagogo-Jack,Approach to the Patient with New-Onset Diabetes after Transplant (NODAT), J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
- 40. SUMMARY NODAT can affectup to 40% of patients long term The non modifiable risk factors should be known to identify high risk individuals And the modifiable and potentially modifiable risk factors are identified to optimize the management of NODAT The central pathophysiologic defect is pancreatic B-cell dysfunction in the context of insulin resistance Cyclosporine A and TACROLIMUS form complexes with the immunophilins cyclophilin A and FKBP12 (FK506-binding protein), respectively, and inhibit calcineurin phosphatase activity NODAT is associated with increased risk of graft failure and mortality Insulin is the preferred agent in the management of inpatient hyper-glycemia Management of NODAT is comprised of dietary and lifestyle modification, modification of immunosupprssive agents and and adequate monitoring of patients
- 41. Thank you forlistening!