Objectives Kidney Complications With Diabetes Brian Boerner, MD Diabetes, Endocrinology, and Metabolism University of Nebraska Medical Center Review screening for, and management of, albuminuria Review when patients with diabetes should be referred to a nephrologist Discuss goals and considerations for management of hyperglycemia in patients with chronic kidney disease Discuss treatment of diabetes in kidney transplant recipients vol 2 Figure. Trends in the number of incident cases of ESRD, in thousands, by modality, in the U.S. population, 980 202 vol 2 Figure.7 Trends in (a) ESRD incident cases, in thousands, and (b) adjusted* ESRD incidence rate, per million/year, by primary cause of ESRD, in the U.S. population, 980 202 (a) Incident Cases (b) Incidence Rates Data Source: Reference tables A., A.2(2). *Adjusted for age, sex, and race. The standard population was the U.S. population in 20. Abbreviation: ESRD, end stage renal disease. Data Source: Reference table D. Abbreviation: ESRD, end stage renal disease. Source: USRDS 20 Annual Data Report, Vol 2 http://www.usrds.org/20/view/default.aspx Source: USRDS 20 Annual Data Report, Vol 2 http://www.usrds.org/20/view/default.aspx Case A A) Normal Glomerulus A 6 yo patient with years of type 2 diabetes presents to your clinic as a new patient. He smokes ½ ppd. Exam: Weight 260 lbs, BMI kg/m 2, BP 2/9. Meds: Metformin 000 mg BID, glipizide 0 mg BID, 0 mg daily In the context of diabetic kidney disease, what suggestions do you make for his care at this time? HbAc 7.8% <.7% Serum. 0.6. mg/dl egfr 6 >60 ml/min Spot urine alb:cr ratio 0 <0 mg/g B) Diabetic Nephropathy Thickened basement membrane Mesangial expansion (Kimmelstein-Wilson bodies) B 6
Diabetic Nephropathy Non modifiable risk factors Family history Race: Blacks, Mexican Americans Modifiable risk factors Poorly controlled blood glucoses Hypertension Smoking Obesity* Measures to prevent/delay diabetic nephropathy Glycemic control HbAc goal 7% or less for most patients with DM BP control BP goal <0/90 (<0/80 for select individuals) ACE inhibitor or ARB Albuminuria Yearly UAC ratio ACE Inhibitor or ARB if UAC > 0 Smoking cessation Risk of Microvascular Complications vs. AC in Type Diabetes Relative risk 20 0 0 Results From the DCCT Retinopathy progression Neuropathy progression Microalbuminuria progression 6 7 8 9 0 2 AC (%) Skyler JS. Endocrinol Metab Clin North Am. 996;2:2-2 8 When to refer to a nephrologist Case GFR < 60 ml/min* GFR < 0 GFR < 60 + proteinuria and/or GFR declining Severely increased albuminuria Difficult to control hypertension Patients with a kidney transplant A 6 yo patient with years of type 2 diabetes presents to your clinic as a new patient. He smokes ½ ppd. Exam: Weight 260 lbs, BMI kg/m 2, BP 2/9. Meds: Metformin 000 mg BID, glipizide 0 mg BID, 0 mg daily In the context of diabetic kidney disease, what suggestions do you make for his care at this time? HbAc 7.8% <.7% Serum. 0.6. mg/dl egfr 6 >60 ml/min Spot urine alb:cr ratio 0 <0 mg/g. Improve BG control a. Needs another agent, maybe insulin b. Weight loss 2. Monitor Cr closely with use of metformin. Recommend smoking cessation. Start ACE I or ARB. Consider referral to nephrologist Nephrol Dial Transplant. 2002;7(Suppl 7):9 0 Kidney Int Suppl (20). 20;:2 9 Case years later Kidney and Glucose Metabolism Your patient, now 60 yo, returns for follow up. Follows with nephrologist Renal function slowly declining Meds: Lantus 2 units BID, Humalog 0 units with meals + sliding scale PRN, lisinopril, amlodipine, As his kidney function declines, what would you expect to happen to his insulin dose requirements? Increase? Decrease? No significant change? HbAc 7.6% <.7% Serum 2. 0.6. mg/dl egfr 28 >60 ml/min The kidney plays a significant role in glucose metabolism Glucose production Provides up to 20% of gluconeogenesis in the fasting state Glucose utilization Glucose reabsorption SGLT2 Insulin metabolism 2
Kidney and Insulin Metabolism Insulin therapy in CKD/ESRD Reduced renal function impairment of insulin clearance Kidney metabolizes ~0 0% of secreted insulin Degradation occurs primarily in the proximal tubules Clearance of insulin reduced up to 90% in poorly functioning kidneys (animal study) Risk of hypoglycemia may be up to x higher in DM patients with CKD Higher risk in DM2 also Rabkin R et al. Diabetologia 98 Diabetic Medicine Volume 20, Issue 8, pages 62 6, 2 JUL 200 DOI: 0.06/j.6 9.200.002.x http://onlinelibrary.wiley.com/doi/0.06/j.6 9.200.002.x/full#f Little data/consensus on insulin regimens to use in CKD/ESRD Longer acting insulins (NPH, detemir, glargine) Theoretically, may be more problematic due to duration of action Little data to support any specific insulin regimen Insulin is not dialyzed Case years later Case years later Your patient, now 60 yo, returns for follow up. Follows with nephrologist Renal function slowly declining Meds: Lantus units BID, Humalog 8 units with meals + sliding scale PRN, As his kidney function declines, what would you expect to happen to his insulin dose requirements? HbAc 7.6% <.7% Serum 2. 0.6. mg/dl egfr 28 >60 ml/min Likely decrease insulin dose, may stay somewhat stable. Very unlikely to have increased insulin needs. Each individual patient may respond differently. Your patient, now 6 yo, returns for follow up. Renal function has declined further, plans being made for HD Meds: Lantus 0 units once a day, Humalog 2 units with meals, He is having intermittent hypoglycemic events, and would prefer a non insulin diabetes medication Is he a candidate for any noninsulin diabetes medications? What should be his goal HbAc? HbAc 7.% <.7% Serum.0 0.6. mg/dl egfr 2 >60 ml/min Diabetes Medications Diabetes Medications and Renal Function Medication Metformin Sulfonylureas Considerations in CKD/ESRD CI with Cr >. (females), >. (males) risk of lactic acidosis* Glyburide renally excreted (avoid). Glipizide and glimepiride primarily liver metabolized (still risk of hypoglycemia, use cautiously in CKD/ESRD) DPP inhibitors Limited data in CKD. Less risk of hypoglycemia. All but linagliptin require dose adjustment for renal function. SGLT 2 inhibitors Use not recommended with GFR < or 60, CI if GFR < 0 Thiazolidinediones Risk of fluid retention and heart failure (avoid) Alpha glucosidase Not recommended if Cr > 2 mg/dl inhibitors GLP receptor agonsists Not recommended with CrCl <0 60 ml/min
Glycemic targets in CKD Case years later Goal HbAc < 7%? HbAc may not be accurate in CKD/ESRD HbAc target for patients with CKD not established K/DOQI and KDIGO recommend HbAc goal of 7% Exception: Risk of hypoglycemia, significant co morbidities, limited life expectancy Reasons for inaccurate HbAc Your patient, now 6 yo, returns for follow up. Renal function has declined further, plans being made for HD Meds: Lantus 0 units once a day, Humalog 2 units with meals, He is having intermittent hypoglycemic events, and would prefer a non insulin diabetes medication Is he a candidate for any noninsulin diabetes medications? What should be his goal HbAc? HbAc 7.% <.7% Serum.0 0.6. mg/dl egfr 2 >60 ml/min Consider stopping insulin therapy, depending on home SMBG. Could consider glipizide or DPP inhibitor. Goal HbAc ~7%, assuming can be accomplished without significant hypoglycemia Case 6 years later Your patient was referred for kidney transplant Received living donor kidney transplant 2 weeks ago He is now on tacrolimus, mycophenolate mofetil, and prednisone mg daily for immunosuppression Blood glucoses over the past week: 80 20 mg/dl, on SSI insulin alone What treatment considerations do you need to make now that he is posttransplant? HbAc 7.2% <.7% Serum.2 0.6. mg/dl egfr 6 >60 ml/min Kidney transplantation Source: NIDDK (http://www.kidney.niddk.nih.gov) Relative Risk of Death *Adapted from Wolfe RA et al. NEJM 999. Risk Survival Equal 2. Equal 2. 0. 06 2 0 0 90 8 6 8 Days Since Transplantation Adjusted relative risk of death among 2,27 recipients of a first cadaveric kidney transplant Impact of kidney graft loss on patient survival Djamali A et al. CJASN 2006 Management of Diabetes After Kidney Transplant Several factors change post transplant that alter insulin requirements Improved renal function insulin requirements Immunosuppressants insulin requirements Steroids Tacrolimus (Prograf) Sirolimus (Rapamune) Weight gain insulin requirements Average weight gain 0 % in first year post transplant Management of Diabetes After Kidney Transplant Oral medications Metformin controversial, even with appropriate renal function Sulfonylureas Little data, risk of hypoglycemia and weight gain DPP inhibitors Some data, no effect on immunosuppressant (IS) levels, appear safe and reasonably effective GLP agonists very little data, concerns about effects of slowed gastric motility on IS levels Thiazolidinediones Little data, concern for fluid retention and risk of bone loss Insulin frequently required post transplant
Insulin therapy in Kidney Transplant Recipients Transplant specific situations Illness/infection Likely to change insulin requirements at least temporarily Education and communication Frequent blood glucose monitoring Kidney transplant allograft dysfunction decreased renal function Likely will require decrease in insulin doses, dose adjustments of oral medications Diabetes Care after Kidney Transplant Cardiovascular disease (CVD) Most common cause of death after kidney transplant Most common reason for loss of kidney graft = death (due to CVD) Management of blood sugars, lipids, smoking, BP, weight are paramount to reduce CVD risk Yearly flu shots Pneumonia vaccines NOT candidates for Shingles vaccine (live virus vaccine) Case 6 years later Conclusions Your patient was referred for kidney transplant Received living donor kidney transplant 2 weeks ago He is now on tacrolimus, mycophenolate mofetil, and prednisone mg daily for immunosuppression Blood glucoses over the past week: 80 20 mg/dl, on SSI insulin alone What treatment considerations do you need to make now that he is posttransplant? HbAc 7.2% <.7% Serum.2 0.6. mg/dl egfr 6 >60 ml/min Likely resume insulin therapy, given significant elevation in blood glucoses due to immunosuppressants and improvement in renal function. Monitor renal function closely. Discuss weight management. Aggressive lipid, BP management DM = most common cause of CKD/ESRD CKD can be prevented/delayed with aggressive management of DM, BP, albuminuria Early referral to nephrology for diabetic nephropathy is appropriate Treatment of DM in CKD requires diligence; review of oral meds for CI, side effects; frequently reduction in insulin doses Many non insulin medications not well studied in kidney transplant recipients; insulin frequently mainstay of therapy