Glucose Intolerance in Potential Kidney Donors Fasika M. Tedla, MD, MSc Associate Professor of Clinical Medicine Medical Director of Kidney Transplanation SUNY Downstate Medical Center 11th Annual International Conference on Nephrology and Hypertension January 19, 2018

Case Presentation 29-year-old potential donor to his 63-year-old diabetic mother Both parents have DM BMI=26 OGTT: fasting=91, 2hr=135 HgbA1c=5.6 eGFR=144ml/min 24hr protein excretion = 51mg

Clinical Question Is the risk-benefit ratio of him donating a kidney to his mother favorable? Does he have normal glucose metabolism? What is his risk of developing diabetes? What is his risk of developing renal failure without donation? Will donation accelerate his progression to renal failure? What is the impact of transplantation on his mother’s survival?

Diabetes - Magnitude 422 million worldwide in 2014 Prevalence in US ~ ¼ (24%) undiagnosed 34% (84.1 million) adults - prediabetes High prevalence in Black and Mexican Americans ~ 114 million American adults– diabetes or prediabetes https://www.who.int/diabetes/global-report/en/ https://www.cdc.gov/diabetes/data/statistics/statistics-report.html

Diabetes and ESRD USRDS ADR - 2018

ADA Criteria Fasting Glucose (mg/dL) 2-hour OGTT (mg/dL) Random blood glucose Normal <100 <140 Impaired 100 –125 140-199 DM ≥126 ≥200 ≥200 + symptoms HgbA1c (%) <5.7 5.7-6.4 ≥6.5 ADA. Diabetes Care. 2011;34 Suppl 1:S11-61

ADA criteria - basis Diabetes Care 25(Suppl 1): S5–S20, 2002

ADA criteria - basis McCance et al. BMJ 1994;308:1323-8

Glucose Homeostasis Glu Production intake Glu Disposal Hepatic resistance Peripheral resistance Curry et al. Endocrinology. 1968. 83:572.

Diabetes: Insulin Secretion vs. Sensitvity Rare Syndromes Type I Diabetes Type II Diabetes Insulin sensitivity Insulin Secretion

Oral Glucose Tolerance Test Nathan et al. Diabetes Care. 2007. 30(3):753-9.

The Road To Type II Diabetes 2593 aged 45-64 10yr follow up DM from National health service registry 2h OGTT HR <92 1 92-110 2.2 111-139 4.4 140-200 17.3 Qiao et al. Diabetic Medicine.2003:20 (12); 1027-1033.

The Road To Type II Diabetes Knowler et al. N Engl J Med. 2002. 346(6):393-403.

The Road To Type II Diabetes Lancet Diabetes Endocrinol. 2015 Nov;3(11):866-75

The Road To Type II Diabetes 50-81 82-86 87-90 90-94 95-99 Incidence for Q1 = ~ 1/700 person-years; mean follow up 5.7 years Tirosh et al. N Engl J Med. 2005. 353(14):1454-62.

The Road To Type II Diabetes Tirosh et al. N Engl J Med. 2005. 353(14):1454-62.

The Road To Type II Diabetes Tirosh et al. N Engl J Med. 2005. 353(14):1454-62.

The Road To Type II Diabetes Nichols et al. Am J Med. 2008 Jun;121(6):519-24.

The Road To Type II Diabetes Martin et al. Lancet. 1992; 340:925-929

Clinical Question Is the risk-benefit ratio of kidney donation to his mother favorable? Does he have normal glucose tolerance? What is his risk of developing diabetes? What is his risk of developing renal failure without donation? Will donation accelerate his progression to renal failure? What is the impact of transplantation on his mother’s survival?

Risk of Nephropathy in DM Ritz E, Orth SR. N Engl J Med. 1999; 341:1127-1133

Risk of Nephropathy in DM Ritz E, Orth SR. New Engl J Med. 1999; 341:1127-1133

Impact of Family History No diabetic nephropathy 11 probands, mean duration = 26yrs 12 siblings,mean duration = 18yrs Diabetic nephropathy 26 probands, mean duration = 23 yrs 29 siblings, mean duration=22 yrs Rate of nephropathy in sibs 17% with DN- Vs. 83% with DN+ probands No Δ in duration of DM, BP, HgbA1C Seaquist et al. N Engl J Med. 1989; 320: 1161–1165

Clinical Question Is the risk-benefit ratio of kidney donation to his mother favorable? Does he have normal glucose tolerance? What is his risk of developing diabetes? What is his risk of developing renal failure without donation? Will donation accelerate his progression to renal failure? What is the impact of transplantation on his mother’s survival?

Risk of Kidney Disease in Donors Norwegian donors vs controls:1 HR for ESRD 11.4 Longer duration of follow up for donors (44 vs 26 yrs) All donors with ESRD related to recipients and most had immunologic kidney disease Low event rates: 9 donor ESRD, 31 total OPTN Vs. NHANES2 96,217 donors (1994-2011) vs 9364 NHANES III (1988-1994) Matched with replacement Adjusted cumulative incidence of ESRD at 15 yrs: 30.8 vs 3.9 per 10000 Underestimate of risk in non-donors Non-donors: longer follow up and low event rates, repeatedly sampled Competing risk : non-donors more likely to die than develop ESRD Ascertainment bias: non-donors with advanced CKD may not be on wait list Mjoen et al. Kidney Int. 2014;86(1):162-7. Muzaale et al. JAMA. 2014; 311(6):579-86.

Identifying High-Risk Potential Donors http://www.transplantmodels.com/esrdrisk Estimates 15-year and lifetime risk of ESRD Based on 7 cohorts (US [5], Candada [1], Israel [1]), median follow up 4-16 years but most 6-8 range) Commonly recognized predictors – (Age, gender, race, systolic BP, BMI, smoking, eGFR, ACR, DM, BP medication) 98% US donors had predicted 15-year incidence of < 2% Utility? e.g. family history of kidney disease, relevance to lifetime risk Grams et al. N Engl J Med. 2016;374(5):411-21.

Non-linear Risk After Donation Incidence of ESRD after donation increases with time1 10/10,000 at 10 years 85/10,000 at 25 years GN-related ESRD appears earlier; diabetic and HTN ESRD later Aggregation of risk factors may accelerate loss of renal function in donors2 HTN, DM, proteinuria Family history increases risk of HTN and DM after donation3 Young age at donation a risk for black but not white donors4 Anjum et al. Am J Transplant. 2016 Dec;16(12):3540-3547 Ibrahim et al. J Transplant. 2017 Dec;17(12):3141-3148 Lentine et al. Transplantation. 2011 Jun 15;91(11):1227-32. Wainright et al. Am J Transplant. 2018 May;18(5):1129-1139.

Diabetic Nephropathy After Donation No human study comparing impact of diabetes on donors and two-kidney controls Donor with vs without post donation DM Difference in rate of decline of GFR with aggregation of risk factors1 HTN, DM, proteinuria Likely confounded by Difference in underlying renal disease Hyperfiltration in early DN Ibrahim et al. J Transplant. 2017 Dec;17(12):3141-3148

Diabetic Nephropathy After Donation Zheng et al. Nephron Exp Nephrol. 2011;119(1):e21-32.

Diabetic Nephropathy After Donation Zheng et al. Nephron Exp Nephrol. 2011;119(1):e21-32.

Clinical Question Is the risk-benefit ratio of kidney donation to his mother favorable? Does he have normal glucose tolerance? What is his risk of developing diabetes? What is his risk of developing renal failure without donation? Will donation accelerate his progression to renal failure? What is the impact of transplantation on his mother’s survival?

Gain in Survival After Transplantation Wolfe et al. New Engl J Med. 1999; 341(23):1725-30

Gain in Survival After Transplantation Age Gain in years All 10 0 –19 13 20 – 39 17 40 – 59 11 60 – 64 4.3 65 – 69 2.8 70 – 74 1 Wolfe et al. N Engl J Med. 1999;341(23):1725-30

Clinical Question Is the risk-benefit ratio of kidney donation to his mother favorable? Does he have normal glucose metabolism? What is his risk of developing diabetes? What is his risk of developing renal failure without donation? Will donation accelerate his progression to renal failure? What is the impact of transplantation on his mother’s survival?

Conclusion OGTT results - interpret within context History of diabetes in first-degree relatives History of diabetic ESRD in first-degree relatives Abnormalities of glucose metabolism - continuum Kidney donation – risk low in short to intermediate time range. Current data likely underestimate longterm risk Donor evaluation – focus on informing individualized risk and uncertainties rather than declaring safety of donation Risk of kidney donation in those at risk for diabetes – likely higher Caution in the young Recipient prognosis?