Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes and implications for management

Table 1 Selection of studies that reported rates of new-onset diabetes after transplantation or other dysglycemic states

Ref.	Criteria	n	Rates
Cosio et al[3]	Use of medications, F BGL	490	13% at 1 yr
			33% dysglycemic
Hjelmesaeth et al[4]	Use of medications, F BGL, oGTT	201	20% at 3 mo
Vincenti et al[5]	oGTT	682	30% at 6 mo dysglycemic
Delgado et al[6]	oGTT, F BGL	374	6.7% at 4.1 yr
			25.1% dysglycemic
Ramesh Prasad et al[7]	F BGL or R BGL	151	20.5%
Luan et al[8]	oGTT	203	11.8% at 10 wk
			47.8% dysglycemic
Bayer et al[9]	Use of medications, F BGL, R BGL	640	31.4% at 1 yr
Bergrem et al[10]	Use of medications, F BGL, R BGL	301	13% at 10 wk
Valderhaug et al[11]	oGTT	1410	17% at 10 wk
			38% dysglycemic
Ciancio et al[12]	Use of medications	150	15%-22% at 4 yr
Israni et al[13]	Medications, F BGL	1840	13% at 5 yr
Wauters et al[14]	Use of medications, F BGL	1146	14.1% at 1 mo, 11.1% at 4 mo, 13.4% at 1 yr
			27%, 34.3% and 29.8% dysglycemic
Chan et al[15]	oGTT	292	24% at 6 mo
Vacher-Coponat et al[16]	Use of medications	289	16.8%-18.8% at 3 yr
Tillman et al[17]	oGTT	200	5% at 39 mo
			30.5% dysglycemic
Bonet et al[18]	F BGL, R BGL, oGTT	138	13% at 6 mo
Cole et al[19]	Use of medications, F BGL, oGTT	49	4% at 6 mo
Nagaraja et al[20]	Use of medications, F BGL	118	21% at 3 mo, 37% at 1 yr
First et al[21]	Use of medications, F BGL, HbA1c	634	17.8%-36.5% at 1 yr
Nagaraja et al[22]	oGTT	76	13% at 5 yr, 24% at 11 yr
			42% and 61% dysglycemic
Tokodai et al[23]	Use of medications, F BGL, R BGL	145	11.7% at 1 yr
Viecelli et al[24]	oGTT	83	17% at 3 mo, 15% at 15 mo
			31% and 21% dysglycemic
Weng et al[25]	Use of medications, F BGL, R BGL	166	29.5%
Schweer et al[26]	R BGL, HbA1c	526	16.7%
Prasad et al[27]	oGTT	439	20% at 3 mo
			33% dysglycemic
Silva et al[28]	HbA1c	638	21.3%-41.1% at 4 yr
Lv et al[29]	F BGL	428	20.3% at 5.7 yr

Definitions diabetes: F BGL ≥ 7.0 mmol/L (126 mg/dL) or ≥ 11.1 mmol/L (200 mg/dL) on oGTT or R BGL ≥ 11.1 mmol/L (200 mg/dL) plus symptoms. Other dysglycemic states. IFG: ADA criteria 5.6-6.9 mmol/L (100-125 mg/dL); WHO criteria 6.1-6.9 mmol/dL (100-125 mg/dL); IGT: oGTT 7.8-11.0 mmol/L (140-199 mg/dL). F BGL: Fasting blood glucose level; R BGL: Random blood glucose level; oGTT: 2-h oral glucose tolerance test.

Table 2 The rates of unrecognized dysglycemia in patients on the transplant waiting list

Ref.	Unrecognised on waiting list - diabetes	Unrecognised on waiting list - dysglycemia
Ramesh Prasad et al[7]	-	15%
Hornum et al[33]	-	33%
Bergrem et al[30]	8.1%	45.2%
Iida et al[32]	4%	30.4%
Caillard et al[31]	3.3%	15.2%
Bonet et al[18]	< 0.1%	8.9%

Table 3 Modifiable and non-modifiable risk factors associated with new-onset diabetes after transplantation or dysglycemic state

Variable	Ref.	Comment
ATG-divided dose	Stevens et al[48]	Increased dysglycemia compared to single dose in patients treated with Tac and sirolimus
African American	Kasiske et al[49] Shah et al[50] Johnston et al[51] Bayer et al[9]	OR = 1.68 RR = 1.38 HR = 1.56 HR = 1.35
Age	Kasiske et al[49]	Strong independent risk factor
		RR: 1.9-2.6
	Cole et al[52]	27707 registry patients OR: 1.33
		If > 60 yr
	Ghisdal et al[53]	OR 1.03 of NODAT for each
		6 mo of age
	Luan et al[8]	Increasing age associated with dysglycemia and new onset metabolic syndrome
	Luan et al[46]	Analysis of 25837 registry patients, increase in NODAT in each categorised group compared to reference 18-34 years old
	Israni et al[13]	HR: 1.33 of NODAT at 60 mo
	Tillmann et al[17]	Increase in dysglycemia at mean of 56 M post-transplant; RR of 1.28 for each 5 yr
	Mccaughan et al[54]	OR 1.4 per decade in 427 Northern Irish patients
	Schweer et al[26]	NODAT 56.1 yr vs 47.9 yr; P < 0.01
APCKD	de Mattos et al[55]	Increased 1 yr incidence in a matched cohort
	Hamer et al[56]	Multivariate analysis OR 2.4
	Johnston et al[51]	No increase found in 21564 USRDS patients
	Luan et al[46]	Multivariate analysis OR: 1.17
	Ruderman et al[57]	No increased risk found
Basiliximab	Aasebø et al[58]	Basilixmab (n = 134) vs no induction historical control; increased dysglycemic state P = 0.017
	Prasad et al[27]	In living recipients who elected to receive basiliximab OR 2.34 for NODAT at 3 mo
BMI	Kasiske et al[49]	Increased BMI, NODAT RR: 1.7
	Cole et al[52]	Multivariate analysis OR 1.76 for NODAT
	Luan et al[46]	Analysis of 25837 registry patients. increase in NODAT in each categorised group of BMI compared to reference < 20
	Israni et al[13]	BMI ≥ 30, HR 1.69 for NODAT at 60 mo
CMV	Hjelmesaeth et al[59]	Asymptomatic infection OR: 4.0 for NODAT at 10 wk
CNI –	Chan et al[15]	NODAT 17% vs 31%, low dose vs standard dose Tac
Higher levels	Cole et al[19]	Single arm study of 49 patients with a 4% 6 mo incidence of NODAT. Early glucocorticoid reduction and low dose CsA
	Suszynski et al[60]	Higher Tac levels (plus sirolimus) compared to lower Tac (plus sirolimus) or CsA/MMF higher rates of NODAT with 10 yr FU
CNI –	Vincenti et al[5]	RCT. Dysglycemia at 6 mo higher in Tac/MMF vs CsA/MMF: P = 0.05
Tac vs CsA	Cole et al[52]	27707 registry patients OR 1.51 for NODAT
	Luan et al[46]	Analysis of 25837 registry patients. Increase in NODAT OR: 1.24
	Vacher-Coponat et al[16]	No difference in CsA/Aza vs Tac/MMF in RCT (n = 289)
	Cotovio et al[44]	Retrospective multivariate analysis higher Tac not CsA levels associated with NODAT
Family history of diabetes	Bora et al[61]	Recipients from living related donors
	Santos et al[62]	Retrospective (n = 303). RR: 3.6 for NODAT
Gender	Kasiske et al[49]	Greater risk in males in registry patients
	McCaughan et al[54]	OR 2.2 for male gender in 427 Northern Irish patients
Genetic polymorphisms	Ghisdal et al[53]	rs7903146 polymorphism of TCF7L2 OR 1.6 of NODAT at 6 mol/L, but not associated with IGT
	Ghisdal et al[63]	Summarises known associations
	Kurzawski et al[64]	Polish Caucasian patients. Increasing SNPs associated with increased risk, OR = 1.37
	Yao et al[65]	Fok1 vitamin D polymorphism associated with NODAT OR 11.8 P = 0.012
	McCaughan et al[54]	7 SNPs involved with β-cell apoptosis associated with NODAT
	Nicoletto et al[66]	Adiponectin gene polymorphism associated with NODAT
	Tavira et al[67]	Mitochondrial haplogroup H associated with NODAT in Tac treated patients
Glucocorticoids	Boots et al[68]	Early glucocorticoid withdrawal associated with reduced NODAT incidence in the first year
	Ghisdal et al[53]	OR 2.78 of NODAT at 6 mol/L if AR treated with glucocorticoids
	Luan et al[46]	Analysis of 25837 registry patients. OR 1.42 for NODAT if discharged on maintenance. Glucocorticoid only induction associated with increase in NODAT OR: 1.31
	Rizzari et al[69]	Significant reduction in NODAT compared with historical control when glucocorticoids rapidly tapered
	Cole et al[19]	Single arm study of 49 patients with a 4% 6 mo incidence of NODAT. Early glucocorticoid reduction and low dose CsA
	Schweer et al[26]	Pulse glucocorticoid for BPAR associated with increasing NODAT incidence
HCV +	Kasiske et al[49]	HCV+, NODAT RR: 1.3
	Cole et al[52]	27707 registry patients OR for NODAT 1.82
	Johnston et al[51]	21564 USRDS registry patients, HR: 1.7 for NODAT
	Baid-Agrawal et al[70]	14 HCV+ 24 HCV- patients. HCV+ increased insulin resistance; P = 0.008
	Luan et al[46]	Analysis of 25837 registry patients. Increase in NODAT OR: 1.43
	Lv et al[29]	Cohort of 428 Chinese patients. NODAT associated with HCV at mean 5.6 yr follow up, OR = 2.72
	Prasad et al[27]	439 Indian patients, OR = 6.37
Hyper-parathyroidism post transplant	Ivarsson et al[71]	PTH > 13.8 pmol/L associated with NODAT at 1 yr, OR = 4.25
Impaired glycemic state pre-transplant	Ramesh Prasad et al[7]	Higher within the normal range random BSL associated with NODAT
	Bora et al[61]	IGT at time of transplant associated with NODAT
	Hornum et al[33]	IGT NOT predictive of NODAT
	Cotovio et al[44]	Higher fasting BGL associated with NODAT
Magnesium post-transplant	Garg et al[72]	1 mol/L lower Mg associated with dysglycemia; no association with 1M CNI trough level
Magnesium pre-transplant	Augusto et al[73]	Lower magnesium immediately pre-transplant associated with NODAT; P < 0.02
Metabolic syndrome post-transplant	Israni et al[13]	MS in first 6-12 mo associated with NODAT by 60 mo, HR = 3.46
	Luan et al[8]	10 W dysglycemia associated with MS
	Nagaraja et al[22]	Development of MS predicts progressive dysglycemia
Metabolic syndrome pre-transplant	Bayer et al[9]	HR: 1.34 for NODAT at 1 yr
Sirolimus	Teutonico et al[74]	No improvement when changing from CNI to sirolimus
	Ekberg et al[75]	Low dose sirolimus may confer less risk than low dose Tac
	Johnston et al[51]	20124 registry patients. Compared to CsA + MMF/AZA: Sirolimus + CsA HR 1.61; Sirolimus + Tac HR 1.66; Sirolimus + MMF/AZA HR 1.36
	Guerra et al[76]	RCT (n = 150) Tac/sirolimus vs Tac/MMF vs CsA/sirolimus. No difference in NODAT
	Gyurus et al[77]	Retrospective (n = 514). Sirolimus HR 3.5 for NODAT over 10 yr
	Veroux et al[78]	21 NODAT converted to sirolimus, 80% remission of NODAT on basis of F BGL
	Suszynski et al[60]	Increased risk with high dose Tac/low dose sirolimus combination

F BGL: Fasting blood glucose level; oGTT: 2-h oral glucose tolerance test; NODAT: New-onset diabetes after transplantation; ATG: Antithymocyte globulin; USRDS: United States Renal Data System; BMI: Body mass index; CMV: Cytomegalovirus; CNI: Calcineurin inhibitors; Tac: Tacrolimus; MMF: Mycophenolate mofetil.

Table 4 Risk of mortality, cardiovascular events and graft loss associated with new-onset diabetes after transplantation or dysglycemic state

	Mortality	CV event/death	Graft loss	Ref.
Diabetes at	3 mo: 37% at 8 yr (HR = 2.1)	20% (death) at 8 yr (HR = 3.5)		Hjelmesaeth et al[4]
	10 wk: 34% at 6.7 yr (HR = 2.0)			Valderhaug et al[11]
	1 yr: 44% at 11 yr (HR = 2.2)	Death HR: 2.72		Nagaraja et al[20]
Dysglycemia at	10 wk: 29% at 6.7 yr (HR = 1.78) each	Events increased with increased F BGL		Cosio et al[3]
	1 mmol/L oGTT: 5% risk increase
	4 mo: 0.5 mmol/L increase	1 mmol/L oGTT: 6% risk increase in death		Valderhaug et al[11]
	F BGL: 4% risk increase
	12 mo: 0.5 mmol/L increase F BGL: 15% risk increase	12 mo: 0.5 mmol/L increase F BGL: 11% risk increase for event		Wauters et al[14]
			3 mo: RR 3.6 at 6 yr	Wojtusciszyn et al[41]

F BGL: Fasting blood glucose level; oGTT: 2-h oral glucose tolerance test.