Is Non-Adherence Associated with Adverse Outcomes in Kidney Transplant Recipients? The Role of Non-Adherence as a Risk and Predictor Factor for Graft Loss and Death

Figures & data

Table 1 Non-Adherence Definition and Assessment Methods

Name	Definition	Assessment	Timeframe
Holistic non-adherence (HNA)	It is the modification or non-compliance with the therapeutic regimen that endangers the graft’s survival or functionality, made by the patient consciously or unconsciously, openly or secretly, intentionally or unintentionally. Operationally, a non-adherent patient fails to attend monthly check-ups, omits or modifies the doses of his medications, or persistently disobeys medical orders regarding taking biopsies, hospitalization, laboratory tests, and/or careful behavior.	Semi-structured interview by the mental health group. Self-base information and medical records.	Since the transplant.
Immunosuppression non-adherence (INA)	Any failure in immunosuppression compliance. Understand by having missed one or more doses of immunosuppressive medication, poor knowledge of the daily medication, modification of the treatment without medical indication and inappropriate time of the immunosuppressors intake.	Semi-structured interview by the mental health group. Self-base information.	In the last month.
Suboptimal immunosuppressor levels (SIL)	Immunosuppressor levels are requested for dose adjustment and regarding the patient’s clinical condition. The main factors contributing to the need for follow-up include the worsening of renal function, instances of acute rejection, clinical or laboratory findings indicating toxicity, recurrent infections, secondary or adverse events, and modifications to pharmaceutical treatment that affect the metabolism of immunosuppressants. The suboptimal levels are considered only after adequate levels were obtained, and defined as tacrolimus <5 ng/mL, sirolimus <4 ng/mL, everolimus <4 ng/mL and cyclosporine <100 ng/mL.	Medical records.	Since the transplant
Appointment non-adherence (ANA)	One or more failures to attend the medical appointments after transplant.	Medical records.	Since the transplant
Procedure non-adherence (PNA)	One or more episodes of disobeying medical procedure orders (taking biopsies, hospitalization, laboratory tests) after transplant	Medical records.	Since the transplant

Table 2 Characterization of Adherent and Non-Adherent Patients and Their Outcomes

	Adherent (N=527)	Non-Adherent (N=212)	Total (N=739)	P-value
Age in years, median [IQR]	47.0 [36,58]	45.5 [35.7,57]	47.0 [37,58.5]	0.139^a
Age categories, n (%)
Less than 10	1 (0.2%)	0 (0%)	1 (0.1%)	0.687 ^b
Between 11–20	15 (2.8%)	12 (5.7%)	27 (3.7%)
Between 21–65	455 (86.3%)	180 (84.9%)	635 (85.9%)
More than 65	56 (10.6%)	20 (9.4%)	76 (10.3%)
Sex, n (%)
Female	235 (44.6)	83 (39.2)	318 (43.0)	0.204^b
Male	292 (55.4)	129 (60.8)	421 (57.0)
Marital status, n (%)
Single	154 (29.2)	68 (32.1)	222 (30.0)	0.014*^b
Stable marital union	313 (59.4)	107 (50.5)	420 (56.8)
Dissolved marital union	32 (6.1)	12 (5.7)	44 (6.0)
Underage	6 (1.1)	8 (3.8)	14 (1.9)
Other	22 (4.2)	17 (8.0)	39 (5.3)
Social support, n (%)
Functional	463 (87.9)	167 (78.8)	630 (85.3)	0.020*
Poor	48 (9.1)	29 (13.7)	77 (10.4)
Inadequate	16 (3.0)	16 (7.5)	32 (4.3)
Transplant group, n (%)
Single-center transplant care by our group	417 (79.1)	119 (56.1)	536 (72.5)	<0.001**^b
Divided transplant care	110 (20.9)	93 (43.9)	203 (27.5)
Time after transplantation, n (%)
Between 0 and 12 months	93 (17.6)	18 (8.5)	111 (15.0)	<0.001**^b
Between 13 and 60 months	224 (42.5)	76 (35.8)	300 (40.6)
61 months or more	210 (39.8)	118 (55.7)	328 (44.4)
Number of transplants, n (%)
First	512 (97.2)	207 (97.6)	719 (97.3)	0.905^b
Second or more	15 (2.8)	5 (2.4)	20 (2.7)
Donor type, n (%)
Cadaveric	342 (64.9)	144 (67.9)	486 (65.8)	0.484^b
Living	185 (35.1)	68 (32.1)	253 (34.2)
Socioeconomical status, n (%)
Low	343 (65.1%)	134 (63.2%)	477 (64.5%)	0.311 ^b
Medium	171 (32.4%)	76 (35.8%)	247 (33.4%)
High	13 (2.5%)	2 (0.9%)	15 (2.0%)
Graft rejection, n (%)
No	503 (95.4)	194 (91.5)	697 (94.3)	0.055^b
Yes	24 (4.6)	18 (8.5)	42 (5.7)
Graft loss, n (%)
No	518 (98.3)	194 (91.5)	712 (96.3)	<0.001**^b
Yes	9 (1.7)	18 (8.5)	27 (3.7)
Mortality, n(%)
No	506 (96.0)	193 (91.0)	699 (94.6)	0.011*^b
Yes	21 (4.0)	19 (9.0)	40 (5.4)

Notes: ^aComparison by Mann-Whitney U-test. ^bComparison by chi-square test *Statistically significant result p<0.05 **Very statistically significant p < 0.005.

Figure 1 Venn diagram of non-adherence patients by definition. HNA: Holistic non-adherence; PNA: Procedure non-adherence; ANA: Appointment non-adherence; INA: Immunosuppression non-adherence and SIL: Suboptimal immunosuppression.

Table 3 Multivariate Analysis of the Main and Secondary Outcomes

	Mortality				Graft Loss				Graft Rejection
	Un-Adjusted OR		Adjusted OR^a		Un-Adjusted OR		Adjusted OR^a		Un-Adjusted OR		Adjusted OR^a
	OR (CI 95%)	p-value	OR (CI 95%)	p-value	OR (CI 95%)	p-value	OR (CI 95%)	p-value	OR (CI 95%)	p-value	OR (CI 95%)	p-value
Age (years)	1.05 (1.02–1.07)	<0.001 **	1.05 (1.02–1.08)	<0.001 **	0.96 (0.93–0.99)	0.012*	0.93 (0.90–0.97)	0.001*	0.95 (0.93–0.98)	<0.001 **	0.96 (0.94–0.98)	0.002**
Sex (Reference feminine)
Masculine	1.81 (0.93–3.76)	0.091			0.94 (0.43–2.08)	0.880			1.007 (0.53–1.91)	0.981
Marital status (Reference stable marital union)
Single	4.73 (0.18–1.04)	0.084			1.23 (0.54–2.85)	0.562	0.60 (0.21–1.60)	0.322	1.75 (0.88–3.44)	0.104
Dissolved marital union	1.06 (0.24–3.18)	0.920			0.62 (0.03–3.21)	0.656	1.06 (0.05–6.13)	0.956	0.49 (0.02–2.45)	0.493
Underage	EV	0.988			EV	0.988	EV	0.986	5.75 (1.22–20.33)	0.015*
Other	1.21 (0.28–3.65)	0.760			0.71 (0.03–3.65)	0.744	5.38 (0.02–3.06)	0.566	1.14 (0.17–4.14)	0.862
Transplant care group (Single-center care by Colombiana de trasplantes)
Divided transplant care	1.85 (0.93–3.48)	0.071			1.86 (0.82–4.04)	0.121			0.51 (0.20–1.10)	0.112
Support network† (Reference functional)
Poor	2.24 (0.92–4.85)	0.052			0.34 (0.01–1.68)	0.304			1.57 (0.57–3.65)	0.798
Inadequate	0.62 (0.03–3.05)	0.647			2.73 (0.62–8.44)	0.118			2.66 (0.75–7.32)	0.081
Time after transplant (Reference between 0 and 12 months)
Between 13 and 60 months	2.29 (0.75–9.94)	0.189			0.35 (0.11–1.05)	0.058	0.21 (0.06–0.71)	0.011*	0.39 (0.18–0.83)	0.014*	0.36 (0.16–0.79)	0.010*
61 months or more	2.21 (0.73–9.55)	0.208			0.61 (0.24–1.66)	0.310	0.36 (0.12–1.14)	0.075	0.26 (0.11–0.58)	0.001**	0.257 (0.10–0.60)	0.001**
Number of transplants (Reference first transplant)
Second or more	0.91 (0.05–4.60)	0.934			1.40 (0.07–7.17)	0.746			3.07 (0.69–9.65)	0.082	3.29 (0.72–10.9)	0.075
Donor type (Reference Cadaveric)
Living	0.39 (0.15–0.84)	0.026*			0.45 (0.14–1.05)	0.088	0.27 (0.08–0.74)	0.017*	1.81 (0.96–3.38)	0.063
Socioeconomical status (Reference Low)
Medium	1.37 (0.69–2.62)	0.348			0.42 (0.14–1.05)	0.090			0.78 (0.38–1.53)	0.501
High	1.40 (0.0.7–7.44)	0.750			EV	0.988			1.10 (0.05–5.79)	0.925
Adherence (Reference Adherent)
Non-adherent	2.37 (1.23–4.51)	0.008**	2.66 (1.37–5.15)	0.003**	5.34(2.41–12.64)	<0.001 **	6.44 (2.71–16.6)	<0.001 **	1.94 (0.01–3.64)	0.039*	2.28 (1.15–4.47)	0.016*

Notes: ^aAdjusted ORs were obtained from the reduced logistic model *Statistically significant result p<0.05 **Very statistically significant p < 0.005.

Abbreviations: EV, extreme values; OR, odds ratio.

Table 4 Adherence Definitions Non-Adjusted Odds Ratios (OR) and Area Under the Curve (AUC) for Each Outcome

	Mortality			Graft Loss			Graft Rejection
	OR (CI 95%)	p-value	AUC	OR (CI 95%)	p-value	AUC	OR (CI 95%)	p-value	AUC
Holistic non-adherence (Reference Adherence)	2.37 (1.23–4.51)	0.008*	0.66	5.34 (2.41–12.65)	<0.001 **	0.69	1.94 (1.01–3.64)	0.039*	0.47
Immunosuppression non-adherence (Reference Compliance)	2.1 (1.06–4.04)	0.028*	0.57	3.83 (1.75–8.43)	<0.001 **	0.70	1.94 (0.98–3.69)	0.047*	0.49
Suboptimal immunosuppressor levels (Reference Optimal levels)	0.78 (0.26–1.87)	0.615	0.53	2.92 (1.22–6.52)	0.011*	0.58	2.06 (0.96–4.13)	0.047*	0.54
Appointment non-adherence (Reference adherence)	1.46 (0.76–2.77)	0.244	0.68	1.56 (0.72–3.42)	0.253	0.61	1.32 (0.70–2.47)	0.381	0.59
Procedures non-adherence (Reference adherence)	0.80 (0.39–1.55)	0.527	0.52	2.54 (1.17–5.71)	0.019*	0.78	0.93 (0.47–1.76)	0.836	0.53

Notes: *Statistically significant result p<0.05 **Very statistically significant p < 0.005.

Abbreviations: OR, odds ratio; AUC, area under the curve.

Figure 2 ROC curves for (A) mortality, (B) graft loss and (C) graft rejection.