Clinical events and healthcare resource utilization associated with neutropenia and leukopenia among adult kidney transplant recipients receiving valganciclovir

Table 1 Patient baseline characteristics

Characteristics	n = 15398
Age (years), mean (SD)	52.39 (13.18)
Age category, n (%)
18 to < 45	4395 (28.54)
45 to < 65	8111 (52.68)
65 to < 75	2670 (17.34)
≥ 75	222 (1.44)
Sex, n (%)
Male	9039 (58.70)
Female	6359 (41.30)
Region1, n (%)
South	7890 (51.24)
Northeast	4324 (28.08)
Midwest	1951 (12.67)
West	1233 (8.01)
Induction immunosuppressive therapy, n (%)
Thymoglobulin/anti-thymocyte globulin	5570 (36.17)
Basiliximab	2236 (14.52)
Alemtuzumab	1524 (9.90)
Rituximab	143 (0.93)
Initial maintenance immunosuppressive therapy, n (%)
Calcineurin inhibitors	15292 (99.31)
Tacrolimus	15250 (99.04)
Cyclosporine non-modified	451 (2.93)
Cyclosporine modified	0 (0.00)
Mycophenolic acid	12675 (82.32)
Azathioprine	330 (2.14)
Sirolimus	165 (1.07)
Everolimus	133 (0.86)
Corticosteroid therapy within 3 months post kidney transplantation, n (%)	14156 (91.93)
Prednisone	14048 (91.23)
Methyl prednisone	2927 (19.01)
Prednisolone	237 (1.54)
Calendar year of transplant, n (%)
2012	780 (5.07)
2013	1063 (6.90)
2014	1158 (7.52)
2015	1564 (10.16)
2016	1791 (11.63)
2017	2087 (13.55)
2018	2378 (15.44)
2019	2638 (17.13)
2020	1933 (12.55)
2021	6 (0.04)
Modified CCI2, mean (SD)	1.22 (1.97)
Modified CCI category, n (%)
0	8064 (52.37)
1-2	4669 (30.32)
3-4	1661 (10.79)
≥ 5	1004 (6.52)
CCI comorbidity, n (%)
Chronic diabetes	4118 (26.74)
Congestive heart failure	1951 (12.67)
Peripheral vascular disease	1974 (12.82)
Chronic pulmonary disease	1351 (8.77)
Mild to moderate diabetes	1112 (7.22)
Mild liver disease	1006 (6.53)
Cerebrovascular disease	1000 (6.49)
Myocardial infarction	732 (4.75)
Cancer	704 (4.57)
Rheumatologic disease	623 (4.05)
Moderate liver disease	516 (3.35)
Metastatic solid tumor	308 (2.00)
AIDS	298 (1.94)
Peptic ulcer disease	205 (1.33)
Hemiplegia	79 (0.51)
Dementia	27 (0.18)

¹Region was categorized based on United States Census Bureau.

²Charlson Comorbidity Index (CCI) was calculated based on a modification of the method described in Quan et al[28] (2005).The Quan method was modified to omit renal disease from the calculation of CCI and from the list of comorbid conditions included.

AIDS: Acquired immunodeficiency syndrome; CCI: Charlson Comorbidity Index.

Table 2 Adjusted clinical event rates for recurring events, by year after kidney transplantation

Number of events per person-year	Year 1 of follow-up with leukopenia/neutropenia, n = 11524 (A)		Year 1 of follow-up without leukopenia/neutropenia, n = 3874 (B)		Relative risk A/B	Year 2-5 of follow-up with leukopenia/neutropenia, n = 55831 (A)		Year 2-5 of follow-up without leukopenia/neutropenia, n = 90351 (B)		Relative risk A/B
	Event rate (%)	SE (%)	Event rate (%)	SE (%)		Event rate (%)	SE (%)	Event rate (%)	SE (%)
CMV DNAemia1	3	0.037	1.8	0.083	1.67	1.25	0.061	0.69	0.084	1.81
CMV disease	0.09	0.001	0.02	0.001	3.95	0.06	0.001	0.01	0	5.14
Opportunistic infections (excluding CMV)	2.19	0.009	1.57	0.012	1.4	1.15	0.007	0.76	0.005	1.52
G-CSF use	0.9	0.004	0.24	0.003	3.76	0.27	0.003	0.09	0.001	3.04
All-cause rehospitalization	2.24	0.013	1.52	0.013	1.47	0.95	0.011	0.52	0.005	1.84

¹Only patients with available cytomegalovirus DNAemia lab data were considered in the denominator for the rate of this event. In year 1 follow-up, this included 652 patients with leukopenia/neutropenia and 106 patients without leukopenia/neutropenia. In years 2-5 of follow-up, this included 258 patients with leukopenia/neutropenia and 148 patients without leukopenia/neutropenia.

CMV: Cytomegalovirus; G-CSF: Granulocyte colony stimulating factor.

Table 3 Adjusted clinical event rates for one-time events, by year after kidney transplantation

Proportion of patients with events	Year 1 of follow-up with leukopenia/neutropenia, n = 119971 (A)		Year 1 of follow-up without leukopenia/neutropenia, n = 34011 (B)		Relative risk A/B	Year 2-5 of follow-up with leukopenia/neutropenia2 (A)		Year 2-5 of follow-up without leukopenia/neutropenia2 (B)		Relative risk A/B
	Event rate (%)	SE (%)	Event rate (%)	SE (%)		Event rate (%)	SE (%)	Event rate (%)	SE (%)
Acute graft rejection	21.14	0.27	13.23	0.63	1.6	13.26	0.27	10.3	0.63	1.29
Graft loss	11.56	0.28	7.86	1.15	1.47	11.48	0.28	6.96	1.15	1.65
All-cause mortality	0.06	3.21	0.02	17.69	2.55	9.04	3.21	9.46	17.69	0.96

¹One-time events were evaluated over the entire duration of follow-up. Hence, the cohort of neutropenia or leukopenia was also defined using the lab data through the entire duration of follow-up. The n represented the number of patients at risk at day 0.

²The number of patients at risk after year 1 of follow-up among those with leukopenia/neutropenia by clinical event was: n = 9651 (acute graft rejection), n = 10685 (graft loss), and n = 11990 (all-cause mortality). The number of patients at risk after year 1 of follow-up among those without leukopenia/neutropenia by clinical event was: n = 2977 (acute graft rejection), n = 3141 (graft loss), and n = 3401 (all-cause mortality).

Table 4 Adjusted proportion with no events except mortality, by year after kidney transplantation

Proportion of patients with no event (except for mortality)	Year 1 of follow-up, n = 15398			Year 2-5 of follow-up, n = 14618
	With leukopenia/neutropenia, n = 11524 (A), %	Without leukopenia/neutropenia, n = 3874 (B), %	Relative risk A/B	With leukopenia/neutropenia, n = 5583 (A), %	Without leukopenia/neutropenia, n = 9035 (B), %	Relative risk A/B
No event	17.78	27.54	0.65	18.88	32.77	0.58

Table 5 Healthcare resource utilization by year after kidney transplantation

All-cause healthcare resource utilization	Year 1, n = 153901		Year 2-5, n = 345132
	With leukopenia/neutropenia, n = 11516	Without leukopenia/neutropenia, n = 3874	With leukopenia/neutropenia, n = 9264	Without leukopenia/neutropenia, n = 25249
Inpatient
Patients with admission, n (%)	7441 (64.61)	2205 (56.92)	3408 (36.79)	6471 (25.63)
Number of admissions, mean ± SD (median)	3.47 ± 5.07 (2)	2.76 ± 3.63 (2)	2.70 ± 3.01 (2)	2.29 ± 2.57 (1)
Length of stay (days) among patients who had ≥ 1 admission, mean ± SD (median)	6.68 ± 27.26 (4)	7.55 ± 36.70 (4)	7.50 ± 29.83 (4.5)	5.92 ± 24.40 (3)
Emergency department/other
Patients with visits, n (%)	3383 (29.38)	988 (25.50)	1927 (20.80)	4036 (15.98)
Number of visits, mean ± SD (median)	1.81 ± 1.37 (1)	1.74 ± 1.43 (1)	1.87 ± 1.69 (1)	1.77 ± 1.65 (1)
Outpatient
Patients with visits, n (%)	11304 (98.16)	3813 (98.43)	9130 (98.55)	24460 (96.88)
Number of visits, mean ± SD (median)	48.97 ± 37.34 (37)	34.42 ± 28.18 (25)	31.73 ± 27.63 (25)	15.59 ± 18.53 (9)
Other3
Patients with other visits, n (%)	162 (1.41)	74 (1.91)	122 (1.32)	442 (1.75)
Number of other visits, mean ± SD (median)	2.85 ± 7.62 (1)	5.05 ± 12.84 (1.5)	3.25 ± 3.84 (2)	2.17 ± 2.11 (1)
Unknown
Patients with visits, n (%)	7702 (66.88)	2142 (55.29)	7473 (80.67)	14820 (58.70)
Number of visits, mean ± SD (median)	36.74 ± 31.57 (28)	28.27 ± 30.78 (16)	17.85 ± 18.30 (13)	13.48 ± 16.19 (8)
Any labs
Patients with any labs, n (%)	11475 (99.64)	3832 (98.92)	9264 (100.00)	25249 (100.00)
Number of any labs, mean ± SD (median)	1654.55 ± 984.16 (1485)	1182.27 ± 755.58 (1084)	622.37 ± 706.25 (419)	327.89 ± 374.36 (222)

¹The n represented the number of patients with a full year of follow-up during year 1.

²The n represented the number of patient observations with a full year of follow-up during years 2-5. Patients with multiple full years of follow-up were counted for each year.

³Other visits included home health visits, pre-admission encounters, and virtual visits.