Kidney involvement in tuberous sclerosis complex: the impact on healthcare resource use and costs

Figures & data

Table 1. Renal angiomyolipoma staging criteria.

Stage	Number of angiomyolipomata	Angiomyolipoma size	Kidney anatomy
0	None^a		Normal
1	≤5	1–3.5 cm	Normal
2	>5	1–3.5 cm	Normal
3	≤5	At least 1 ≥3.5 cm	Kidney intact
4	>5	1–4 ≥3.5 cm	Kidney intact
5	>5	5 or more ≥3.5 cm	Kidney recognizable
6	>5	At least 1 ≥5.0 cm	Kidney not recognizable

^aNot able to definitely determine via CT scan if lesions <1 cm in longest diameter are angiomyolipomata.

Figure 1. GFR by patient age. Age range depicted includes ages for which there are at least 10 patients in the current study. GFR from UMCU cohort of patients with TSC: Mean GFR among patients at a given age, estimated from serum creatinine using the CKD-EPI formula. The same patient may contribute multiple observations to a given age and to multiple ages. Shading depicts 95% confidence interval for the mean. GFR from normal population: Based on GFR estimated from serum creatinine for Caucasian males and females using the CKD-EPI formula, reported in a 2007 population-based cross-sectional study conducted in the eastern part of the Netherlands19^,20. Plot depicts weighted averages of median GFR reported for males and females. Weights equal to the proportion of each gender within a given age cohort of the current study.

Table 2. Patient characteristics by CKD stage.^a

	Stage 1 (n = 354)	Stage 2 (n = 138)	Stage 3 (n = 54)	Stage 4 (n = 25)	Stage 5 (n = 18)	p value
Patient age, mean (SD)	32.42 (13.7)	43.20 (12.9)	46.60 (12.9)	44.78 (14.5)	46.76 (13.7)	<0.001
TSC diagnosis, n (%)
Definite	351 (99.2)	136 (98.6)	54 (100.0)	25 (100.0)	18 (100.0)	NA
Suspected	3 (0.8)	2 (1.4)	–	–	–	NA
Gender, n (%)
Male	182 (51.4)	54 (39.1)	14 (25.9)	6 (24.0)	4 (22.2)	<0.001
Female	172 (48.6)	84 (60.9)	40 (74.1)	19 (76.0)	14 (77.8)
Years of follow-up time in open cohort, mean (SD)	12.14 (6.9)	4.67 (4.2)	4.36 (4.6)	1.81 (2.5)	3.29 (3.1)	<0.001
Highest LAM severity during follow-up time in cohort, n (%)
No LAM	152 (42.9)	63 (45.7)	16 (29.6)	4 (16.0)	6 (33.3)	0.226
Mild	13 (3.7)	12 (8.7)	7 (13.0)	2 (8.0)	2 (11.1)	0.091
Moderate	8 (2.3)	10 (7.2)	5 (9.3)	3 (12.0)	3 (16.7)	<0.001
Severe	–	2 (1.4)	4 (7.4)	2 (8.0)	–	0.145
Missing^b	181 (51.1)	51 (37.0)	22 (40.7)	14 (56.0)	7 (38.9)	0.002
Most advanced AML stage during follow-up time in cohort, n (%)
0	70 (19.8)	18 (13.0)	2 (3.7)	–	1 (5.6)	<0.001
1	40 (11.3)	14 (10.1)	3 (5.6)	1 (4.0)	2 (11.1)	0.910
2	47 (13.3)	15 (10.9)	6 (11.1)	1 (4.0)	1 (5.6)	0.766
3	7 (2.0)	6 (4.3)	4 (7.4)	2 (8.0)	1 (5.6)	0.122
4	73 (20.6)	38 (27.5)	9 (16.7)	1 (4.0)	1 (5.6)	0.004
5	15 (4.2)	16 (11.6)	9 (16.7)	3 (12.0)	2 (11.1)	0.007
6	22 (6.2)	18 (13.0)	13 (24.1)	10 (40.0)	7 (38.9)	0.001
Missing	80 (22.6)	13 (9.4)	8 (14.8)	7 (28.0)	3 (16.7)	0.006
Max AML size during follow-up time in cohort, n (%)
<3.5 cm	237 (66.9)	60 (43.5)	19 (35.2)	9 (36.0)	7 (38.9)	<0.001
≥3.5 cm	117 (33.1)	78 (56.5)	35 (64.8)	16 (64.0)	11 (61.1)	<0.001
Embolization status during follow-up time in cohort n (%)
Embolized	90 (25.4)	66 (47.8)	32 (59.3)	17 (68.0)	14 (77.8)	<0.001
Not embolized	264 (74.6)	72 (52.2)	22 (40.7)	8 (32.0)	4 (22.2)

^aCKD stages 1–5 include patients with GFR in the following ranges (in mL/min/1.73 m²): Stage 1, ≥90; Stage 2, 60–89; Stage 3, 30–59; Stage 4, 15–29; Stage 5, <15. CKD Stage 5 also includes patients on dialysis. Source for GFR ranges is The Renal Association22.

^bAmong patients with missing LAM severity data during follow-up, 87 (61%) are male.

Table 3. Patient characteristics by renal angiomyolipoma (AML) size.

	Renal AML <3.5 cm (n = 365)	Renal AML ≥3.5 cm (n = 154)	p value
Patient age, mean (SD)	32.77 (14.7)	39.62 (13.2)	<0.001
TSC diagnosis, n (%)
Definite	362 (99.2)	152 (98.7)	NA
Suspected	3 (0.8)	2 (1.3)	NA
Gender, n (%)
Male	184 (50.4)	81 (52.6)	0.864
Female	181 (49.6)	73 (47.4)
Years of follow-up time in open cohort, mean (SD)	11.93 (6.8)	6.03 (3.3)	<0.001

Figure 2. HCRU rates by CKD stage. Overall consists of specialists, scans, non-surgical procedures, and kidney surgeries, as well as non-kidney surgeries, medication, and dialysis (not shown). Dashed lines depict 95% confidence interval of utilization rates.

Table 4. Healthcare costs by CKD stage.

	Patients	Person-years	Cost PPPY (2012 €)	Cost difference (2012 €)	95% CI^a	p value^a
Overall cost
CKD Stage 1	354	4297	1275	–	–	–
CKD Stage 2	138	644	2012	737	287–1182	<0.001
CKD Stage 3	54	236	2322	1047	457–1627	<0.001
CKD Stage 4	25	45	2547	1272	411–1971	0.004
CKD Stage 5	18	59	31,916	30,641	26,873–33,788	<0.001
Scans
CKD Stage 1	354	4297	113	–	–	–
CKD Stage 2	138	644	214	101	70–131	<0.001
CKD Stage 3	54	236	266	153	108–192	<0.001
CKD Stage 4	25	45	324	211	142–283	<0.001
CKD Stage 5	18	59	219	105	39–153	0.006
Surgery
CKD Stage 1	354	4297	577	–	–	–
CKD Stage 2	138	644	902	325	−25–678	0.064
CKD Stage 3	54	236	698	120	−375–562	0.595
CKD Stage 4	25	45	454	−123	−817–341	0.763
CKD Stage 5	18	59	800	222	−669–716	0.438
Kidney surgery
CKD Stage 1	354	4297	10	–	–	–
CKD Stage 2	138	644	3	−7	−21–2	0.236
CKD Stage 3	54	236	53	43	7–68	0.026
CKD Stage 4	25	45	12	1	−41–15	0.745
CKD Stage 5	18	59	631	620	515–728	<0.001
Non-surgical procedures
CKD Stage 1	354	4297	64	–	–	–
CKD Stage 2	138	644	185	121	44–217	<0.001
CKD Stage 3	54	236	169	105	25–154	0.008
CKD Stage 4	25	45	394	330	200–427	<0.001
CKD Stage 5	18	59	252	188	58–264	0.012
Specialists
CKD Stage 1	354	4297	92	–	–	–
CKD Stage 2	138	644	184	93	64–120	<0.001
CKD Stage 3	54	236	232	141	97–181	<0.001
CKD Stage 4	25	45	200	108	54–159	<0.001
CKD Stage 5	18	59	222	131	72–179	<0.001
Medication
CKD Stage 1	354	4297	429	–	–	–
CKD Stage 2	138	644	525	96	−86–264	0.294
CKD Stage 3	54	236	957	529	235–771	0.004
CKD Stage 4	25	45	1176	747	325–1 112	0.004
CKD Stage 5	18	59	1508	1079	503–1 489	<0.001
Dialysis
CKD Stage 1	354	4297	0	–	–	–
CKD Stage 2	138	644	0	0	–	–
CKD Stage 3	54	236	0	0	–	–
CKD Stage 4	25	45	0	0	–	–
CKD Stage 5	18	59	28,915	28,915	25,357–32,061	<0.001

^aConfidence intervals and p values estimated by bootstrap. p < 0.05 indicates that the cost difference relative to CKD Stage 1 is not equal to €0.

Table 5. Rates of HCRU by angiomyolipoma (AML) size.

	Patients	Events	Person-years	Utilization rate		Rate ratio	p value
				Rate (PPPY)	95% CI
Scans
AML Size <3.5 cm	365	2660	4353	0.611	0.588–0.635	–	–
AML Size ≥3.5 cm	154	1230	928	1.326	1.254–1.402	2.169	<0.001
Surgery
AML Size <3.5 cm	365	338	4353	0.078	0.070–0.086	–	–
AML Size ≥3.5 cm	154	84	928	0.091	0.073–0.112	1.166	0.208
Kidney surgery
AML Size <3.5 cm	365	24	4353	0.006	0.004–0.008	–	–
AML Size ≥3.5 cm	154	11	928	0.012	0.007–0.021	2.150	0.035
Non-surgical procedures
AML Size <3.5 cm	365	938	4353	0.215	0.202–0.230	–	–
AML Size ≥3.5 cm	154	457	928	0.493	0.449–0.540	2.286	<0.001
Specialists
AML Size <3.5 cm	365	5866	4353	1.347	1.313–1.382	–	–
AML Size ≥3.5 cm	154	2553	928	2.751	2.647–2.860	2.042	<0.001
Medication
AML Size <3.5 cm	365	4826	4353	1.109	1.078–1.140	–	–
AML Size ≥3.5 cm	154	1766	928	1.903	1.816–1.994	1.716	<0.001
Dialysis
AML Size <3.5 cm	365	15	4353	0.003	0.002–0.006	–	–
AML Size ≥3.5 cm	154	14	928	0.015	0.009–0.025	4.177	<0.001

Table 6. Healthcare costs by angiomyolipoma (AML) size.

	Patients	Person-years	Cost PPPY (2012 €)	Cost difference (2012 €)	95% CI^a	p value^a
Overall cost
AML Size <3.5 cm	365	4353	1451	–	–	–
AML Size ≥3.5 cm	154	928	3243	1792	906–2726	<0.001
Scans
AML Size <3.5 cm	365	4353	108	–	–	–
AML Size ≥3.5 cm	154	928	265	57	133–180	<0.001
Surgery
AML Size <3.5 cm	365	4353	592	–	–	–
AML Size ≥3.5 cm	154	928	772	180	−136–486	0.254
Kidney surgery
AML Size <3.5 cm	365	4353	15	–	–	–
AML Size ≥3.5 cm	154	928	35	20	−1–40	0.076
Non-surgical procedures
AML Size <3.5 cm	365	4353	60	–	–	–
AML Size ≥3.5 cm	154	928	222	162	104–211	<0.001
Specialists
AML Size <3.5 cm	365	4353	94	–	–	–
AML Size ≥3.5 cm	154	928	192	98	70–124	<0.001
Medication
AML Size <3.5 cm	365	4353	389	–	–	–
AML Size ≥3.5 cm	154	928	924	535	333–725	<0.001
Dialysis
AML Size <3.5 cm	365	4353	208	–	–	–
AML Size ≥3.5 cm	154	928	869	661	−177–1471	0.104

^aConfidence intervals and p values estimated by bootstrap. p < 0.05 indicates that the cost difference relative to AML size <3.5 cm is not equal to €0.

Table 7. Predictive factors for HCRU.^a

Covariate	Rate ratio	95% CI	p value
Female (ref: Male)	0.851	0.790–0.917	<0.001
Definite TSC diagnosis (ref: Suspected)	1.557	0.916–2.646	0.102
Age (ref: 0–19 years)
20–39 years	0.987	0.889–1.096	0.813
40–59 years	1.138	0.959–1.349	0.139
60 or older	1.085	0.811–1.453	0.582
Max angiomyolipoma size ≥3.5 cm (ref: <3.5 cm)	1.221	1.083–1.377	0.001
Highest CKD stage (ref: Stage 1)
Stage 2	1.467	1.301–1.655	<0.001
Stage 3	1.776	1.471–2.144	<0.001
Stage 4	2.677	1.859–3.855	<0.001
Stage 5	2.131	1.448–3.135	<0.001
History of embolization (ref: Never embolized)	1.393	1.208–1.606	<0.001
Highest LAM severity (ref: No LAM)
Mild	0.873	0.675–1.130	0.303
Moderate or severe	1.518	1.171–1.968	0.002
Mean HCRU PPPY	3.953
Patients	364
Patient-years in follow-up	5293

^aRandom effects Poisson regression of annualized total patient healthcare resource utilization in each year of follow-up. p Values and confidence intervals estimated by bootstrap. p < 0.05 indicates that the rate ratio is not equal to 1, indicating a significant difference in HCRU relative to the reference group.

Table 8. Predictive factors for healthcare costs.^a

Covariate	Incremental cost PPPY (2012 €)	95% CI	p value
Female (ref: Male)	67	−221–372	0.575
Definite TSC diagnosis (ref: Suspected)	629	−9–1 289	0.050
Age (ref: 0–19 years)
20–39 years	−321	−748–138	0.184
40–59 years	−625	−1 086–48	0.062
60 or older	−1 757	−2 666–−664	<0.001
Max angiomyolipoma size ≥3.5 cm (ref: <3.5 cm)	771	238–1 318	0.002
Highest CKD stage (ref: Stage 1)
Stage 2	388	−147–832	0.154
Stage 3	950	−200–1 919	0.090
Stage 4	2152	−233–4 338	0.074
Stage 5	19,268	12 707–25 533	<0.001
History of embolization (ref: Never embolized)	−152	−609–410	0.701
Highest LAM severity (ref: No LAM)
Mild	1 722	−476–3 814	0.124
Moderate or severe	3 324	1365–5663	0.002
Mean (SD) annual cost PPPY, 2012 €	1780 (6232)
Patients	364
Patient-years in follow-up	5293

^aRandom effects linear regression of annualized patient costs in each year of follow-up. p values and confidence intervals estimated by bootstrap. p < 0.05 indicates that the cost difference relative to the reference group is not equal to €0.

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