General characteristics of the cohort
Median age at presentation was 36 (IQR 7–66) months. At the last visit median age was 15 (IQR 9–18) years. Mean duration of follow up was 10.1 ± 5.58 years. The demographic and clinical characteristics of the cohort are presented in Table 1.
Table 1
Variable
|
Median (IQR) or n (%)
(n = 20)
|
Median age at presentation
|
36 (IQR 7–66) months
|
Male/female
|
12/8 (60%/40%)
|
Median age at study visit
|
15 (IQR 9–18) years
|
Genetic testing
|
3 (15%)
|
Mutations
|
TSC1 (del exons 19–23)
TSC2 exon 41 (c.5227C > T p.Arg1743Trp)
TSC2 (del exons 1–29)
|
Prenatal diagnosis
|
None
|
Family history
|
8 (40%)
|
Presenting symptom
|
Neurological 17 (85%)
Renal 1 (5%)
Asymptomatic 2 (10%)
|
Kidney imaging modality (%)
|
MRI 16 (80%)
US 4 (20%)
|
Angiomyolipoma
|
9 (45%)
|
Multiple
|
9 (100%)
|
Bilateral
|
9 (100%)
|
Size > 3mm
|
6
|
Cysts
|
4 (20%)
|
Multiple
|
2 (50%)
|
Bilateral
|
1 (25%)
|
Size > 3mm
|
2 (50%)
|
Treatment
|
|
Everolimus
|
8 (40%), 2 patients are treated for angiomyolipoma
|
Anti-epileptic drugs
|
10 (50%)
|
MRI: magnetic resonance imaging, US: ultrasound, IQR: interquartile range |
Kidney Function
Mean GFRSchwartz at presentation was 101.81 ± 14.02 ml/min/1.73m2. At end of follow up mean GFRSchwartz was 125.89 ± 25.78 ml/min/1.73m2 resulting in mean deltaGFRSchwartz of 23.90 ± 30.91 ml/min/1.73m2. At last visit mean GFRDTPA was 98.85 ± 14.37 ml/min/1.73m2. GFRBedside Schwartz and GFRCKiD equations provided equivalent results to GFRDTPA values (Table 2).
Table 2
Comparison of GFR equations with GFRDTPA
Equation
|
Mean ± SD
|
Meandiff±SDdiff
|
Limits of agreement
|
ICC
|
GFRSchwartz
|
125.89 ± 25.78
|
-27.04 ± 23.44*
|
(-91.88,18.9)
|
-0.56*
|
GFRBedside Schwartz
|
92.85 ± 16.25
|
6 ± 19.15
|
(31.53,43.53)
|
-0.12
|
GFRCystatin−C
|
108.85 ± 21.37
|
-10 ± 19.06*
|
(-47.35,27.35)
|
-0.42
|
GFRCKiD
|
95.35 ± 14.62
|
3.5 ± 14.63
|
(25.17,32.13)
|
-0.02
|
SD: standard deviation, ICC: intercorrelation coefficient |
*p < 0.05 |
There were no patients with GFR < 60 ml/min/1.73m2 or albuminuria. However, four patients presented with stage 2 CKD at the end of follow up. No patient presented with hyperfiltration.
GFR levels did not differ between patients by presence of AML, cysts, or hypertension. DeltaGFRSchwartz was higher in those with ambulatory BP hypertension, but the difference did not reach significance. However, deltaGFRSchwartz adjusted for age at presentation, current age and sex, was statistically significant higher in those with ambulatory BP hypertension (EMMs 43.90 95%CI 29.06–58.75 versus 16.48, 95%CI 8.99–24.01 in normotensives, p < 0.005). Moreover, deltaGFRSchwartz adjusted for age at presentation, current age and sex, was higher in those with AML or cysts but did not reach significance (EMMs 26.57 95% CI 17.51–35.63 versus 15.05 95%CI 5.23–24.88 in normal imaging, p = 0.08).
Blood Pressure
BP z scores levels did not differ significantly between patients with AML or cysts and those with no findings on kidney imaging (Table 3). Five patients (26.5%) had office hypertension. AML or cysts was found in 3 out of 5 children (60%) with office hypertension (Fig. 1a). Amongst 17 patients who underwent ABPM, 4 (23.5%) patients had hypertension. All patients with ambulatory BP hypertension had AML or cysts (Fig. 1b). They were all male, half of them had a positive family history of tuberous sclerosis, 3 had multiple bilateral AMLs with maximum size ≥ 10mm (Table 4). None of the hypertensive patients identified was receiving antihypertensive therapy, while 3 were receiving treatments with everolimus (Table 4). Finally, there was no difference in height adjusted z scores of PWV and cSBP among those with with AML or cysts and those with no findings on kidney imaging.
Table 3
Office and ABPM parameters
Variable
|
Normal kidney imaging
(n = 10)
|
Angiomyolipoma or cyst
(n = 10)
|
Office SBP (mmHg)
|
104.00 ± 9.12
|
118.50 ± 21.22*
|
Office DBP (mmHg)
|
63.67 ± 14.15
|
69.80 ± 11.51
|
Office SBP z score
|
-0.06 ± 1.22
|
0.98 ± 1.59
|
Office DBP z score
|
-0.94 ± 2.67
|
0.18 ± 2.75
|
24h SBP (mmHg)
|
107.88 ± 8.39
|
118.67 ± 10.77*
|
24h DBP (mmHg)
|
63.38 ± 3.66
|
69.22 ± 9.02
|
24h MAP (mmHg)
|
83.88 ± 5.11
|
91.78 ± 9.15*
|
24h SBP z score
|
-0.43 ± 1.15
|
0.29 ± 1.04
|
24h DBP z score
|
-0.68 ± .74
|
0.13 ± 1.85
|
24h MAP z score
|
0.57 ± .91
|
1.46 ± 1.30
|
Daytime SBP (mmHg)
|
110.00 ± 9.59
|
119.89 ± 11.06*
|
Daytime DBP (mmHg)
|
64.75 ± 3.80
|
70.00 ± 9.42
|
Daytime MAP (mmHg)
|
85.63 ± 5.93
|
91.00 ± 11.94
|
Daytime SBP z score
|
-0.77 ± 1.21
|
-0.25 ± 1.14
|
Daytime DBP z score
|
-1.31 ± .68
|
-0.49 ± 1.50
|
Daytime MAP z score
|
0.03 ± .91
|
0.48 ± 1.63
|
Night-time SBP (mmHg)
|
101.86 ± 8.63
|
115.33 ± 8.50*
|
Night-time DBP mmHg)
|
56.14 ± 3.44
|
66.50 ± 4.51
|
Night-time MAP (mmHg)
|
77.29 ± 5.71
|
89.17 ± 5.71*
|
Night-time SBP z score
|
0.15 ± 1.18
|
1.17 ± .81
|
Night-time DBP z score
|
0.13 ± .58
|
1.73 ± .70
|
Night-time MAP z score
|
1.05 ± .92
|
3.09 ± 1.30
|
24h cSBP (mmHg)
|
107.13 ± 9.63
|
117.44 ± 14.46
|
24h cSBP z score
|
1.81 ± 1.46
|
2.05 ± 1.39
|
24h PWV (m/sec)
|
4.42 ± .24
|
4.83 ± .43*
|
24h PWV z score
|
-0.27 ± 1.23
|
0.11 ± 1.01
|
ABPM: ambulatory blood pressure monitoring, SBP: systolic blood pressure, DBP: diastolic blood pressure, MAP: mean arterial pressure, cSBP: central systolic blood pressure, PWV: pulse wave velocity |
*p < 0.05 |
Table 4
Characteristics of patients with ambulatory BP hypertension.
Characteristic
|
Patient 1
|
Patient 2
|
Patient 3
|
Patient 4
|
Age (y)
|
17
|
18
|
22
|
16
|
Sex
|
Male
|
Male
|
Male
|
Male
|
Genetic testing
|
Not performed
|
TSC2 (c.5227C > T p.Arg1743Trp)
|
Not performed
|
TSC1
(del exons 19–23)
|
Family history
|
Positive
|
Negative
|
Negative
|
Positive
|
Presenting symptom
|
No available data
|
Neurological
|
Neurological
|
Neurological
|
Kidney imaging modality
|
MRI
|
MRI
|
MRI
|
MRI
|
Angiomyolipoma
|
Bilateral
|
Bilateral
|
Bilateral
|
No
|
Number
|
27
|
8
|
14
|
|
Max size (mm)
|
71
|
14
|
10
|
|
Cysts
|
Unilateral
|
No
|
No
|
Unilateral
|
Number
|
3
|
|
|
1
|
Max size (mm)
|
5
|
|
|
2
|
Treatment with Everolimus
|
Yes+
|
Yes*
|
Yes*
|
No
|
*Treatment for subependymal giant cell astrocytoma (SEGA) |
+Treatment for angiomyolipoma |
GFRDTPA values were associated with daytime SBP z score (R2 = 0.42, p < 0.005), daytime MAP z score (R2 = 0.38, p < 0.05), 24hSBP z score, (R2 = 0.39, p < 0.05), 24h MAP z score (R2 = 0.38, p < 0.05), 24h cSBP z score (R2 = 0.32, p < 0.05), and 24h PWV z score (R2 = 0.29, p < 0.05), but not with office BP parameters.