Shrunken pore syndrome in childhood cancer survivors treated with potentially nephrotoxic therapy

Figures & data

Table 1. Overview of the estimated glomerular filtration rate equations used in this study.

2021 CKD-EPIcr without race
Female	sCr ≤ 0.7	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cr}}=144\mathrm{*}{\left(\frac{\mathrm{sCr}}{0.7}\right)}^{-0.241}\mathrm{*}{0.994}^{\mathrm{age}}$
	sCr > 0.7	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cr}}=\mathrm{ }144\mathrm{*}{\left(\frac{\mathrm{sCr}}{0.7}\right)}^{-1.200}\mathrm{*}{0.994}^{\mathrm{age}}$
Male	sCr ≤ 0.9	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cr}}=142\mathrm{*}{\left(\frac{\mathrm{sCr}}{0.9}\right)}^{-0.302}\mathrm{*}{0.994}^{\mathrm{age}}$
	sCr > 0.9	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cr}}=142\mathrm{*}{\left(\frac{\mathrm{sCr}}{0.9}\right)}^{-1.200}\mathrm{*}{0.994}^{\mathrm{age}}$
2012 CKD-EPIcys
Female	sCys ≤ 0.8	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cys}}=133\mathrm{*}{\left(\frac{\mathrm{sCys}}{0.8}\right)}^{-0.499}\mathrm{*}{0.996}^{\mathrm{age}}\mathrm{*}0.932$
	sCys > 0.8	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cys}}=133\mathrm{*}{\left(\frac{\mathrm{sCys}}{0.8}\right)}^{-1.328}\mathrm{*}{0.996}^{\mathrm{age}}\mathrm{*}0.932$
Male	sCys ≤ 0.8	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cys}}=133\mathrm{*}{\left(\frac{\mathrm{sCys}}{0.8}\right)}^{-0.499}\mathrm{*}{0.996}^{\mathrm{age}}$
	sCys > 0.8	${\text{eGFR CKD}-\mathrm{EPI}}_{\mathrm{cys}}=133\mathrm{*}{\left(\frac{\mathrm{sCys}}{0.8}\right)}^{-1.328}\mathrm{*}{0.996}^{\mathrm{age}}$
FASage
Age	18-40 years	$\text{eGFR FASag}\mathrm{e}=107.3/(\mathrm{Scr}/{\mathrm{Q}}^{\mathrm{•}})$
	> 40 years	$\text{eGFR FASage}=\frac{107.3}{(\mathrm{sCr}/{\mathrm{Q}}^{\mathrm{•}})}\mathrm{*}\mathrm{ }{0.9880}^{\mathrm{ag}e-40}$ ^•with Q being the sex-specific median concentration of creatinine in a healthy population. Q = 0.70 mg/dL for females and Q = 0.90 mg/dL for males.
FAScys
Age	18-40 years	$\text{eGFR FAScy}s=107.3/(\mathrm{sCys}/{\mathrm{Q}}^{\mathrm{•}})$
	> 40 years	$\text{eGFR FAScys}=\frac{107.3}{\mathrm{sCys}/{\mathrm{Q}}^{\mathrm{•}}}* {0.9880}^{\mathrm{ag}e-40}$ ^•with Q being the median concentration of cystatin C in a healthy population. Q = 0.82 mg/L for all sex and ages < 70 years.
LMR
Female	pCr < 150	eGFR LMR = e^x −0.0158 * age ^+ 0.438 * ln (age) with x = 2.50 + 0.0121 * (150-Scr)
	pCr ≥ 150	eGFR LMR = e^x −0.0158 * ag ^+ 0.438 * ln (age) with x = 2.50-0.926 * ln(pCr/150)
Male	pCr < 180	eGFR LMR = e^x −0.0158 * age ^+ 0.438 * ln (age) with x = 2.56 + 0.00968 * (180-pCr)
	pCr ≥ 180	eGFR LMR = e^x −0.0158 * age ^+ 0.438 * ln (age) with x = 2.56-0.926 * ln(pCr/180)
CAPA		eGFR CAPA = 130 * cystatin C^-1.069 * age^-0.117 − 7

CAPA: Caucasian, Asian, pediatric and adults cohorts [34]; CKD-EPI_cr: Chronic Kidney Disease Epidemiology Collaboration creatinine equation [29]; CKD-EPI_cys: Chronic Kidney Disease Epidemiology Collaboration cystatin C equation [30]; eGFR: estimated glomerular filtration rate in ml/min/1.73m²; FAS_age: Full Age Spectrum creatinine equation based on age [31]; FAS_cys: Full Age Spectrum cystatin C equation [32]; LMR: Lund-Malmö Revised equation [33]; pCr: plasma creatinine concentration in µmol/L; sCR: serum creatinine concentration in mg/dl; sCys: serum cystatin C concentration in mg/l.

Figure 1. Flowchart study cohort. DCCSS: Dutch Childhood Cancer Survivor Study; IC: informed consent.

Table 2. Baseline characteristics study cohort.

	Underlying cohort	Invited study population	Non- participants^b	Participants	Controls
Characteristics	N = 6,165	N = 1,881	N = 787	N = 1,024	N = 500
Sex, n (%)
Male	3,433 (55.7)	1,009 (53.6)	484 (61.5)	505 (49.3)	241 (48.2)
Female	2,731 (44.3)	872 (46.4)	303 (38.5)	519 (50.7)	259 (51.8)
Transgender	1 (0.01)	0 (0)	0 (0)	0 (0)	0 (0)
Primary childhood cancer (ICCC), n (%)
Leukemias, myeloproliferative diseases and myelodysplastic diseases	2,094 (34.0)	569 (30.2)	225 (28.6)	317 (31.0)	–
Lymphomas and reticuloendothelial neoplasms	1,062 (17.2)	150 (8.0)	68 (8.6)	79 (7.7)	–
CNS and miscellaneous intracranial and intraspinal neoplasms	844 (13.7)	121 (6.4)	55 (7.0)	62 (6.1)	–
Neuroblastoma and other peripheral nervous cell tumors	324 (5.3)	94 (5.0)	28 (3.6)	65 (6.3)	–
Retinoblastoma	33 (0.5)	2 (0.1)	1 (0.1)	1 (0.1)	–
Renal tumors	596 (9.7)	476 (25.3)	200 (25.4)	254 (24.8)	–
Hepatic tumors	52 (0.8)	34 (1.8)	22 (2.8)	12 (1.2)	–
Bone tumors	370 (6.0)	148 (7.9)	67 (8.5)	78 (7.6)	–
Soft tissue and other extraosseous sarcomas	450 (7.3)	168 (8.9)	72 (9.1)	92 (9.0)	–
Germ cell tumors, trophoblastic tumors, and neoplasms of gonads	232 (3.8)	99 (5.3)	41 (5.2)	52 (5.1)	–
Other malignant epithelial neoplasms and malignant melanomas	102 (1.7)	18 (1.0)	8 (1.0)	10 (1.0)	–
Other and unspecified malignant neoplasms	6 (0.1)	2 (0.1)	0 (0)	2 (0.2)	–
Age at diagnosis (yr), n (%)*
0-4	2,727 (45.3)	994 (52.9)	417 (53.1)	537 (52.4)	–
5-9	1,628 (27.1)	476 (25.3)	198 (25.2)	265 (25.9)	–
10-14	1,285 (21.4)	312 (16.6)	128 (16.3)	171 (16.7)	–
15-17	376 (6.3)	98 (5.2)	43 (5.5)	51 (5.0)	–
Treatment period, n (%)
1963-1969	119 (1.9)	20 (1.1)	6 (0.8)	14 (1.4)	–
1970-1979	978 (15.9)	130 (6.9)	54 (6.9)	72 (7.0)	–
1980-1989	1,931 (31.3)	477 (25.4)	184 (23.4)	272 (26.6)	–
1990-1999	2,541 (41.2)	1,093 (58.1)	479 (60.9)	576 (56.3)	–
2000-2001	596 (9.7)	161 (8.6)	64 (8.1)	90 (8.8)	–
Age at participation/invitation (yr), n (%)^#
<18	49 (1.2)	0 (0)	0 (0)	0 (0)	0 (0)
18-30	1,313 (32.9)	640 (39.1)	205 (37.8)	381 (37.2)	182 (36.4)
30-40	1,511 (37.9)	709 (43.3)	244 (45.1)	446 (43.6)	216 (43.2)
>40	1,118 (28.0)	286 (17.5)	92 (17.0)	197 (19.2)	102 (20.4)
Follow-up time since childhood cancer diagnosis (yr), n (%)
10-20	981 (15.9)	328 (17.4)	133 (16.9)	186 (18.2)	–
20-30	1,931 (31.3)	1,078 (57.3)	469 (59.6)	569 (55.6)	–
30-40	1,393 (22.6)	351 (18.7)	136 (17.3)	197 (19.2)	–
40-50	460 (7.5)	112 (6.0)	48 (6.1)	61 (6.0)	–
50-60	46 (0.7)	12 (0.6)	1 (0.1)	11 (1.1)	–
Surgery, n (%)^a
No	2,912 (47.2)	694 (36.9)	281 (35.7)	385 (37.6)	–
Yes	3,185 (51.7)	1,182 (62.8)	503 (63.9)	637 (62.2)	–
Missing	68 (1.1)	5 (0.3)	3 (0.4)	2 (0.2)	–
Radiotherapy, n (%)^a
No	3,608 (58.5)	1,177 (62.6)	533 (67.7)	596 (58.2)	–
Yes	2,527 (41.0)	703 (37.4)	254 (32.3)	427 (41.7)	–
Missing	30 (0.5)	1 (0.05)	0 (0)	1 (0.1)	–
Chemotherapy, n (%)^a
No	1,123 (18.2)	35 (1.9)	15 (1.9)	20 (2.0)	–
Yes	5,005 (81.2)	1,845 (98.1)	771 (98.0)	1004 (98.0)	–
Missing	37 (0.6)	1 (0.05)	1 (0.1)	0 (0)	–
Hematopoietic stem cell transplantation, n (%)^a*
No	5,532 (89.7)	1,624 (86.4)	698 (88.8)	863 (84.3)	–
Autologous stem cell transplant	155 (2.5)	90 (4.8)	34 (4.3)	56 (5.5)	–
Allogenic stem cell transplant	231 (3.7)	153 (8.1)	51 (6.5)	95 (9.3)	–
Missing	98 (1.6)	13 (0.7)	3 (0.4)	10 (1.0)	–
Therapy, n (%)
No treatment	61 (1.0)	0 (0)	0 (0)	0 (0)	–
Surgery only	575 (9.3)	17 (0.9)	8 (1.0)	9 (0.9)	–
Chemotherapy only (± surgery)	2,967 (48.1)	1,160 (61.7)	525 (66.7)	587 (57.3)	–
Radiotherapy only (± surgery)	484 (7.9)	18 (1.0)	7 (0.9)	11 (1.1)	–
Chemotherapy and radiotherapy (± surgery)	2,030 (32.9)	684 (36.4)	246 (31.3)	416 (40.6)	–
Missing	48 (0.8)	2 (0.1)	1 (0.1)	1 (0.1)	–
Potentially nephrotoxic cancer treatment, n (%)^a
Nephrectomy	622 (10.1)	492 (26.2)	207 (26.3)	264 (25.8)	–
Unilateral	605 (97.3)	478 (97.2)	204 (98.6)	255 (96.6)	–
Bilateral partial	17 (2.7)	14 (2.9)	3 (1.5)	9 (3.4)	–
Radiotherapy renal area	467 (7.6)	273 (14.5)	90 (11.4)	175 (17.1)	–
Total body irradiation	221 (3.6)	143 (7.6)	52 (6.6)	85 (8.3)	–
Ifosfamide	714 (11.6)	524 (27.9)	206 (26.2)	300 (29.3)	–
HD-cyclophosphamide	833 (13.5)	504 (26.8)	208 (26.4)	278 (27.1)	–
Cisplatin	457 (7.4)	328 (17.4)	142 (18.0)	175 (17.1)	–
Carboplatin	422 (6.9)	284 (15.1)	125 (15.9)	151 (14.7)	–
Hematopoietic stem cell transplantation	231 (3.8)	153 (8.1)	51 (6.5)	95 (9.3)	–
BMI (kg/m^2), n (%)
<18.5				47 (4.6)	4 (0.8)
20-25	–	–	–	582 (56.8)	270 (54.0)
25-30	–	–	–	284 (27.7)	169 (33.8)
>30	–	–	–	92 (9.0)	57 (11.4)
Missing	–	–	–	19 (1.9)	0 (0)
Current corticosteroid treatment, n (%)
No	–	–	–	1003 (97.9)	500 (100)
Yes	–	–	–	21 (2.1)	0 (0)
eGFR (ml/min/1.73m^2), mean (SD)^c
CKD-EPI-2021cr	–	–	–	104.3 (19.0)	107.9 (13.6)
CKD-EPI-2012cys				102.8 (19.5)	103.7 (13.9)
FASage	–	–	–	99.6 (20.1)	101.5 (14.8)
FAScys	–	–	–	104.8 (20.4)	104.6 (15.5)
LMR				88.3 (14.8)	90.5 (9.8)
CAPA				98.8 (21.7)	98.9 (16.4)
CKD-EPIcys- CKD-EPIcr ratio				1.0 (0.16)	0.97 (0.15)
FAScys-FASage ratio				1.07 (0.19)	1.05 (0.18)
CAPA-LMR ratio				1.12 (0.20)	1.10 (0.18)

^aFor primary cancer and recurrences.

^bNon-participants includes refusers and non-responders. CCS with informed consent without participation (n = 53), being pregnant (n = 8) or with a history of kidney transplantation (n = 9) were not included in this table because they were willing to participate.

^cFor participants with complete creatinine and cystatin C measurement.

*Missing for survivors refusing registration, n = 149.

^#Missing for survivors refusing participation, n = 2,174.

BMI: body mass index; CAPA: Caucasian, Asian, pediatric and adults cohorts; CCS: childhood cancer survivors; CKD-EPIcr: Chronic Kidney Disease Epidemiology Collaboration creatinine equation; CKD-EPIcys: Chronic Kidney Disease Epidemiology Collaboration cystatin C equation; eGFR: estimated glomerular filtration rat; FASage: Full Age Spectrum creatinine equation; FAScys: Full Age Spectrum cystatin C equation; HD: high dose;  LMR: Lund-Malmo Revised equation; n: number; SD: standard deviation, yr: year.

Bold = p-value <0.05.

Table 3. Prevalence of participants with a eGFR_cys/eGFR_cr ratio <0.6.

eGFRcys / eGFRcr <0.6	CCS	Controls	p-value
CKD-EPIcys / CKD-EPIcr	9/934 (1.0%)	0/500 (0%)	.03
FAScys / FASage	2/934 (0.2%)	1/500 (0.2%)	1.00
CAPA / LMR	5/934 (0.5%)	0/500 (0%)	.17

CAPA: Caucasian, Asian, pediatric and adults cohorts; CCS: childhood cancer survivors; CKD-EPI_cr: Chronic Kidney Disease Epidemiology Collaboration creatinine equation; CKD-EPI_cys: Chronic Kidney Disease Epidemiology Collaboration cystatin C equation; eGFR_cr: estimated glomerular filtration rate based on creatinine; eGFR_cys: estimated glomerular filtration rate based on cystatin C; FAS_age: Full Age Spectrum creatinine equation; FAS_cys: Full Age Spectrum cystatin C equation; LMR: Lund-Malmö Revised equation.

Table 4a. Overview of childhood cancer survivors with a CKD-EPI_cys/CKD-EPI_cr ratio <0.6.

Age	Sex	Diagnosis	Treatment	FU-time (yr)	CKD-EPIcys/ CKD-EPIcr	Classification	CKD-EPIcr	CKD-EPIcys	ACR	FT4	BMI
31^a	M	Rhabdomyosarcoma	RT abdominal + ifosfamide	27	0.49	SPS	126	62	0.5	17.00	38
43^b	F	Lymphoid leukemia	HD-cyclophosphamide	33	0.50	SPS	99	49	17.2	16.50	30
50	M	Wilms tumor	Nephrectomy + RT abdominal	49	0.58	SPS	98	56	2.1	18.60	32
45	F	Neuroblastoma	Nephrectomy + RT abdominal	42	0.58	Underweight	101	59	1.1	18.20	18
24	M	Neuroblastoma	Carboplatin + ifosfamide	23	0.57	Hyperthyreoidism	120	69	4.5	26.10	19
34^c	F	Myelodysplastic syndrome	Total body irradiation	24	0.49	Hyperthyreoidism	110	54	2.3	35.10	25
23^d	F	Astrocytoma	Carboplatin	21	0.49	Steroids + hyperthyreoidism	131	65	2.0	29.20	26
36	F	Osteosarcoma	Cisplatin	28	0.51	Steroids + amputation	40	20	–	13.40	25
45^e	F	Wilms tumor	Nephrectomy + RT abdominal	41	0.57	Hyperthyreoidism	15	9	–	45.50	21

ACR: albumin-to-creatinine ratio; BMI: body mass index; CKD-EPI_cr: Chronic Kidney Disease Epidemiology Collaboration creatinine equation; CKD-EPI_cys: Chronic Kidney Disease Epidemiology Collaboration cystatin C equation; HD: high-dose; FT4: free thyroxine 4; FU: follow-up; RT: radiotherapy; SPS: shrunken pore syndrome; yr: year.

^a,b,c,d,e: participants identified with eGFRcys/eGFRcr ratio <0.6 with different glomerular filtration estimating equations pairs.

Table 4b. Overview of patients with a FAS_cys/FAS_cr ratio <0.6.

Age	Sex	Diagnosis	Treatment	FU-time (yr)	FAScys/ FAScreat	Classification	FAS-age	FAS-cys	ACR	FT4	BMI
31^a	M	Rhabdomyosarcoma	RT abdominal + ifosfamide	27	0.51	SPS	133	68	0.5	17.00	38
23^b	F	Astrocytoma	Carboplatin	21	0.54	Steroids + hyperthyreodism	133	72	2.0	29.20	26
Controls
22	M	NA	NA	NA	0.45	SPS	213	96	0.7	20.20	20

ACR: albumin-to-creatinine ratio; BMI: body mass index; FAS_age: Full Age Spectrum creatinine equation; FAS_cys: Full Age Spectrum cystatin C equation; FT4: free thyroxine 4; FU: follow-up; RT: radiotherapy; SPS: shrunken pore syndrome; yr: year.

^a,b: participants identified with eGFRcys/eGFRcr ratio <0.6 according with different glomerular filtration estimating equations pairs.

Table 4c. Overview of childhood cancer survivors with a CAPA/LMR ratio <0.6.

Age	Sex	Diagnosis	Treatment	FU-time (yr)	CAPA/ LMR	Classification	LMR	CAPA	ACR	FT4	BMI
31^a	M	Rhabdomyosarcoma	RT abdominal + ifosfamide	27	0.54	SPS	110	59	0.5	17.00	38
43^b	F	Lymphoid leukemia	HD-cyclophosphamide	33	0.59	SPS	86	51	17.2	16.50	30
34^c	F	Myelodysplastic syndrome	Total body irradiation	24	0.59	Hyperthyreoidism	93	56	2.2	35.10	25
23^d	F	Astrocytoma	Carboplatin	21	0.59	Steroids + hyperthyreodism	112	66	2.0	29.20	26
45^e	F	Wilms tumor	Nephrectomy + RT Abdominal	41	0.47	Hyperthyreodism	16	7	–	45.50	21

ACR: albumin-to-creatinine ratio; BMI: body mass index; CAPA: Caucasian, Asian, pediatric and adults cohorts; HD: high-dose; FT4: free thyroxine 4; FU: follow-up; LMR: Lund-Malmö Revised equation; SPS: shrunken pore syndrome; yr: year.

^a,b,c,d,e: participants identified with eGFRcys/eGFRcr ratio <0.6 with different multiple glomerular filtration estimating equations pairs.

Grubb A, Horio M, Hansson LO, et al. Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator. Clin Chem. 2014;60(7):974–986.

 PubMed Web of Science ®Google Scholar

Inker LA, Eneanya ND, Coresh J, Chronic Kidney Disease Epidemiology Collaboration, et al. New creatinine- and cystatin C-Based equations to estimate GFR without race. N Engl J Med. 2021;385(19):1737–1749.

 PubMed Web of Science ®Google Scholar

Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. The new England journal of medicine. N Engl J Med. 2012;367(1):20–29.

 PubMed Web of Science ®Google Scholar

Pottel H, Hoste L, Dubourg L, et al. An estimated glomerular filtration rate equation for the full age spectrum. Nephrol Dial Transplant. 2016;31(5):798–806.

 PubMed Web of Science ®Google Scholar

Pottel H, Delanaye P, Schaeffner E, et al. Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Nephrol Dial Transplant. 2017;32(3):497–507.

 PubMed Web of Science ®Google Scholar

Björk J, Grubb A, Sterner G, et al. Revised equations for estimating glomerular filtration rate based on the Lund-Malmö study cohort. Scand J Clin Lab Invest. 2011; 71(3):232–239.

 PubMed Web of Science ®Google Scholar