Sickle cell nephropathy: A review of novel biomarkers and their potential roles in early detection of renal involvement

Table 3 Summary of studies of novel biomarkers

Ref.	Study design	Sample size	Endpoints	Finding(s)	Criteria fulfillment
KIM-1
Sundaram et al[41]	Cross-sectional (United States)	116 (ages 5-65 yr, mean age: 18 yr)	MiA: UACR 3.39-33.90 mg/mmol MaA: UACR > 33.90 mg/mmol	KIM-1 detectable in all SCD samples, increased with MiA (P = 0.005), further increased with MaA (P = 0.0015)	Early detection (MiA); reflects severity; localized damage to PCT; detected in urine
Niss et al[12]	Prospective longitudinal, mean FU 23 mo (United States)	303 (2-64 yr, mean age: 21 yr)	Albuminuria: Urine albumin ≥ 11.3 mg/mmol)	KIM-1 linked to baseline and persistent albuminuria with P < 0.001	Applicable to larger samples
MCP-1
Laurentino et al[13]	Prospective cohort (Brazil)	50(33.2 ± 10.2 yr)	ELISA, urine sample	Increased urinary MCP-1 in SCD (SSHU: 168.2 ± 90.1 and SS: 231.4 ± 123.7) P < 0.0001 relative to the control group (42.1 ± 27.6)	Reflects oxidative stress; localized damage to PCT + glomerulus; detected in urine
Belisário et al[15]	Prospective longitudinal, mean FU 1.1 yr	213 (1.6-19yr)	ELISA	Increased urinary MCP-1 positively related to ACR with P < 0.0001	Positively correlated with other biomarkers; detected in urine
Ceruloplasmin
Jerebtsova et al[46]	Cross-sectional cohort	54	Hemoglobinuria: Hgb/CRE > 0.8 ng/mL CKD stage: Stage 0: eGFR > 1 mL/s/1.73 m2; Stage 1: eGFR > 1.5 mL/s/1.73 m2; Stage 2: eGFR 1-1.49 mL/s/1.73 m2; Stage 3: eGFR 0.5-0.99 mL/s/1.73 m2; Stage 5: eGFR < 0.25 mL/s/1.73 m2	CP significantly (31 ×) higher among samples with hemoglobinuria with P = 1.8 × 105; Urinary CP/CRE, TF/CRE, and Ftn/CRE were all significantly higher than in non-SCD controls; CP/CRE (only) positively correlated with CKD stage (n = 34, P = 0.0008); ROC analysis: Sensitivity, 68.75%; specificity, 95.65%	Reflects iron handling defects in SCN; high sensitivity/specificity; detected in urine
Orosomucoid
Jerebtsova et al[47]	Cross-sectional cohort	54	Hemoglobinuria: Hgb/CRE > 0.8 ng/ mL and CKD stage	ORM significantly higher among samples with hemoglobinuria with P = 8.4 × 103; ORM positively correlated with CKD stage (n = 34, r = 0.51, P = 0.0014); ROC analysis: Sensitivity, 87.1%; specificity, 86.6%	Acute-phase protein; high sensitivity/specificity; detected in urine
Jerebtsova et al[48]	Cross-sectional cohort	51 HbSSand 15 HbSC	Hemoglobinuria: Hgb/CRE > 0.8 ng/ mL and CKD stage	PORM significantly higher among HbSS population with UORM/CRE; positively correlated with CKD progression (P = 0.0013); ROC analysis: Sensitivity, 60%; specificity, 78.26%	Acute-phase protein; high sensitivity/specificity; detected in urine
Nephrin
Heimlich et al[50]	Prospective cohort	101 [median age: 9 yr (IQR: 4-11 yr)]	Urine albumin: Creatinine ≥ 3.39 mg/mmol	Urinary NCR higher in HbSS than in HbAA; NCR significantly associated with albuminuria (odds ratio = 1.002, 95% confidence interval: 1.001-1.003, P = 0.0003); at an NCR cut-off value of 622 ng/mg: R (albuminuria × 45.9); at NCR ≥ 622 ng/mg: Sensitivity, 96%; specificity, 64%	Reflects glomerular injury; localized damage to glomerulus; detected in urine; modest specificity, PPV; high sensitivity and negative predictive value
Cation Channels
Brewin et al[51]	Prospective cohort (Brazil)	112 (10.7 ± 4.1 yr; 4-19 yr)	Hyperfiltration: GFR > 2.34 mL/s/1.73 m2; microalbuminuria: > 3 mg/mmol	eGFR, modestly positively correlated with Gardos channel and Psickle (r = 0.234, P = 0.002) and (r = 0.326, P = 0.005), respectively; ACR, positively correlated with Gardos channel (r = 0.246, P = 0.013) and Psickle (r = 0.207, P = 0.033) activity; KCC activity, negatively associated with ACR (r = 0.334, P = 0.007), suggesting renoprotection	Reflects RBC permeability; detected in RBC samples; strong predictor of microalbuminuria
Endothelial Injury
Youssry et al[53]	Prospective cross-sectional (Egypt)	47	PCR, blood samples	Urinary NCR higher in HbSS than in HbAA NCR significantly associated with albuminuria (odds ratio = 1.002, 95% confidence interval: 1.001-1.003, P = 0.0003); at NCR cut-off value of 622 ng/mg: R (albuminuria × 45.9); at NCR ≥ 622 ng/mg: Sensitivity, 96%; specificity, 64%	Reflects glomerular injury; localized damage to glomerulus; detected in urine; modest specificity, PPV; high sensitivity and negative predictive value

ACR: Albumin/creatinine ratio; CP: Ceruloplasmin; CP/CRE: Ceruloplasmin/creatinine ratio; CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate; ELISA: Enzyme-linked immunosorbent assay; Ftn/CRE: Ferritin/creatinine ratio; FU: Follow-up; Hgb/CRE: Hemoglobin/creatinine ratio; Hgb/CRE: Hemoglobin/creatinine ratio; IQR: Inter-quartile range; KIM-1: Kidney injury molecule-1; KCC: KCl co-transporter; MaA: Macroalbuminuria; MiA: Microalbuminuria; MCP-1: Monocyte chemoattractant protein-1; NCR: Nephrin/creatinine ratio; ORM: Orosomucoid; PCR: Polymerase chain reaction; PCT: Proximal convoluted tubules; PORM: Plasma ORM; PPV: Positive predictive value; ROC: Receiver operating characteristic; RBC: Red blood cell; SCD: Sickle cell disease; SS: Sickle cell disease patients not taking hydroxyurea; SSHU: Sickle cell disease patients taking hydroxyurea; TF/CRE : Transferrin/creatinine ratio; UACR: Urine albumin/creatinine ratio; UORM: Urinary orosomucoid.