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

Table 1 Estimated glomerular filtration rate formulas employed in sickle cell nephropathy

Formula	Equation
CKD-EPI (Cr)	F with Cr ≤ 62 μmol/L (≤ 0.7 mg/dL): 144 × (creatinine/0.7) - 0.329 × 0.993 age (× 1.159 if Black); F with Cr > 62 μmol/L (> 0.7 mg/dL): 144 × (creatinine/0.7) - 1.209 × 0.993 age (× 1.159 if Black)
	M with Cr ≤ 80 μmol/L (≤ 0.9 mg/dL): 141 × (creatinine/0.9) - 0.411 × 0.993 age (× 1.159 if Black); M with Cr > 80 μmol/L (> 0.9 mg/dL): 141 × (creatinine/0.9) - 1.209 × 0.993 age (× 1.159 if Black)
MDRD	175 × creatinine - 1.154 × age - 0.203 × 0.742 (if female)
Schwartz	0.413 × [height (cm)/creatinine]
CKD-EPI (Cystatin C)	Cystatin C ≤ 0.8 mg/L: 133 × (cystatin C/0.8) - 0.499 × 0.996 age (× 0.932 if female); Cystatin C > 0.8 mg/L: 133 × (cystatin C/0.8) - 1.328 × 0.996 age (× 0.932 if female)

CKD-EPI: Chronic kidney disease epidemiology; Cr: Creatinine; F: Female, M: Male; MDRD: Modification of diet in renal disease.

Table 2 Ideal features of biomarkers used to detect drug-induced kidney toxicity

	Features
(1)	Identifies kidney injury early (before renal reserve is dissipated and levels of serum creatinine increase)
(2)	Reflects the degree of toxicity, in order to characterize dose dependence
(3)	Displays similar reliability across species, including humans
(4)	Localizes to the site of kidney injury
(5)	Tracks the progression of injury and recovery from damage
(6)	Is well characterized with respect to the limitations of its capacities
(7)	Is accessible in readily available body fluids or tissues

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.