Diagnosis and Emerging Biomarkers of Cystic Fibrosis-Related Kidney Disease (CFKD)
Abstract
1. Introduction
2. Conventional Laboratory Tests for Kidney Function and the Detection of Kidney Disease
2.1. Serum Creatinine Concentration and Glomerular Filtration Rate (eGFR)
2.2. Serum Cystatin C
eGFR Formula | Population | Age Group | Characteristics |
---|---|---|---|
CKiD U25 eGFR | CKiD | 1–25 years | Age, sex, height, serum creatinine, and serum Cystatin C [32,33] |
CKD-EPI 2021 (Creatinine) | General adult population | ≥18 years | Age, sex, and serum creatinine [32] |
MDRD Study | CKD | ≥18 years | Age, sex, race, and serum creatinine [34] |
Schwartz Formula | Pediatric population (general) | 1–18 years | Height and serum creatinine [35] |
CKD-EPI 2012 (Creatinine-Cystatin C) | General adult population | ≥18 years | Age, sex, race, serum creatinine, and serum Cystatin C [36] |
2.3. Urine Protein Composition and Concentration
2.4. Other Tests
Kidney Complication | Laboratory/Imaging Test for Detection |
---|---|
AKI | Serum creatinine, BUN, urinalysis, urine microscopy, FeNa, FeUrea, and urine output monitoring [49] |
Pseudo-Bartter syndrome | Serum electrolytes, venous blood gas, and urine electrolytes [50] |
AA amyloidosis | Serum amyloid A, kidney biopsy, and SAP scintigraphy [51,52] |
IgA nephropathy | Urinalysis, urine microscopy, UPCR, and kidney biopsy [53] |
Diabetic glomerulopathy | Urinalysis, UACR, eGFR, and kidney biopsy [54] |
Tubulointerstitial nephritis | Urinalysis, kidney ultrasound, and kidney biopsy [55,56] |
CKD | eGFR, UACR, UPCR, and urinalysis [57] |
LMW proteinuria (non-glomerular) | Urine β2MG, and UPEP [58] |
Hypercalciuria/ nephrolithiasis/ nephrocalcinosis | UCaCR, 24 h urinary analysis calcium excretion, urine microscopy, serum 25-hydroxyvitamin D, and kidney ultrasound [59,60,61] |
3. Emerging Biomarkers of Early Kidney Injury in the General Population and PwCF
Biomarker/Test | Type | Early Stage (Subclinical Injury) | Intermediate Stage (Functional Decline) |
Late Stage
(Established CKD) |
---|---|---|---|---|
Serum creatinine [70,71] | Functional decline | Normal | Starts increasing | High in late-stage CKD |
BUN [72,73] | Functional decline | Normal | Increases moderately | High in severe CKD |
Cystatin C [74,75] | Functional decline | Normal or slightly elevated | Moderately increased | High in severe CKD |
eGFR [76] | Functional decline | Normal or even high | Progressive decline | Severely reduced in CKD |
Proteinuria [77] | Glomerular dysfunction | Slight increase | Increases significantly | Severe elevation in CKD |
KIM-1 [78] | Tubular injury marker | Early rise | Decreases with chronicity | Low but persists in CKD |
β2MG [79,80] | Glomerular dysfunction | Normal or slightly elevated | Moderately increased | High in severe CKD |
NGAL [81] | Tubular injury marker | Early and rapid increase | Fluctuates with injury | Persistent in progressive CKD |
IL-18 [82,83] | Inflammatory marker | Early marker of tubular damage | Moderate increase | Can persist in CKD |
TNFα [84,85] | Inflammatory marker | Low or normal | Elevated due to chronic inflammation | Persistently high in late CKD |
Clinical Utility of Biomarkers in CFKD
4. Potential Genetic Modifiers of CFKD in PwCF
Modifier | Role in PwCF | Role in CKD |
---|---|---|
TGFβ1 | The most established genetic modifier in CF. Several TGFβ1 polymorphisms are associated with CF progression and P. aeruginosa infection [110]. | Drives HNF1β-induced ADTKD [113]. Susceptibility to IgAN [114], polycystic kidney diseases [115], and CKD [116]. |
ACE | The D/I polymorphism is associated with disease severity [117]. Expression and localization are controlled by CFTR [118,119]. | DD genotype is a risk factor for CKD [120]. ID/DD genotypes are associated with chronic lesions, such as capsular adhesions or glomerulosclerosis and proteinuria in severe IgAN [121]. |
MBL2 | Decreased survival and increased susceptibility to infections to P. aeruginosa and worse lung functions [122,123]. The pathogenic variants are Gly54Asp (the B allele, rs1800450), Gly57Glu (the C allele, rs1800451), and Arg52Cys (the D allele, rs5030737), which together referred to as 0 allele [124]. | Glomerular deposition of MBL has been consistently observed in kidney biopsy specimens in people with IgAN [125,126]. High serum levels are also associated with the development and progression of diabetic nephropathy [127]. |
AAT | The most abundant proteinase inhibitor in the lung with anti-inflammatory effects. Genetic modifier protecting against disease progression [128,129,130,131]. M (normal), S (264Glu → Val) and Z (342Glu → Lys) [132]. Contradictory results for the effect of S and Z alleles [130,132,133,134]. | Rapid rise in serum levels predicts AKI in experimental and clinical settings [135,136]. S and Z alleles were associated with high levels of the antigen of ANCA in Granulomatosis with polyangiitis [137]. In CKD, AAT has a protective effect [138]. |
β2AR | Stimulation results in improved lung function [139]. The Gly16Glu27 genetic variant upregulates CFTR activity [140,141]. | Expressed in proximal tubules, glomeruli, and podocytes [142]. Anti-inflammatory [143]. |
TNFα | (-308 GA, rs1800629) polymorphism is associated with CF [124]. +691g ins/del polymorphic locus is associated with the severity of lung disease and. aeruginosa infection [144]. TNFα -308GA promoter polymorphism (rs1800629) that were associated with high TNFα transcription, CF and AKI severity [145,146,147]. | High levels disrupt the localization of PC2 to the plasma membrane and primary cilia in ADPKD [148,149]. |
IL-10 | Anti-inflammatory cytokines present at low levels in PwCF. The haplotype GCC/ACC is significantly associated with P. aeruginosa infection and CF severity [150]. A significant association was found between the −1082GG genotype and colonization with A. fumigatus and allergic bronchopulmonary aspergillosis [151]. | Important role in normal physiology, AKI and CKD progression [152]. Polymorphisms are associated with AKI [147]. L-10 -1082 A/G polymorphism was associated with an increased risk of AKI [153] and primary glomerulonephritis [154]. |
NOS | Low levels of exhaled NO [155,156]. NOS1 and NOS2 polymorphisms are associated with disease severity and inflammation [157,158]. G847T polymorphism in the NOS3 gene, is associated with high NO production had a slower decline in lung function [159,160]. | Levels are reduced in CKD. NOS inhibition causes systemic and glomerular hypertension, glomerular ischemia, glomerulosclerosis, tubulointerstitial injury, and proteinuria [161]. Presence of the two NOS3 gene polymorphisms, Glu298Asp polymorphisms 4 b/a and -786T > C is a risk of ESKD in patients with CKD and ADPKD [162,163]. |
GST | M1 (GSTM1) allele associated with worse lung disease [164]. GSTM3*B allele contributes to clinical severity in CF [165]. | GSTM1, GSTT1, and GSTP1 polymorphisms are risk of ESKD [166]. GSTM1 deletion is associated with more rapid progression of pediatric CKD [167]. |
5. Future Directions of Research on Kidney Function in PwCF
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CF | Cystic Fibrosis |
CFTR | CF Transmembrane Conductance Regulator |
HEMT | Highly effective modulator therapy |
PwCF | People with CF |
CKD | Chronic kidney disease |
CFKD | CF-related kidney disease |
ESKD | End-stage kidney disease |
AKI | Acute kidney injury |
GFR | Acute kidney injury |
eGFR | Estimate GFR |
IDMS | Isotope dilution mass spectrometry |
HPLC | High-performance liquid chromatography |
CKiD | Chronic Kidney Disease in Children |
CKD-EPI | Chronic kidney disease epidemiology collaboration |
MDRD | Modification of diet in renal disease |
UACR | Urine albumin to creatinine ratio |
LMW | Low molecular weight |
β2MG | Beta-2 microglobulin |
RBP | Retinol-binding protein |
ELISA | Enzyme-linked immunosorbent assay |
SDS-PAGE | Sodium dodecyl sulfate-polyacrylamide gel electrophoresis |
LC-MS | Liquid chromatography-tandem mass spectrometry |
UPEP | Urine protein electrophoresis |
KDIGO | Kidney Disease Improving Global Outcomes |
FeNa | Fractional excretion of sodium |
FeUrea | Fractional excretion of urea |
ATN | Acute tubular necrosis |
RBC | Red blood cell |
WBC | White blood cell |
BUN | Blood urea nitrogen |
SAP | Serum amyloid P component |
IgA | Immunoglobulin A |
UPCR | Urine protein to creatinine ratio |
UCaCR | Urine calcium to creatinine ratio |
KIM-1 | Kidney injury molecule-1 |
IL-18 | Interleukin-18 |
TIMP-2 | Tissue inhibitor of metalloproteinases-2 |
IGFBP7 | Insulin-like growth factor-binding protein 7 |
FDA | Food and Drug Administration |
SBP1 | Selenium-binding protein 1 |
NGAL | Neutrophil gelatinase-associated lipocalin |
TNFα | Tumor necrosis factor α |
NAG | N-acetyl-β-D-glucosaminidase |
sFas | Soluble Fas |
EVs | Extracellular vesicles |
uEVs | Urinary extracellular vesicles |
ATF3 | Activating transcription factor-3 |
AQP2 | Aquaporin-2 |
CD133 | Prominin-1 |
WT-1 | Wilms tumor-1 |
MUC1 | Mucin 1 |
MGAM | Maltase-glucoamylase |
TGFβ1 | Transforming growth factor β1 |
HNF1β | Hepatocyte nuclear factor 1-beta |
ADTKD | Autosomal dominant tubulointerstitial kidney disease |
IgAN | Immunoglobulin A nephropathy |
ACE | Angiotensin-converting enzyme |
MBL2 | Mannose-binding lectin |
AAT | α1-antitrypsin |
ANCA | Antineutrophil cytoplasm antibodies |
β2AR | Beta-2-adrenergic receptor |
PC2 | Polycystin 2 |
ADPKD | Autosomal dominant polycystic kidney disease |
IL-10 | Interleukin-1 |
NOS | Nitric oxide synthase |
NO | Nitric oxide |
GST | Glutathione S-transferase |
CaCC | Calcium-activated chloride conductance |
GSTM1 | Glutathione S-transferase M1 |
SK | Shwachman–Kulczycki |
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Yavuz, H.; Kumar, M.; Goswami, H.B.; Erdbrügger, U.; Harris, W.T.; Skopelja-Gardner, S.; Graber, M.; Swiatecka-Urban, A. Diagnosis and Emerging Biomarkers of Cystic Fibrosis-Related Kidney Disease (CFKD). J. Clin. Med. 2025, 14, 5585. https://doi.org/10.3390/jcm14155585
Yavuz H, Kumar M, Goswami HB, Erdbrügger U, Harris WT, Skopelja-Gardner S, Graber M, Swiatecka-Urban A. Diagnosis and Emerging Biomarkers of Cystic Fibrosis-Related Kidney Disease (CFKD). Journal of Clinical Medicine. 2025; 14(15):5585. https://doi.org/10.3390/jcm14155585
Chicago/Turabian StyleYavuz, Hayrettin, Manish Kumar, Himanshu Ballav Goswami, Uta Erdbrügger, William Thomas Harris, Sladjana Skopelja-Gardner, Martha Graber, and Agnieszka Swiatecka-Urban. 2025. "Diagnosis and Emerging Biomarkers of Cystic Fibrosis-Related Kidney Disease (CFKD)" Journal of Clinical Medicine 14, no. 15: 5585. https://doi.org/10.3390/jcm14155585
APA StyleYavuz, H., Kumar, M., Goswami, H. B., Erdbrügger, U., Harris, W. T., Skopelja-Gardner, S., Graber, M., & Swiatecka-Urban, A. (2025). Diagnosis and Emerging Biomarkers of Cystic Fibrosis-Related Kidney Disease (CFKD). Journal of Clinical Medicine, 14(15), 5585. https://doi.org/10.3390/jcm14155585