Urinary retinol binding protein is a marker of the extent of interstitial kidney fibrosis

Abstract

Currently, a non-invasive method to estimate the degree of interstitial fibrosis (IF) in chronic kidney disease is not available in routine. The aim of our study was to evaluate the diagnostic performance of the measurement of urinary low molecular weight (LMW) protein concentrations as a method to determine the extent of IF. The urines specimen from 162 consecutive patients who underwent renal biopsy were used in the analysis. Numerical quantification software based on the colorimetric analysis of fibrous areas was used to assess the percentage IF. Total proteinuria, albuminuria, and the urinary levels of retinol binding protein (RBP), alpha1-microglobulin (α1MG), beta 2-microglobulin (β2MG), transferrin, and IgG immunoglobulins were measured. There was a significant correlation between the degree of IF and the RBP/creatinine (creat) ratio (R2: 0.11, p<0.0001). IF was associated to a lesser extent with urinary β2MG and α1MG; however, there was no association with total proteinuria or high molecular weight (HMW) proteinuria. The correlation between IF and RBP/creat remained significant after adjustment to the estimated glomerular filtration rate, age, body mass index, α1MG, and β2MG. The specificity of the test for diagnosing a fibrosis score of >25% of the parenchyma was 95% when using a threshold of 20 mg/g creat. In conclusion, RBP appears to be a quantitative and non-invasive marker for the independent prediction of the extent of kidney IF. Because methods for the measurement of urinary RBP are available in most clinical chemistry departments, RBP measurement is appealing for implementation in the routine care of patients with chronic kidney disease.

Figure 1. Distribution of estimated glomerular filtration rates.

A. Histogram showing the distribution of the study population according to the eGFR level at inclusion. B. Histogram showing eGFR values according to the type of kidney disease. eGFR is expressed as the mean ± sem. *p<0.05, **p<0.01, ***p<0.001 compared to glomerular disease using Student's T test; the Mann-Whitney test was used for the glomerular vs. comparison with non-specific lesions. Glom: glomerular diseases; Tub-Int: tubular and/or interstitial diseases; Vasc: vascular diseases; Non-spe: non-specific.

Figure 2. Expression patterns of proteinuria.

A, B. Best-fit slope of the linear regression between RBP and β2MG (A) and RBP and Alb (B). C, D, E. Histogram showing Alb (A), RBP (B), and IgG (C) values according to the type of kidney disease. Protein concentrations are expressed as the mean ± sem. **p<0.01, ***p<0.001 compared to glomerular disease using Student's T test; the Mann-Whitney test was used for the glomerular vs. comparison with non-specific lesions. Glom: glomerular diseases; Tub-Int: tubular and/or interstitial diseases; Vasc: vascular diseases; Non-spe: non-specific.

Figure 3. Distribution of proteinuria according to the estimated glomerular filtration rate.

A, B, C. Histogram showing Alb (A), RBP (B), and total proteinuria (C) values according to the level of eGFR. Protein concentrations are expressed as the mean ± sem. **p<0.01, ***p<0.001 compared to eGFR <30 ml/min, using Student's T test.

Figure 4. Correlation between the estimated glomerular filtration rate and extent of interstitial fibrosis.

A. Best-fit slope of the linear regression between eGFR and extent of fibrosis. B, C, D. Best-fit slope of the linear regression between eGFR and extent of fibrosis in glomerular disease (B), tubular disease (C), and vascular disease (D). E. Histogram of the distribution of the extent of interstitial fibrosis according to the type of kidney disease. The percentages of interstitial fibrosis are expressed as the mean ± sem. *p<0.05 compared to glomerular disease, using Student's T test; the Mann-Whitney test was used for the glomerular vs. non specific lesions comparison. Glom: glomerular diseases; Tub-Int: tubular and/or interstitial diseases; Vasc: vascular diseases; Non-spe: non-specific.

Figure 5. Correlation between proteinuria and the extent of interstitial fibrosis.

A, B. Best-fit slope of the linear regression between RBP (A) and Alb (B) and extent of fibrosis extent.