Circulating uromodulin may help identify kidney dysfunction in sickle cell disease while conventional kidney markers remain within reference range, as demonstrated in a recent collaborative study conducted with Euroimmun, University Hospital Essen, Germany and other academic and clinical partners.
A diagnostic challenge
Sickle cell nephropathy is a major cause of illness and early death in people with sickle cell disease but remains difficult to identify using conventional laboratory tests alone.
Serum creatinine, a widely used marker of kidney function, can be affected by low muscle mass, increased tubular secretion and glomerular hyperfiltration in these patients, resulting in deceptively low levels even when kidney damage is developing. Cystatin C (CysC) may also remain within the normal range during early stages of disease, while albuminuria, an established marker of kidney involvement with both glomerular and tubular components, may fail to detect the initial phases of tubular damage.
What is uromodulin?
Uromodulin is a kidney-specific glycoprotein produced by epithelial cells of the thick ascending limb of the loop of Henle. Because it is produced exclusively by these tubular cells and reflects tubular integrity, it has the potential to detect sickle cell nephropathy before conventional filtration markers show abnormalities.
Study design and key findings
In this retrospective study, serum uromodulin (sUmod) concentrations were measured in adults with sickle cell disease using ELISA. Kidney function was assessed by enzymatic serum creatinine (e-SCr), CysC, beta-2 microglobulin (B2M), estimated glomerular filtration rate (eGFR), urine protein and albumin measurements.
Across serial measurements, lower sUmod concentrations were consistently associated with a less favourable kidney function profile. Patients with lower sUmod levels had higher e-SCr, CysC and B2M concentrations. The same relationship was seen when kidney function was expressed as eGFR, a more commonly used clinical measure.
Importantly, a subset of patients showed abnormally low sUmod despite normal e-SCr or CysC, but none showed the opposite pattern. This suggests that tubular stress may be detectable before changes in blood-based kidney markers or filtration estimates become apparent.
Conclusions
These findings support circulating uromodulin as a kidney-specific biomarker that could complement established measures of kidney function, particularly when creatinine and CysC remain within conventional ranges. This could be especially relevant in young adults with sickle cell disease, as hyperfiltration and low baseline creatinine levels can mask early kidney decline in this population.
sUmod may also have potential for monitoring treatment responses. In exploratory analyses, patients receiving hydroxycarbamide showed numerically more stable sUmod trajectories than untreated patents, although this difference was not statistically significant. Further prospective studies should determine whether serial sUmod measurements can improve risk stratification, enable earlier detection of tubular injury and support treatment monitoring in sickle cell nephropathy.
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