DKK3 and kidney

For the first time, a diagnosis is possible using a simple urine test

ReFiNE is an IVDR-certified test for the diagnosis of an active or progressive kidney damage, based on ELISA technology. It is performed in a spontaneously collected urine sample. The measured Dkk3 value can be used to detect as yet unknown kidney damage or to reliably confirm progressive kidney disease. In addition, the level of Dkk3 measured in the urine predicts the future loss of kidney function in people with confirmed CKD, i.e. it correlates significantly with the individual's loss of GFR in the subsequent period [Zewinger et al, J Am Soc Nephrol 2018; Schunk et al, Lancet 2019; Schunk et al, Kidney Int 2021; Husain-Syed et al, Nephrol Dial Transplant 2021; Sanchez-Alamo et al, Nephrol Dial Transplant 2021; Roscigno et al, J Am Coll Cardiol 2021, Speer et al, Lancet Child & Adolescent Health 2023].

In people with healthy kidneys, Dkk3 is not detectable in the urine at all or only in very small quantities. In the course of kidney damage, Dkk3 is released very early by "stressed" renal tubule cells to limit further damage to the kidney tissue. Ultimately, however, the continuous, uncontrolled release of Dkk3, which has a pro-fibrotic effect, leads to progressive scarring of the tissue, a so-called tubulointerstitial fibrosis [Federico et al, J Clin Invest Insight 2016]. This term describes the uniform scarring of the renal medulla, which in itself is not specific to a particular underlying kidney disease. However, the extent of scarring significantly determines the prognosis of any kidney disease.

In which patients is a Dkk3 measurement in urine indicated?

Adults with (long-term) arterial hypertension (high blood pressure)
Adults with (long-term) metabolic syndrome or diabetes mellitus
Adults and children/adolescents with primary kidney diseases such as glomerulonephritis or cystic kidney diseases
Adults and children/adolescents with diseases that can cause chronic kidney damage, such as heart or lung failure
Adults and children/adolescents with systemic diseases such as vasculitis or systemic lupus erythematosus (SLE)
Adults and children/adolescents with acute kidney failure due to severe infections, after major surgical procedures or diagnostic measures such as the application of contrast media
Adults and children/adolescents with suspected kidney damage due to nephrotoxic medication or therapies (non-steroidal anti-inflammatory drugs, chemotherapy, immunosuppressants, etc.)
Adults and children/adolescents with an unclear impairment of kidney function, i.e. with a reduced GFR
Adults and children/adolescents after successful kidney transplantation

The Kidney Disease: Improving Global Outcomes classification is used to diagnose and classify the severity of CKD based on GFR and albumin excretion rate in urine (figure). The measurement of Dkk3 in urine in conjunction with the determination of eGFR also allows a better assessment of the individual course of CKD. In older people in particular, the GFR can be reduced due to age without any significant structural or pathological changes in the kidney tissue. The determination of urinary Dkk3 can provide clarity about the condition of the kidneys, as a negative result rules out active kidney damage or CKD with a high degree of certainty.

Disadvantage of CKD staging according to KDIGO

The classification only predicts the "rough" risk of further progression of kidney damage for all persons who belong to a certain KDIGO category. The actual individual progression depends on many other factors, such as changing activity of the kidney disease, concomitant and intercurrent diseases, intake of harmful medication or smoking. It is not clear whether a "risk patient" actually has progressive CKD. The further individual course of the kidney disease therefore also remains unclear!

Advantage through Dkk3 detection in urine

Dkk3 is released into the urine by "stressed" or damaged renal tubule cells. Significant kidney damage is therefore indicated at a very early stage. As the disease progresses, the amount of Dkk3 excreted in the urine increases in parallel with the severity or activity of the damage process in the renal medulla. The newly developed Dkk3 ELISA (ReFiNE) therefore enables the early detection of progressive kidney damage with a simple determination of Dkk3 in urine. The test is ideally suited as additional information to the eGFR in order to better predict individual CKD progression.

Preanalytics - Dkk3 is preferably measured in fresh morning urine

Dkk3 is stable for at least 24 hours in refrigerated urine samples (at 4 °C), but longer storage should be avoided. Alternatively, the urine samples can be frozen immediately at -20 °C until determination. Repeated thawing and freezing should be avoided.

Decreased values: Improper urine storage
Elevated values: Non-centrifuged urine, in case of fever/infections (e.g. urinary tract infection) or acute interstitial kidney damage

Damage

The kidneys are damaged → positive test (accuracy almost 100%)

Characteristic

How severe is the kidney damage → relative level of the Dkk3 value

The Dkk3 results should always be interpreted in conjunction with the eGFR

Dkk3 <200 pg/mg creatinine

There is no progressive kidney damage. In the presence of risk factors, such as diabetes mellitus and/or high blood pressure, a check-up should be carried out every 6-12 months.

Dkk3 >200 pg/mg creatinine

There is a high probability of active kidney damage. The individual loss of GFR correlates with the Dkk3 concentration in the urine. The annual eGFR loss with urinary Dkk3 values >1,000 pg/mg creatinine is significant.

Dkk3 >4,000 pg/mg creatinine

is associated with a mean annual eGFR loss of 7.6% compared to urinary Dkk3 levels <200 pg/mg creatinine [Zewinger et al, J Am Soc Nephrol 2018].

Confirmation or exclusion of active and, above all, progressive kidney damage (CKD progression) - knowledge advantage
Education of the patient - clear result, clear message for the patient
Better blood pressure control and/or better blood sugar control
Avoidance of further kidney damage (nephrotoxic drugs, etc.)
Efficient diagnostics and reporting to the referring physician

Dickkopf 3 (Dkk3) - sensitive biomarker of progressive kidney damage