The impact of chronic kidney diseases (CKDs) on human life expectancy is dramatically increasing and it is estimated that CKD will climb to the number five cause for global years of life lost by the year 2040 [1]. This goes in parallel with an ‘unseen’ CKD epidemic recently proclaimed in a joint statement of three major nephrology societies (https://web.era-edta.org/uploads/180627-press-era-asn-isn.pdf). They highlighted the fact that many aspects of kidney diseases have so far been underestimated because progressive CKD is associated with substantial comorbidity, reduced life expectancy and the risk of reaching end-stage kidney disease (ESKD), necessitating renal replacement therapy [2]. Reliable identification of patients with ongoing CKD progression thus has broad consequences not only for their well-being, but also for saving of healthcare resources. This aspect becomes increasingly eminent with emerging new treatment options to halt CKD progression, such as sodium–glucose cotransporter 2 inhibitors and/or non-steroidal mineralocorticoid receptor antagonists [3, 4], with targeted intervention in patients with a high progression risk being of particular interest.
Unfortunately, no standardized definition for CKD progression exists worldwide and the choice of definition is usually influenced by the type of cohort under observation and the duration of the prospective observation period. CKD progression is commonly defined by a decrease in various aspects of kidney function until ESKD is reached. Typical ‘renal’ endpoints are surrogates of the estimated glomerular filtration rate (eGFR) slope, such as a 50% decrease in eGFR over time and/or the need for renal replacement therapy, or particular indices of kidney damage such as the onset and/or worsening of proteinuria. In fact, in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, patients with CKD of different aetiologies are categorized as having low, moderate, high or very high risk for CKD progression according to their eGFR and albuminuria [5]. However, the individual CKD course is difficult to predict even within a specific risk category, particularly under disease-modifying therapeutic interventions or altering comorbidities, e.g. blood pressure changes. Indeed, long-term studies have shown that patterns of individual CKD progression may differ considerably [6]. In general, studies on CKD progression suggest yearly progression rates of ~0.3–1.0 mL/min/1.73 m2 among participants without proteinuria or comorbidity and rates of ~2–3 times higher among participants with proteinuria or comorbidity [5]. Thus, identifying subjects at risk for accelerated CKD progression—whatever the cause may be—remains challenging.
In experimental studies and epidemiological cohort studies, several biomarkers for the assessment of CKD progression have been tested, using also newer sophisticated technologies such as proteomics. However, so far none of the tested biomarkers has been able to improve prediction of CKD progression in large-scale validation cohorts beyond that of the currently used clinical models or baseline eGFR and albuminuria [7], and particularly not to predict individual loss of kidney function. Nevertheless, from results of molecular biology studies, it became clear that the renal tubulointerstitial compartment plays a pivotal role in CKD progression, regardless of the cause of injury. It represents the major compartment of the kidney, with tubular epithelia cells (TECs) identified as a key driving force in progressive kidney damage. In response to injury, TECs can undergo unfavorable changes in phenotype and function and subsequently act as pro-inflammatory and pro-fibrotic cells that perpetuate the damage, eventually leading to irreversible renal scaring. This is referred to as tubulointerstitial fibrosis and represents the common pathological hallmark of aetiologically different CKD entities that finally results in organ failure. Recently, persistent Wingless-Int1 (Wnt)/β-catenin signaling has been recognized as a key molecular event involved in different types of kidney injury [8]. Particularly in CKD progression, spatial and temporal modulation of this specific pathway in TECs results in the development of tubulointerstitial fibrosis and progressive kidney function decline.
In this issue of the journal, Sanchez-Alamo et al. [9] report on urinary Dickkopf-3 (uDKK3) as a promising new biomarker for the evaluation of CKD progression. The glycoprotein DKK3, a member of the Dickkopf family, is a known ligand of the Wnt/β-catenin pathway and experimental data imply that DKK3 is produced by TECs under stress conditions and subsequently secreted into the urine, but they may also act in a paracrine manner to drive tubulointerstitial fibrosis [8]. Therefore the measurement of uDKK3 potentially serves as a non-invasive diagnostic biomarker for ongoing TEC injury and thereby progressive CKD. Sanchez-Alamo et al. [9] prospectively studied two independent cohorts comprising 351 patients with CKD Stages 2–3. The combined primary outcome consisted of a 50% increase in serum creatinine, ESKD or death. The first cohort (‘Progreser’) included 250 patients with heterogeneous CKD aetiologies recruited in 13 Spanish hospitals, whereas the second cohort (‘Pronedi’) comprised 101 patients with clinically confirmed progressive diabetic nephropathy and a urine protein:creatinine ratio ≥0.3 g/g on two separate occasions. Both cohorts had a median follow-up of 36 months. The authors found significantly higher baseline uDKK3 in patients who reached the primary outcome during the follow-up. In the Cox proportional hazards model, the highest levels of uDKK3 were found to be an independent factor for CKD progression {Progreser cohort: hazard ratio [HR] 1.91 [95% confidence interval (CI) 1.04–3.52]; Pronedi cohort: HR 3.03 [95% CI 1.03–8.92]}. Moreover, uDKK3 gradually increased over time in both cohorts, especially in patients with higher proteinuria, probably in line with ongoing kidney disease progression. The authors concluded that uDKK3 identifies patients at high risk of CKD progression regardless of the cause of kidney injury and beyond the established biomarkers serum creatinine and albuminuria [9]. It might thus serve as a diagnostic tool to optimize staging for CKD progression and to monitor the response to potential treatments for slowing down CKD progression.
The results of Sanchez-Alamo et al. [9] are in line with other published studies in humans, be it in the setting of CKD or in the setting of acute kidney injury (AKI) and its transition into progressive CKD, that is the AKI–CKD transition [10–13]. In the prospective CARE FOR HOME study, with a mean follow-up of 5.1 years, comprising 575 patients of various CKD aetiologies, uDKK3 concentrations were significantly associated with an eGFR decline in the subsequent 12 months after full adjustment for confounders including baseline eGFR and albuminuria [10]. This finding was confirmed in a cohort comprising patients with biopsy-proven immunoglobulin A nephropathy (STOP-IgAN trial) [10]. Here, the prediction of CKD progression was independent from the randomization to the treatment arms. In an additional analysis from the CARE FOR HOME study, uDKK3 was also significantly and independently associated with cardiovascular events during the follow-up period (Figure 1), revealing the known intimate relationship between progressive CKD and cardiovascular comorbidity. It is therefore not surprising that the clinical utility of uDKK3 as a biomarker of AKI–CKD transition has been confirmed in individuals with substantial cardiovascular comorbidity undergoing elective cardiac surgery [11] and in individuals receiving iodinated contrast medium during invasive cardiovascular procedures [12]. In the former study, elevated preoperative uDKK3 independently predicted the risk of AKI after elective cardiac surgery and the ensuing loss of kidney function during long-term follow-up in a non-selected cohort (n = 733) and a high-risk cohort preselected based on the Cleveland risk score (n = 240) [11]. Importantly, uDKK3 also predicted AKI in patients with apparently normal kidney function, i.e. normal eGFR before surgery. In the later study, uDKK3 markedly improved identification of patients with known CKD (i.e. eGFR <30 mL/min/1.73 m2) at risk for AKI and persistent kidney dysfunction after an invasive cardiovascular procedure with application of contrast media [12]. In this study comprising 458 individuals, a baseline uDKK3 ≥322 pg/mg was the best threshold for prediction of persistent kidney dysfunction defined as a permanent decrease in eGFR of >25% at 1 month after exposure to contrast media. Adding baseline uDKK3 to different clinical prediction scores derived based on the patient’s clinical and laboratory data, including kidney (dys)function parameters, e.g. Mehran, Gurm and National Cardiovascular Data Registry scores, significantly increased integrated discrimination improvement (IDI) and net reclassification improvement (NRI) in all of these scores (all P < 0.001) [12]. Furthermore, Seibert et al. [13] prospectively studied 490 patients undergoing coronary angiography and found uDKK3 to be an independent predictor of contrast-induced AKI even in the absence of overt CKD. Finally, in a prospective multicentre observational study, Schunk et al. [14] evaluated uDKK3 as a marker for the identification of progressive kidney injury in a non-CKD cohort of 2314 patients with chronic obstructive pulmonary disease [14]. Baseline uDKK3, but not eGFR or proteinuria, identified patients with high risk for a significant eGFR decline during the follow-up. The superiority of uDKK3 was particularly evident in patients with an eGFR >90 mL/min/1.73 m2 and no proteinuria, establishing uDKK3 as a potential tool for early identification of clinically ‘silent’ progressive CKD.
Urinary DKK3 and the risk of atherosclerotic cardiovascular events in the CARE FOR HOME study. Cardiovascular events were defined as any of the following: myocardial infarction, coronary artery or lower limb artery angioplasty/stenting/bypass surgery, major stroke, carotid endarterectomy/stenting or non-traumatic lower extremity amputation. The multivariate model is adjusted for age, gender, body mass index, hypertension, smoking, diabetes, lipid-lowering therapy, eGFR and proteinuria.
The findings of Sanchez-Alamo et al. [9], taken together with the data reported from large prospective observational studies, highlight the measurement of uDKK3 as a precision medicine approach for assessment of individual CKD progression, regardless of the aetiology of CKD and beyond established biomarkers such as eGFR and proteinuria. This new tool may also be a significant step forward for monitoring of therapeutic measures applied in order to halt CKD progression.
FUNDING
D.F. is supported by the Deutsche Forschungsgemeinschaft (SFB TRR-219).
CONFLICT OF INTEREST STATEMENT
D.F. is associated with DiaRen.
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