Identifying Patients at High Risk for Short-Term Chronic Kidney Disease Progression: Still a Challenge?

The number of patients with chronic kidney disease (CKD) increases steadily. However, the individual course of kidney disease may be variable, and accurate identification of patients who will definitely experience progression is challenging (1).

Established biomarkers for prediction of CKD progression are estimated GFR (eGFR) and albuminuria. In the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, patients with CKD of different causes are categorized as having a low, moderate, high, or very high risk for kidney disease progression, according to their (baseline) eGFR and albuminuria (2). Nevertheless, in 1.7 million participants from 35 cohorts with 12,344 ESRD events, CKD progression was highly variable even in patients within the same KDIGO risk category (3). Therefore, the use of kidney failure risk equations for prediction of eGFR loss during long-term follow-up was recently proposed, because these equations include additional clinical and biochemical variables besides eGFR and albuminuria (4). Whereas refining these equations with the inclusion of even more putative progression factors can improve their accuracy, the individual CKD course is variable and difficult to predict by general equations, particularly under disease-modifying interventions. In addition, recent studies revealed that (e.g., in many patients with diabetes) advanced CKD (i.e., eGFR <60 mL/min per 1.73 m2) may be present even in the absence of higher-grade albuminuria (5). Therefore, biomarkers that indicate (short-term) eGFR loss are desirable.

Recently, Dickkopf-3 (DKK3) has been identified as a stress-induced, renal tubular epithelia-derived, secreted glycoprotein that induces tubulointerstitial fibrosis in experimental animals through its action on the canonical Wnt/β-catenin signaling pathway (6). Genetic and antibody-mediated abrogation of DKK3 led to significantly decreased interstitial matrix accumulation, reduced tubular atrophy, and hence preserved kidney function in various mouse models of CKD. Notably, the profibrotic effects of DKK3 in the kidney were independent of the cause of initial damage. Mechanistically, DKK3 deficiency caused diminished canonical Wnt/β-catenin signaling in tubular epithelial cells, which was accompanied by an antifibrogenic inflammatory response within the injured kidney, highlighting the crucial role of the Wnt/β-catenin pathway in renal tubulointerstitial injury.

Importantly, DKK3 is embryonically expressed and is detectable in urine after birth only under tubular stress conditions. It may then serve as a noninvasive diagnostic tool for ongoing kidney injury and (short-term) eGFR loss. This was tested by Zewinger et al. (7) in 575 patients with CKD of various causes from the CARE FOR HOMe study, in which eGFR and urinary DKK3 levels were assessed in one-year blocks at regular follow-up visits (in total, 2035 patient years were available for analysis).

After complete adjustment for all potential progression confounders such as age, gender, blood pressure, smoking, diabetes, eGFR, and albuminuria, urinary DKK3 remained a significant and independent indicator of eGFR decline within the following 12-month period. Moreover, urinary DKK3 significantly improved prediction of kidney function loss in comparison with eGFR or albuminuria alone—a finding that underlines the independent role of urinary DKK3 as a significant marker for CKD progression. In this respect, urinary DKK3/creatinine above 4000 pg/mg was independently associated with a mean annual decline in eGFR of 7.6% (95% confidence interval −10.9 to −4.2%; p <0.001).

The results of the CARE FOR HOMe study were further validated in patients with IgA nephropathy (IgAN) from the randomized STOP-IgAN trial (8). In this multicenter randomized controlled trial, patients with active biopsy-proven IgAN entered a 6-month run-in phase, in which supportive care therapy (e.g., strict blood pressure control including blockade of the renin-angiotensin system) was optimized.

Patients who had persistent proteinuria of at least 0.75 g per day were randomly assigned to receive either supportive care alone or supportive care plus immunosuppressive therapy. Urinary DKK3 was measured in all available urine samples from participants in the 6-month run-in phase and the 6-month early randomized treatment phase (7). During the run-in phase, urinary DKK3 above median was associated with a mean eGFR decline of 19.1% (95% confidence interval −24.2 to −14.0%; p <0.001 vs. reference) after adjustment for all potential confounders.

Also, in participants of the STOP-IgAN trial, the addition of DKK3 to a model comprising eGFR and albuminuria significantly increased its predictive power for short-term eGFR loss (7). During the early treatment phase, a rise in urinary DKK3/creatinine concentrations was associated with a significant decline of eGFR, whereas stable or decreasing urinary DKK3/creatinine levels indicated a more favorable course of kidney function (Figure 1). Changes in urinary DKK3 were independently associated with changes in eGFR even after adjustment for albuminuria or randomization to the treatment arms. The former finding is of particular interest, inasmuch as the development of albuminuria—a putative indicator of glomerular damage—and increased tubular secretion of DKK3 in the urine may not be related to the same pathophysiologic mechanism. This is corroborated by the CARE FOR HOMe study results, in which increased urinary DKK3 indicated significant loss of kidney function even in the absence of albuminuria. Therefore, it might be inferred that persistently elevated urinary DKK3 levels indicate ongoing tubular “stress” and lead to progressive tubulointerstitial fibrosis independent of eGFR and albuminuria and of the type of kidney disease.

Figure 1.

Restricted cubic spline plot of the association between change in eGFR and urinary concentrations of Dickkopf-3 (DKK) and creatinine during the early treatment phase in participants of the STOP-IgAN trial

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Adjustments were made for age, gender, body mass index, systolic blood pressure, smoking status, eGFR, and log albuminuria. Blue spikes indicate individual changes of urinary DKK/creatinine concentrations. Note that rising urinary DKK/creatinine concentrations (values >0) are associated with loss of kidney function, whereas declining urinary DKK/creatinine concentrations (values <0) are associated with stable or even improving kidney function within the 6-month early treatment period.

As discussed above, the high individual variability of CKD progression could be well observed in the early treatment phase of the STOP-IgAN trial. Here, a carefully selected cohort of patients with active disease experienced an unpredictable course of kidney function within 6 months. Nevertheless, changes in urinary DKK3/creatinine concentrations helped to identify those patients with fast eGFR decline during this period.

Based on these observations, urinary DKK3 not only may represent a biomarker for short-term eGFR loss but may be involved in its pathogenesis, as indicated by experimental studies. Measurement of DKK3 in urine therefore represents a novel tool for the identification of patients at high risk for short-term eGFR loss, regardless of the cause of kidney injury and beyond currently established biomarkers. In this respect, monitoring of DKK3 excretion in the urine may improve the treatment of patients with CKD as a personalized medicine approach, because urinary DKK3/creatinine levels could be used as a tool to supervise and, if necessary, also intensify therapeutic intervention to halt CKD progression.

March 2019 (Vol. 11, Number 3)

References

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2. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 2013; [Suppl 3]:1–150.

3. Coresh J, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA 2014; 311:2518–2531.

4. Tangri N, et al. Multinational assessment of accuracy of equations for predicting risk of kidney failure: A meta-analysis. JAMA 2016; 315:164–174.

5. Porrini E, et al. Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes. Lancet Diab Endocrinol 2015; 3:382–391.

6. Federico G, et al. Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis. J Clin Invest Insight 2016; 1:e84916.

7. Zewinger S, et al. Dickkopf-3 (DKK3) in urine identifies patients with short-term risk of eGFR loss. J Am Soc Nephrol 2018; 29:2722–2733.

8. Rauen T, et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med 2015; 373:2225–2236.