Copeptin: a marker for ADPKD progression?

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) accounts for ∼5–10% of patients with end-stage renal disease (ESRD) [1]. Mutations in the PKD1 and PKD2 gene, encoding polycystin-1 (PC-1) and -2 (PC-2), account for ∼85 and 15% of diseases, respectively. PC-1 interacts with PC-2 to build a multifunctional signalling complex that regulates intracellular Ca signalling, and epithelial development and repair, which are essential mechanisms for maintaining a differentiated phenotype of renal epithelial cells [2, 3]. The exact pathology underlying renal cyst formation is still unknown, but it is generally accepted that adenosine3′-5′-cyclic monophosphate (cAMP) agonists accelerate cyst growth by stimulating mural epithelial cell proliferation and transepithelial Cl secretion coupled to osmotic water flow [4]. Glomerular filtration rate (GFR) is recognized as a poor predictive marker of renal function decline in ADPKD [5] as glomerular hyperfiltration in functioning nephrons is able to compensate for the ongoing loss of renal tissue. In early ADPKD, the change in total kidney volume still appears to be the most sensitive marker of disease progression [6]. The antidiuretic hormone arginine vasopressin (AVP) essentially regulates the adenylyl cyclase activity and cAMP production by binding to the vasopressin-2 receptor (V2R) in the principal cells of the collecting duct, the predominant sites for cyst formation in ADPKD [7]. Experimental studies have described a detrimental role of V2R overexpression and hyperactivation in the pathophysiological process of ADPKD [8, 9]. Moreover, the pharmacological inhibition [8, 10, 11] or physiological suppression [12] of AVP activity in animal models of polycystic kidney disease results in an ameliorated cyst formation and maintenance of renal function. However, sophisticated studies looking at the association between endogenous AVP release and severity of ADPKD have long been missed, which may be because AVP is difficult to measure due to its small size, binding to platelets and extremely high ex vivo instability [13, 14]. The recently developed copeptin assay is a readily available method for indirect AVP determination. Copeptin is the glycosylated, 39-amino acid long C-terminal part of the 164-amino acid AVP precursor peptide, which is released together with AVP from the neurohypophysis during precursor processing. More importantly, it provides a much higher ex vivo stability than the bioactive AVP [15, 16], and because of its larger size, copeptin can be measured by a highly sensitive sandwich immunoassay with two polyclonal antibodies, demonstrating a robust performance with an analytical detection limit of 0.4 pmol/L and an availability of results in a few hours instead of several days [15, 16]. As a marker of endogenous AVP secretion, prognostic and diagnostic properties of copeptin are well described in various clinical areas of cardiovascular and renal disease [17–19]. Moreover, recently a direct intrarenal pro-albuminuric effect of AVP has been hypothesized [20], although convincing data investigating additional effects on the Gs signalling pathway are still missing. Against this background, Boertin et al., in this issue of Nephrology Dialysis Transplantation, report in a prospective investigation the association of copeptin levels with disease severity in 79 subjects with ADPKD followed up for >11 years. Study participants (43% male, age 36.8 ± 10.1 years, baseline GFR 96.8 ± 18.2 mL/min/1.73 m) had a median copeptin concentration of 2.7 pmol/L that inversely correlated to changes in inulin clearance at 3.3-year follow-up and estimated GFR (eGFR) at 11.2 years. The inverse association between copeptin levels and renal function was statistically independent of patients’ age, gender, blood pressure and baseline GFR values. Subjects starting renal replacement therapy during long-term follow-up revealed a baseline copeptin concentration above the median. These findings are in accordance with the results of a previous cross-sectional study from the same investigators [21] and provide some additional arguments that copeptin is associated with the renal outcome in patients with ADPKD. It remains to be determined if this effect is specific to ADPKD or rather is a more general association between reflecting the hormone response to chronic kidney disease [18, 19]. Several specific questions arise from this data. First and most importantly, the estimated GFR is probably not the most appropriate parameter to assess alterations in renal function in ADPKD [5], and the fact that the long-term outcome of kidney function was evaluated by eGFR measurement does essentially weaken the proposed inverse association between copeptin and kidney function in ADPKD. Secondly, copeptin like AVP, are stress hormones influenced by a number of different conditions and blood drawing procedures. These processes require careful

DOI: 10.1093/ndt/gfs353

Cite this paper

@article{Fenske2012CopeptinAM, title={Copeptin: a marker for ADPKD progression?}, author={Wiebke K Fenske and Christoph Wanner}, journal={Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, year={2012}, volume={27 11}, pages={3985-7} }