Emergent Early Markers of Renal Progression in Autosomal-Dominant Polycystic Kidney Disease Patients: Implications for Prevention and TreatmentHelal I. · Reed B. · Schrier R.W.
Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colo., USA Corresponding Author
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common single cause of end-stage renal disease after diabetes, hypertension and glomerulonephritis. The clinical course of ADPKD is highly variable. Even with optimal care and therapy monitoring, currently the progression of ADPKD is slowed but not stopped. Newer treatments will no doubt become available in the future, but their side effect profiles will always need to be considered. Therefore, markers to distinguish ADPKD patients with a poor versus a good prognosis will be helpful. Several risk factors influencing kidney disease progression in ADPKD have been identified in the current era. The present review will discuss the spectrum of early markers of ADPKD renal disease progression. Specifically, the volume of total kidney, hypertension, glomerular hyperfiltration, renal blood flow, microalbuminuria, uric acid, and urinary molecular markers will be discussed. On this background, implications for the prevention and treatment of kidney disease progression in ADPKD are also discussed.
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Autosomal-dominant polycystic kidney disease (ADPKD) is the primary genetic cause of kidney disease and the 4th most common cause of end-stage renal disease (ESRD) after diabetes, hypertension and glomerulonephritis [1,2]. ADPKD constitutes 2.3% of patients on chronic dialysis , and may present with a faster decline in glomerular filtration rate (GFR) than other renal diseases . The clinical course of ADPKD is highly variable, and progression to ESRD occurs between the 4th and 6th decades , although severe disease may occur in children . In adults with ADPKD, several risk factors for faster progression have been identified, including PKD-1 gene mutation, male gender, young age at diagnosis, presence of hypertension, hematuria, proteinuria, and young age at onset of hypertension [4,5,6,7].
Early onset of hypertension, even in childhood, has been found to occur in ADPKD . Moreover, compared to matched patients with essential hypertension, plasma renin activity and aldosterone are more stimulated in hypertensive ADPKD patients . Furthermore, all components of the renin-angiotensin system (RAS) have been found in ADPKD kidneys . With the availability of RAS inhibitors, these agents have become the initial therapy in treating hypertension in ADPKD. While cause and effect remains to be proven, there are several epidemiological studies which demonstrate improved prognosis in ADPKD in association with better control of hypertension and RAS inhibition [11,12]. Nevertheless, even with this improved care which has been associated with later progression to ESRD  and improved survival  in ADPKD, there is a great need to identify early risk factors and more definitive treatment.
Currently, kidney function in ADPKD patients is monitored by observing changes in serum creatinine and estimated GFR. However, kidney function may remain preserved until the 4th to 6th decade of life, when advanced renal cystic involvement has occurred. Clinical markers are therefore needed to identify the early progression of ADPKD. Recent advances have led to greater understanding of the mechanisms of ADPKD and several potential early markers have been found to be associated with renal disease progression (fig. 1).
|Fig. 1. Mechanisms of ADPKD.|
Total Kidney Volume
ADPKD is a systemic disorder characterized by gross enlargement of the kidneys over time due to multiple cysts that originate from the tubular epithelium of the nephrons. Recent evidence indicates that the progressive increase in kidney volume in patients with ADPKD is primarily due to the accumulation of fluid within innumerable cysts and the proliferation of mural epithelial cells [13,14]. It is evident that kidneys of patients with ADPKD progressively increase in volume beginning at birth and progress through life. . According to several cross-sectional and longitudinal human studies, an inverse correlation between GFR and total kidney volume (TKV) has been described [3,15,16,17]. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study (CRISP) funded by the National Institutes of Health was established to develop methods that reliably measure disease progression in ADPKD over a relatively short period of time . The CRISP cohort confirmed with MRI that cystic growth and renal enlargement is significant prior to impairment of renal function , as had been shown with renal ultrasound . The CRISP cohort also revealed that normotensive patients have smaller cyst and renal volumes compared to hypertensive counterparts . Renal ultrasound studies in children have also demonstrated this relationship between kidney volumes and blood pressure . Longitudinal studies of animal models support the hypothesis that reducing the rate of kidney volume enlargement may improve kidney prognosis in ADPKD patients .
Noninvasive radiologic methods have therefore been developed to monitor the rates of renal cyst and volume enlargement in ADPKD patients [18,19]. Thus, it has been proposed that TKV can be used as a marker of ADPKD progression. For clinicians, incorporating measurements of TKV by ultrasonography , computed tomography  or MRI  may allow prediction of the kidney enlargement rate of ADPKD patients [3,20]. Moreover, intervals as short as 6–12 months between measurements may be adequate to determine an effect of treatment to reduce the rate of kidney volume progression . Estimating the growth rate of TKV therefore can be important in stratifying at-risk ADPKD patients [16,20]. The patients with the more rapid kidney enlargement should be monitored more frequently and receive optimal care, including blood pressure control. There is a prospective, randomized study in hypertensive ADPKD patients which demonstrated that reversal of left ventricular hypertrophy was significantly better with a blood pressure goal of less than 120/80 mm Hg as compared to 140/90 mm Hg .
The Food and Drug Administration co-organized a scientific workshop with the Polycystic Kidney Disease Foundation to discuss and identify potential markers of disease progression in ADPKD. While effects of any new ADPKD treatment on kidney volume may occur earlier than diminished renal function, TKV is considered a surrogate endpoint while serum creatinine and GFR are considered harder endpoints.
Hypertension may occur in children with ADPKD  and recent evidence suggests that early treatment may be necessary to dramatically change the course of ADPKD . In a randomized study in ADPKD children with borderline hypertension (75th to 95th percentiles), control of blood pressure with an angiotensin-converting enzyme inhibitor stabilized kidney function and left ventricular mass compared to untreated children . In ADPKD adults, however, 80–90% are already hypertensive, therefore blood pressure cannot be used as an early marker of renal progression . The 10–20% of ADPKD adults without hypertension can, however, have a much better prognosis than the hypertensive ADPKD patients .
As noted, most patients with ADPKD have renal function which remains within the normal range for several decades, despite progressive renal enlargement . This phenomenon is related to compensatory glomerular hyperfiltration (GH) in surviving nephrons. Serum creatinine levels only start to rise appreciably above baseline when more than 50% of functioning parenchyma has been destroyed. Thus, waiting to intervene in ADPKD once the serum creatinine begins to rise may not be optimal. Moreover, this is a time when GH may be damaging the remaining nephrons secondary to glomerular hypertension. There are very few studies that have examined GH in patients with ADPKD, but GH has been proposed to be a potential early clinical marker of ADPKD [23,24]. A recent study demonstrated that young adults with ADPKD have an increased filtration fraction, which is compatible with GH . Recently, we have shown in a longitudinal study that GH (GH defined as creatinine clearance ≥140 ml/min/1.73 m2) is associated with a faster rate of renal function decline and an increased rate of kidney enlargement in children with ADPKD . Thus, GH, combined with increased TKV, may be used as an early marker for more severe progression of ADPKD in children.
Identifying GH as a risk factor for renal progression in ADPKD patients could enable early intervention. GH in ADPKD children may be attenuated by blocking the vasoconstriction of the glomerular efferent arteriole by angiotensin II. This could reverse the glomerular hypertension associated with GH. A future prospective randomized interventional study is needed to compare RAS blockers with placebo in ADPKD children with GH.
Increases in serum uric acid level have been shown to be a harbinger of renal progression in patients with chronic kidney disease (CKD) . Moreover, there are experimental results which suggest that uric acid is not just a marker of hypertension, but is a pathological factor involved activation of the RAS . In a recent study of over 800 ADKPD patients, we have shown in a multivariate analysis that increased uric acid correlates independently with hypertension and renal progression [unpubl. data].
Renal Blood Flow
Measurement of renal blood flow (RBF) is useful for assessment of renal function in a variety of renal disorders. A reduction in RBF occurs early and may precede the development of hypertension  and also has been found in the early stages of disease in ADPKD patients [30,31,32]. Activation of the RAS [33,34], increased sympathetic activity , enhanced synthesis of endothelin [35,36,37], and impaired production of nitric oxide  may contribute not only to hypertension in ADPKD patients, but also to renal vasoconstriction, remodeling of the microcirculation, and development of chronic kidney disease. Recent improvements in MRI technology have allowed for precise determinations of RBF with single breath hold MRI acquisitions . MRI measurements of RBF therefore were analyzed with respect to progression of ADPKD. The CRISP study demonstrated that RBF is reduced early in ADPKD, before loss of renal function, and is associated with increased TKV [15,40,41]. Moreover, in a recent study a decrease in RBF was observed in young adults with ADPKD .
Thus, RBF may be a more sensitive index of early disease progression than changes in GFR and perhaps even TKV. MRI measurements of RBF, therefore, deserve further consideration as a potential surrogate marker of renal progression in ADPKD patients.
Urine and Blood Emergent Early Markers
Measurement of RBF and TKV is time consuming and expensive. Therefore, interest has grown in urinary and blood biomarkers. These biomarkers are relatively easy to obtain and inexpensive to measure. Because ADPKD is a disease characterized by structural abnormalities of renal tubules, interstitial inflammation and fibrosis, urinary biomarkers reflecting tubular damage and inflammation could be promising candidate markers to assess disease severity. On cross-sectional analysis  in ADPKD patients, RBF and GFR values were associated with urinary excretion of β2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL), and heart-type fatty acid-binding protein (H-FABP) independent of urine albumin excretion (UAE). TKV was associated with kidney injury molecule-1 (KIM-1), NGAL, and monocyte chemotactic protein-1 (MCP-1) independent of UAE. Another study identified a unique urinary biomarker profile in patients with ADPKD . Thus, these urinary biomarkers could be of value for determination of disease severity in patients with ADPKD.
Arginine vasopressin (AVP), or antidiuretic hormone (ADH), is a neurohypophysial hormone which increases water permeability of kidney collecting duct. Vasopressin promotes cAMP production by acting on V2 receptors in the distal nephron and collecting ducts. Experimental studies have suggested an important role for cAMP in promoting cyst growth in ADPKD . In experimental studies, cAMP stimulated cyst formation by promoting chloride-driven fluid secretion and by stimulating activation and proliferation of cyst-derived cells . The potential role of vasopressin was confirmed by the findings in animal models of ADPKD, in which blocking the effect of vasopressin by a pharmacologic agent [19,45,46,47,48] or by drinking more water  led to reduction of cyst formation and renal function preservation. On cross-sectional analysis [50,] investigators demonstrated that copeptin, a surrogate marker of vasopressin, was associated with disease severity in ADPKD patients. These results suggest that vasopressin antagonists may have a protective effect in ADPKD. The TEMPO study is evaluating this possibility and is near completion . Secreted frizzled-related protein 4 (sFRP4) is up-regulated in human ADPKD and is detected in the urine. . Antagonism of the vasopressin 2 receptor (V2R) blocks tubular sFRP4 expression. Therefore, this protein may be a potential biomarker for monitoring the progression of ADPKD.
It is apparent that vascular changes and remodeling must occur in order to support the massive growth of cysts in ADPKD patients. Angiogenesis has been implicated in the pathogenesis of renal cyst growth in ADPKD [52,53]. Moreover, the identification of angiogenic growth factors, such as vascular endothelial growth factor, in the fluid from both human renal and hepatic cysts [52,54], and up-regulated expression of angiopoietin-1 and -2, and their endothelial tyrosine kinase-2 receptor in ADPKD cholangiocytes supports a role of angiogenic growth factors in mediating angiogenesis in ADPKD . Recently, it was shown that angiogenic growth factors significantly correlated with structural change in both the kidney and the heart as well as with urinary protein excretion . Thus, the correlation between angiogenic growth factors with both renal and cardiac disease severity supports a possible role for angiogenesis in the early progression of disease in ADPKD.
A recent study has identified three potentially modifiable factors that may influence the clinical course of ADPKD . Lower serum HDL-cholesterol, increased urine sodium excretion and higher 24-hour urine osmolality at baseline was associated with increased cyst growth and kidney progression in ADPKD patients .
Summary and Future Perspectives
A better understanding of the pathophysiology of the ADPKD and the availability of animal models has identified promising early markers of renal progression. Several clinical, imaging, urine and blood markers have been associated with renal progression in ADPKD. These markers may be useful tools in clinical practice in the future. Recognizing these emergent early markers may identify high-risk ADPKD patients and allow more intensive intervention. To date, however, it is not known whether these markers are primarily determined by renal function progression or whether these markers are factors in causing loss of renal function. Prospective, randomized studies in ADPKD will be necessary to determine whether these factors are merely markers of disease progression or are active pathogenetic factors in the progression of ADPKD.
I.H. has received an International Society of Nephrology-funded fellowship and support from the Laboratory of Kidney Pathology (LR00SP01-Pr Ben Maiz Hedi), Charles Nicolle Hospital, Tunis, Tunisia.
This research was supported by the Zell Family Foundation.
None of the authors have a conflict of interest to declare.
Robert W. Schrier
University of Colorado Denver, Division of Renal Diseases and Hypertension
Box C-281, 1270 East 19th, RC2 7th floor, Room 7001
Aurora, CO 80045 (USA)
Tel. +1 303 724 4837, E-Mail Robert.firstname.lastname@example.org
Received: February 6, 2012
Accepted June 22, 2012
Published online: July 26, 2012
Number of Print Pages : 6
Number of Figures : 1, Number of Tables : 0, Number of References : 57
American Journal of Nephrology
Vol. 36, No. 2, Year 2012 (Cover Date: August 2012)
Journal Editor: Bakris G. (Chicago, Ill.)
ISSN: 0250-8095 (Print), eISSN: 1421-9670 (Online)
For additional information: http://www.karger.com/AJN