Perspective Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy Ahsan Alam, MD,1 Neera K. Dahl, MD,2 Joshua H. Lipschutz, MD,3 Sandro Rossetti, MD,4 Patricia Smith, PhD,5 Daniel Sapir, MD,6 Jordan Weinstein, MD,7 Philip McFarlane, MD,7 and Daniel G. Bichet, MD8 Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials. Am J Kidney Dis. -(-):---. ª 2015 by the National Kidney Foundation, Inc. INDEX WORDS: Total kidney volume (TKV); autosomal dominant polycystic kidney disease (ADPKD); decline in renal function; decreased kidney function; decreased renal function; ADPKD biomarker; outcome measure; renal cyst; cystogenesis; disease progression.

A

utosomal dominant polycystic kidney disease (ADPKD) is a chronic inherited kidney disease characterized by progressive development and expansion of fluid-filled cysts in the kidneys.1 Other organs, most notably the liver, can also be affected. If one were to combine the prevalence of the other wellknown genetic disorders cystic fibrosis, Down syndrome, hemophilia, Huntington disease, muscular dystrophy, and sickle cell anemia, the total would still fall short of the total prevalence of ADPKD.2 It is the most common form of inherited nephropathy, with an estimated prevalence of 1:400 to 1:1,000, and (after diabetes, hypertension, and glomerulonephritis) the fourth leading cause of end-stage renal disease (ESRD), accounting for w4.6% of all cases of ESRD.3 There is currently no approved treatment available to prevent, slow the progression of, or cure ADPKD. Existing ADPKD therapies relate to generic chronic kidney disease management or the treatment of acute symptoms, but they have had little, if any, impact on delaying the time to onset of ESRD to date. By the age of 65 years, an estimated 45% to 70% of patients with ADPKD progress to ESRD and require dialysis therapy or transplantation.4 Am J Kidney Dis. 2015;-(-):---

However, recently, understanding of the underlying mechanisms of cystogenesis in this disease has led to a proliferation of research into targeted therapies for ADPKD itself. Some of the pathways that have been investigated include mediators of cell proliferation (eg, sarcoma [src]-family kinases, mammalian target of rapamycin [mTOR], mitogen-activated protein kinase [MAPK] inhibition5-7), intracellular calcium From the 1McGill University Health Centre, Montreal, Quebec, Canada; 2Yale School of Medicine, New Haven, CT; 3Medical University of South Carolina, Charleston, SC; 4Otsuka America Pharmaceutical, Inc, Princeton, NJ; 5Otsuka Canada Pharmaceutical, Inc, Montreal, Quebec; 6Halton Healthcare Services, Oakville; 7St. Michael’s Hospital, Toronto, Ontario; and 8Hôpital du Sacré-Cœur de Montréal, Department of Medicine, Molecular and Integrative Physiology, University of Montreal, Montreal, Quebec, Canada. Received August 31, 2014. Accepted in revised form January 22, 2015. Address correspondence to Ahsan Alam, MD, Division of Nephrology, McGill University Health Centre–Royal Victoria Hospital, 687 Pine Avenue West, Ross 2.38, Montreal, Quebec, Canada H3A 1A1. E-mail: [email protected]  2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.01.030 1

Alam et al

regulation (eg, calcimimetics and polycystin 2 [PC-2] agonists8,9), and intracellular cyclic adenosine monophosphate (cAMP) regulation (eg, vasopressin V2 receptor and somatostatin analogues10,11). As more and more therapies are being evaluated for this common disease, it is critically important to establish common outcome measures that can be used to quantify the effects of those interventions on the course of the disease. Traditional measures of kidney function used in the evaluation of interventions for other kidney diseases (eg, changes in glomerular filtration rate [GFR]) may not be applicable to ADPKD, particularly in its earlier stages when kidney function is preserved. This raises the need to identify early markers of disease progression. Recent advances have led to better understanding of the pathophysiology of ADPKD. Fluid secretion and cell proliferation causing cyst development and enlargement have been identified as central pathogenic factors in ADPKD,12 cystogenesis in ADPKD has been correlated with enlargement of the kidney as a whole,13 and increases in kidney volume are reflective of progression of the disease. Data from the CRISP (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease) study, a prospective observational cohort of 241 patients with ADPKD with preserved kidney function who were carefully characterized by serial kidney magnetic resonance imaging (MRI) and iothalamate clearance, have shown that increases in height-adjusted total kidney volume (TKV) are associated with more frequent and severe complications of ADPKD (eg, hypertension, gross hematuria, and proteinuria) and also with loss of kidney function.14-16 Given that TKV can be quantified by various imaging modalities (eg, MRI, computed tomography, or ultrasonography),17 measuring TKV may provide an opportunity to assess the degree of disease progression, as well as monitor the efficacy of interventions in patients with ADPKD early in the disease, before functional decline of the kidneys has occurred. The goal of this article is to provide an informed perspective on whether TKV is a suitable biomarker for disease progression and whether TKV is an appropriate efficacy end point for clinical trials. This is done by way of a summary of the pathophysiology and natural history of ADPKD, a discussion of the various methods that can be used to measure TKV, and a summary of published research that has reported correlations between TKV and clinical manifestations of ADPKD, discussed the suitability of TKV as a biomarker for disease progression, and used TKV as an efficacy end point in clinical trials. Although we conducted a search of the published literature, supplemented by the authors’ knowledge of additional publications (see Fig S1, provided as 2

online supplementary material), we did not perform a formal systematic review. Furthermore, no formal grading of the quality of evidence or assessment of bias was conducted.

PATHOPHYSIOLOGY AND NATURAL HISTORY OF ADPKD ADPKD is characterized by the development and progressive enlargement of multiple kidney cysts, associated with a progressive increase in TKV leading eventually to a decline in kidney function and ultimately to ESRD in midadult life for most patients with ADPKD. Two ADPKD-associated genes have been cloned and characterized: PKD1 (localized on chromosome 16p13.3 and encoding polycystin 1 [PC-1]1,18) and PKD2 (localized on chromosome 4q21 and encoding PC-21,18). PC-1 and -2 are transmembrane glycoproteins that colocalize to the primary cilium of kidney tubular epithelial cells.18 Both proteins have been described in other cellular compartments also.19 Mutations in PC-1 or -2 lead to lower intracellular levels of calcium and increased intracellular cAMP, 2 key intracellular secondary messengers, causing cell proliferation and fluid secretion into the expanding cyst.20,21 Some of the pathways affected (eg, cAMP) have been investigated as possible targets for treatment.5-11 Of note, cAMP also results from stimulation or upregulation of the vasopressin V2 receptor. It is the dysregulation of cAMP that has been linked to both the proliferation of the cyst-lining epithelium and the chloride-driven fluid secretion into these cysts.21-23 Increased cAMP signaling stimulates several molecular pathways, including the MAPK/ERK (MAPK/ extracellular signal–regulated kinase) pathway (Fig 1).24 This ultimately leads to altered nuclear signaling and cell proliferation, manifested as kidney tubular dilatation and cyst initiation and growth, with fluid secretion into the cyst lumen. This cascade of events initiates the destructive process of the disease through uncontrolled cyst development and expansion within the affected kidney tubules.25-27 There is experimental evidence to suggest that cystogenesis may start as early as in utero, and the initial stages of cyst development have been detected as early as 9 weeks of gestation.28 When formed, the cysts are continuously filled with fluid originating from the glomerular filtrate. With time, most of these cysts become autonomous structures by pinching off from the parent tubule and appearing as isolated sacs that are filled with fluid by transepithelial secretion.12 The continuously expanding fluid-filled cysts cause compression and distortion of the kidney vasculature, with stretching of the vessels lining the Am J Kidney Dis. 2015;-(-):---

Total Kidney Volume in ADPKD

Figure 1. Hypothetical pathways in polycystic kidney disease and rationale for treatments. Abbreviations: AC6, adenylate cyclase 6; Ca21, calcium; Cl2, chloride; CFTR, cystic fibrosis transmembrane conductance regulator; Gi & Gs, G proteins; mTOR, mammalian target of rapamycin; PC1, polycystin 1; PC2, polycystin 2; PKA, protein kinase A; R, somatostatin receptor; V2R, vasopressin 2 receptor.

expanding cysts. This leads to renin release and activation of the renin-angiotensin-aldosterone system (RAAS). Furthermore, tubular obstruction in ADPKD likely parallels ureteral obstruction models, leading to the release of various chemokines, cytokines, and fibrogenic mediators.15,29-31 The extent of the damage resulting from these events depends on the location of the cyst; because of the progressive convergence of collecting ducts from the cortex to the medulla of the kidney, a cyst located further downstream in the medulla has a greater impact than a cyst located further upstream in the cortex.12 Contrast-enhanced MRI and computed tomography have shown that functional kidney tissue is lost many years before a clinically significant decline in GFR is observed.12,15 In children with ADPKD, glomerular hyperfiltration has been found to be associated with a higher rate of kidney enlargement over time.32 It is understood that the stress placed on the healthy glomeruli to compensate through hyperfiltration leads to glomerular hypertension, which progressively damages the remaining unaffected nephrons.12 As the disease progresses, formation and enlargement of the cysts continues unabated, causing further destruction of the kidney parenchyma and reduced ability to compensate for this destruction, until kidney function declines sharply and irreversibly. A significant decline in kidney function is not usually evident until kidney volume has increased by a factor of 5, or until at least 50% of the parenchyma has been destroyed.15,33,34 Consequently, in most patients, loss of kidney function and ESRD usually occur between the ages of 50 and 70 years, whereas cyst development and its destructive consequences begin many decades before.12,35-37 Data from the CRISP study have provided useful information related to kidney disease progression and its genetic determinants; Am J Kidney Dis. 2015;-(-):---

individuals with PKD1 mutations were found to have significantly larger kidney volume and a more severe disease course than individuals with PKD2 mutations14 and typically reach ESRD 20 years earlier than PKD2 patients.38

MEASURING TKV T1-weighted MRI can be used to determine the volumes of individual kidneys by adding the products of the area measurements and slice thickness from a series of contiguous images.14 Average TKV in individuals with no known history of intrinsic kidney disease is w400 and w300 mL in men and women, respectively.39 Recently, it was shown that cyst and kidney volumes can be estimated through the acquisition of MRI data and the application of a simple equation.40 This equation uses the area of the midslice measurement multiplied by the total number of slices in the coronal magnetic resonance images, then this product is multiplied by a factor of 0.61 to 0.64.40 This estimation would significantly reduce the time traditionally required for processing magnetic resonance images. Other efforts have also been made to develop simpler more practical standardized methods to estimate TKV. One such method is use of the ellipsoid formula [kidney volume 5 length 3 width 3 thickness 3 (p/6)].41 This method was compared to the more time-consuming stereology method in a study including 590 patients with ADPKD.42 TKV estimated by the ellipsoid formula (TKVe) correlated well with TKV calculated using stereology measured by computed tomography/MRI (R2 5 0.98), without systematic under- or overestimation. In addition, the average time needed to measure TKVe was only 7 minutes, compared with the 45 minutes required to measure TKV by stereology. 3

Alam et al

Although ultrasonographic measurement of TKV is not sufficiently precise to measure short-term disease progression, mainly due to high intra- and interobserver variability,43 it has been found to be useful in stratifying patients according to risk for disease progression.43 More recently, the CRISP investigators assessed the utility of simply using kidney length as a predictor of future decline in kidney function.44 They found that kidney length measured by ultrasonography correlated well with TKV measured by MRI (r 5 0.98), and both were predictive of stage 3 chronic kidney disease.44 Despite its limitations, ultrasonography remains a useful tool for diagnosis and screening in ADPKD. The application of newer techniques that decrease operator dependence, such as 3-dimensional ultrasonography, which has been used successfully in other diseases,45,46 may extend the use of ultrasonography to measure disease progression in patients with ADPKD.

KIDNEY GROWTH AND CLINICAL MANIFESTATIONS IN ADPKD Clinical manifestations occur prior to GFR decline and are directly related to cyst expansion, structural damage to organ architecture, and kidney enlargement. Data from the CRISP cohort, with 11 years of follow-up for 202 patients, show that a high mean baseline height-adjusted TKV is associated significantly with a higher incidence of hypertension, hematuria, and pain.47 Pain is common in ADPKD, occurring in w60% of patients, and is the most difficult symptom to manage.1,15,48-51 It may occur at any stage of the disease, often despite normal kidney function.52 Chronic kidney pain in ADPKD is caused by progressive cyst growth, leading to capsule stretching, pedicle traction, and occlusion of the collecting ducts.48,49 It may manifest as lower-back pain (71.3%), radiculopathies (26.9%), or abdominal pain (61.4%).50 In w50% of patients with ADPKD, the increase in kidney volume reaches such a magnitude that the size and shape of the abdomen become altered significantly.53 The added abdominal mass caused by the enlarged kidneys can distort the patient’s posture and lead to chronic lower-back pain. The direct relationship between kidney size and chronic pain is supported by the observation that cyst decompression and volumetric reduction produce significant pain relief in some patients with ADPKD.48,49 Acute kidney pain is most often secondary to cyst rupture and bleeding, kidney stones, or cyst infections.48,49 Cyst rupture is caused by structural changes in the kidney, as well as excessive angiogenesis, characterized by fragile and stretched vessels that are susceptible to bleeding upon minimal insult. 4

Blood can leak into the cyst, causing it to expand rapidly and provoking intense pain.15 If intracyst bleeding continues, it could lead to even more expansion and stretching of the cyst walls, which may eventually rupture. Cysts can rupture into the collecting ducts, causing gross hematuria, or they may rupture into the subcapsular compartment and eventually into the retroperitoneal space, causing massive bleeding into the flank and abdomen.15 It is estimated that hematuria occurs in w60% of patients with ADPKD15,54,55 and that intracyst hemorrhage occurs in .90% of patients.1,15,54 There is strong evidence supporting the positive correlation between larger kidney size and risk of hematuria.15,49,54,55 Hematuria usually occurs several years or decades before a decline in kidney function is detectable.54,56 The prevalence of nephrolithiasis in patients with ADPKD is 8% to 36%,57-59 approximately twice that observed in the general population. There are a number of potential factors that, alone or in combination, make stone formation more likely among patients with ADPKD. These include cyst-associated structural abnormalities and kidney tubular stasis, as well as the comorbid metabolic disorders.57-59 Nephrolithiasis has been shown to be associated with enlarged kidneys.15,59 Hypertension occurs in 50% of patients aged 20 to 34 years with ADPKD with normal kidney function and increases to w100% in patients with ESRD; it is associated with faster progression to ESRD and is an important risk factor for cardiovascular morbidity and mortality in those patients.1,60-63 In ADPKD, hypertension is caused by cyst expansion, which leads to compression of the adjacent parenchyma and vasculature, causing glomerular hypoxia and ischemia, which activate the local RAAS.1,60,61 The development of hypertension can be observed in patients with ADPKD who are otherwise asymptomatic and not exhibiting a decline in GFR.1,60-63 In a study of 85 patients with ADPKD aged 4 to 21 years who were followed up for 5 years, there was a strong association between TKV increase and hypertension.37 Hypertensive patients also experienced significantly higher rates of increase in TKV, total cyst volume, and number of cysts compared with borderline-hypertensive patients. These results are corroborated by other studies in children with ADPKD.15,33,64,65 Similar associations between hypertension and TKV have been reported in adults,1,13,15,60,61,62 including in the CRISP study, which demonstrated that hypertensive individuals had higher TKV, total cyst volume, and cyst volume as a percentage of kidney volume compared with normotensive individuals.13 Other urinary markers, such as proteinuria13,66 and low baseline urine osmolality,67 have also been associated Am J Kidney Dis. 2015;-(-):---

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with increased kidney volume, providing further insight into the likelihood of disease progression.

TKV AS A BIOMARKER FOR KIDNEY DISEASE PROGRESSION IN ADPKD Several cross-sectional and longitudinal studies have found an inverse correlation between TKV and GFR (Table 1).13,14,16,66,68-73 The most important data in this area come from the CRISP study, which demonstrated that TKV, total cyst volume, and percentage of kidney volume occupied by cysts were significantly and inversely correlated to GFR after 3 years.14 In a subgroup of 201 CRISP patients followed up for up to 8 years, the correlation between baseline height-adjusted TKV and GFR increased from 20.22 at baseline to 20.65 at year 8.16 These data demonstrate that the relationship between GFR and TKV is stronger during the later stages of ADPKD, when the effect of compensatory glomerular hyperfiltration has been compromised. This may also explain the large variability in the magnitude of correlation between GFR and TKV reported in the literature (Table 1), where the stage of the disease examined and duration of follow-up vary. The quality and size of these studies vary considerably; the evidence provided by these studies therefore needs to be interpreted and weighed accordingly. Given that increased kidney enlargement usually precedes the development of decreased kidney function by 4 decades or more, the prognostic value of TKV has been a subject of special interest. In the CRISP study, increased baseline TKV was observed to be associated with a significantly faster decline in GFR14 and a higher likelihood of decreased kidney function.16 The CRISP study reported that higher baseline height-adjusted TKV predicts the development of stage 3 chronic kidney disease within 8 years (odds ratio per 100 mL/m, 1.48; 95% confidence interval, 1.29-1.70). This association was stronger than other known risk factors such as age, serum creatinine level, serum urea nitrogen level, or urinary albumin or monocyte chemoattractant protein 1 excretion. This association was also independent of ADPKD genotype, sex, race, and age.16 The association between kidney volume and decline in kidney function has also been demonstrated in several other studies.14,16,68,73-77 Baseline TKV has been shown to be a predictor of impaired kidney function, with each doubling of kidney volume being associated with a significant 1.7- to 2.4-fold increase in risk of decreased kidney function.75 Using nested case-control analysis, studies have shown that patients with clinically important GFR decline or those progressing to dialysis therapy have higher baseline TKV earlier in the disease.68,74 Am J Kidney Dis. 2015;-(-):---

In conclusion, these studies support the use of TKV as a biomarker of decreased kidney function in patients with ADPKD.

USE OF TKV IN HUMAN CLINICAL TRIALS Given that severely distorted kidney architecture is already well established by the time GFR starts to decline, delaying treatment until kidney function is decreased is not ideal. Prevention of cyst development and growth therefore could have a disease-modifying effect, resulting in slowing the loss of kidney function and delaying time to ESRD. It is also likely that clinical trials using conventional kidney measures (eg, GFR) during the early stages of the disease would require unreasonably long periods of follow-up (ie, decades) to show benefit. Therefore, GFR is not the ideal primary end point for evaluating the efficacy of interventions targeting cyst formation and growth in early stages of disease. However, changes in TKV can be detected early in the disease and are correlated with clinical outcomes, including GFR decline, supporting TKV as a useful biomarker.15,78 A considerable number of clinical trials using TKV as a primary efficacy end point have been completed and others are ongoing. The completed trials include phase 3 studies evaluating the vasopressin 2 antagonist tolvaptan,11 the mTOR inhibitors everolimus and sirolimus,79-85 the somatostatin analogue octreotide (in a long-acting release formulation),10,86,87,88 the HMG-CoA (3-hydroxy-3-methylglutaryl–coenzyme A) reductase inhibitor pravastatin,89 and antihypertensives targeting the RAAS90 (Table 2). The widespread use of TKV in clinical trials91 highlights its feasibility, utility, and increasing acceptability as a surrogate for disease progression and therapeutic efficacy in ADPKD. However, areas of controversy still exist, suggesting that TKV may not be a universally suitable biomarker to assess therapeutic efficacy in ADPKD.92 Additionally, there are practical difficulties that might make TKV unsuitable for use in individual patients. One recent study, for example, showed that atypical cyst burden (eg, cysts in a single kidney) occurs in w10% (52/ 590) of patients.42 This type of disease presentation would make measurement and interpretation of TKV problematic, particularly using simplified methods (eg, ellipsoid formula). Data from randomized clinical trials using mTOR inhibitors, somatostatin analogues, and RAAS inhibitors have shown that the relationship between cyst burden and decreases in kidney function may not be straightforward, suggesting that the 2 outcomes may not always be linked.90,92 Several factors may account for this discordance, including trial design (heterogeneous patient populations, late-stage 5

Alam et al Table 1. Studies Examining the Association Between Kidney Volume and Kidney Function in ADPKD Study

TEMPO 3:473

N

Patient Profile

1,445 eGFR $ 60 mL/min/1.73 m2

HALT-PKD66

558 eGFR . 60 mL/min/1.73 m2

CRISP I13,14

241 CLcr . 70 mL/min

CRISP II16

201 CLcr . 70 mL/min

Fick-Brosnahan et al68

229 Mean baseline GFR 5 71 6 22 mL/ min/1.73 m2

Lee & Lee71

56 Mean CLcr 5 62 6 27 mL/min/ 1.73 m2

Thomsen et al69

43 Kidney function: normal (.90 mL/ min), n 5 11; moderately decreased (60-89 mL/min), n 5 12; considerably decreased (30-59 mL/min), n 5 8; severely decreased (5-29 mL/min), n 5 12 20 Mean GFR 5 69.3 (range, 23-137) mL/min/1.73 m2

Irazabal et al72

King et al70

9 Initial Scr # 1.3 mg/dL and/or iothalamate clearance $ 60 mL/ min/1.73 m2

Association Examined

Key Findings

Baseline MRI-measured htTKV vs baseline eGFR

A significant inverse correlation exists at baseline between htTKV and eGFR (20.378; P , 0.001) Baseline ln(MRI-measured A significant inverse correlation htTKV) vs baseline eGFR exists at baseline between ln(htTKV) and eGFR (20.339; P , 0.001) MRI-measured TKV vs Age-adjusted kidney volume baseline GFR; TCV vs (20.31; P , 0.0001), TCV baseline GFR; % cyst (20.36; P , 0.0001), and % cyst volume vs baseline GFR; volume (20.35; P , 0.0001) are change in MRI-measured inversely related to GFR; a TKV vs change in GFR significant inverse correlation over 3 y exists between the slope of TKV change and the slope of GFR change (20.186; P 5 0.005) Baseline htTKV vs GFR at A significant inverse correlation baseline and y 1, 2, 3, 6, & 8 exists between baseline htTKV and GFR, which increases from baseline (20.22; P 5 0.02) to y 8 (20.65; P , 0.001) US-measured TKV vs GFR A significant inverse correlation (cross-sectional analysis) exists between TKV and GFR (20.53; P , 0.0001) TKV, MRI-measured TCV, and A significant inverse correlation % cyst volume vs CLcr exists between CLcr and TKV (20.56; P , 0.0001), TCV (cross-sectional analysis) (20.60; P , 0.0001), and % cyst volume (20.57; P , 0.0001) CT-measured TKV vs CLcr A significant inverse linear (cross-sectional analysis) correlation (20.473; P , 0.001) exists between total kidney volume and CLcr

Baseline ln(MRI-measured TKV) vs baseline GFR

A significant inverse correlation exists between ln(TKV) and GFR (20.788; P , 0.001) CT-measured TKV vs baseline A nonsignificant inverse correlation GFR at baseline; CTexists between GFR and TKV measured TCV vs baseline (20.40; P 5 0.28) or TCV GFR; slope of CT-measured (20.64; P 5 0.06); a significant TCV vs slope of GFR inverse correlation exists between the rate of increase in TCV and the rate of GFR decline (20.71; P 5 0.046)

Abbreviations and definitions: ADPKD, autosomal dominant polycystic kidney disease; % cyst volume, percentage of total kidney volume occupied by cysts; CT, computed tomography; CLcr, creatinine clearance; CRISP, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease; (e)GFR, (estimated) glomerular filtration rate; HALT-PKD, Halt Progession of Polycystic Kidney Disease; htTKV, height-adjusted total kidney volume; ln, natural-log-transformed; MRI, magnetic resonance imaging; Scr, serum creatinine; TCV, total cyst volume; TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes; TKV, total kidney volume; US, ultrasonography.

kidney disease,81 relatively small sample size, and short trial duration79,80,87), suboptimal dosing of the treatment agent,79,80 and substantial pharmacologic side effects.79-81,87 An additional contributing factor for this discordance may be related to the mode of action of these drugs. Grantham et al12 stated the importance of “matching the therapeutic agent under 6

study to an appropriate end point,” suggesting that for more advanced disease, studies investigating agents that exert their effects through anti-inflammatory, antiangiogenic, and antifibrotic pathways might be better off using GFR as the primary study end point. However, for trials of agents targeting cell proliferation and/or fluid secretion among patients earlier in Am J Kidney Dis. 2015;-(-):---

Study

TEMPO 3:411 (prospective, multicenter, doubleblind, placebocontrolled)

N

Primary Objective

Population Studied

Primary End Point

1,445 Long-term safety and ADPKD pts (CKD1-3) with Rate of TKV change efficacy of tolvaptan in rapidly progressive over 36 mo ADPKD pts disease: TKV $ 750 mL, eCLcr $ 60 mL/min

HALT-PKD90 (prospective, randomized, doubleblind, placebo controlled)

558 Low (95/60-110/75 mm ADPKD pts with HTN, 15- Annual % change in 49 y old, baseline TKV Hg) vs standard (120/ eGFR . 60 70-130/80 mm Hg) BP target and dual (lisinopril 1 telmisartan) vs single (lisinopril 1 placebo) RAAS inhibition

Walz et al81 (prospective, randomized, doubleblinded, placebocontrolled)

433 Efficacy of everolimus in Clinical diagnosis of both ADPKD ADPKD and CKD2-3 (eGFR 30-89) or CKD1 (eGFR $ 90) plus estimated single kidney volume . 1 L 110 Effect of pravastatin on Pediatric pts with ADPKD htTKV and LVMI and CLcr . 80 mL/min/ 1.73 m2 receiving lisinopril

Cadnapaphornchai et al89 (randomized doubleblind placebo-controlled)

SUISSE ADPKD80 (prospective, randomized, open-label, controlled, singlecenter)

Key Secondary End Point(s)

Key Findings

Composite of time to clinical progression events (worsening kidney function, HTN, proteinuria, pain) Rate of kidney function decline Rate of change in eGFR

Annual DTKV: 12.8% (tolvaptan) vs 15.5% (placebo); P , 0.001 Fewer ADPKD-related events in tolvaptan vs placebo (HR, 0.87; P 5 0.01) Annual change in kidney function (1/Scra): 22.61 (tolvaptan) vs 23.81 (placebo); P , 0.001 Annual DTKV: 15.6% (low BP target) vs 16.6% (standard BP target); P 5 0.006 Annual DTKV: 16.0% (lisinopril 1 telmisartan) vs 16.2% (lisinopril 1 placebo); P 5 0.52 Annual DeGFR: 22.9 (low BP target) vs 23.0 (standard BP target); P 5 0.55 Annual DeGFR: 23.0 (lisinopril 1 telmisartan) vs 22.9 (lisinopril 1 placebo); P 5 0.55 Mean DTKV at 24 mo: 1230 mL (everolimus) vs 1301 mL (placebo); P 5 0.06 Mean DeGFR at 24 mo: 28.9 (everolimus) vs 27.7 (placebo); P 5 0.15

DTKV over 24 mo

Change from baseline in mean cyst and parenchymal volumes Change in kidney function (eGFR, Scr, UPCR, ESRD) at 24 mo $20% change in $20% increase in the htTKV, LVMI, or UAE individual variables of (composite) over 3 y htTKV, LVMI, and UAE

100 Does sirolimus retard Adult pts with ADPKD and % increase in TKV over GFR, UAER kidney-volume growth eCLcr $ 70 mL/min 18 mo in adults with ADPKD in early-stage CKD

(Continued)

Reached primary end point over 3 y: 69% (pravastatin) vs 88% (placebo); P 5 0.03 Had $20% increase in htTKV over 3 y: 46% (pravastatin) vs 68% (placebo); P 5 0.03 DhtTKV (adj for age, sex, and HTN status) over 3 y: 23% (pravastatin) vs 31% (placebo); P 5 0.02 Median DTKV at 18 mo: 199 mL (sirolimus) vs 197 mL (control); P 5 0.26 Mean DGFR at 18 mo: 10.2 (sirolimus) vs 23.5 (control); P 5 0.07 DUACR at 18 mo: 11.1 (sirolimus) vs 0.0 (control); P 5 0.05

Total Kidney Volume in ADPKD

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Table 2. Randomized Clinical Trials With Kidney Volume as a Major End Point

7

8 Table 2 (Cont’d). Randomized Clinical Trials With Kidney Volume as a Major End Point Study

N

Primary Objective

Population Studied

Primary End Point

Key Secondary End Point(s)

75 Effect of 3 y of octreotide LAR treatment on kidney and cyst growth and kidney function decline

ADPKD and eGFR $ 40 with evaluable MRI scans at 1 y F/U

DTKV at 1 and 3 y F/U DTCV, DGFR

RAPYD82 (prospective, open-label, randomized)

55 Can sirolimus (1 ramipril) reduce progressive increase in TCV and TKV; identify optimal sirolimus dose

ADPKD caused by PKD1 mutations; eGFR 5 40-80

Reduction in TKV and Safety and adverse events TCV over 24 mo Rate of kidney function decline (DeGFR over time)

Hogan et al87 (pilot randomized, placebocontrolled, double-blind)

42 Efficacy and safety of Severe PLD from ADPKD octreotide LAR in PLD or ADPLD and PKD

% change in liver Changes in total kidney volume from baseline volume over 1 y to 1 y DiGFR over 1 y

(Continued)

Absolute DTKV at 1 y: 146.2 mL (octreotide LAR) vs 1143.7 mL (placebo); P 5 0.03 Absolute DTKV at 3 y: 1220.1 mL (octreotide LAR) vs 1454.3 mL (placebo); P 5 0.25 Absolute DTCV at 1 y: 133.0 mL (octreotide LAR) vs 1108.5 mL (placebo); P 5 0.02 Absolute DTCV at 3 y: 1183.8 mL (octreotide LAR) vs 1394.7 mL (placebo); P 5 0.11 Annual slope of DGFR, 0-3 y: 23.85 (octreotide LAR) vs 24.95 (placebo); P 5 0.03 No significant differenceb in mean DTKV at 24 mo: ramipril: 136 mL; ramipril 1 highdose sirolimus: 115 mL; ramipril 1 lowdose sirolimus: 114 mL Differences observedb in DTCV at 24 mo; ramipril: 13 mL; ramipril 1 high-dose sirolimus: 215 mL; ramipril 1 low-dose sirolimus: 216 mL No significant differenceb in DeGFR at 24 mo: ramipril: 23.6; ramipril 1 high-dose sirolimus: 14.5; ramipril 1 low-dose sirolimus: 10.8 mL Change in total liver volume at 1 y: 24.95% (octreotide LAR) vs 10.92% (placebo); P 5 0.05 Among patients with ADPKD, DTKV at 1 y: 10.25% (octreotide LAR) vs 18.61% (placebo); P 5 0.05 DGFR at 1 y: 25.1% (octreotide LAR) vs 27.2% (placebo); P 5 0.98

Alam et al

Am J Kidney Dis. 2015;-(-):---

ALADIN10 (multicenter, randomized, singleblind, placebocontrolled, parallelgroup)

Key Findings

Study

N

Primary Objective

Population Studied

Primary End Point

Braun et al85 (open-label pilot study)

30 Can more accurate ADPKD and iGFR $ 25 measure of change in GFR (iGFR) reveal a treatment effect with low-dose sirolimus

DiGFR at 12 mo

SIRENA79 (prospective, proof-of-concept, randomized, crossover)

21 Formally assess the risk/benefit profile of sirolimus in PKD

ADPKD and normal or moderately decreased kidney function

DTKV over 6 mo

Soliman et al84 (randomized, singleblind, parallelassignment, safety/ efficacy study)

16 Can sirolimus retard cyst growth and slow functional deterioration among pts with ADPKD

ADPKD, 30-50 y old, with Scr , 2 mg/dL or GFR . 30, UPER # 0.5 g/d, and documented TKV progression

DTKV over 12 and 24

Ruggenenti et al86 (randomized, longitudinal, crossover)

12 Safety and tolerability of ADPKD and Scr , 3.0 mg/ DTKV over 6 mo somatostatin dL, but .1.2 mg/dL (_) treatment in ADPKD or .1.0 mg/dL (\)

mo

Key Secondary End Point(s)

Key Findings

DeGFRCKD-EPI at 12 mo DTKV at 12 mo

Mean DiGFR at 12 mo: 17.7 (low-dose sirolimus) vs 11.6 (standard-dose sirolimus) vs 211.2 (standard care); lowdose vs standard care: P , 0.01; standard-dose vs standard care: P 5 0.07 Mean DeGFR at 12 mo: 23.2 (low-dose sirolimus) vs 12.6 (standard-dose sirolimus) vs 10.4 (standard care); ANOVA overall P 5 0.58 Association between kidney Total DTKV at 6 mo: 146 mL (sirolimus) volume changes and vs 170 mL (conventional therapy); P 5 0.45 DGFR (assessed by Mean DGFR: 22.4 (sirolimus) vs 10.5 standard techniques) (conventional therapy); P 5 NS Change in kidney function at Mean DTKV at 12 mo: 1536 mL 12 and 24 mo (sirolimus 1 telmisartan) vs 11,013 mL (placebo 1 telmisartan); P , 0.05c Mean DTKV at 24 mo: 11,056 mL (sirolimus 1 telmisartan) vs 11,109 mL (placebo 1 telmisartan); P 5 NSc Kidney function (Scr): stable in 4, improved in 2, worsened in 2 (sirolimus); stable in 4, improved in 1, worsened in 3 (placebo); actual values NR Change in cyst and Mean DTKV at 6 mo: 12.2% (octreotide parenchymal volume over LAR) vs 15.9% (placebo); P , 0.01 6 mo Mean change in cyst volume at 6 mo: 13.0% (octreotide LAR) vs 15.6% DGFR over 6 mo (placebo); P 5 NSc Mean change in parenchymal volume at 6 mo: 24.4% (octreotide LAR) vs 12.5% (placebo); P 5 NSc

Abbreviations: adj, adjusted; BP, blood pressure; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; (e)CLcr, (estimated) creatinine clearance; ESRD, end-stage renal disease; (e)GFR: (estimated) glomerular filtration rate (in mL/min/1.73 m2); F/U, follow-up; HTN, hypertension; htTKV, height-corrected total kidney volume; iGFR, GFR measured by 125I-iothalamate; LAR, long-acting release; LVMI, left ventricular mass index; NS, not significant; NR, not reported; (AD)PKD, (autosomal dominant) polycystic kidney disease; (AD)PLD: (autosomal dominant) polycystic liver disease; pts, patients; RAAS, renin-angiotensin-aldosterone system; Scr, serum creatinine; TCV, total cyst volume; TKV, total kidney volume; UAER, urinary albumin excretion rate; UPCR, urinary protein-creatinine ratio; UPER, urinary protein excretion rate. a Units are reciprocal of mg/mL per year. b Exact P values for between-group differences not reported. c Exact P value not reported.

Total Kidney Volume in ADPKD

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Table 2 (Cont’d). Randomized Clinical Trials With Kidney Volume as a Major End Point

9

Alam et al

the course of the disease, TKV would remain the most suitable primary end point.

CONCLUSIONS AND OVERALL PERSPECTIVES ADPKD is a hereditary kidney disease that begins as early as in utero and progresses to ESRD in many patients by midadult life. The disease is characterized by polycystic kidney enlargement that precedes the decline in GFR by several decades. Therefore, markers of kidney function such as GFR fail to determine the extent of the disease progression, particularly in the early disease stages. With the new emerging treatment paradigms, consisting of interventions in the early course of the disease with the aim of delaying the onset of decreased kidney function, sequential TKV measurements appear to be an appropriate end point for selected agents targeting cell proliferation and/or fluid secretion. The utility of TKV as a surrogate marker of disease progression, as well as its sensitivity as a prognostic marker of decreased kidney function, is gaining wider acceptance, but its utility throughout the stages of CKD and its role in those with atypical cyst burden remain to be validated. TKV assessment is well tolerated and, if it can be measured easily and accurately, should enable the evaluation of therapies decades before changes in GFR would be expected to occur and before kidney architecture is irreversibly damaged.

ACKNOWLEDGMENTS Support: A medical writer (Mr Scott Moffat) provided assistance with the writing and editing of the manuscript. Funding for these services was provided by Otsuka Canada Pharmaceutical, Inc, which manufactures tolvaptan. The article sponsor’s role in the collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication was limited to the participation of Otsuka employees Drs Rossetti and Smith as coauthors. The final decision on the main points to be communicated, including the conclusions drawn, was made by consensus of the authors. Financial Disclosure: Drs Rossetti and Smith are employees of Otsuka American Pharmaceutical Inc and Otsuka Canada Pharmaceutical Inc, respectively. Drs Alam and McFarlane are consultants for and have received research grant funding from Otsuka Canada Pharmaceutical, Inc. Dr Dahl is a consultant for Otsuka America Pharmaceutical, Inc and Otsuka Canada Pharmaceutical, Inc and a principal investigator for several Otsuka-sponsored clinical studies. Dr Lipschutz is a consultant for Otsuka America Pharmaceutical, Inc and the principal investigator of a PKDrelated grant (VA Merit Award I01 BX000820). Drs Sapir and Weinstein have received honoraria from Otsuka Canada Pharmaceutical, Inc supporting the development of educational materials for ADPKD. Dr Bichet is a consultant for Otsuka Canada Pharmaceutical, Inc and an investigator for Otsuka-sponsored clinical studies.

SUPPLEMENTARY MATERIAL Figure S1: Literature search and included articles. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2015.01.030) is available at www.ajkd.org

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