1. How does the genetic profile of ADPKD impact the disease course?
Dr. York Pei 1

2. Genotype-Phenotype Correlations in ADPKD
PKD1 mutations ~75% of cases
PKD2 mutations ~25% of cases
Phenotype:
More cysts than PKD2
Median age at ESRD ~55 years and more severe disease associated with truncating mutations
Mild disease similar to PKD2 with most non-truncating mutations
Phenotype:
Fewer cysts than PKD1
Median age at ESRD ~75 years
Associated with less renal and extrarenal complications than PKD1
There are two major genetic mutations that underlie the pathophysiologic changes characteristic of ADPKD. These are mutations in the PKD1 or PKD2 genes. Generally speaking, the two types of mutations lead to distinctive phenotypes, with PKD1 mutations causing more severe, faster-progressing disease than PKD2 mutations. It should be noted, however, that many non-truncating mutations of the PKD1 gene produce an ADPKD phenotype similar to PKD2 mutation.
Importantly for patient counseling, the anticipated age of end-stage renal disease is markedly different depending on the genetic mutation. PKD2 patients can expect approximately 20 years of dialysis-free living compared to those with PKD1 mutations.
References:
Barua M, Cil O, Paterson AD, et al. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol 2009; 20(8):
Cornec-Le Gall E, Audrézet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013; 24(6):
Adapted from:
Barua M, et al. J Am Soc Nephrol 2009; 20:
Cornec-Le Gall E, et al. J Am Soc Nephrol 2013; 24(6):

3. Truncating Mutations Cause More Severe Disease in PKD1 than PKD2
NB: Median age at ESRD occurs ~20 years earlier in PKD1 than PKD21
These data come from a multicentre survey that compared clinical data from 333 people with PKD1 (31 families) with data from 291 people with PKD2 (31 families). Geographically matched controls were also included.
The median age at death or onset of end-stage renal disease was 53.0 years (95% CI ) among individuals with PKD1, 69.1 years ( ) in those with PKD2, and 78.0 years ( ) in controls.
Reference:
Hateboer N, v Dijk MA, Bogdanova N, et al. Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. Lancet 1999; 353(9147):103-7.
1. Hateboer N, et al. Lancet 1999; 353(9147):103-7.

4. PKD Mutation Classes Influence Renal Survival
Truncating mutations cause more severe disease in PKD1 than PKD21
Truncating PKD1 mutations cause more severe disease than non-truncating PKD1 mutations1
Some non-truncating PKD1 mutations may function as hypomorphic alleles associated with very mild renal disease2
The median age at ESRD for truncating PKD1, non-truncating PKD1, and PKD2 mutations are 55.6, , and 79.7 years, respectively1
The data in the figure come from a study of 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort.1
The data from this cohort show that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations.
They also showed that the type of PKD1 mutation, but not its position, correlated strongly with renal survival; the median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation.
This supports other research, which has shown that some PKD1 mutations function as “hypomorphic” mutations, in which the polycystin protein retains some of its function.2
References:
1. Cornec-Le Gall E, Audrézet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013; 24(6):
2. Pei Y, Lan Z, Wang K, et al. A missense mutation in PKD1 attenuates the severity of renal disease. Kidney Int 2012; 81(4):412-7
Adapted from:
1. Cornec-Le Gall E, et al. J Am Soc Nephrol 2013; 24(6):
2. Pei Y, et al. Kidney Int 2012; 81(4):412-7.

5. What is the typical pattern of cyst development and progression in Adpkd?
Dr. Philip McFarlane 2

6. Timeline of Cyst Burden and Kidney Function in ADPKD
Over time, as ADPKD progresses, there is a steady growth of kidney size, directly correlated to increases in cyst volume. As this process occurs, kidney function is initially largely preserved, as the kidney compensates through hyperfiltration. However, as the disease progresses further and the kidney volume increases further, a threshold is reached where the compensatory capacity is lost and the kidney function begins to decline precipitously.
Also during the course of the disease, renal vascularity is lost as the cysts grow.
Reference:
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354(20):
GFR: glomerular filtration rate.
Adapted from: Grantham JJ, et al. N Eng J Med 2006; 354(20):

7. Normal TKV is ~250 mL in women and ~350 mL in men.
Over Time, Cysts Develop and Expand Resulting in Loss of Kidney Function
Example of Progression in One Patient
Over 13 years, TKV increased by 300% with a 53% loss of kidney function
This slide shows a typical progression pattern with ADPKD, as illustrated by the case of one individual with the disease. Diagnosed at age 30, he had a total kidney volume of 1441 mL (normal would be approximately 350 mL). Over the following 13 years, further development and growth of cysts was associated with 300% increase in kidney volume and a 53% loss of kidney function.
Age 30
CKD Stage 1
GFR 93 mL/min
TKV 1441 mL
Age 37
CKD Stage 2
GFR 61 mL/min
TKV 2775 mL
Age 43
CKD Stage 3
GFR 44 mL/min
TKV 4459 mL
Normal TKV is ~250 mL in women and ~350 mL in men.
GFR: glomerular filtration rate; CKD: chronic kidney disease; TKV: total kidney volume.

8. Total Kidney Volume Correlates with Total Cyst Volume
Examples of correlations in individual patients
In the CRISP cohort, at baseline, the mean total kidney volume was 1076 mL and the total cyst volume was 534 mL among the 241 patients. In most patients, polycystic kidneys and cysts increased in volume from year to year, although there was a great deal of interpatient variability, as shown in the graphs.
The total kidney volume increased during the three-year period by an average of 204 mL (p<0.001 vs. baseline). Total cyst volume increased by an average of 218 mL (p<0.001).
Reference:
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354(20):
Kidney growth is highly variable and each individual has their own growth curve.
Measurement variability = inter-observer 2.1%, intra-observer 2.4%, day-to-day 2.4%.
Adapted from Grantham JJ, et al. N Eng J Med 2006; 354(20):

9. What are the risk factors for adpkd disease progression?
Dr. Neera Dahl 3

10. PKD Mutation Classes Influence Renal Survival
Truncating mutations cause more severe disease in PKD1 than PKD21
Truncating PKD1 mutations cause more severe disease than non-truncating PKD1 mutations1
Some non-truncating PKD1 mutations may function as hypomorphic alleles associated with very mild renal disease2
The median age at ESRD for truncating PKD1, non-truncating PKD1, and PKD2 mutations are 55.6, , and 79.7 years, respectively1
The data in the figure come from a study of 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort.1
The data from this cohort show that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations.
They also showed that the type of PKD1 mutation, but not its position, correlated strongly with renal survival; the median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation.
This supports other research, which has shown that some PKD1 mutations function as “hypomorphic” mutations, in which the polycystin protein retains some of its function.2
References:
1. Cornec-Le Gall E, Audrézet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013; 24(6):
2. Pei Y, Lan Z, Wang K, et al. A missense mutation in PKD1 attenuates the severity of renal disease. Kidney Int 2012; 81(4):412-7
Adapted from:
1. Cornec-Le Gall E, et al. J Am Soc Nephrol 2013; 24(6):
2. Pei Y, et al. Kidney Int 2012; 81(4):412-7.

11. TKV Expansion is a sensitive measure of disease progression in ADPKD
GFR remains stable due to renal compensation despite TKV expansion (on average ~5%/yr) and is an insensitive marker of renal disease progression.
The progressive increase of cyst volume (and, by extension, total kidney volume) is the hallmark characteristic of ADPKD. In earlier stages of the disease, this progressive increase in kidney size is not mirrored by equivalent reductions in kidney function, as hyperfiltration partially compensates.
As such, total kidney volume is a more sensitive measure of disease progression than kidney function, particularly in earlier stages of ADPKD.
Reference:
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354(20):
GFR: glomerular filtration rate.
Adapted from: Grantham JJ, et al. N Eng J Med 2006; 354(20):

12. Clinical Risk Factors in ADPKD
Potentially modifiable traits that are associated with poorer prognosis in ADPKD:
Lower serum HDL-cholesterol1
Greater urine sodium excretion1
Higher urine osmolality1
Higher serum uric acid2
Greater body surface area, body mass index1
Higher protein intake1
Higher blood pressure1
Albuminuria1
Diabetes3
There are a number of clinical factors that have been associated with poor prognosis among patients with ADPKD.
References:
1. Torres VE, Grantham JJ, Chapman AB, et al. Potentially modifiable factors affecting the progression of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2011; 6(3):640-7.
2. Helal I, McFann K, Reed B, et al. Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease. Nephrol Dial Transplant 2013; 28(2):380-5.
3. Reed B, Helal I, McFann K, et al. The impact of type II diabetes mellitus in patients with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2012; 27(7):
Adapted from:
1. Torres V, et al. Clin J Am Soc Nephrol 2011; 6(3):640-7.
2. Helal I, et al. Nephrol Dial Transplant 2013; 28(2):380-5.
3. Reed B, et al. Nephrol Dial Transplant 2012; 27(7):

13. What is the relationship between growth in kidney volume and kidney function in adpkd?
Dr. Philip McFarlane 4

14. TKV Expansion is a sensitive measure of disease progression in ADPKD
GFR remains stable due to renal compensation despite TKV expansion (on average ~5%/yr) and is an insensitive marker of renal disease progression.
The progressive increase of cyst volume (and, by extension, total kidney volume) is the hallmark characteristic of ADPKD. In earlier stages of the disease, this progressive increase in kidney size is not mirrored by equivalent reductions in kidney function, as hyperfiltration partially compensates.
As such, total kidney volume is a more sensitive measure of disease progression than kidney function, particularly in earlier stages of ADPKD.
Reference:
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354(20):
GFR: glomerular filtration rate.
Adapted from: Grantham JJ, et al. N Eng J Med 2006; 354(20):

15. Volume Progression in PKD: Relationship Between TKV and GFR
Using data from the CRISP cohort, investigators quantified the slope of the change in the glomerular filtration rate from baseline to year 3.
To determine whether kidney enlargement was uniformly associated with decreasing renal function, they stratified the cohort into three groups according to baseline total kidney volume.
Among the subgroups defined according to the initial total kidney volume, the differences between the slopes of total kidney volume (expressed as milliliters per year or percent per year) were significant (p<0.001). 
Reference:
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354(20):
Adapted from: Grantham JJ, et al. N Engl J Med 2006; 354(20):

16. Changes in Height-adjusted TKV and eGFR Over Time in ADPKD
As shown in these two line graphs, increase in total kidney volume precedes the decline in renal function by several years.
Reference:
Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7(3):479-86
htTKV: height-adjusted total kidney volume; GFR by iothalamate clearance.
NIH CRISP Studies. Chapman AB, et al. Clin J Am Soc Nephrol 2012; 7(3): (supplemental data)

17. What is the role of TKv in practice?
Dr. Neera Dahl 5

18. Controversies with Total Kidney Volume
Should TKV be used to measure disease progression in clinical trials for ADPKD?
Which imaging approach should be used?
Should TKV be used to ascertain prognosis and monitor disease progression in clinical practice? How?
The answers to these questions is currently not known and is likely to continue to be the focus of debate in learned nephrology circles for years to come.

19. TKV: Finding a Place in Research and the Clinic
Data from CRISP supports the inclusion of TKV as a tool for study population enrichment and as a primary endpoint in RCTs
Further data informing the association between TKV and outcomes would be welcome
There is no current consensus on the use of renal imaging as part of routine care
There is no consensus on the preferred imaging modality (US, MRI or CT) or formula for measuring/estimating TKV

20. Imaging Modalities for Total Kidney Volume: Strengths and Limitations
Modality
Strengths
Limitations
MRI
Greatest accuracy
Method used in clinical trials evaluating TKV
Limited availability, long wait times
Inter-observer variability
Calculation of results is time intensive
Ultrasound
Readily available
Short/no wait times
Less accurate than MRI CT
More accurate than ultrasound
Shorter wait times than MRI
Patient exposure to radiation
There are strengths and limitations for each of the advanced imaging modalities that can be used to assess total kidney volume. In short MRI is the most sensitive and accurate, but is difficult to access and is costly. Ultrasound is accessible, but is the least accurate.

21. How do you diagnose adpkd and what is the role of genetic testing?
Dr. Ahsan Alam 6

22. Ultrasonographic Diagnostic Criteria for ADPKD
Population
Criteria for Diagnosis of ADPKD
At-risk individuals from ADPKD families of unknown genotype
Ages 15 to 39 years
≥ 3 (unilateral or bilateral) renal cysts
Ages 40 to 59 years
≥ 2 cysts in each kidney
For at-risk individuals aged 60 yr, in whom renal cysts are numerous in both PKD1 and PKD2 and among whom simple cysts are frequently found
≥ 4 cysts in each kidney
NB. < 2 renal cysts in at-risk individuals aged ≥40 years is sufficient to exclude the disease
Pei Y, et al. J Am Soc Nephrol 2009; 20:

23. Counselling Before Screening for an Individual with a Family History of ADPKD
Counsel first and make the decision to test on a case-by-case basis
POSSIBLE BENEFITS OF TESTING
POTENTIAL DRAWBACKS OF TESTING
Certainty regarding diagnosis that may influence family planning and insurability (including negative test results)
The potential for discrimination
(e.g., health insurability, employment)
Early detection and treatment of
disease complications
Psychological burden of a chronic disease
Identification of genetically unaffected family members for living related-donor renal transplantation
When a patient is diagnosed with ADPKD and has relatives that have not yet been tested, the decision on whether to test those relatives for ADPKD needs to be made on a case-by-case basis.
Interestingly, one of the reasons many people consider for not testing is that a positive test results would complicate their lives (e.g., with respect to health insurability, employment). On the flipside, a negative test might allow the patient to successfully apply for health insurance.

24. Genetics of ADPKD
Mutation screening of PKD1 is challenging due to duplication of its first 33 exons in six highly homologous genes with very similar DNA sequence identity
The proteins encoded by PKD1 and PKD2 (i.e., polycystin-1 and -2) interact as a macromolecular signaling complex
Mutations of either gene can interrupt polycystin signaling pathway resulting in similar clinical manifestations
Although genetic screening for ADPKD can provide a great deal of prognostic information, it is a challenging process, as described. Clinically, it is very difficult to predict the type of genetic mutation by the disease’s presentation. Since the products of the PKD1 and PKD2 genes (polycystin-1 and polycystin-2, respectively) interact in their signalling, mutations with either gene can lead to similar clinical manifestations.
Reference:
Barua M, Pei Y. Diagnosis of autosomal-dominant polycystic kidney disease: an integrated approach. Semin Nephrol 2010; 30(4):
Adapted from Barua M, et al. Semin Nephrol 2010; 30:

25. What is the evidence supporting the use of water therapy for ADPKD? 7
Dr. York Pei

26. Rationale for Water Therapy in ADPKD
cAMP is one of the key drivers of cyst enlargement
In animal models, ingestion of large amounts of water promotes diuresis by suppressing plasma levels of arginine vasopressin (AVP) and renal levels of cAMP, slowing cyst progression
Reference:
Wang CJ, Creed C, Winklhofer FT, et al. Water prescription in autosomal dominant polycystic kidney disease: a pilot study. Clin J Am Soc Nephrol 2011; 6(1):192-7
Adapted from: Wang CJ, et al. Clin J Am Soc Nephrol 2011; 6(1):192-7.

27. Controls Post- Water Load
Evidence for Water Therapy in ADPKD: Changes in Urine cAMP Linked to Osmolality
p < 0.001
p = 0.03
cAMPS/Osm (µmol/Osm)
The goal of this study was to evaluate the impact of water loading on urine osmolality in patients with ADPKD.
The study was conducted in ADPKD patients eating typical diets. Osmolality and volume were measured in 24-hour urine collections. The amount of additional ingested water required daily to achieve a mean urine osmolality of 285 ± 45 mosm/kg was determined. Participants were instructed to distribute the prescribed water over waking hours for each of 5 days. Blood chemistries, 24-hour urine collections, BP, and weight were measured before and after the period of supplemental water intake.
Five patients achieved the 285 mosm/kg urine target without difficulty. Mean urine osmolality decreased and mean urine volume increased; serum sodium, weight, and BP were unchanged. Daily osmolar excretion remained constant, indicating a stable ad lib dietary intake of solutes and protein over the 2-week study period.
The authors concluded that amount of additional water needed to achieve a urine osmolality target can be approximated from the urine osmolar excretion in ADPKD patients eating typical diets, providing a quantitative method to prescribe supplemental water for such individuals.
Reference:
Wang CJ, Creed C, Winklhofer FT, Grantham JJ. Water prescription in autosomal dominant polycystic kidney disease: a pilot study. Clin J Am Soc Nephrol 2011;6(1):192-7.
Control
Controls Post- Water Load
ADPKD Thirsting
ADPKD Post- Water Load
n=8
Adapted from: Wang CJ, et al. Clin J Am Soc Nephrol 2011;6(1):192-7.

28. Observational Study: No Benefit from Water Therapy in ADPKD
Total Kidney Volume
eGFR
P = 0.047
P = 0.39
P = 0.011
P = 0.35
Change of total kidney volume (mL / year)
Change of eGFR(Eq) slope (mL / min / 1.73m2 / year)
The goal of this study was to determine the clinical effects of increased water intake on autosomal dominant polycystic kidney disease (ADPKD) progression.
The study included 34 patients with ADPKD and creatinine clearance ≧ 50 mL/min/1.73 m2. They were divided into high (n = 18) and free (n = 16) water-intake groups, mainly according to their preference. Prior to the study, 30 patients underwent annual evaluation of total kidney volume (TKV) and 24-h oururine for an average of 33 months. During the 1-year study period, TKV and 24-h urine were analyzed at the beginning and end of the study and every 4 months, respectively.
During the pre-study period, urine volume (UV) in the H-group was higher (P = 0.034), but TKV and kidney function and their slopes were not significantly different between the two groups. After the study commenced, UV further increased (p<0.001) in the H-group but not in the F-group.
During the study period, TKV and kidney function slopes were not significantly different between the two groups (primary endpoint). TKV and kidney function slopes became worse (p=0.047 and 0.011, respectively) after high water intake (H-group) but not in the F-group.
The authors concluded that “Although the main endpoint was not significant, high water intake enhanced disease progression in the H-group when compared with the pre-study period. These findings necessitate a long-term randomized study before drawing a final conclusion.”
Reference:
Higashihara E, Nutahara K, Tanbo M, et al. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease? Nephrol Dial Transplant 2014;29(9):
High water intake group
Free water intake group
Key limitations of the study
Small sample size
One-year duration
Underpowered, inconclusive
Adapted from: Higashihara E, et al. Nephrol Dial Transplant 2014;29(9):

29. Summary: Current Understanding of Water Therapy for ADPKD
There is no consensus as to whether increased water can alter the natural course of disease
The size and quality of the limited available evidence makes definitive conclusions impossible at this point
There is no consensus or evidence on the appropriate volume of water to recommend
3-4 L daily may be appropriate
It is unknown if goals can be achieved over the longer term
Increased water consumption does have known benefits for prevention of nephrolithiasis1
Adherence to water therapy is difficult for many patients
1. Hall PM. Cleve Clin J Med 2009; 76(10):

30. What is the presumed mechanism of action of tolvaptan?
Dr. Philip McFarlane 8

31. Mechanism of Action of Vasopressin-2-receptor Antagonists in ADPKD
ADPKD mutations lead to lower intracellular levels of calcium and increased intracellular cyclic adenosine monophosphate (cAMP), two key intracellular secondary messengers, causing cell proliferation and fluid secretion into the expanding cyst. Some of the pathways affected have been investigated as possible targets for treatment. Vasopressin-2-receptor antagonists (e.g., tolvaptan) are an example of this type of intervention.
Referece:
Alam A, et al. Am J Kidney Dis 2015; in press.
AC6: adenylate cyclase 6; Ca2+: calcium; Cl-: 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.
Adapted from Alam A, et al. Am J Kidney Dis 2015; in press.

32. Mechanism of Action of Tolvaptan
Administration of tolvaptan
↓ binding of vasopressin at the V2 receptor in the kidney
↓ adenylate cyclase activity
↓ intracellular cAMP concentrations
↑ in free water clearance (i.e., aquaresis)
↓ in urine osmolality
↓ rate of growth of total kidney volume
↓ rate of formation and enlargement of kidney cysts
cAMP: adenosine 3′, 5′-cyclic monophosphate
Adapted from Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

33. What role can modulation of the RAAS and blood pressure play in the treatment of ADPKD?
Dr. Ahsan Alam 9

34. Possible imbalance in randomization: mutations
Impact of Different BP Targets in Early ADPKD: Design of the HALT-PKD Study A
Double-blind, placebo-controlled trial
558 hypertensive participants with ADPKD
15 to 49 years old
Baseline eGFR >60 mL/min/1.73 m2
2 randomizations:
BP target: standard (120/70 to 130/80 mmHg) or low (95/60 to 110/75 mmHg) target range
RAAS blockade: ACE inhibitor (lisinopril) + placebo or an ARB (telmisartan)
Followed for 5 years
Primary efficacy outcome: Annual % change in total kidney volume
Possible imbalance in randomization: mutations
The objective of this double-blind, placebo-controlled trial (HALT-PKD) was to evaluate differing blood pressure targets and different renin-angiotensin-aldosterone system (RAAS)-blocking strategies, with respect to disease-specific outcomes among patients with early ADPKD. There was also a companion study conducted simultaneously which evaluated single vs. dual RAAS blockade in a cohort of patients with more advanced ADPKD.
Reference:
Schrier RW, Abebe KZ, Perrone RD, et al. Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2014 Nov 15. [Epub ahead of print].
Adapted from Schrier RW, et al. N Engl J Med. 2014 Nov 15. [Epub ahead of print].

35. Different BP Targets in Early ADPKD: Changes in Total Kidney Volume and eGFR (HALT-PKD Study A)
Changes in TKV
Changes in eGFR
6.9
7.0
7.1
7.2
7.3
7.4
Standard blood pressure
Standard blood pressure
Low blood pressure 40 50 60 80 90 70
Low blood pressure
Ln Total Kidney Volume (mL)
Observed eGFR (mL/min/1.73 m2)
Low blood pressure, 5.6%/yr Standard blood pressure, 6.6%/yr
Difference, -1.0 percentage points/yr (95% CI, -1.6 to -0.2)
P=0.006
Low blood pressure, -2.9 mL/min/1.73 m2/yr Standard blood pressure, -3.0 mL/min/1.73 m2/yr
Difference, -0.1 mL/min/1.73 m2/yr (95% CI, -0.3 to 0.6)
P=0.55
Note to facilitator: Mention that we will be coming back to the HALT studies when we discuss disease-modifying treatments in the next section. This analysis was included at this point in the presentation because this is where we are discussing hypertension.
In this study, baseline TKV was 1185 mL among those in the low-BP-target group and 1240 mL in the standard-BP-target group.
Over the study’s five years, there was a significant difference observed in favour of the low-blood-pressure-target group. Individuals in that group experienced a growth in total kidney volume (TKV) of 5.6% per year, which was significantly lower than the 6.6% per year observed in the standard blood pressure target group (p=0.006).
In relative terms, this translated into a 14.2% slower annual increase in TKV for the low target group compared to the standard target group. Over the five years of the study, the TKV increase in the low target group was 38%, compared to 44.25% in the standard-target group.
There was not, however, a significant difference between groups with respect to changes in eGFR. The mean annual decrease in eGFR was 2.9 mL/min/1.73 m2 for those with a low BP target and 3.0 mL/min/1.73 m2 among those randomized to the standard BP target.
Reference:
Schrier RW, Abebe KZ, Perrone RD, et al. Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 2014;371(24): 24 48 60 24 48 72 12 36 60 84 96
Follow-up (mo)
Follow-up (mo)
Conclusion of the BP analysis: As compared with standard BP control, rigorous BP control was associated with a slower increase in TKV, no overall change in the eGFR, a greater decline in the LMVI, and greater reduction in UAE.
BP: blood pressure; TKV: total kidney volume; eGFR: estimated glomerular filtration rate; LVMI: left-ventricular mass index; UAE: urinary albumin excretion.
Adapted from Schrier RW, et al. N Engl J Med 2014;371(24):

36. What are the DaTa sUpporting use of tolvaptan for ADPKD?
Dr. Neera Dahl 10

37. Tolvaptan in ADPKD: Design of the Pivotal TEMPO 3:4 Trial
3-year, placebo-controlled trial
Interventions: Tolvaptan twice daily or placebo
Subjects: 1,445 patients with ADPKD
Baseline TKV > 750 mL by MRI (mean baseline 1705 mL in tolvaptan group; mL in placebo group)
Baseline estimated creatinine clearance ≥60 mL/min (mean baseline mL/min in both groups)
Primary outcome: Annual rate of change in TKV
Composite secondary outcome: time to progression (worsening kidney function,* clinically significant kidney pain,† worsening hypertension‡ or worsening albuminuria§)
Additional secondary outcome: Change in the slope of kidney function, measured by the reciprocal of the serum creatinine level
* ≥25% reduction in the reciprocal of the serum creatinine level from the value at the end of the dose-adjustment period, reproduced after at least 2 weeks); †necessitating medical leave, pharmacologic treatment (narcotic or last-resort analgesic agents), or invasive intervention; ‡changes in blood-pressure category, as defined in the protocol, or worsening of hypertension requiring an increase in hypertensive treatment; § according to sex-specified categories as defined in the protocol
TKV: Total kidney volume
Adapted from Torres VE, et al. N Engl J Med 2012; 367(25):

38. Tolvaptan in ADPKD: Impact on TKV (TEMPO 3:4 Primary Outcome)
Placebo
Placebo growth: 5.5%/yr
Tolvaptan growth: 2.8%/yr
p<0.0001
Change in Total Kidney Volume (%)
Over the 3-year period, total kidney volume increased by 2.8% per year (95% confidence interval [CI], 2.5 to 3.1) with tolvaptan versus 5.5% per year (95% CI, 5.1 to 6.0) with placebo. Tolvaptan changed the rate of growth by −2.7 percentage points per year (95% CI, −3.3 to −2.1); the ratio of the geometric means of growth rate was 0.97 (95% CI, 0.97 to 0.98; p<0.001).
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):
Dropouts:
Tolvaptan: 23.0%
Placebo: 13.8%
Baseline 12 24 36
Months
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

39. Change in Kidney Function eciprocal serum creatinine {mg/mL}-1)
Tolvaptan in ADPKD: Impact on Kidney Function (TEMPO 3:4 Secondary Outcome)
Tolvaptan
Placebo
Change in reciprocal of the sCr level:
Tolvaptan: −2.61 mg/mL −1/yr
Placebo: −3.81 mg/mL−1/yr
p<0.001
Change in Kidney Function eciprocal serum creatinine {mg/mL}-1)
The first noncomposite secondary endpoint, the slope of kidney function (as assessed by means of the reciprocal of the serum creatinine level) from the end of dose escalation to month 36, favoured tolvaptan, with a slope of −2.61 (mg per milliliter)−1 per year, as compared with −3.81 (mg per milliliter)−1 per year with placebo; the treatment effect was an increase of 1.20 (mg per milliliter)−1 per year (95% CI, 0.62 to 1.78; p<0.001).
This treatment effect was confirmed by comparing data from pretreatment baseline and post-treatment visits, which showed an increase of 4.93 (mg per milliliter)−1 over the 3-year period for tolvaptan, as compared with placebo (p<0.001). This corresponds to an increase in the mean serum creatinine level from 1.05 mg/dL (93 μmol/L) to 1.21 mg/dL (107 μmol/L) in the tolvaptan group, as compared with an increase from 1.04 mg/dL (92 μmol/L) to 1.27 mg/dL (112 μmol/L) in the placebo group (mean difference, −0.09 mg/dL [−8 μmol/L]; 95% CI, −0.13 to −0.06; p<0.001).
Analysis of the annual estimated GFR slope gave results similar to those of the slopes of the reciprocal of the serum creatinine level, with an estimated GFR slope of −2.72 mL/min/1.73 m2 per year in the tolvaptan group versus −3.70 in the placebo group (treatment effect, an increase of 0.98 mL/min/1.73 m2 per year; 95% CI, 0.60 to 1.36; p<0.001).
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):
Baseline 12 8 4 24 20 16 36 32 28
Months
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

40. Cumulative Event Hazard
Tolvaptan in ADPKD: Impact on Kidney Pain (TEMPO 3:4 Secondary Outcome)
Hazard ratio, 0.64 (95% CI, )
P=0.007 by Cox model
Placebo
Cumulative Event Hazard
Tolvaptan
In the TEMPO trial, the kidney pain endpoint was defined as clinically significant kidney pain necessitating medical leave, pharmacologic treatment (narcotic or last-resort analgesic agents), or invasive intervention. For this endpoint, tolvaptan was associated with a significant reduction in risk compared to placebo (HR 0.64, 95% CI 0.47 to 0.89, p=0.007).
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367(25):
Baseline
Study Months
No. At Risk
Tolvaptan
961
870
835
811
792
776
763
752
744
642
Placebo
483
472
463
454
446
438
428
422
418
359
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

41. Tolvaptan: The First Approved Treatment For Slowing Disease Progression in ADPKD
Tolvaptan is indicated to slow the progression of kidney enlargement in patients with autosomal dominant polycystic kidney disease (ADPKD)
In ADPKD, kidney enlargement reflects renal cyst burden
Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

42. What is the status of the evidence for the use of mTOR inhibitors for ADPKD?
Dr. Paul Tam 11

43. Clinical Study of mTOR Inhibition in ADPKD: Sirolimus
18-month, open-label, RCT (n=100)
Interventions: Sirolimus 2 mg daily vs. standard care
Baseline TKV: 875 mL in sirolimus group, 987 mL in control group
Baseline eGFR: 92 mL/min
Primary endpoint: total kidney volume at 18 months
The objective of this 18-month, open-label, randomized, controlled trial was to determine the impact of sirolimus on growth in total kidney volume (TKV) among patients with ADPKD.
The subjects were 100 patients aged years. They were randomized to receive sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute (mean 92 mL/min).
TKV was measured by serial magnetic resonance imaging. The primary outcome was TKV at 18 months. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months.
At randomization, the median TKV was 907 mL in the sirolimus group and 1003 mL in the control group.
NB: The limitations listed on the slide were the observations of the content development team of this educational program.
Reference:
Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363(9):820-9.
Key limitations of the study
Small numbers
Short duration
Non-maximal dosing of the drug?
Strictly an early PKD cohort
Adapted from Serra AL, et al. N Engl J Med 2010; 363(9):820-9.

44. Changes in Total Kidney Volume: Sirolimus (mTOR inhibitor) vs. Control
2.4
2.6
2.8
3.0
3.2
3.4
3.6
Median changes in TKV:
Control: +97 mL
Sirolimus: +99 mL
p=0.26
Log10 Total Kidney Volume (cm3)
Control
Sirolimus
The median increase in TKV in this study was 99 mL for sirolimus and 97 mL for the control group over the 18-month study period (p=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group.
Reference:
Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010;363(9):820-9. 12 18 24 6
Months since Randomization
Key results:
No significant difference between sirolimus & standard care for TKV over 18 months (primary endpoint).
No significant difference in eGFR.
Adapted from Serra AL, et al. N Engl J Med 2010; 363(9):820-9.

45. mTOR Inhibition in ADPKD: Everolimus
 2-year, double-blind trial (n=433)
Interventions: Everolimus 2.5 mg b.i.d. vs. placebo
Baseline TKV: 2028 mL in everolimus group; 1911 mL in placebo group
Baseline eGFR: 53 ml/min in everolimus; 56 ml/min in placebo
Primary outcome: Change in TKV
The objective of this 2-year, double-blind study was to investigate the impact of everolimus treatment on change in total kidney volume (TKV) among patients with ADPKD.
The subjects were 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The co-primary outcomes were the change in total kidney volume at 12 and 24 months, measured by magnetic resonance imaging.
NB: The limitations listed on the slide were the observations of the content development team of this educational program.
Reference:
Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363(9):
Key limitations of the study
32.7% of the treated patients dropped out: no MRIs were available
Investigators estimated the missing data by imputation (i.e., analysis was not ITT)
Adapted from Walz G, et al. N Engl J Med. 2010;363(9):

46. Change in Total Kidney Volume (mL)
Changes in Total Kidney Volume: Everolimus (mTOR inhibitor) vs. Control
+ 301 mL
Key results:
Borderline significant difference between everolimus & placebo for TKV over 2 years (primary endpoint).
Mean change in eGFR at 2 years (mL/min/1.73 m2):
Placebo: 7.7
Everolimus: 8.9 (p=0.15)
Placebo
+ 157 mL
Change in Total Kidney Volume (mL)
+ 230 mL
In this study, TKV increased by 102 mL in the everolimus group and 157 mL in the placebo group at 12 months (p=0.02). However, at two years, there was no longer statistical significance between the two arms. The change from baseline to 24 months was 230 mL for everolimus and 301 mL for placebo (p=0.06).
The mean change in the estimated glomerular filtration rate after two years was 8.9 mL/min/1.73 m2 for everolimus group and 7.7 mL/min/1.73 m2 in the placebo group (p=0.15).
The rates of serious adverse events were 37.4% in the everolimus group and 23.5% of the placebo group (p=0.002). The proportions of patients who dropped out of the study were 32.7% of the everolimus group and 23.7% of the placebo group.
Reference:
Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010;363(9):
Everolimus
+ 102 mL
Adapted from Walz G, et al. N Engl J Med 2010;363(9):
Weeks

47. mTOR Inhibition for ADPKD: Summary of Current Knowledge
Conclusion of recent meta-analysis of sirolimus studies (4 RCTs):1
In ADPKD patients, treatment with sirolimus is safe and can effectively slow kidney growth, but it seems not to slow down the decrease of GFR
However, data are not currently strong enough to recommend the use of these therapies in ADPKD
It appears from the study by Walz et al that mTOR inhibitors are poorly tolerated at higher doses
Further study is required
The first bullet and sub-bullet are the conclusions of the study listed below.
The bottom three bullets are the conclusions of the content development team of this educational program.
Reference:
Liu YM, Shao YQ, He Q. Sirolimus for treatment of autosomal-dominant polycystic kidney disease: a meta-analysis of randomized controlled trials. Transplant Proc 2014; 46(1):66-74.
1. Liu YM, et al. Transplant Proc 2014; 46(1):66-74. 

48. Should we be screening for intracranial aneurysms in ADPKD patients?
Dr. Navdeep Tangri 12

49. Cardiovascular Complications of PKD: Intracranial Aneurysms
Higher prevalence in ADPKD (9-12%) than in the general population (2-3%)1-6
In ADPKD prevalence is ~20-27% among those with a family history and ~6% in those lacking a family history1-5,7
Account for 4-7 % of all deaths in ADPKD8
Screening:
A family history of ruptured aneurysms or sudden death is a strong indication for MRI-based screening1
Repeating negative screens in patient with positive family history can be done in 5-10 years, but there are no data to guide rescreening
If positive – refer to neuro/vascular surgery for treatment or follow up
Screening in those without a family history is controversial – can be based on physician and patient preferences
References:
1. Ruggieri P, Poulos N, Masaryk T, et al. Occult intracranial aneurysms in polycystic kidney disease: screening with MR angiography. Radiology 1994;191:33-9.
2. Irazabal MV, Huston J, 3rd, Kubly V, et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2011;6:
3. Huston J, Torres VE, Sullivan PP, et al. Value of magnetic resonance angiography for detection of intracranial aneurysm in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1993;3:
4. Xu HW, Yu SQ, Mei CL, et al. Screening for intracranial aneurysm in 355 patients with autosomal-dominant polycystic kidney disease. Stroke 2011;42:204-6.
5. Graf S, Schischma A, Eberhardt KE, et al. Intracranial aneurysms and dolichoectasia in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2002;17:
6. Vlak MH, Algra A, Brandenburg R, et al. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011;10:
7. Chapman AB, Rubinstein D, Hughes R, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Eng J Med 1992;327:
8. Ecder T, et al. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat Rev Nephrol 2009;5(4):221-8.
1. Ruggieri P, et al. Radiology 1994; 91:33-9.
2. Irazabal MV, et al. Clin J Am Soc Nephrol 2011;6:
3. Huston J, et al. J Am Soc Nephrol 1993;3:
4. Xu HW, et al. Stroke 2011;42:204-6.
5. Graf S, et al. Nephrol Dial Transplant 2002;17:
6. Vlak MH, et al. Lancet Neurol 2011;10:
7. Chapman AB, et al. N Eng J Med 1992;327:
8. Ecder T, et al. Nat Rev Nephrol 2009;5(4):221-8.

50. Additional Factors to Consider When Deciding Whether or Not to Screen For and Treat Intracranial Aneurysms1-3
Expected survival (e.g., age, health of patient)
Patient’s willingness to undergo intervention
Potential benefit vs. potential safety concerns of the intervention (vascular clipping or endovascular coil)2,3
In a retrospective analysis of 3738 patients with aneurysm clipping and 3498 with endovascular coiling, several key complications occurred more frequently in the clipped population:2
Complication
Clip (%)
Coil (%)
OR (95% CI) p
Hospital mortality
1.61
0.57
2.83 (1.7 – 4.71)
<0.0001
Intracerebral hemorrhage
2.38
1.37
1.75 (1.23 – 4.49)
0.002
Post-operative stroke
6.71
2.92
2.39 (1.89 – 3.03)
<0.0001)
Besides family history, there are certain other factors that need to be considered when deciding whether or not to screen for aneurysms.
In general, the endovascular approach to management appears to be safer than the open surgical (clipping) method. However, each individual patient and his/her family will need to weigh the potential benefits of intervening with the potential risks of the interventions.
References:
1. Rozenfeld MN, Ansari SA, Shaibani A, et al. Should patients with autosomal dominant polycystic kidney disease be screened for cerebral aneurysms? AJNR Am J Neuroradiol 2014; 35(1):3-9.
2. Alshekhlee A, Mehta S, Edgell RC, et al. Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm. Stroke 2010;41(7):
3. Brinjikji W, et al. Better outcomes with treatment by coiling relative to clipping of unruptured intracranial aneurysms in the United States, AJNR Am J Neuroradiol 2011;32:
1. Rozenfeld MN, et al. AJNR Am J Neuroradiol 2014;35:3-9.
2. Alshekhlee A, et al. Stroke 2010; 41:
3. Brinjikji W, et al. AJNR Am J Neuroradiol 2011;32:

51. How is tolvaptan dosed and titrated?
Dr. Philip McFarlane 13

52. Recommended Dosing of Tolvaptan for ADPKD
Regimen overview
2 doses daily: one (larger dose) upon waking and one (smaller dose) 8 hours later
Available dosages
45+15 mg, mg, mg
Usual initial dosage
45+15 mg
Target dose
Highest tolerated dose, up to mg
Titration
At least weekly intervals between titrations
Adequacy of vasopressin suppression at a given dose of tolvaptan can be monitored through measurement of urine osmolality and may be used to optimize the clinical benefit of tolvaptan in ADPKD patients.
Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

53. What potential drug interactions should we be aware of with tolvaptan?
Dr. Paul Tam 14

54. Potential Drug Interactions with Tolvaptan
Tolvaptan is a substrate of CYP3A
Recommendation(s)
Examples
Substantial dose reduction of tolvaptan is required for patients prescribed strong CYP 3A inhibitors, especially for those also having P-gp inhibitory properties
Ketoconazole, clarithromycin, ritonavir, saquinavir
Concomitant use with moderate CYP 3A inhibitors, also requires lowered dosing of tolvaptan
Verapamil, fluconazole, erythromycin
Tolvaptan should not be taken with grapefruit juice
Concomitant use of tolvaptan with strong CYP 3A inducers should be avoided
Rifampin, phenytoin, carbamazepine, St. John’s wort
Reduction in the dose of tolvaptan may be required in patients concomitantly treated with P-glycoprotein (P-gp) inhibitors
Cyclosporine, quinidine
Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

55. What is the tolvaptan Hepatic Safety and Monitoring Programme (HSMP)?
Dr. Navdeep Tangri 15

56. Key Elements of the Tolvaptan Hepatic Safety Monitoring and Distribution (HSMD) Programme
Restriction of prescription to physicians experienced in the diagnosis and treatment of PKD
Deliver tolvaptan and HSMD education to healthcare professionals
Patient education
Patient-prescriber agreement form (PPAF) prior to initiation of treatment
Controlled distribution of tolvaptan supply to pharmacies
Tracking liver enzymes and function tests
The goals of the tolvaptan Hepatic Safety Monitoring and Distribution (HSMD) programme are:
To minimize the risk of liver injury associated with tolvaptan;
To ensure appropriate patient selection for the treatment with tolvaptan;
To document and ensure appropriate laboratory monitoring of hepatic function while on treatment; and
To inform health care providers and patients about the serious risk and safe use conditions of tolvaptan.
Otsuka Canada Pharmaceuticals Inc. Information on file.

57. Reporting LFT Result Status and Clinically Significant Elevations with Tolvaptan
Personnel from the tolvaptan HSMD Programme will send a monthly fax to each prescriber of tolvaptan
List of all patients in the practice taking tolvaptan for ADPKD
Physician (or proxy) will need to tick off checkboxes indicating whether or not their tolvaptan patients:
Have done their blood work according to schedule
Have had normal results from the liver function testing
Completed form is to be returned by fax
For more information on the tolvaptan hepatic safety monitoring and distribution programme, click here
Otsuka Canada Pharmaceuticals Inc. Information on file.

58. The Patient-Prescriber Agreement Form (PPAF) for Tolvaptan in ADPKD
When the patient and provider decide to undertake treatment with tolvaptan, a signed, duly-documented, product-specific patient- prescriber agreement(PPAF) is required
The PPAF outlines:
Relevant patient selection criteria
Expected benefits and risks of treatment
Need for mandatory hepatic function monitoring
That tolvaptan is a long-tem therapy and avoiding interruptions/discontinuations is recommended
Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

59. How should we assess total kidney volume?
Dr. Neera Dahl 16

60. Total Kidney Volume in ADPKD: Overview
ADPKD is characterized by progressive cystic kidney enlargement preceding the decline in GFR by several decades
Markers of renal function (e.g., GFR) do not accurately reflect disease progression, particularly in mild-moderate disease
TKV increases progressively throughout the course of disease
TKV is imperfect as a marker, but does correlate with complications of disease (e.g., hypertension, gross hematuria, microalbuminuria, proteinuria)
To date, there is no consensus on the best method or schedule for measuring TKV

61. Imaging Modalities for Total Kidney Volume: Strengths and Limitations
Modality
Strengths
Limitations
MRI
Greatest accuracy
Method used in clinical trials evaluating TKV
Limited availability, long wait times
Inter-observer variability
Calculation of results is time intensive
Ultrasound
Readily available
Short/no wait times
Less accurate than MRI CT
More accurate than ultrasound
Shorter wait times than MRI
Patient exposure to radiation
There are strengths and limitations for each of the advanced imaging modalities that can be used to assess total kidney volume. In short MRI is the most sensitive and accurate, but is difficult to access and is costly. Ultrasound is accessible, but is the least accurate.

62. What is the liver toxicity profile of tolvaptan in ADPKD?
Dr. York Pei 17

63. Liver Abnormalities with Tolvaptan in the TEMPO 3:4 Study
Placebo
Abnomality
Subjects
Subjects Meeting Criteria %
ALT >3x ULN
961 42
4.4
483 5
1.0
Hy’s Law Criteria* 2‡
0.2
Death or Liver Failure
In the TEMPO trial, there was an important signal of drug-induced liver toxicity, with two patients meeting Hy’s Law laboratory criteria (ALT >3 x ULN and bilirubin >2x ULN, but ALP <2x ULN).
Hy's law is a rule of thumb that a drug is at high risk of causing a fatal drug-induced liver injury (DILI) when given to a large population, if it caused cases of liver injury that satisfied certain criteria when given to a smaller population. 
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):
*Hy’s Law Criteria: ALT >3x ULN with bilirubin >2x, but ALP <2x ULN
‡1 additional Hy’s Law case in the Open-Label Trial ( )
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

64. Proportion of Subjects with Elevation
Time to First Elevation in ALT (>3x ULN) With Tolvaptan: 18-Month “Window of Susceptibility”
Adjudicated as ʺProbableʺ or ʺHighly Likelyʺ (TLV: 16/35 in Study 251)
Hy’s Law:
Hy’s Law: (Open-Label)
Proportion of Subjects with Elevation
Tolvaptan
Placebo
Further analysis of the liver toxicity events in the TEMPO trial showed that the most serious events all occurred within the first year of drug exposure, and very few liver events occurred beyond 18 months.
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):
Data on file, Otsuka Pharmaceutical Canada Inc .
Months in Study
Days in Study
100
200
300
400
500
600
700
800
900
1000
1100
Tolvaptan N=
961
884
836
812
769
774
765
751
740
734
726
268
Placebo N=
483
476
468
459
452
445
442
433
425
422
415
147
Torres VE, Chapman AB, Devuyst O, et al. N Engl J Med 2012;367(25):
Data on file, Otsuka Pharmaceutical Canada Inc .

65. Warning on Hepatic Toxicity with Tolvaptan
WARNING: IDIOSYNCRATIC HEPATIC TOXICITY
Tolvaptan use has led to idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT & AST), rarely associated with concomitant elevations of total bilirubin. To help mitigate the risk of liver injury, blood testing for hepatic transaminases is required prior to initiation of tolvaptan, then continuing monthly for 18 months, every 3 months for the next 12 months, and then every 3-6 months thereafter during treatment with tolvaptan
In clinical trials, 3 individuals experienced ALT >3x ULN with bilirubin >2x ULN
Includes 2 of 957 patients in the TEMPO study and 1 in an open-label study
All 3 returned to normal liver function after stopping tolvaptan
Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

66. What is the presumed mechanism of action of tolvaptan and what is the evidence of efficacy?
Dr. Navdeep Tangri 18

67. Mechanism of Action of JINARC™ (tolvaptan)
Administration of tolvaptan
↓ binding of vasopressin at the V2 receptor in the kidney
↓ adenylate cyclase activity
↓ intracellular cAMP concentrations
↑ in free water clearance (i.e., aquaresis)
↓ in urine osmolality
↓ rate of growth of total kidney volume
↓ rate of formation and enlargement of kidney cysts
cAMP: adenosine 3′, 5′-cyclic monophosphate
Adapted from Otsuka Canada Pharmaceuticals Inc. PrJINARC™ Product monograph. Date of Preparation: February 11, 2015.

68. Tolvaptan in ADPKD: Impact on TKV (TEMPO 3:4 Primary Outcome)
Placebo
Placebo growth: 5.5%/yr
Tolvaptan growth: 2.8%/yr
p<0.0001
Change in Total Kidney Volume (%)
Over the 3-year period, total kidney volume increased by 2.8% per year (95% confidence interval [CI], 2.5 to 3.1) with tolvaptan versus 5.5% per year (95% CI, 5.1 to 6.0) with placebo. Tolvaptan changed the rate of growth by −2.7 percentage points per year (95% CI, −3.3 to −2.1); the ratio of the geometric means of growth rate was 0.97 (95% CI, 0.97 to 0.98; p<0.001).
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):
Dropouts:
Tolvaptan: 23.0%
Placebo: 13.8%
Baseline 12 24 36
Months
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

69. Change in Kidney Function eciprocal serum creatinine {mg/mL}-1)
Tolvaptan in ADPKD: Impact on Kidney Function (TEMPO 3:4 Secondary Outcome)
Tolvaptan
Placebo
Change in reciprocal of the sCr level:
Tolvaptan: −2.61 mg/mL −1/yr
Placebo: −3.81 mg/mL−1/yr
p<0.001
Change in Kidney Function eciprocal serum creatinine {mg/mL}-1)
The first noncomposite secondary endpoint, the slope of kidney function (as assessed by means of the reciprocal of the serum creatinine level) from the end of dose escalation to month 36, favoured tolvaptan, with a slope of −2.61 (mg per milliliter)−1 per year, as compared with −3.81 (mg per milliliter)−1 per year with placebo; the treatment effect was an increase of 1.20 (mg per milliliter)−1 per year (95% CI, 0.62 to 1.78; p<0.001).
This treatment effect was confirmed by comparing data from pretreatment baseline and post-treatment visits, which showed an increase of 4.93 (mg per milliliter)−1 over the 3-year period for tolvaptan, as compared with placebo (p<0.001). This corresponds to an increase in the mean serum creatinine level from 1.05 mg/dL (93 μmol/L) to 1.21 mg/dL (107 μmol/L) in the tolvaptan group, as compared with an increase from 1.04 mg/dL (92 μmol/L) to 1.27 mg/dL (112 μmol/L) in the placebo group (mean difference, −0.09 mg/dL [−8 μmol/L]; 95% CI, −0.13 to −0.06; p<0.001).
Analysis of the annual estimated GFR slope gave results similar to those of the slopes of the reciprocal of the serum creatinine level, with an estimated GFR slope of −2.72 mL/min/1.73 m2 per year in the tolvaptan group versus −3.70 in the placebo group (treatment effect, an increase of 0.98 mL/min/1.73 m2 per year; 95% CI, 0.60 to 1.36; p<0.001).
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25):
Baseline 12 8 4 24 20 16 36 32 28
Months
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

70. Cumulative Event Hazard
Tolvaptan in ADPKD: Impact on Kidney Pain (TEMPO 3:4 Secondary Outcome)
Hazard ratio, 0.64 (95% CI, )
P=0.007 by Cox model
Placebo
Cumulative Event Hazard
Tolvaptan
In the TEMPO trial, the kidney pain endpoint was defined as clinically significant kidney pain necessitating medical leave, pharmacologic treatment (narcotic or last-resort analgesic agents), or invasive intervention. For this endpoint, tolvaptan was associated with a significant reduction in risk compared to placebo (HR 0.64, 95% CI 0.47 to 0.89, p=0.007).
Reference:
Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367(25):
Baseline
Study Months
No. At Risk
Tolvaptan
961
870
835
811
792
776
763
752
744
642
Placebo
483
472
463
454
446
438
428
422
418
359
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

71. Tolvaptan for the Treatment of ADPKD: Conclusions on Efficacy
In the pivotal clinical study, tolvaptan showed efficacy in:
Slows progression of increase in kidney volume
Slows deterioration of kidney function
Improves symptoms (e.g., pain)
These conclusions are those of the content development team of this educational program.

72. Effect of Tolvaptan Across CKD Stages
Overall tolvaptan reduced the rate of TKV growth from 5.5% per year to 2.8% per year
Analysis by CKD subgroup showed a consistent and significant effect favoring tolvaptan
Analysis of eGFR slopes showed a statistically significant effect favoring tolvaptan in subjects in CKD stages 2 and 3

73. What happens if you stop tolvaptan therapy?
Dr. Neera Dahl 19

74. What happens if you stop tolvaptan therapy?
When tolvaptan is stopped, polyuria and polydipsia return rapidly (within 24 hours) to pre-tolvaptan values.
Tolvaptan interruptions were discouraged during the TEMPO trial but could happen due to surgery or various concomitant diseases with a risk of acute alteration of fluid balance.
Tolvaptan was stopped for short periods of times (less than 27 consecutive days) during the TEMPO trial and these interruptions have not been associated with untowards side effects nor with evidence of increased total kidney volume or deterioration of renal function. However, when tolvaptan is interrupted for longer durations eg. for more than a month, an increased rate of kidney volume growth is seen which returns to a slower level of growth after resuming therapy with tolvaptan. It is expected that an ADPKD patient stopping tolvaptan will have a progression of his/her kidney deterioration similar to what was happening before starting to take tolvaptan.
Short term (7days) administration of tolvaptan has been demonstrated to decrease total kidney volume (Kidney Int Aug; 80(3): 295–301) but there is no published data on clinical measurements obtained after stopping tolvaptan.