1. Workshop on ADPKD Role of Primary Care Physician Sameena Iqbal
Nephrologist, CIUSSS de l’Ouest de l’Ile de Montreal

2. Disclosure Honorarium for Consulting on the Reprise trial from Otsuka
Mayo clinic preceptorship for PKD with Dr. Torres’ team, sponsored by Otsuka

3. What is ADPKD?
ADPKD...
Is a dominantly inherited, systemic disease characterized by multiple kidney cysts
Is a form of tubular obstructive nephropathy
Results in slow, gradual, and massive bilateral kidney enlargement
Results in kidney failure in the majority of individuals by the fifth or sixth decade
References:
Chapman AB, et al. Autosomal dominant polycystic kidney disease: time for a change? J Am Soc Nephrol 2007;18(5):
Galarreta CI, et al. Tubular obstruction leads to progressive proximal tubular injury and atubular glomeruli in polycystic kidney disease. Am J Pathol  2014; 184(7):
Adapted from: Chapman AB, et al. J Am Soc Nephrol 2007;18(5):
Galarreta CI, et al. Am J Pathol 2014;184(7):

4. Epidemiology: ADPKD Is the Most Common Inherited Kidney Disease
Birth prevalence: 1:400 to 1:
Affects 30,000-60,000 people in Canada
Fourth common cause leading to end-stage renal disease
There are no published epidemiologic statistics for ADPKD in Canada. The estimated incidence shown on the slide is derived from the range of birth prevalence reported in the literature.
Although it is not a disease that is widely known among those not affected by it, ADPKD is much more common than many other inherited diseases, as shown on the slide.
References:
1. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 2009; 76(2):
2.Reeders ST. Autosomal dominant polycystic kidney disease. Q J Med 1991; 79(290):
3. Davies F, Coles GA, Harper PS, et al. Polycystic kidney disease re-evaluated: a population-based study. Q J Med 1991; 79(290):
4. Iglesias CG, Torres VE, Offord KP, et al. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: Am J Kidney Dis 1983; 2(6):630-9.
5. Belibi FA, Edelstein CL. Novel targets for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Investig Drugs 2010; 19(3):
6. Gabow PA. Autosomal dominant polycystic kidney disease. N Engl J Med 1993; 329(5):
Adapted from:
1. Torres VE, et al. Kidney Int 2009; 76(2):
2. Reeders ST. Q J Med 1991; 79(3):
3. Davies F, et al. Q J Med 1991; 79:
4. Iglesias C, et al. Am J Kidney Dis 1983; 2:630-9.
5. Belibi FA, et al. Expert Opin Investig Drugs 2010; 19(3):
6. Gabow PA. N Engl J Med 1993; 329(5):

5. Diagnosis
Diagnosis of ADPKD is usually dependent on imaging of the kidneys
Due to cost and accessibility, ultrasound is the main choice
If there is family history then the following criteria are used to make a diagnosis
Age greater than or equal to 3 cysts unilateral or bilateral
Age at least two cysts in each kidney
Age 60 and older at least four cysts in each kidney

6. Who to screen Family history of ADPKD
Signs or symptoms of ADPKD such as hypertension at an early age, hematuria, renal stones, urinary infections, kidney pain, abnormal renal function, etc.
Signs or symptoms of ADPKD associated medical conditions such as cerebral aneurysm, polycystic liver disease, large abdominal wall hernias, etc
If considering to become a live kidney donor

7. 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 Engl J Med 2006; 354(20):

8. 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):

9. Progression of ADPKD
Usually starts to decline renal function in fourth decade
GFR decline ml/min/year (Torres et, Autosomal dominant polycystic kidney disease, the last 3 years, KI 2009)
TKV decline by about 5% per year
Risk factors worsen decline: PKD1 vs PKD2, Hypertension, proteinuria, Male gender, increased kidney size, increased LV mass index, low birth weight, decreased renal blood flow, increased urinary sodium excretion, increased LDL, and higher uric acid levels

10. Impact of ADPKD on Other Aspects of Life
Chronic pain
Insurability
Anxiety
Kidney
transplant
ADPKD
Depression
Dialysis
When considering the impact of ADPKD on affected individuals, recognize that the disease impacts many aspects of life, many of which are shown in this figure.
Impact on
family planning
Decisions around genetic testing

11. Medical care team Dietician Pharmacist Nurse General Practioner
Nephrologist
Dietician
Nurse
Urologist
Neurosurgeon
Medical geneticist
Pharmacist

12. 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
Reference:
Hall PM. Nephrolithiasis: treatment, causes, and prevention. Cleve Clin J Med 2009;76(10):
1. Hall PM. Cleve Clin J Med 2009;76(10):

13. Non Pharmalogical therapiest
Lifestyle Modification
Regular exercise
Smoking cessation
Sodium intake restriction

14. 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;371(24):
Adapted from Schrier RW, et al. N Engl J Med 2014;371(24):

15. 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):

16. HMG-CoA Reductase Inhibitors (Statins) for ADPKD: Mechanism of Action
Mechanism of action in ADPKD is currently unknown, but presumed to be independent of cholesterol lowering
Potential mechanisms (from animal studies):1,2
Enhanced renal blood flow
Attenuate of vascular inflammation through vascular and glomerular nitric oxide production
Inhibition of G proteins with resultant decreased cell proliferation
Experimental models have shown that statins may ameliorate progressive nephropathy.1-5 Some of the possible mechanisms that have been suggested include those listed in the slide.1, 6-10
References:
1. Hafez KS, Inman SR, Stowe NT, et al. Renal hemodynamic effects of lovastatin in a renal ablation model. Urology 1996;48:862-7.
2. Glazer AA, Inman SR, Stowe NT, et al. Renal microcirculatory effects of lovastatin in a rat model of reduced renal mass. Urology 1997;50:812-7.
3. Inman SR, Stowe NT, Cressman MD, et al. Lovastatin preserves renal function in experimental diabetes. Am J Med Sci 1999;317:
4. Joyce M, Kelly C, Winter D, et al. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates renal injury in an experimental model of ischemia-reperfusion. J Surg Res 2001; 101:79-84.
5. Bianchi S, Bigazzi R, Caiazza A, et al. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003;41:
6. van Dijk MA, Kamper AM, van Veen S, et al. Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2001;16:
7. Stowe NT, Inman SR, Tapolyai M, et al. Lovastatin has direct renal hemodynamic effects in a rodent model. J Urol 1996;156:
8. McFarlane SI, Muniyappa R, Francisco R, et al. Clinical review 145: Pleiotropic effects of statins: Lipid reduction and beyond. J Clin Endocrinol Metab 2002;87:
9. Gile RD, Cowley BD Jr, Gattone VH 2nd, et al. Effect of lovastatin on the development of polycystic kidney disease in the Han:SPRD rat. Am J Kidney Dis 1995;26:501-7.
10. Zafar I, Tao Y, Falk S, et al. Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model. Am J Physiol Renal Physiol 2007;293:F854–F859.
The above cited in: Cadnapaphornchai MA, et al. Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2014;9(5):  
Adapted from
1. Cadnapaphornchai MA, et al. Clin J Am Soc Nephrol 2014;9(5):  
2. Zafar I, et al. Am J Physiol Renal Physiol 2007; 293:F854–F859.

17. Pravastatin for the Treatment of ADPKD in Children
 3-year, placebo-controlled trial (n=110) in children and adolescents
Interventions: Pravastatin mg daily or placebo
Baseline TKV: 571 mL in pravastatin group; 522 mL in placebo group
Primary outcomes: Proportion with ≥ 20% change in height-adjusted TKV, LVMI, or UAE over 3 years (composite)
Key limitations of the study
Small sample size
Strictly early disease in children and adolescents
The patients were not genotyped – randomization of PKD1/PKD2 may not be balanced which may impact interpretation of outcomes
The objective of this randomized double-blind placebo-controlled phase III clinical trial was to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD.
The subjects were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril. They were randomized to treatment with pravastatin or placebo for a three-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a ≥20% change in HtTKV, LVMI, or urinary albumin excretion over the study period.
Reference:
Cadnapaphornchai MA, George DM, McFann K, et al. Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2014;9(5):
Adapted from Cadnapaphornchai MA, et al. Clin J Am Soc Nephrol 2014;9(5):  

18. Percent of participants with ≥20% increase over study period
Pravastatin for the Treatment of ADPKD in Children: Primary Composite Endpoint and Components
Key results:
Fewer participants receiving pravastatin reached the primary endpoint compared with placebo (69% vs. 88%)
Increase in HtTKV was significantly lower with pravastatin vs. placebo (23% vs. 31%)
Pravastatin
P=0.03
Placebo
P=0.03
Percent of participants with ≥20% increase over study period
P=0.50
P=0.18
In this study, the proportions reaching the combined primary endpoint were 69% in the pravastatin group and 88% in the placebo group (p=0.03). This was driven primarily to the between-group difference in the proportions reaching the 20% increase in HtTKV (46% in the pravastatin arm and 68% in the placebo arm; p=0.03).
Reference:
Cadnapaphornchai MA, George DM, McFann K, et al. Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2014;9(5):
Any of HtTKV, LVMI, or UAE
HtTKV
LVMI
UAE
HtTKV: height-adjusted total kidney volume; LVMI: left-ventricular mass index. UAE: Urinary albumin excretion.
Adapted from Cadnapaphornchai MA, et al. Clin J Am Soc Nephrol 2014;9(5):  

19. Statin Therapy in ADPKD: Conclusion
The results of the study with pravastatin in children with ADPKD are suggestive
While disease modification has not yet been proven based on this single trial it should be the subject of further research
Mechanism of action has not been established
Many patients with CKD would have indications for statin therapy independent of the cause of their disease (for cardiovascular protection)
These conclusions are those of the content development team of this educational program.

20. Tolvaptan (Vasopressin-2-receptor Antagonist) in ADPKD: TEMPO 3:4
3-year, placebo-controlled trial (n=1,445)
Interventions: Tolvaptan twice daily or placebo
Baseline TKV: 1705 mL in tolvaptan group; 1668 mL in placebo group
Baseline reciprocal of serum creatinine: 102 mg/mL in tolvaptan group; mg/mL in placebo group
Primary outcome: Annual rate of change in TKV
The pivotal clinical trial for tolvaptan was the TEMPO 3:4 study. This was a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial in which 1,445 patients with ADPKD were randomized to tolvaptan, titrated to the highest of three twice-daily dose regimens that the patient found tolerable, or placebo.
Inclusion criteria were: age years, TKV of 750 mL or greater and an estimated creatinine clearance of 60 mL per minute or more. The mean baseline TKV in this study was 1705 mL in the tolvaptan group and 1668 mL in the placebo group. TKV was measured by a serial MRI imaging using a standardized protocol.
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):
Key limitation of the study
All patients in both groups were asked to maintain good hydration and avoid thirst.
Suppression of vasopressin release in the placebo group may have led to an underestimation of the beneficial effect of tolvaptan
Adapted from Torres VE, et al. N Engl J Med 2012; 367(25):

21. 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 (%)
Dropouts:
Tolvaptan: 23.0%
Placebo: 13.8%
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):
Baseline 12 24 36
Months
Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

22. Important Manifestations of ADPKD
Common extrarenal manifestations:
Renal manifestations:
Pain and discomfort
Kidney stones
Bleeding into cysts
Infected cysts
Declining renal function / kidney failure
Hypertension
Intracranial aneurysm
Cardiovascular
(e.g., heart valve abnormalities)
In addition to the kidney-specific complications of ADPKD (e.g., pain, stones) as shown on the left of this slide, ADPKD is also associated with numerous extrarenal manifestations. The most important to keep in mind are those highlighted first – intracranial aneurysm, hepatic cysts, cardiovascular disease risk and diverticulosis. The other possible manifestations are less common and of lesser importance.
References:
Pirson Y. Extrarenal manifestations of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis 2010;17(2):
Bennet WM, Torres VE. Extrarenal manifestations of autosomal dominant polycystic kidney disease. uptodate.com; last updated Nov. 11, 2013.
Hepatic cysts
Adapted from:
Braun WE. Cleve Clin J Med 2009;76(2):
Torres VE, et al. Lancet 2007;369(9569):
Pirson Y. Adv Chronic Kidney Dis 2010;17(2):
Bennett WM, et al. uptodate.com; last updated Nov. 11, 2013.

23. Take home points
ADPKD is more common than we think and has implications, since early intervention will impact on disease progression
GP’s important role in screening and identifying cases and have a shared care model with nephrology
A team looks after ADPKD patients
Non pharmacological and pharmacological interventions that should be started as soon as a patient is identified with a condition
Keep a look out for disease associated complications for timely treatment