Hypertension in Autosomal Dominant Polycystic Kidney Disease

2016 ADPKD, what have the last 10 years taught us? Arlene B. Chapman MD Professor of Medicine Director, Section of Nephrology University of Chicago

2016

Can we TRUMP the cysts? Disclosures

Consultant for KADMON, GENZYME, OTSUKA ADPKD

• 4th leading cause of ESRD • No race is favored • Dominantly inherited • >3,000,000 worldwide • Cysts ― Kidneys ―Liver ―Pancreas ―Spleen ―Brain • Begins in utero

Grantham JJ. N Engl J Med. 2008;359:1477-1485. Disorder MIM Frequency Gene Chromosome Protein Length Protein Exon SNP (bp) size (aa) # HEREDITARY RENAL CYSTIC DISEASES ADPKD 601313 1:700 PKD1 16p13.3 Polycystin 1 14138 4303 46 592 1:15,000 PKD2 4q22.1 Polycystin 2 5056 968 15 62 ARPKD 606702 1:40,000 PKHD1 6p12.2 Polyductin 16282 4074 67 356 (fibrocystin) TSC 191100 1:10,000 TSCI 9q34.13 Hamartin 8604 1164 23 52 613254 TSC2 16p13.3 Tuberin 6156 1807 42 136 GCKD 137920 Not HNF-1ß 17cen-q21.3 TCF2 protein 2977 557 9 available MCKD 174000 1:50,000 MCKD1 1q21 11 47 MCKD2 16p12.3 Uromodulin 2315 640 (UMOD) FJN 256100 1:100,000 NPHP1 2q13 Nephrocystin-1 2752 732 20 50 602088 NPHP2/INVS 9q31 Inversin 2968 895 17 79 NPHP3 3q22.1 Nephrocystin-3 4362 1330 27 103 NPHP4 1p36.22 Nephroretinin 4994 1426 30 84 NPHP5/IQCB1 3q13.33 Nephrocystin-5 2594 598 15 36 NPHP6/CEP29 12q21.32 Nephrocystin-6 7948 2479 54 63 0 16p13.3 Nephrocystin-7 4469 524 6 42 NPHP7/GLIS2 16q12.2 Nephrocystin-8 5936 1235 27 99 NPHP8/RPGRI 17q11.1 Nephrocystin-9 2858 692 15 47 P1L NPHP9/NEK8 VHL 193300 1:53,000 VHL 3p25.3 Von hippel 3737 213 3 36 lindau Current Ultrasound Diagnostic Criteria for ADPKD Family History No Family History < 40 years: 20 cysts distributed 3 cysts bilaterally bilaterally with a 40-60 years: consistent phenotype 4 cysts bilaterally  60 years: Revised Pei 8 cysts bilaterally Criteria 2009, 2012

Extra-renal Manifestations of ADPKD: Liver Cystic Disease

Renal Morbidities Associated With ADPKD

By age 30, over 50% have at least one complication

Chapman A. et.al. American Society of Nephrology Meeting 2010. Polycystins 1 and 2

Two genotypes:

PKD1 85% ESRD age 55

PKD 2 15% ESRD age 72

Gallagher AR et al. Adv Chronic Kidney Dis. 2010;17:118-130. Genetic factors of progression in ADPKD

•Strong genic and allelic effect on phenotype

Cumulative Probability of Survival to ESRD P<0.00 Mutation of PKD2: 1 Median age at ESRD: 77.8 yrs

Non truncating mutation of PKD1: Median age at ESRD: 65.8 yrs

N=1271 Truncating mutation of PKD1: median age at ESRD: 55.1 yrs

Cornec-Le Gall E, JASN 2013 Genkyst Cohort update: 2015, non published data Current Results of Genetic Screening in ADPKD • Identification of >95% of PKD2 mutations • Identification of 85% of PKD1 mutations • Cost of sequencing for mutation detection in PKD1/PKD2 is high (>$3,000) and pre- approval for insurance coverage is difficult • Mutation confirmation in other family members required for potential mutations in PKD1 more so than PKD2 individuals

Cell Calcium Is Involved in Promoting Cell Proliferation

Torres VE. Adv Chronic Kidney Dis. 2010;17:190-204. Mechanism of Fluid Secretion Into Cysts in Response to AVP

Wallace DP. Biochim Biophys Acta. 2011;1812:1291-1300. Sullivan LP et al. Physiol Rev. 1998;78:1165-1191. Characteristics of ADPKD That Associate with ESRD • Genotype: > 95% PKD1 individuals demonstrate renal cysts by age 30 • Hypertension: occurs in 60% with intact renal function by age 30 • Proteinuria: is not a common feature of this disease, but has important prognostic implications • Gross hematuria: > 50% will have had an episode by age 40 ALL CHARACTERISTICS HAVE NOW BEEN SHOWN TO MEDIATE THEIR RISK THROUGH KIDNEY VOLUME Cyst Burden and Patient Complications in ADPKD

Healthy Tissue

Cyst Development and Enlargement

Vasculature

Function

Age Urinary Concentrating Defects Hypertension

Dull Pain & Discomfort Signs & Proteinuria Symptoms ADPKD Progression 100

Concentrating defect, Hypertension, Proteinuria 80

Kidney (%) function Kidney Pain, Hematuria, Stones, Infections 0 0 10 20 30 40 50 60 Age (years)

Torres Mayo

Inter-observer variability: 2.1% Intra-observer variability:2.4% Day-to-day variability: 2.4% Increased Kidney Volume is Due to Increased Cyst Volume

Total Kidney Volume Total Cyst Volume

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% Grantham, NEJM CRISP 2006; Chapman Kidney Int 64; 1035–1045, 2003

Change in Kidney Volume Precedes Change in Kidney Function

1.0 1 htTKV Unit 0.5

0.0 GFR -0.5 Change from Baseline

Average Standardized Average -1.0

0 1 2 3 4 6 8 Years of follow-up p<0.05 for htTKV change from baseline; # p<0.05 for GFR change from baseline; htTKV=Height- adjusted total kidney volume; 1 Percent Change Standardized to a common unit; NIH CRISP Studies; Chapman CJASN 7:479, 2012 1.00 0.75

0.50 AUROC = 0.84

Sensitivity 95% CI = (0.79, 0.90) Sensitivity = 74% 0.25 Specificity = 75% Cut Point = 600 (cc/m) 0.00 0.00 0.25 0.50 0.75 1.00

1 - Specificity

Baseline predictors of CKD Stage 3 endpoint 95%CI of Variable Units AUC Sensitivity Specificity Cut-point AUC P* htTKV cc/m 0.84 0.74 0.7 600 (0.79, 0.90) Serum Creatinine mg/dL 0.75 0.58 0.81 1.1 (0.67, 0.82) 0.02 BUN mg/dL 0.76 0.63 0.79 16 (0.70, 0.83) 0.04 Urine Albumin mg/d 0.70 0.66 0.67 30 (0.61, 0.78) 0.002 MCP-1 pg/mg 0.75 0.80 0.62 410 (0.68, 0.83) 0.02 Baseline age y 0.66 0.60 0.65 35 (0.59, 0.74) < 0.001 Effect of Kidney Growth Rate on Development of ESRD

Chapman, AB. 2012. Unpublished. GFR Compensation for Loss of Parenchyma

Loss of Compensated Nephrons

Grantham JJ et al. Clin J Am Soc Nephrol. 2006;1:148-157. Progressive Rise in Total Kidney Volume Signs and Symptoms of Injury Develop Long Before ADPKD Reaches End Stage

Grantham JJ. 2012. Unpublished. Estimating TKV Using the Ellipsoid Equation

W D L

Typical values for a cystic kidney L = 15 cm, W = 8 cm, D = 7 cm Volume = 3.14/6 x 15 x 8 x 7 = 440 cc Volume/height = 440 cc/1.73 m = 254 cc/m

O’Neill WC et al. Am J Kidney Dis. 2005;46:1058-1064. Predicting CKD Stage 3 (iothalamate clearance) utilizing MR and US within 8 years Assessment of TKV and Kidney Length Predictors of CKD Stage 3 in CRISP Participants

Method AUC ROC sensitivity specificity Optimal cut point

htTKV (MR) ml/m 0.84 74.0% 75.0% 600 ml

htTKV (US) ml/m 0.87 79.5% 73.2% 630 ml

KL (MR) cm 0.87 85.4% 92.3% 16.7 cm

KL (US) cm 0.86 82.9% 80.8% 16.8 cm Classification by Estimated Rate of Growth (from age and starting HtTKV = 150 ml/m)

20000 1E Subclass 1E > 6% 10000 8000 Subclass 1D 6000 4.5 – 6%

4000 Subclass 1C

2000 3 – 4.5% 1C

1000 Subclass 1B 800 1.5 – 3% 600 HtTKV(mL/m) 400 Subclass 1A ≤1.5% 200 1A

100 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Patient Age (Years)

Irazabal. J Am Soc Nephrol 26: 160–172, 2015 SUMMARY OF CRISP FINDINGS • Renal progression in ADPKD is marked by cyst expansion and increases in renal volume prior to loss of renal function • Complications including hypertension, gross hematuria, pain, nephrolithiasis, and urinary tract infections occur long before reductions in GFR • htTKV significantly associates with a decline in GFR and the relationship between htTKV and GFR increases with increasing time of followup. • HtTKV significantly predicts decline in GFR years before its occurrence

Baseline TKV and eGFR in ADPKD clinical trials

0.35

Ong. A et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet vol 385 (2015) Effect of therapeutic interventions

Ong. A et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet vol 385 (2015) Vasopressin-V2 Receptor Antagonists

Modified from Torres Lancet TOLVAPTAN IN ADPKD

• Tolvaptan - a highly potent and selective AVP V2 receptor antagonist . • Has been shown to slow the progression of PKD in preclinical trials. • Currently approved for the treatment of hypervolemic and euvolemic hyponatremia in US • Approved in Japan, Canada and Europe as a therapy to slow down the progression of ADPKD in patients with rapidly growing kidneys.

LaRiviere WB, Irazabal MV, Torres VE. Novel therapeutic approaches to Autosomal Dominant Polycystic Kidney Disease. Translational research : the journal of laboratory and clinical medicine. 2015;165(4):488-498. TEMPO 3:4 TRIAL

• The Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes (TEMPO) 3:4 trial • Phase 3, multicenter, randomized, double- blinded, placebo-controlled, parallel-group clinical study, designed to assess the impact of tolvaptan therapy on the progression of ADPKD. Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. TEMPO 3:4 TRIAL

• 1445 ADPKD patients, 18-50 years, with a TKV >750 mL and CrCL>60 mL/min, across 129 sites worldwide were enrolled in the study between January 2007 and January 2009.

• Tolvaptan group therapy: high dose (120mg/day, n=404), medium dose (90mg/day, n=157), or low dose (60mg/day, n=179). Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. TEMPO 3:4 TRIAL

• Primary end point: annual rate of percent change in TKV as measured by MRI.

• Secondary endpoints: measurable decline renal function, including a composite endpoint of investigator-assessed disease progression.

Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. TEMPO 3:4 TRIAL

• Results:

The intention-to-treat analysis of this study showed that tolvaptan slowed the rate of TKV growth (primary endpoint) by 49% from5.5 to 2.8% per year, and the rate of estimated GFR (eGFR) loss on treatment (secondary endpoint) by 26% from 3.70 to 2.72 mL/min/1.73 m2 per year during the median observation period of 3 years.

Gansevoort RT, Arici M, Benzing T, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice.Nephrology Dialysis Transplantation. 2016;31(3):337-348. TEMPO 3:4 TRIAL

Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001).