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 (bp)
Protein size (aa)
Exon #
SNP
HEREDITARY RENAL CYSTIC DISEASES
ADPKD 601313 1:700 1:15,000
PKD1 PKD2
16p13.3 4q22.1
Polycystin 1 Polycystin 2
14138 5056
4303 968
46 15
592 62
ARPKD 606702 1:40,000 PKHD1 6p12.2 Polyductin (fibrocystin)
16282 4074 67 356
TSC 191100 613254
1:10,000 TSCI TSC2
9q34.13 16p13.3
Hamartin Tuberin
8604 6156
1164 1807
23 42
52 136
GCKD 137920 Not available
HNF-1ß 17cen-q21.3 TCF2 protein 2977 557 9
MCKD
174000 1:50,000 MCKD1 MCKD2 (UMOD)
1q21 16p12.3
Uromodulin
2315
640
11 47
FJN 256100 602088
1:100,000 NPHP1 NPHP2/INVS NPHP3 NPHP4 NPHP5/IQCB1 NPHP6/CEP290 NPHP7/GLIS2 NPHP8/RPGRIP1L NPHP9/NEK8
2q13 9q31 3q22.1 1p36.22 3q13.33 12q21.32 16p13.3 16q12.2 17q11.1
Nephrocystin-1 Inversin Nephrocystin-3 Nephroretinin Nephrocystin-5 Nephrocystin-6 Nephrocystin-7 Nephrocystin-8 Nephrocystin-9
2752 2968 4362 4994 2594 7948 4469 5936 2858
732 895 1330 1426 598 2479 524 1235 692
20 17 27 30 15 54
6 27 15
50 79
103 84 36 63 42 99 47
VHL 193300 1:53,000 VHL 3p25.3 Von hippel lindau
3737 213 3 36
Current Ultrasound Diagnostic Criteria for ADPKD
Family History < 40 years:
3 cysts bilaterally 40-60 years:
4 cysts bilaterally 60 years:
8 cysts bilaterally
No Family History 20 cysts distributed
bilaterally with a consistent phenotype
Revised Pei Criteria 2009, 2012
Extra-renal Manifestations of ADPKD: Liver Cystic Disease
Renal Morbidities Associated With ADPKD
Chapman A. et.al. American Society of Nephrology Meeting 2010.
By age 30, over 50% have at least one complication
Polycystins 1 and 2
Gallagher AR et al. Adv Chronic Kidney Dis. 2010;17:118-130.
Two genotypes: PKD1 85% ESRD age 55 PKD 2 15% ESRD age 72
•Strong genic and allelic effect on phenotype
Genetic factors of progression in ADPKD
Cumulative Probability of Survival to ESRD
P<0.001
N=1271 Truncating mutation of PKD1: median age at ESRD: 55.1 yrs
Non truncating mutation of PKD1: Median age at ESRD: 65.8 yrs
Mutation of PKD2: Median age at ESRD: 77.8 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
Torres VE. Adv Chronic Kidney Dis. 2010;17:190-204.
Cell Calcium Is Involved in Promoting Cell Proliferation
Wallace DP. Biochim Biophys Acta. 2011;1812:1291-1300. Sullivan LP et al. Physiol Rev. 1998;78:1165-1191.
Mechanism of Fluid Secretion Into Cysts in Response to AVP
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
Signs & Symptoms
Healthy Tissue
Cyst Development and Enlargement
Vasculature
Function
Age Urinary Concentrating Defects
Hypertension
Proteinuria
Dull Pain & Discomfort
Cyst Burden and Patient Complications in ADPKD
ADPKD Progression
0
20
40
60
80
100
0 10 20 30 40 50 60
Kid
ney
func
tion
(%)
Age (years) Torres Mayo <aupCP1047707-9
Concentrating defect, Hypertension, Proteinuria
Pain, Hematuria, Stones, Infections
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
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
Total Kidney Volume Total Cyst Volume
Kidney growth is highly variable and each individual has their own growth curve
Change in Kidney Volume Precedes Change in Kidney Function
1.0
0.5
0.0
-0.5
-1.0 Aver
age
Stan
dard
ized
Uni
t 1
Cha
nge
from
Bas
elin
e
0 1 2 3 4 6 8 Years of follow-up
GFR
htTKV
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
Baseline predictors of CKD Stage 3 endpoint
Variable Units AUC Sensitivity Specificity Cut-point 95%CI of
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
95% CI = (0.79, 0.90)Sensitivity = 74%Specificity = 75%Cut Point = 600 (cc/m)
0.00
0.25
0.50
0.75
1.00
Sens
itivity
0.00 0.25 0.50 0.75 1.00
1 - Specificity
AUROC = 0.84
Effect of Kidney Growth Rate on Development of ESRD
Chapman, AB. 2012. Unpublished.
Grantham JJ et al. Clin J Am Soc Nephrol. 2006;1:148-157.
GFR Compensation for Loss of Parenchyma
Loss of Compensated Nephrons
Progressive Rise in Total Kidney Volume Signs and Symptoms of Injury Develop
Long Before ADPKD Reaches End Stage
Grantham JJ. 2012. Unpublished.
L D W
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.
Estimating TKV Using the Ellipsoid Equation
Predicting CKD Stage 3 (iothalamate clearance) utilizing MR and US within 8 years
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
Assessment of TKV and Kidney Length Predictors of CKD Stage 3 in CRISP Participants
100
1000
10000
15 20 25 30 35 40 45 50 55 60 65 70 75 80
HtT
KV
(mL/
m)
Patient Age (Years)
20000
8000 6000
4000
2000
800 600
400
200
Subclass 1A ≤1.5%
Subclass 1B 1.5 – 3%
Subclass 1C 3 – 4.5%
Subclass 1D 4.5 – 6%
Subclass 1E > 6%
1E
1C
1A
Classification by Estimated Rate of Growth (from age and starting HtTKV = 150 ml/m)
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
0.35
Baseline TKV and eGFR in ADPKD clinical trials
Ong. A et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet vol 385 (2015)
Ong. A et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet vol 385 (2015)
Effect of therapeutic interventions
Modified from Torres Lancet
Vasopressin-V2 Receptor Antagonists
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
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.
• 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.
TEMPO 3:4 TRIAL
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.
• 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).
TEMPO 3:4 TRIAL
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.
• 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.
TEMPO 3:4 TRIAL
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.
• 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.
TEMPO 3:4 TRIAL
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.
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).
TEMPO 3:4 TRIAL
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.
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, also favored tolvaptan,
TEMPO 3:4 TRIAL
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.
Tolvaptan over placebo had lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001)
TEMPO 3:4 TRIAL
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.
The decrease in kidney pain occurred early and throughout treatment, possibly reflecting a rapid effect on fluid secretion and intracystic pressure.
TEMPO 3:4 TRIAL
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.
• There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23% vs. 14% in the placebo group).
TEMPO 4:4 EXTENSION TRIAL
Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.
• Two-year open-label extension of the TEMPO 3:4 trial.
• 976 ADPKD patients received open-label tolvaptan at their highest tolerated dose.
• Those receiving tolvaptan in TEMPO 3:4 were considered early treatment, and those that received placebo were considered delayed treatment.
TEMPO 4:4 EXTENSION TRIAL
Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.
Results: • Significant improvement in the eGFR slope
after switching from placebo to tolvaptan (from -3.59 to -2.85 mL/min/1.73m2/yr, treatment effect 21%, p=0.048) despite the time difference leading to an increased proportion starting in CKD 3 at TEMPO 4:4’s baseline compared to their own earlier TEMPO 3:4 baseline (37 vs. 15%)
TEMPO 4:4 EXTENSION TRIAL
Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.
TEMPO 4:4 EXTENSION TRIAL
Torres VE, Chapman AB, Devuyst O,et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the tempo 4:4 extension trial. Nephrol. Dial. Transplant.(2014) 29 (suppl 3): iii5-iii6.
• 5-year early treatment slope (N=554) in TEMPO 3:4 and TEMPO 4:4 combined remained significantly different from the delayed treatment placebo slope (N=422) in TEMPO 3:4 (-2.92 vs.-3.63 mL/min/1.73m2/yr, treatment effect 20%, p<0.0001) (see Figure).
TEMPO 3:4 POST HOC ANALYSIS-1
Torres VE, Higashihara E, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial. Clin J Am Soc Nephrol. 2016 Feb 23. pii: CJN.06300615.
• Patients were randomly assigned 2:1 to split-dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo.
• The primary endpoint was annualized rate of TKV change.
• Clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.
TEMPO 3:4 POST HOC ANALYSIS-2
• Effects of tolvaptan on albuminuria as a continuous variable.
• Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR).
• Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR).
Gansevoort RT, Meijer E, Chapman AB, Czerwiec FS, Devuyst O, Grantham JJ, Higashihara E, Krasa HB, Ouyang J, Perrone RD, Torres VE; TEMPO 3:4 Investigators. Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial. Nephrol Dial Transplant. 2015 Dec 17. pii: gfv422.
TEMPO 3:4 POST HOC ANALYSIS-2
• During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV.
• During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol).
• The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR.
Gansevoort RT, Meijer E, Chapman AB, Czerwiec FS, Devuyst O, Grantham JJ, Higashihara E, Krasa HB, Ouyang J, Perrone RD, Torres VE; TEMPO 3:4 Investigators. Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial. Nephrol Dial Transplant. 2015 Dec 17. pii: gfv422.
TOLVAPTAN IN VARIOUS LEVELS OF KIDNEY FUNCTION • To determine whether the renal
hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR.
• Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively).
Boertien WE, Meijer E, de Jong PE, et al. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis. 2015 Jun;65(6):833-41.
TOLVAPTAN IN VARIOUS LEVELS OF KIDNEY FUNCTION • OUTCOMES: Change in markers for
aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers).
Boertien WE, Meijer E, de Jong PE, et al. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis. 2015 Jun;65(6):833-41.
TOLVAPTAN IN VARIOUS LEVELS OF KIDNEY FUNCTION • In patients with ADPKD with
decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.
Boertien WE, Meijer E, de Jong PE, et al. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis. 2015 Jun;65(6):833-41.
Changes in Medical Management in ADPKD
Age of diagnosis: before 1950: 39 years 1951-1974: 27 years BP medication use 1991:32% 2008:62% ACEI/ARB use: 1991: 7% 2008: 46% SBP/DBP mmHg 1991: 142/85 2008: 133/80
Patch et al, Lancet, 2013
Hypotheses
Study A: Low (95-110/60-75 mmHg) versus standard (120-130/70-80 mmHg) BP control will reduce the rate of disease progression measured by change in TKV.
Study A and B: Dual blockade of the RAAS with ACE-I and ARB will reduce the rate of disease progression as compared to ACE-I therapy alone.
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Two Clinical Trials: HALT A and B Study A 15-49 years and healthy baseline eGFR > 60 mls/min Study B: 18-65 years baseline eGFR > 25 and < 60 mls/min Outcomes: Primary and secondary differ
63
64
Primary and Secondary Endpoints
Primary Study A: Percent change in TKV Study B: Time to death, ESRD or 50% reduction in eGFR
Secondary • Slope of eGFR • Urine albumin and aldosterone excretion • LVMI, RBF and RVR (Study A only) • Frequency of all-cause and cardiovascular hospitalizations • QOL, pain, PKD related symptoms
Home BP and Urinary Aldosterone Excretion Levels
65
A
Low slope=-8.50%/yr Standard slope=-7.39%/yr Diff (95% CI)= -1.19 (-3.07, 0.60) p=0.19
B
SBP end of study ∆ = 13.4 (11.8, 15.0) DBP end of study ∆ = 9.3 (7.9, 10.8) NEJM Nov 15, 2014 (online)
Annualized % Change in TKV
66
Low slope=5.67%/year Standard slope=6.57%/year Diff (95% CI)=-0.96 (-1.55, -0.24) P=0.006
Ln(T
KV)
ml
NEJM Nov 15, 2014 (online)
eGFR Slope
Low -3.1 ml/min/4 mo Standard +0.5 ml/min/4 mo p<0.001
Low -3.1 ml/min/4 mo Standa +0.5 ml/min/4 mo p<0.001
Low long term slope = -2.7 ml/min/yr Standard long term slope = -3.1 ml/min/yr p=0.05
Low overall slope = -2.9 ml/min/yr Standard overall slope = -3.0 ml/min/yr p=0.55
NEJM Nov 15, 2014 (online)
Conclusions Low blood pressure treatment in young healthy
hypertensive ADPKD patients with RAAS blockade is
Well tolerated and Safe
And results in a 14.2% slower rate of TKV growth over 5 years
• Reducing proliferation, fluid secretion and normalizing cell-cell interactions are important in ADPKD. Early intervention at specific times of growth may be most beneficial.
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THANK YOU!
Acknowledgements
National Institutes of Health
PKD Foundation
All PKD patients and their families
The CRISP and HALT UO1 Consortium Members
Boehringer-Ingelheim Pharmaceuticals Inc
Merck & Co Inc
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