2016 adpkd, what have the last 10 years taught us?. a... · 2016-10-14 · esrd age 72 . the cause...

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.

Presenter

Presentation Notes

Most common hereditary disorder causing ESRD Relatively common in nephrology practices although technically a ‘Rare Disease’. ADPKD develops in both kidneys although there are rare instances of unilateral or markedly asymmetric disease. Liver cysts develop later in > 80 %; women more severely affected. Develop early proximal tubules but later primarily collecting ducts. Relatively few cysts in light of 1 million nephrons/kidney Cysts injure kidneys by crowding and disrupting flow in interstitial capillaries, arterioles and by occluding adjacent tubules as blocking the flow of urine flow in the parent tubule. Collecting Duct tubules can affect function of hundreds of upstream nephrons that drain into them. Most cysts are in fact benign, slowly growing tumors full of secreted fluid.

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

Presenter

Presentation Notes

Acquired cystic disease of dialysis

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

Presenter

Presentation Notes

In addition to ESRD, the CRISP study found that several renal morbidities appeared in some patients in early childhood and the prevalence increased progressively with age. There were stronger associations between total kidney volume and hypertension and gross hematuria than between total kidney volume pain and urinary tract infections.

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

Presenter

Presentation Notes

The cause of ADPKD is mutated DNA passed on as a dominant trait, i.e. offspring are at 50 % risk. Two genotypes: PKD1 (most common) goes to ESRD ~ age 55; PKD2 at ~age 69. PKD1 kidneys larger and have more cysts than PKD2. Polycystin1 is a large, complex protein with a complex array of extracellular domains that probably bind to activating molecules in the extracellular fluid and as well as to epitopes on adjacent cells. Polycystin1 and Polycystin2 appear to serve as a receptor and transducer of extracellular signals. Extracellular signals are passed along an 11 membrane spanning protein and through a across a coiled-coil connection, shown in green, to interact with polycystin 2. Polycystin2 functions as a calcium entry channel. The polycystins are normally activated during renal development and in the repair of injured renal cells and are thought to be integral to those critically important processes.

•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

Presenter

Presentation Notes

Cilia are microtubule structures found on almost every vertebrate cell. Cilia comprise a unique compartment that is devoid of intracellular compounds such as membrane bound vesicles and ribosomes. It is a hair like structure on the cell surface that consists of a microtubule based axoneme covered by a special membrane.

Torres VE. Adv Chronic Kidney Dis. 2010;17:190-204.

Cell Calcium Is Involved in Promoting Cell Proliferation

Presenter

Presentation Notes

In cysts derived from collecting ducts, AVP stimulates the increased production of cyclic AMP and PKA as noted previously. Mutations in PKD1 and PKD2 alter cell calcium levels leading to a phenotype transition in renal tubule cells favoring proliferation in response to AVP action. Renal tubule cells normally do NOT proliferate in response to increased levels of cyclic AMP whereas cells bearing mutations in either polycystin 1 or 2 do replicate at increased rates in response to increased cAMP/PKA. Man is a terrestrial mammal and normally antidiuretic, meaning that collecting duct cysts are usually being stimulated by AVP. That is why AVP has become a target for reduction in patients with ADPKD.

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

Presenter

Presentation Notes

Mechanism of Fluid Secretion in Cysts The rate of fluid secretion into cysts derived from collecting ducts is stimulated by arginine vasopressin and depends on the primary transport of chloride and secondary transport of sodium. Chloride (red arrows) enters the cells from the interstitium via the furosemide-sensitive NKCC1 cotransporter. Chloride enters the urine through a channel created by the cystic fibrosis transmembrane regulator (CFTR). Na+ enters the urine through cation selective tight junctions. NaCl added to the urine increases the osmolality leading to the osmotic flow of water from the interstitium into the urine. AVP binds to and activates the AVP-V2 receptor increasing the synthesis of cyclic AMP, which activates protein kinase A. PKA increases the permeability of CFTR to chloride thereby facilitating the increased movement of NaCl and fluid into the cyst.

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

Presenter

Presentation Notes

Rasters CP1047707 8a.jpg, 8b.jpg, 8c.jpg, 8d.jpg

Inter-observer variability: 2.1%

Intra-observer variability:2.4%

Day-to-day variability: 2.4%

Presenter

Presentation Notes

Therefore the CRISP consortium was developed to determine if radiologic measures including magnetic resonance imaging, could detect small differences in renal and cyst size over short periods of time. The participating clinical sites for this trial included Emory University, the Mayo Foundation with Dr. Torres, the University of Kansas with Dr. Grantham and the University of Alabama with Dr. Lisa Guay Woodford. Initially, phantoms made of agarose with water filled balloons and both phantoms and 4 patients were sent to four participating sites to determine the reproducibility and reliability of MR imaging techniques.

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.

Presenter

Presentation Notes

The formation and growth of individual cysts damages renal function. The cumulative volumes of these cysts is what causes TKV to increase year after year. Consequently, kidney volume is an easily accessible indicator of disease progression. TKV data from CRISP was used to estimate when ESRD might be detected. Enrollment TKV data was used, so this would be like trying to assess when the patient might need dialysis the first time you see them in the office. A model was used to construct the plots in this graph relating TKV to age. The different curved lines show how fast TKV might increase if the annual rate of growth was 2.5, 5, 10 or 20 % / year. The model displays TKV, referenced to height in meters. The dashed horizontal line is a cut-point that defines the TKV above which the patient can expect to reach CKD Stage 3, i.e., an eGFR less than 60 ml/min/1.73 m2 , within 8 years. The baseline TKV at age 18 used in this model is only slightly larger than normal, so these are conservative estimates. TKV crosses the dashed line at 24, 30, 42 and 66 years of age; it is obvious that kidneys growing at the faster rates cross the dashed line at younger ages. The potential gain in useful renal function of reducing the TKV growth rate from 20 % to 10 %, 10 % to 5 % and 5 % to 2.5 %/ y is 6, 12 and 24 years, respectively. Reducing TKV is, therefore, one strategy for preserving long-term renal function. The annual TKV growth rate (% / year) can be estimated the first time TKV is measured in an adult. Assume a value for TKV at age 18 of 186 ml/m and solve the equation: ln(TKV/186)*100/Age - 18

Grantham JJ et al. Clin J Am Soc Nephrol. 2006;1:148-157.

GFR Compensation for Loss of Parenchyma

Loss of Compensated Nephrons

Presenter

Presentation Notes

Renal failure is the most feared complication of ADPKD. As shown in the serial MR right kidney scans of this hypothetical patient the cysts become more numerous and larger with age, eventually destroying most of the functioning parenchyma. However, as shown by the line connecting the red dots the actual damage is obscured by a robust compensatory hyper-filtration program. The loss of nephrons injured by cysts inspires those remaining to filter greater amounts of plasma that keeps the GFR within the range of normal for several decades. The line connecting the black dots shows what actually happens; the number of filtering nephrons declines steadily beginning in childhood. At around age 30 in this example, maximally compensated nephrons are also lost to disease and the GFR begins to fall at an escalating rate. From birth to age 40 the physician and the patient was lulled into thinking the GFR was excellent only to discover in the 5th and 6th decades that damage had been going on for years.

Progressive Rise in Total Kidney Volume Signs and Symptoms of Injury Develop

Long Before ADPKD Reaches End Stage

Grantham JJ. 2012. Unpublished.

Presenter

Presentation Notes

The progressive rise in total kidney volume (TKV) beginning in childhood had an exponential form as shown here by the average values in a curved line indicating an average annual growth rate of 5.4 %. The ages that hypertension, renal pain and hematuria first appeared are noted; these signs and symptoms continued to develop in previously unaffected patients as kidney volume increased. It is important to note that the onset of hypertension, pain or hematuria are signals that serious renal injury occurs decades before GFR decline can be confidently detected by measurement of plasma creatinine concentration.

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

Presenter

Presentation Notes

In the CRISP study, TKV at enrollment predicted the risk of developing ESRD. TKV can be estimated with the ellipsoid equation from ultrasound, computed tomography or MR measurements of kidney length, width and depth. The example in the figure represents a single kidney of a pair. Measurements from the other kidney would be added to give TKV.

http://homepage.ufp.pt/biblioteca/WebBasPrinTectonics/BasPrincTectonics/Page2.htm

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

Presenter

Presentation Notes

Tolvaptan, a specific vasopressin 2 receptor antagonist,developed by Otsuka International is an an important candidate therapy for ADPKD. Given the increase in vasopressin, the V2receptor, and intracellular cAMP found in PKD epithelia, blockade of this pathway would help to reduce intracellular cAMP levels, inhibit the production of PKA and Src, stabilize the mTOR pathway, ultimately reducing cellular proliferation and chloride secretion.

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


• 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


• 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


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


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


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


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


• 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.



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%)



Presenter

Presentation Notes

�



• 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.


• 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.


• 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).


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.


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.

62

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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2016 adpkd, what have the last 10 years taught us?. a... · 2016-10-14 · esrd age 72 . the cause...

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