Autosomal Dominant Polycystic Kidney Disease. Dr. Sameena Iqbal Nephrologist CIUSSS West Island

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1 Autosomal Dominant Polycystic Kidney Disease Dr. Sameena Iqbal Nephrologist CIUSSS West Island

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 Adapted from: Chapman AB. J Am Soc Nephrol 2007;18(5): Galarreta CI, et al. Am J Pathol 2014;184(7):

4 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 Adapted from Barua M, et al. Semin Nephrol 2010; 30:

5 Effects of ADPKD Mutations on Polycystin Function Polycystin-1 (PC1) and -2 (PC2) interact through their intracellular tails to regulate multiple critical functions of tubular epithelial cells including proliferation, fluid secretion, and maintenance of tubular geometry Truncating (e.g., stop codon, frameshift) PKD1 mutations render PC1 nonfunctional Many but not all missense mutations that alter a highly conserved amino acid residue in PC1 may result in a partially functional protein; they are termed hypomorphic mutations Adapted from: Wilson PD, et al. N Engl J Med 2004; 350(2): Rossetti S, et al. Kidney Int 2009;75(8):

6 Two-Hit Model: A Common Mechanism of Cystogenesis Fluid accumulation All the epithelial cells in a renal tubule contain the same germline PKD mutation. Somatic mutation of the PKD allele from the unaffected parent within an individual epithelial cell. Clonal proliferation of this epithelial cell results in tubular dilatation and cyst formation. Adapted from: Pei Y, et al. Trends Mol Med 2001; 7(4):151-6.

7 Family History of Disease Severity Predicts ADPKD Mutation Type If a family member developed ESRD after the age of 70, it is highly predictive of PKD2 PPV 100%, sensitivity 74% If a family member developed ESRD <55, it is highly predictive of the severe form of PKD1 PPV 100%, sensitivity 72% PPV: positive predictive value. Barua M, et al. J Am Soc Nephrol 2009; 20(8):

8 Natural History of ADPKD: Overview Characterized by focal and sporadic development of renal cysts with increasing age Expansion of kidney volume by innumerable cysts results in an obstructive nephropathy Compressive cyst expansion also triggers inflammation, fibrosis, and tubular dropout, resulting in a loss of functional nephrons Glomerular filtration rate remains stable for several decades due to compensatory hyperfiltration of a subset of nephrons

9 Clinical Complications Are More Frequent in Patients with Big Kidneys GFR: glomerular filtration rate. Adapted from: Grantham JJ, et al. N Eng J Med 2006; 354(20):

10 Over Time, Cysts Develop and Expand Resulting in Loss of Kidney Function Illustration of Different Severities of Disease Mild disease TKV 470 ml Moderate disease TKV 3.0 L Severe disease TKV 4.1 L Normal TKV is ~250 ml in women and ~350 ml in men. TKV: total kidney volume.

11 A Simplified Explanation of Pathogenic Mechanisms for Cyst Enlargement Genetic mutations of ADPKD Inhibition of intracellular Ca+ Other pathways (e.g., mtor, MAPK) Cyclic adenosine monophosphate (camp) Disruption of flow sensing and tubulogenesis Transepithelial fluid secretion Proliferation and de-differentiation camp: cyclic adenosine monophosphate. Adapted from: Devuyst O, et al. Curr Opin Nephrol Hypertens 2013; 22(4):

12 A Simplified Explanation of Pathogenic Mechanisms of Cyst Enlargement: Role of V2 Receptor Genetic mutations of ADPKD Inhibition of intracellular Ca+ Vasopressin Other pathways (e.g., mtor, MAPK) Cyclic adenosine monophosphate (camp) Disruption of flow sensing and tubulogenesis Transepithelial fluid secretion Proliferation and de-differentiation V2 receptor antagonism may normalize [camp]i Devuyst O, et al. Curr Opin Nephrol Hypertens 2013; 22(4):

13 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 Adapted from: Wang CJ, et al. Clin J Am Soc Nephrol 2011; 6(1):192-7.

14 Evidence for Water Therapy in ADPKD: Changes in Urine camp Linked to Osmolality 9 p < p = 0.03 camps/osm (µmol/osm) 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.

15 Observational Study: No Benefit from Water Therapy in ADPKD Change of total kidney volume (ml / year) Total Kidney Volume P = P = P = P = High water intake group Change of egfr(eq) slope (ml / min / 1.73m 2 / year) Key limitations of the study Small sample size One-year duration Underpowered, inconclusive egfr Free water intake group Adapted from: Higashihara E, et al. Nephrol Dial Transplant 2014;29(9):

16 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 nephrolithiasis 1 Adherence to water therapy is difficult for many patients 1. Hall PM. Cleve Clin J Med 2009;76(10):

17 Different BP Targets in Early ADPKD: Changes in Total Kidney Volume and egfr (HALT-PKD Study A) Changes in TKV Changes in egfr L n Total Kidney Volume (ml) Standard blood pressure Low blood pressure 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= 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, BP: blood pressure; TKV: total kidney volume; egfr: estimated glomerular filtration rate; a greater decline in the LMVI, and greater reduction in UAE. LVMI: left-ventricular mass index; UAE: urinary albumin excretion. Observed egfr (ml/min/1.73 m 2 ) Low blood pressure, -2.9 ml/min/1.73 m 2 /yr Standard blood pressure, -3.0 ml/min/1.73 m 2 /yr Difference, -0.1 ml/min/1.73 m 2 /yr (95% CI, -0.3 to 0.6) P= Follow-up (mo) Standard blood pressure Low blood pressure Adapted from Schrier RW, et al. N Engl J Med 2014;371(24):

18 Percent of participants with 20% increase over study period Pravastatin for the Treatment of ADPKD in Children: Primary Composite Endpoint and Components P=0.03 Any of HtTKV, LVMI, or UAE P=0.03 P=0.18 Pravastatin Placebo P=0.50 HtTKV LVMI UAE 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%) 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 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 1. Liu YM, et al. Transplant Proc 2014;46(1):66-74.

20 Mechanism of Action of Vasopressin-2-receptor Antagonists in ADPKD 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.

21 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 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):

22 Tolvaptan in ADPKD: Impact on TKV (TEMPO 3:4 Primary Outcome) Change in Total Kidney Volume (%) Baseline Tolvaptan Placebo Months Placebo growth: 5.5%/yr Tolvaptan growth: 2.8%/yr p< Dropouts: Tolvaptan: 23.0% Placebo: 13.8% Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

23 Tolvaptan in ADPKD: Impact on Kidney Function (TEMPO 3:4 Secondary Outcome) Tolvaptan Placebo Change in Kidney Function eciprocalserum creatinine {mg/ml}-1) Baseline Months Change in reciprocal of the scr level: Tolvaptan: 2.61 mg/ml 1 /yr Placebo: 3.81 mg/ml 1 /yr p<0.001 Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

24 Tolvaptan in ADPKD: Impact on Kidney Pain (TEMPO 3:4 Secondary Outcome) Cumulative Event Hazard Hazard ratio, 0.64 (95% CI, ) P=0.007 by Cox model Placebo Tolvaptan 0 Baseline No. At Risk Study Months Tolvaptan Placebo Adapted from Torres VE, et al. N Engl J Med 2012;367(25):

25 Tolvaptan for the Treatment of ADPKD: Conclusions In the pivotal clinical study, tolvaptan showed efficacy in: Slowing progression of increase in kidney volume Slowing deterioration of kidney function Improving symptoms (e.g., pain) Signal of liver toxicity in the pivotal trial led to the recommendations for monitoring at baseline and throughout treatment

26 Approach to ADPKD Identify cases early to intervene with non pharmacologic and pharmacological therapies Non pharmacologic therapies: life style modifications, low sodium intake, smoking cessation, healthy diet, water intake Pharmacological therapies: Ace inhibition, statins, tolvaptan Look out for complications: nephrolithiasis, cerebral aneurysm, LV mass index, venous thrombosis and hernias