Genetic Kidney Disease

Dr Daniel Gale Clinician Scientist and Consultant Nephrologist UCL Centre for Nephrology Royal Free Hospital

Email: [email protected] Conflict of interest statement

• Payment for consulting and speaking from Alexion, Otsuka and Novartis who make therapies licenced for genetic kidney diseases Outline

• Epidemiology and consequences of kidney failure • Contribution of genetic kidney disease • More detail about the 2 commonest genetic kidney diseases: – Autosomal dominant polycystic kidney disease (ADPKD) – Type IV Collagenopathies: Alport Syndrome and Thin Basement Membrane Nephropathy Dialysis cost is ~£30,000 The costs of kidney per year per patient failure • Total kidney failure is fatal without dialysis or a transplant • Median survival on dialysis is 10 years • 50,000 people in UK receive dialysis or have a transplant • 3% of NHS budget • Additional costs include the quality of life impact of renal replacement therapy and lack of productivity Causes of Kidney Failure in UK adults

Renovascular Data not disease available Known Pyelonephritis 6% 10% 7% unknowns Polycystic Kidney Uncertain Disease aetiology 6% 19% Known genetic Other kidney diseases 14%

Diabetes Hypertension 22% 5% Glomerulo- nephritis Unknown 11% unknowns Byrne et al UK Renal Registry 2009 Family history is a major risk factor for ESKD

18

16

14

12

10

8

6

4 Age Ratio Hazard Age adjusted 2

0

Ethnicity Co-morbidity Smoking

Data from >1.5 million UK residents, Hippisley-Cox and Coupland, BMC Family Practice 2010 Monogenic kidney diseases

Cystic kidney diseases ● Polycystic kidney diseases ● Ciliopathies ● Tubulointerstitial kidney diseases

Devuyst et al Lancet 2014 • Over 200 genes known to be associated with monogenic renal disorders – Most are extremely rare disorders • Advances in sequencing technology means more patients can be given a precise diagnosis • Understanding biology can help advance treatment ADPKD: Clinical case

• 29-year-old Polish man presents to GP with headache and is found to be hypertensive (145/90) • No other past medical history, non smoker • Father received a kidney transplant for Polycystic Kidney Disease aged 43 • Grandmother on dialysis before dying at 57 – No family history of intracerebral bleed • Physical examination normal Diagnosis: ADPKD

• Creatinine 96 umol/l – eGFR 85 ml/min • Ultrasound shows 15cm kidneys, with numerous • What is the prognosis? cysts • Is this treatable? • BP easily controlled on • What should his a single agent (Ramipril) management be? Autosomal Dominant Polycystic Kidney Disease (ADPKD)

• Commonest serious monogenic disease • Major cause of kidney failure worldwide (6% in UK) • 1:800-1000 of the population affected – Similar in all populations studied • Over 50% patients will develop ESKD • Very high penetrance of cysts • Caused by heterozygous mutation of PKD1 or PKD2 – Disease mechanism is somatic second hit • Has extra-renal manifestations Clinical presentation of ADPKD • >40% in UK picked up by family screening • Incidental finding (pregnancy/gallstones etc) • 20-30% present with symptoms of disease – Macroscopic haematuria – Flank pain – Hypertension investigations – End Stage Kidney Failure (very rare in UK) – Subarachnoid haemorrhage (very rarely) • 20-40% of patients lack a family history – Affected parents undiagnosed – De novo mutation (high rate explains high prevalence) Commoner extra-renal manifestations of ADPKD

• Liver cysts – Do not cause liver failure – Can occasionally cause abdominal compression resulting in malnutrition, breathing problems – Liver transplant needed in <1% ADPKD patients • Hypertension – Almost universally present in ADPKD as people age – sometimes before cysts – Easily controllable with renin-angiotensin blockade Rarer extra-renal manifestations of ADPKD

• Intracranial aneurysms and subarachnoid haemorrhage – 3-7% of ADPKD patients have an intracranial aneurysm – 12-15% if a relative has had an aneurysm • Heart valve disease – Clear association with ADPKD but rarely causes problems – Mitral valve prolapse commonest abnormality Kidney cysts develop and grow over time

30cm

10-12 cm 15-25 cm 30cm Normal ADPKD with Removed to patient renal impairment make space for transplant Progression is related to genotype

(127) (356) (172) • ~80% PKD1 mutations N = 655 • ~20% PKD2 mutations

No common founder mutations observed even among 700 Bretons

Cornec-Le Gall JASN 2013 PKD1 more susceptible to mutation than PKD2 • PKD1: very large gene encoding Polycystin 1 (PC1) – mRNA: 14,138 bases, 4303 amino acids – Repetitive and highly mutation-prone

Chr 16

• PKD2: smaller gene encoding Ca2+ channel PC2 – mRNA: 5056 bases, 968 amino acids – Less prone to mutation (germline or somatic)

Chr 4

• This likely explains difference in prevalence and severity of PKD1- and PKD2-associated disease Polycystins decorate primary cilia of renal tubules • Localised Ca2+ influx in response to flow in tubule • Provides directional signal to control proliferation to make a tube • When proliferating cells lack planar cell polarity they form a spherical structure

Tubular flow

Ca2+

Ca2+

Planar cell polarity signal

Renal tubular epithelial cells

Chebib et al Nat Rev Nephrol 2015 Vasopressin in ADPKD

Vasopressin is necessary for cysts to develop in polycystic animals Grantham and Torres Nat Rev Nephrol 2016 Translation: TEMPO 3:4 study

• 1445 patients with ADPKD and GFR >60 ml/min randomised 2:1 to Tolvaptan (V2 blocker) or placebo for 3 years • Compared with placebo on Tolvaptan: – TKV grew 2.8% v 5.5% – eGFR declined less rapidly • ~30% reduction – Reduced cyst pain on drug • Not a cure – but maybe a first step • Discontinuation due to AE: – 23% tolvaptan v 13% placebo, mainly polyuria-related – UTI, haematuria and renal pain more common in placebo group • 2 patients developed severely elevated LFTs Torres VE et al. N Engl J Med 2012 Tolvaptan is NICE approved in England for: • ADPKD and CKD stages 2 and 3 (eGFR 30-90ml/min/1.73m2) • And evidence of rapidly progressive disease: – Rapid loss of eGFR or renal enlargement • High risk for rapidly progressive disease: – Family member with ESKD or death (CVD) <58 yrs old – Age <45 with bipolar kidney length >16.5cm – One of the following at <35 years of age: hypertension; visible haematuria; flank pain • Monthly LFT monitoring is mandated – Only available from designated prescribers/pharmacies ADPKD: Take home messages

• Diagnose if enlarged, cystic kidneys • Prognosis in ADPKD is informed by: – Family history and (if available) genetic diagnosis – Presence of hypertension, urinary tract symptoms and enlarged kidneys at a young age • Vasopressin (ADH) has a significant role in disease progression – Keep patients well hydrated – Avoid diuretics – May benefit from Tolvaptan therapy if poor prognostic markers and relatively well-preserved renal function Microscopic haematuria and Alport Syndrome

• A 28-year-old woman is found to have microscopic haematuria when booking for her first pregnancy • No significant PMH • Maternal uncle developed kidney failure • Examination, blood pressure and blood tests all normal, with creatinine 49 umol/l (eGFR >90 ml/min) and no proteinuria Type IV Collagen Disorders

• By far the commonest genetic causes of haematuria are mutation of genes encoding Type IV Collagen • Renal manifestations: • Isolated microscopic haematuria • +/- Proteinuria • +/- Hypertension • +/- Renal impairment, including ESKD • Deafness and eye abnormalities also sometimes a feature Type IV Collagen disorders

• X-linked Alport Syndrome • Autosomal recessive Alport syndrome • Autosomal dominant Thin Basement Membrane Nephropathy (TBMN)

• Disease is determined by genetic defect and how patient is ascertained Type IV Collagen

Triple helix

Collagen IV α3α4α5 heterotrimer

Encoded by genes: COL4A3 (Chr 2)

COL4A4 (Chr 2) Kalluri 2003 COL4A5 (X Chr) Type IV Collagen network forms structural basement of Glomerular Basement Membrane Also present in ear and eye Type IV Collagenopathies Unaffected X-linked Alport Autosomal AD Thin Syndrome recessive Alport Basement Syndrome Membrane Nephropathy (or AR Alport Syndrome carrier)

Chr 2 Male Female Male Female Male or Female Male or Female COL4A3 X X X COL4A4

X Chr

COL4A5 X X

Chan and Gale, Clinical Med. 2015 High likelihood of ~20% risk of High likelihood of ~20% risk of kidney failure by kidney failure in kidney failure by kidney failure in early adulthood late adulthood early adulthood late adulthood Normal Type IV Lacks normal Defective and Lacks normal Defective and Collagen α3α4α5 Collagen IV normal α5 Collagen IV α3 normal α3 chains α5 chain chain genes chain chain genes Differential diagnosis of 28-year-old woman • Heterozygous COL4A3/COL4A4 mutation? – AD Thin Basement Membrane Nephropathy? – AR Alport Carrier? – Child has 50% risk of AD TBMN or AR Alports carrier – If father affected, 25% risk of AR Alport Syndrome • Heterozygous COL4A5 mutation? – X-linked Alport Syndrome (manifesting) carrier – Male child would have 50% chance of Alport Syndrome • Does she have something else? – Further details of her uncle’s history are critical – Dipstix testing of mother and maternal grandparents would be very helpful Diagnosis and management

• Biopsy can indicate a Type IV Collagen disorder • Genetic test (>90% sensitive) can make diagnosis – Mode of transmission – Prognosis • Current management is aggressive RAS blockade if proteinuria detectable (and not pregnant) • Clinical trials of new therapies are currently underway Other genetic kidney disease categories Cysts • Tubular disorders (KCNJ10, • Tubulointerstitial kidney diseases ATP6V1B1 etc…) (MUC1, UMOD, REN) – Often recessive – Usually dominantly inherited – Typical electrolyte disturbances – Normal urinalysis and BP usually – Sometimes HT, kidney failure, – Biopsy non-diagnostic deafness or stones • Congenital Malformations (PAX2, • Podocytopathies (NPHS1, INF2 EYA1, SALL1, HNF1B, etc…) etc…) – Dominant or recessive – May be recessive or dominant – Highly variable penetrance – Genes important in maintaining – Proteinuria sometimes present glomerular filtration barrier (FSGS) – Structural abnormalities on imaging – Usually heavy proteinuria – Distinctive extra-renal manifestations • Metabolic and complement • Ciliopathies (NPHP1, INVS, etc…) disorders (GLA, CFH, CFHR5 etc…) – Usually recessively inherited – Renal damage from a systemic – Urinalysis and BP may be normal disorder – Often associated with eye/ear/CNS features – Recur following transplantation

Conclusions

• Genetic kidney diseases make a numerically important contribution to burden of renal disease • An accurate (molecular) diagnosis can disclose mode of transmission and inform prognosis • Once diagnosed, specific treatments are available for a growing number of genetic kidney diseases – Tolvaptan for ADPKD – Eculizumab for aHUS – Everolimus for renal involvement in TSC