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Home , Tuberous sclerosis

What is new in nephrology?

Graham Warwick Consultant Nephrologist

25April 2017 Thirst for knowledge

‘All knowledge is of itself of some value. There is nothing so minute or inconsiderable that I would not rather know it than not.’

Samuel Johnson English Poet, Critic and Writer 1709-1784 Topics

• Adult polycystic disease and vasopressin antagonists

• Tuberous sclerosis and mTOR inhibitors

• Atypical haemolytic uraemic syndrome and anti- complement therapy Autosomal dominant polycystic kidney disease

• One of commonest single defects

• Estimated prevalence of genetically affected individuals at birth - 1:400 to 1 :1000

• UK – estimated prevalence – 1:2500

• Genetic in two identified • PKD1 – (Polycystin 1) • PKD2 – chromosome 4 (Polycystin 2)

• Accounts for 6.8% of patients starting renal replacement therapy in UK in 2014 Mechanisms of formation in ADPKD • Multiple theories • Abnormal fluid secretion • Role of cyclic AMP and intracellular calcium • Impaired glucose metabolism and possible role for metformin • Role of JAK-STAT signalling • Angiogenesis • Abnormal cilia function and cell planar polarity

• Recent studies have tested different therapeutic interventions to reduce cyst growth Mechanisms of cyst formation in ADPKD

TEMPO 3:4 study Phase 3 double blind RCT - Tolvaptan vs Placebo

N=1445, 18 to 50 years GFR > 60ml/min, Total kidney volume > 750mls

N Engl J Med 2012; 367:2407-2418

Issues related to Tolvaptan in ADPKD

• Post-hoc analysis of the TEMPO trial suggested modest effect on the rate of eGFR decline by 1.13 and 1.66 mL/min/1.73 m2 per year

• Increased water intake may have suppressed vasopressin levels in the placebo group, resulting in an underestimation of the beneficial effect of tolvaptan.

• Tolvaptan approved for use in ADPKD by regulatory agencies in Japan, Canada, and Western Europe but not in USA by FDA as yet. Summary of NICE guidance Oct 2015

Tolvaptan (Jinarc®) is recommended for the treatment of autosomal dominant polycystic kidney disease in adults when: • the patient has chronic kidney disease stage 2 or 3 at the start of treatment

• there is evidence of ‘rapidly progressing disease ’

• the manufacturer provides tolvaptan (Jinarc®) with the discount agreed in the patient access scheme How is rapid progression defined?

Renal Association summary suggested one of :-

• a sustained decline in eGFR of ≥2.5ml/min/1.73m 2 per year (with at least 5 measurements over 5 years)

• a sustained decline in eGFR of >5ml/min/1.73m 2 per year over 12 months (at least 2 measurements 6 months apart in the absence of other confounding factors)

• an increase in total kidney volume (TKV) (≥5% per year) measured in at least 3 scans (CT or MRI) at least 6 months apart Tolvaptan for treating autosomal dominant polycystic kidney disease • Annual cost of tolvaptan is estimated to be £15,750 per person • Cost of QUALY estimated between £40000-70000 depending on model • NICE estimated 2,285 patients with ADPKD will be eligible for treatment in England (= 4 per 100,000 population). • Otsuka has agreed a patient access scheme providing a discount to the list price of tolvaptan • the level of the discount is commercial in confidence Summary

• APKD is a common cause of ESRF

• Until recently no effective treatments to limit growth of and fall in eGFR (with possible exception of BP control)

• Tolvaptan now available for patients with evidence of ‘rapid progression’

• Gradual role out of therapy but side effects may be limiting

• Cost benefit difficult to calculate Tuberous sclerosis complex

Pathophysiology of tumour formation in TSC

• TSC1 and TSC2 are tumour suppressor genes that function according to the Knudson ‘two-hit’ hypothesis • Hamartin and tuberin form a dimer that mediates a key step in the phosphoinositide 3- (PI3K) signalling pathway • Activation of this pathway results in inhibition of the mammalian target of rapamycin (mTOR), a serine/threonine kinase that regulates cell growth, proliferation, motility and survival • Loss of function of either hamartin or tuberin leads to aberrant cell proliferation • Potential development of in kidneys, brain, , , skin, and eyes

Renal manifestations of TSC

• Renal

• Autosomal dominant polycystic kidney disease

• Isolated renal cysts

• Renal Angiomyolipomas

• AMLs are noted in as many as 80% of persons with TSC. • consist of abnormal , , and blood vessels • often produce nonspecific complaints such as flank pain. • more concern is potentially life-threatening retroperitoneal haemorrhage from rupture of dysplastic, aneurysmal blood vessels. • studies suggest that as many as 75% of AMLs will increase in size over time • Very large AMLs (>6-8 cm in diameter) are likely to progress and often result in haemorrhage, particularly if prominent abnormal vasculature is present.

Dysplastic blood vessels in renal AMLs

Selective embolisation for renal AMLs

• 351 adult patients treated consistently in a single centre over 16 years with pre-emptive embolisation • 144/244 (59%) of patients with AMLs developed Chronic Kidney Disease stage 3 or more • 57 (49%) of the 117 who had embolisation needed 2 or more • 14 (12%) ended up in end stage renal failure • 9 (8%) died from renal related complications.

(Eijkemans et al, 2015) for associated with tuberous sclerosis complex or sporadic (EXIST-2) • TSC patients >8 years with at least one angiomyolipoma 3 cm • primary efficacy endpoint was at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. • 118 patients were randomly assigned to receive everolimus (n=79) or placebo (n=39) over two years • AML response rate was 42% for everolimus v 0% for placebo • response rate difference 42% [24–58%]; p<0·0001. • most common adverse events in the everolimus and placebo groups were stomatitis and -like skin lesions Lancet 2013;381:817 Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2)

Lancet 2013;381:817 Everolimus for treatment of angiomyolipomas associated with tuberous sclerosis • Angiomyolipomas (AMLs) which are 30 mm or greater and which demonstrate interval growth • Monitor effectiveness by MRI scanning; various stop criteria • Estimated 30 new patients per year will start treatment(out of total population of TSC patients of ~5000) • ‘the average per patient cost is £36,000 per year. For the majority of patients, this is a life-long treatment’

Clinical Commissioning Policy Statement Specialised Commissioning Team, NHS England, June 2016 Summary

• TSC is an uncommon which may present to a variety of specialists • The mechanism of disease has been clearly elucidated • Treatment with mTOR inhibitors can reduce the risk of progressive increase in renal AMLs (and other tumours) • More data need on impact of bleeding and on progression to renal failure Haemolytic Uraemic Syndrome (HUS)

• A thrombotic microangiopathy (TMA) characterized by:

• Non-immune Microangiopathic Haemolytic Anaemia (MAHA) • Elevated lactate dehydrogenase, low haptoglobin, schistocytes

• Thrombocytopenia

• Acute Kidney Injury

• Can involve multiple organ systems (CNS, cardiac, pulmonary, , etc)

Atypical haemolytic uremic syndrome

• characterized by acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia • incidence of approximately 0.5-4.0 per million per year. • similar phenotype to Shiga toxin-producing E. coli-associated haemolytic uremic syndrome (STEC-HUS), thrombotic , and other multisystem disorders. • > 50% of patients with aHUS have an underlying inherited and/or acquired complement abnormality • until recently, the prognosis for aHUS was poor, with the majority of patients developing end-stage renal disease within 2 years of presentation. Atypical haemolytic uraemic syndrome v. Thrombotic thrombocytopenic purpura

• Historically, TTP defined by clinical features e.g. fever, neurological involvement • ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), degrades large vWf multimers and decreasing their activity • Genetic and acquired deficiency described and also autoantibodies to ADAMTS13 • TTP now defined by <10% ADAMTS13 activity or ADAMTS13 autoantibody Other Differential Diagnoses

• Pre-eclampsia • Should resolve with delivery, maybe 1-2 days after • Disseminated Intravascular Coagulation (DIC) • PT/INR, PTT normal; not septic • Accelerated hypertension • crisis • • Difficult, but no other systemic disease; renal biopsy • Typical HUS • Without h/o diarrhea atypical HUS=ComplementHUS=Complement----mediatedmediated HUS

• Complement-mediated haemolytic uraemic syndrome • CM-HUS better name than aHUS

• An increase in action of the alternative pathway of the complement system due to dysregulation which leads to endothelial damage and thrombin formation

Genetic and Immunologic Predisposition

• Complement Regulator Protein Deficiencies • e.g. Factor I, H,

• Point Mutations of Regulator

• Autoantibodies to Regulator Proteins • Factor H antibody

• Gain-of-function of genes in alternative pathway 20% Familial 80% Sporadic Genetic complement disorders in CMCM----HUSHUS

• Complement factor H (CFH, 20 - 30 %)

• CD46, previously known as membrane cofactor protein (5 - 15 %)

• Complement factor I (CFI, 4 -10%)

• Complement factor 3 (C3, 2 -10%)

• Complement factor B (CFB, 1 - 4%)

• Thrombomodulin gene (THBD, 3 - 5%) If I’ve had this my whole life… why now?

• Atypical HUS - there is an underlying genetic predisposition that is unmasked with stress-responses

• Triggers HEMOLYTIC UREMIC SYNDROME • Infection Hemolytic Anemia • HIV • Cancer Thrombocytopenia • Organ Transplant • Pregnancy Kidney injury • Chemotherapy • Immunosuppresion (cyclosporine, tacrolimus) Eculizumab

• C5 Inhibitor • Humanized monoclonal Ab • Inhibits cleavage of C5 by C5 convertase • Used for paroxysmal nocturnal haemoglobinuria Eculizumab for aHUS

• 53% normal platelet count by day 7; 86% by week 26

• All people who finished 26 weeks had normalization of platelets

Legendre et al. NEJM 2013; 368:2169-2181 Eculizumab for aHUS

• Dialysis discontinued in 4 of 5 patients

• Earlier intervention with eculizumab was associated with greater improvement in eGFR

Legendre et al. NEJM 2013; 368:2169-2181 Transplants

• Kidney Transplant • 50% recurrence rate after renal transplant • 80-90% of those with recurrence have renal failure • Exception for those with Membrane Co-factor Protein deficiency • MCP is made in the kidney

• Combined Kidney-Liver Transplant • Complement proteins made in liver • Case reports with mixed outcomes NICE guidance: Eculizumab for treating atypical haemolytic uraemic syndrome (28 January 2015) Eculizumab… is recommended for funding for treating aHUS if :-

• coordination of eculizumab use through an expert centre (= Newcastle)

• monitoring systems to record the number of people with a diagnosis of aHUS and the number who have eculizumab, and the dose and duration of treatment

• a national protocol for starting and stopping eculizumab for clinical reasons

• a research programme … to evaluate when stopping treatment or dose adjustment might occur. Eculizumab therapy – Points to Consider

• £340,200 per new patient for first year • Estimated £57.8M in year 1 • Estimated £82M in year 5

• Frequency of dosing (currently every other week)

• When to stop therapy (if ever) – subject of ongoing research Summary • Atypical HUS is a thrombotic microangiopathy caused by dysregulation of the complement pathway • Diagnosis made by excluding typical HUS, TTP and other causes of thrombotic microangiopathy • Usually there is an underlying genetic predisposition that is unmasked with stress- responses leading to clinical symptoms • Atypical HUS must be considered early in the differential for thrombotic microangiopathy because appropriate treatment is most effective when started early • Eculizumab, a C5 inhibitor , is extremely effective in the treatment and prevention of recurrence of atypical HUS; however the cost of the medication creates barriers to treatment What is new in nephrology?

• Examples of targeted treatment

• Dependent on understanding of the molecular mechanisms of genetic diseases

• Diseases relatively uncommon in population but can present to any specialty

• ‘Nice’ and precise treatment – if you can afford it