graham warwick consultant nephrologist 25april 2017
TRANSCRIPT
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What is new in nephrology?
Graham WarwickConsultant Nephrologist
25April 2017
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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
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Topics
• Adult polycystic kidney disease and vasopressin antagonists
• Tuberous sclerosis and mTOR inhibitors
• Atypical haemolytic uraemic syndrome and anti-complement therapy
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Autosomal dominant polycystic kidney disease
• One of commonest single gene defects
• Estimated prevalence of genetically affected individuals at birth - 1:400 to 1 :1000
• UK – estimated prevalence – 1:2500
• Genetic mutations in two identified genes• PKD1 – chromosome 16 (Polycystin 1)
• PKD2 – chromosome 4 (Polycystin 2)
• Accounts for 6.8% of patients starting renal replacement therapy in UK in 2014
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Mechanisms of cyst 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
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Mechanisms of cyst formation in ADPKD
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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
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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.
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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
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How is rapid progression defined?
Renal Association summary suggested one of :-
• a sustained decline in eGFR of ≥2.5ml/min/1.73m2 per year (with at least 5 measurements over 5 years)
• a sustained decline in eGFR of >5ml/min/1.73m2 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
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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
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Summary
• APKD is a common cause of ESRF
• Until recently no effective treatments to limit growth of cysts 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
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Tuberous sclerosis complex
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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-kinase (PI3K) signalling pathway
• Activation of this pathway results in inhibition of the mammalian target of rapamycin (mTOR), a serine/threonine protein 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 hamartomas in kidneys, brain, lungs, heart, skin, and eyes
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Renal manifestations of TSC
• Renal angiomyolipomas
• Autosomal dominant polycystic kidney disease
• Isolated renal cysts
• Renal cell carcinoma
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Renal Angiomyolipomas
• AMLs are noted in as many as 80% of persons with TSC.
• consist of abnormal smooth muscle, fat, 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.
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Dysplastic blood vessels in renal AMLs
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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)
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Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis
(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 acne-like skin lesions
Lancet 2013;381:817
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Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis
(EXIST-2)
Lancet 2013;381:817
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Everolimus for treatment of angiomyolipomasassociated 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
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Summary
• TSC is an uncommon genetic disorder 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
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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, liver, etc)
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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 thrombocytopenic purpura, 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.
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Atypical haemolytic uraemic syndromev.
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
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Other Differential DiagnosesOther Differential DiagnosesOther Differential DiagnosesOther 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
• Scleroderma crisis
• Vasculitis• Difficult, but no other systemic disease; renal biopsy
• Typical HUS• Without h/o diarrhea
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atypical HUS=Complementatypical HUS=Complementatypical HUS=Complementatypical HUS=Complement----mediated mediated mediated mediated HUSHUSHUSHUS
• 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
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Genetic and Immunologic Genetic and Immunologic Genetic and Immunologic Genetic and Immunologic
PredispositionPredispositionPredispositionPredisposition
• Complement Regulator Protein Deficiencies• e.g. Factor I, H,
• Point Mutations of Regulator Proteins
• Autoantibodies to Regulator Proteins• Factor H antibody
• Gain-of-function of genes in alternative pathway
20% Familial 80% Sporadic
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Genetic complement disorders Genetic complement disorders Genetic complement disorders Genetic complement disorders in CMin CMin CMin CM----HUSHUSHUSHUS
• 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%)
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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• Infection
• HIV
• Cancer
• Organ Transplant
• Pregnancy
• Chemotherapy
• Immunosuppresion (cyclosporine, tacrolimus)
HEMOLYTIC UREMIC SYNDROME
Hemolytic Anemia
Thrombocytopenia
Kidney injury
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Eculizumab
• C5 Inhibitor
• Humanized monoclonal Ab
• Inhibits cleavage of C5 by C5 convertase
• Used for paroxysmal nocturnal haemoglobinuria
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Eculizumab for aHUS
Legendre et al. NEJM 2013; 368:2169-2181
• 53% normal platelet count by day 7; 86% by week 26
• All people who finished 26 weeks had normalization of platelets
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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
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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
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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.
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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
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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
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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