Five papers that influenced my practice. Stephen Marks Consultant Paediatric Nephrologist

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1 Five papers that influenced my practice Stephen Marks Consultant Paediatric Nephrologist Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK. Nephrology for the General Paediatrician, Manchester Friday 21 June 2013

2 Introduction Basic scientific and laboratory research Translational research Aetiopathogenesis, investigations and management of renal disorders Influenced practice general paediatricians paediatric nephrologists

3 Antenatal hydronephrosis Urinary tract infections Nephrotic syndrome Renal genetics Prognosis and progression of renal disease Hypertension and obesity-related hypertension Renal replacement therapy Imaging in paediatric nephrology

4 First paper

5 Revised, evidence-based guidelines regarding diagnosis and management of initial urinary tract infections in febrile infants and young children 2m to 2y from AAP subcommittee on UTI

6 Why do we not need to know about VUR in all patients? 1. The number of infants with VUR might be higher then we have believed

7 VUR in 347 kids UTI?UTI Not

8 Occurrence of VUR in 1185 children Hannula et al (2010) Ped Nephrol;25:1463

9 Why do we not need to know about VUR in all patients? 1. The number of infants with VUR might be higher then we have believed 2. VUR has a high tendency to resolve

10 Natural history of VUR

11 Why do we not need to know about VUR in all patients? 1. The number of infants with VUR might be higher then we have believed 2. VUR has a high tendency to resolve 3. Surgical treatment of VUR does not help

12 Importance of VUR for new scarring Olbing et al (1992)J Urol;148:1653-6

13 Medical vs surgical 5-year follow-up Smellie J et al (2001) Lancet;357:

14 Why do we not need to know about VUR in all patients? 1. The number of infants with VUR might be higher then we have believed 2. VUR has a high tendency to resolve 3. Surgical treatment of VUR does not help 4. Prophylactic antibiotics do not help - few good studies until recently - NICE concluded that prophylaxis should not be routinely recommended - AAP concluded should not be used

15 Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age without VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

16 Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade I VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

17 Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade II VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

18 Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade III VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

19 Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade IV VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

20 Estimate of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children 2 to 24 months of age with grade V VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

21 Combined estimates of the effect of antimicrobial prophylaxis on prevention of pyelonephritis in children with VUR, from random-effects modeling. Pediatrics 2011;128:e749-e by American Academy of Pediatrics

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23 Background Childhood-onset SLE variable clinical manifestations unpredictable natural history Epidemiological studies progressive clinical course of SLE significant morbidity and mortality rates 10-17% of proven cases present in childhood with more severe organ involvement than adults

24 Features Renal disease is a major determinant of the long-term outcome of SLE influence management with immunosuppressive agents 66% of childhood SLE have nephritis Haematological and renal disease more severe in patients with childhoodonset (compared to adult-onset) SLE

25 Introduction Conventional therapies steroid-sparing agents AZATHIOPRINE INTRAVENOUS CYCLOPHOSPHAMIDE MMF OTHER IMMUNOSUPPRESSION Different management strategies should be considered in problematic patients

26 Autoantibodies and B cells in SLE ANA and anti-dsdna important diagnostic / prognostic markers related to disease severity / renal damage Foster MH et al (1999):Semin Nephrol 19(2): Adults and children with active disease have profound B cell abnormalities Tangye SG et al (1998) J Exp Med 188: Odendahl M et al (2003) Ann Rheum Dis 62: 851-8

27 Rituximab Monoclonal antibody binds to CD20 Ag located on pre-b and mature B lymphocytes mediates B-cell lysis clinical use prophylaxis and treatment of lymphoma and EBVdriven LPD autoimmune diseases dose of 375mg/m 2 as slow iv infusion in PTLD once weekly for 4 weeks

28 Reasons for treatment Multi-systemic presentation of SLE with life or organ-threatening disease without response to iv methylprednisolone and/or plasma exchange no time to wait for iv cyclophosphamide Active disease after previous treatment with iv cyclophosphamide severe and continuous symptoms eg. ACTIVE SKIN / KIDNEY, POOR GROWTH

29 Six adult female patients with active SLE resistant to standard immunosuppressive therapy treated on an open-label basis during a 2-week period, each patient received two 500mg infusions of rituximab, two 750mg infusions of cyclophosphamide, and high-dose oral corticosteroids

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31 All patients improve

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39 Treatment protocol Day 1 and 15 premedicate with chlorphenamine and paracetamol one hour prior to rituximab infusion in addition a dose of iv methylprednisolone 100mg is given immediately prior to rituximab infusion Day 2 and 16 cyclophosphamide infusion 750mg (500mg if less than 50kg)

40 Rituximab infusion Dilute required dose with 0.9% NaCl or 5% dextrose to a final concentration of 1-4mg/ml Initial infusion rate is 25mg/hour can be increased by increments of 25mg/h q30m maximum of 200mg/h as tolerated Doctor should be present on the ward during the administration of rituximab Resuscitation facilities should be available

41 Steroid doses Post-rituximab therapy oral prednisolone is given for 3 days after the infusion at doses of 30mg, 20mg, 10mg (i.e. days 2, 3 & 4 & days 16, 17 & 18) and then continue with the patient s previous maintenance prednisolone dose

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46 18-month old boy ahus developed 8 days after birth 3 further clinical presentations (3, 9 and 11 months of age); last treated with PE weekly for 20 weeks Normal ADAMTS13 activity, complement C2 - C9, factor H, factor I No mutation of factor H, factor I, and MCP genes Presentation at 18 months of age persistent progressive TMA; severe thrombocytopenia and worsening renal function, raised LDH despite 32 consecutive days PE Eculizumab treatment ongoing for 2.5+ years sustained normalisation haematological parameters sustained stabilisation and near normalisation of renal function including proteinuria

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48 Typical and atypical forms of HUS Typical HUS most common form (90% of cases) triggered by shiga-toxin- (Stx-) producing E. coli (0157:H7) most often associated with diarrheal prodrome renal failure in 55-70% of cases (mostly recovers) Atypical HUS (ahus) represents ~ 10% of cases but poorer outcomes heterogenous group without evidence of Stx can be associated with triggers - infections, viruses, drugs, malignancies, pregnancy, transplantation Noris, J Am Soc Nephrol, 2005

49 What is ahus? ahus is rare, progressive, life-threatening disease characterised by chronic uncontrolled complement activation identifiable complement gene mutation in 60-70% Thrombotic microangiopathy (TMA) microvasculature thrombosis, inflammation and occlusion with renal and systemic manifestations ongoing subclinical disease Clinical triad of: thrombocytopenia (consumptive) microangiopathic haemolytic anaemia renal impairment (± systemic / CNS symptoms) Noris Stahl, Blood, 2008

50 ahus demographics Incidence approx 2/million population prevalence estimates Age at disease onset 59% 18 years of age 41% >18 years of age oldest presentation 83 years Gender 51% male 49% female Noris et al. Semin Nephrol 2010 Jul;30:

51 ahus outcomes Registry of 273 patients at 1 year after diagnosis up to 60% patients die or ESRD at 3 years, up to 70% die or at ESKD All patients at 1 year after diagnosis ~ 40% die or at ESKD at 3 years 56% die or at ESKD Systemic symptoms common Long-term outcomes not well documented Noris, J Am Soc Nephrol, 2010

52 Systemic clinical ahus manifestations Case series report ahus systemic manifestations in up to 48% patients CNS - coma, stroke, seizure, fluctuating focal signs Cardiovascular - cardiomyopathy, diffuse arterial stenosis, atherosclerosis Gastrointestinal - pancreatitis, colitis, hepatic impairment Other cases - pulmonary hemorrhage, pulmonary oedema, ophthalmological ischaemia 1. Noris M, Remuzzi G. N Engl J Med. 2009;361: Noris M, et al. Clin J Am Soc Nephrol. 2010;5: Neuhaus TJ, Arch Dis Child 1997; 76: Hirt-Minkowski P, Nephron Clin Pract 2010;114:c219 c Lee B, Pediatric Research 2009; 66:

53 Current ahus management Plasmapheresis / exchange / infusion no prospective controlled trials Antihypertensives Corticosteroids IVIg Anticoagulation (as applicable) Immunosuppressive therapy Dialysis Nephrectomy Renal transplantation up to 90% recurrence Liver-kidney transplantation

54 Eculizumab blocks terminal complement activation D + B Proximal Weak Anaphylatoxin C3a C3 C3b C5-convertase C3bi C3bBb CR3 Ba C3b Microbial Opsonization Immune Complex Clearance Terminal C5a C5 C5b C6 C7 C8 C9 Eculizumab binds with high affinity to C5 Proximal functions of complement remain intact Terminal complement activity is blocked C5b-9 Terminal Complement Complex

55 Tolerability of eculizumab Well tolerated in PNH but common side-effects headache nausea nasopharyngitis No HAHA Meningococcal infection eculizumab increases susceptibility to meningococal infection all patients must be vaccinated 14 days prior to treatment patient / parent education

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57 What is the gold standard therapy for a child with end-stage kidney disease?

58 What is the gold standard therapy for a child with end-stage kidney disease? Pre-emptive living related renal transplantation

59 End-stage renal failure management Renal transplant ESRF management Peritoneal dialysis Haemo -dialysis

60 End-stage renal failure management Renal transplant ESRF management HOSPITAL or HOME Peritoneal dialysis Haemo -dialysis

61 End-stage renal failure management Renal transplant ESRF management HOSPITAL or HOME Peritoneal dialysis Haemo -dialysis HOSPITAL or HOME

62 End-stage renal failure management PRE-EMPTIVE vs ON DIALYSIS Renal transplant ESRF management DECEASED DONOR - en bloc; DBD and DCD kidneys LIVING RELATED / UNRELATED - altruistic - antibody removal - paired / pooled exchange HOSPITAL or HOME Peritoneal dialysis Haemo -dialysis HOSPITAL or HOME

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64 Nocturnal haemodialysis (NHD) an intensive dialysis modality 6-8 HOURS/SESSION, 3-7 SESSIONS/WEEK associated with a significant improvement of clinical and biochemical parameters compared to conventional dialysis

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66 Nocturnal haemodialysis Two regional adult NHD programmes USRDS data matched cohort study comparing survival between NHD and deceased and living donor kidney transplantation (DTX and LTX) by matching NHD patients to transplant recipients in a 1:3:3 ratio 177 NHD patients matched to 1062 DTX and LTX recipients (1239 patients) followed for a maximum of 12.4y proportion of deaths among NHD, DTX and LTX patients was 14.7%, 14.3% and 8.5%, respectively (p = 0.006) no difference in adjusted survival between NHD and DTX (HR 0.87, 95% CI ; NHD reference group), while LTX survival was better (HR 0.51, 95% CI )

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69 GOSH patient experience Feels empowered and in control Recovery time minutes rather than hours Urine output did not change in the first year then gradual decline No real diet or fluid restrictions More energy Reduced phosphate binders on nocturnal increased/same for evening dialysis as appetite improved

70 Home haemodialysis Home HD is an option for children Increased dialysis time improve uraemic toxins clearance and patient well-being Possibility that nocturnal offers additional advantages Clear requirement for further research specifically in children

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72 Number of UK deceased donor kidney Tx April March 2010 Adults Paediatrics Number Year

73 Number of UK living donor kidney Tx 1 April March 2010 Adults Paediatrics Number Year

74 Number of UK deceased & living RTx 1 April March 2010 Adults Paediatrics Number Year

75 First living donor kidney transplants Adult recipients Paediatric recipients % Graft survival % Graft survival Year of transplant (Number at risk on day 0) 30 Year of transplant (Number at risk on day 0) (448) (745) (1000) (2308) (64) (85) (119) (199) Years since transplant Years since transplant

76 Graft survival: First paediatric kidney only transplants in the UK, % Graft survival Cadaveric/Living 10 Cadaveric living Years since transplant

77 UK LKDT activity

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80 ABOi RTx single centre paediatric & adult RTR from 2001 short-term results comparable with those of ABO-compatible (ABOc) living donor kidney transplantation 20 ABOi RTx > 12m (mean 3y) follow-up included all adult crossmatch negative ABOi kidney recipients (n=15) were compared with an adult ABOc living donor recipient control group (n=30), and all paediatric ABOi kidney recipients (<16 years of age) (n=5) were compared with a group of pediatric ABOc kidney recipients (n=18) No significant difference in patient survival, nor in graft survival or in the incidence of acute rejection in any of the groups

81 ABOi renal transplantation Adult RTR mean GFR equivalent at all time points (79-83 ml/min), as was Deltas-creatinine For paediatric RTR, Deltas-creatinine was similar but GFR lower among the ABOi kidney recipients significant reduction (p < ) without rebound in A/B antibody titres after transplantation (median IgG 1:2 and median IgM 1:1>1 year posttransplant) compared with pretransplant levels (median IgG 1:32 and IgM 1:16) ABOi RTx using Ag-specific immunoadsorption and rituximab is equivalent to ABOc living donor kidney transplantation ABOi transplantation after this protocol does not have a negative impact on long-term graft function

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84 Antibody incompatibility ABOi transplantation transplants where the recipient has a blood group incompatibility with the donor eg. A into O, B into O, A into B, B into A eg. AB into A, AB into B, AB into O HLAi transplantation positive crossmatch positive baseline flow cytometric crossmatch or positive complement dependent cytotoxic crossmatch transplants where the recipient has donor specific antibody, but a negative crossmatch, do not fall into this category

85 Options for patients An antibody compatible living donor is preferred so, 1. Remain on the deceased donor list and avoid a living donor transplant 2. Enter KPD (Kidney Paired Donation) scheme - the National Living Donor Kidney Sharing Scheme (NLDKSS) in the UK 3. Undergo a direct antibody incompatible transplant Recommendations: 1. Ensure no alternative antibody compatible living donor is available 2. The recipient should be counselled about all available options

86 ABO and HLA incompatibility 24% of potential LRD are ABOi (GOSH) 14% of waiting list patients are very highly sensitised PRA / crf > 80%; UNOS Expertise in adult and paediatric units is highly specialised clinical experience, protocols, funding Recommendations: 1. centres not performing ABOi/HLAi transplantation should be formally linked to centres which are 2. all recipients with a blood group incompatible donor should be offered the option of referral to a centre performing ABOi/HLAi transplantation

87 Long term results of ABOi RTx Percent allograft survival Years Tanabe et al (1998); Transplantation

88 ABO incompatibility Excellent results from ABOi transplantation patient and renal allograft survival and AMR outcomes similar to compatible transplants Anti-A and anti-b titres vary significantly typically titres of 1 in 8 are used as a threshold to allow transplantation to proceed important to check baseline antibody titres, since these may be low enough to allow transplantation with little or no additional immunosuppressive therapy Recommendation 1. all patients with a blood group incompatible donor should have baseline haemagglutinin titres measured

89 ABO incompatible Tx protocol T-1m: Intravenous rituximab T - 1w: Oral mycophenolate mofetil Oral tacrolimus +/- PX / DFPP / IA D0: D4: Intravenous methylprednisolone Intravenous basiliximab Intravenous basiliximab

90 Tacrolimus/MMF/prednisolone Rituximab 375 mg/kg IVIG (0.5 g/kg) Anti-A1 IgG titre 1:128 1:64 1:32 1:16 1:8 1:4 1:2 1:1 <1:1 Glycosorb Tx Time (days) Am J Transplant. (2005) 5:

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92 NLDKSS;UK A INTO O 15% B INTO A 36% >85% ABOi match within 4 runs NOT 1 IN 2056 BUT FEW DATA ABOVE 1 IN 256 IN KIDS? URGENCY

93 What are my chances of obtaining a kidney by national Recipient blood group sharing schemes? Recipient blood group O A B AB Donor blood group O 15/114 (13%) 21/42 (50%) 6/22 (27%) 0/1 (0%) A 23/152 (15%) 12/54 (22%) 11/33 (33%) 0/3 (0%) B 6/47 (13%) 10/28 (36%) 0/18 (0%) 1/3 (33%) AB 0/7 (0%) 0/4 (0%) 0/6 (0%) 0/1 (0%)

94 40% Oag anti A Ab anti B Ab 45% 10% Aag (A 1 ~36%, A 2 ~9%) Bag anti A ab anti B Ab AagBag no Ab 5% The likelihood that two unrelated individuals are: - identical is 37.5% - compatible is 26.75% - incompatible is 35.75%

95 No match for kidney paired donation Recommendation: 1. if an ABOi pair are entered into the KPD, the decision should be reviewed if no match has been obtained after 3 or 4 matching runs, and consideration given to direct ABOi transplantation 2. Recipients with low baseline ABO titres can proceed directly to ABOi transplantation - titres of 1 in under 512, 256 or 128

96 Take home messages The future is bright biomarkers Further research RCT in paediatric nephrology RCT in paediatric renal transplantation

97 Any questions?