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Nephrology Update Oklahoma ACP Annual Meeting

Charles J. Foulks, M.D., FACP Professor of Medicine C.S. Lewis, Jr., M.D. Chairman Department of Medicine School of Community Medicine OU-Tulsa. Nephrology Update Oklahoma ACP Annual Meeting. Atherosclerotic RAS. Unselected population: 4-7% of autopsies Only 73% had a diagnosis of HTN

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Nephrology Update Oklahoma ACP Annual Meeting

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  1. Charles J. Foulks, M.D., FACP Professor of Medicine C.S. Lewis, Jr., M.D. Chairman Department of Medicine School of Community Medicine OU-Tulsa Nephrology UpdateOklahoma ACP Annual Meeting

  2. Atherosclerotic RAS • Unselected population: 4-7% of autopsies • Only 73% had a diagnosis of HTN • Population based cohort, n=870 • Duplex doppler US, >60% obstruction: 6.4% with 53% hypertensive • High Risk Populations • Medicare claims data: 5.5% of claims with dx of CKD • Retrospective, n=64, renal angio for ?CKD, >50% obstruction in 48% • “Drive-by renal angio”: >50% in 11-28% of patients • >75% in 5-12% of patients • Autopsy of MI patients: 12%. • Peripheral Arterial Disease: 30-50% with abdominal/peripheral angio

  3. Atherosclerotic RAS • Natural history and progression • 1984 study: worsening in 44%, occlusion in 16% over 4 y. • 1998: 3 year progression in 11%. • Retrospective analysis of patients on statins with serial angios: 6% with progression over 3 years with statins, 30% not on statins. • Diagnosis of ARAS from claims data: • IHD 30% PAD 26% CHF 20% CVA 18% Death 16%. • 2 randomized trials over 2-5 years in ARAS patients: Risk of composite vascular endpoint 10-18%/year Annual mortality 6-8%

  4. Non-Invasive Testing Average of test characteristics for noninvasive diagnosis of atherosclerotic renal artery stenosis Test No. of studies Sensitivity Specificity Positive predictive value False-positive r CTA 1 8 92% (64-100%) 90% (56-99%) 88% (68-98%) 10% (1-44%) MRA 2 10 88% (62-100%) 80% (67-98%) 76% (49-93%) 20% (2-33%) RDS 3 21 85% (50-95%) 92% (73-97%) 84% (29-94%) 8% (3-27%) 1 Best combination of sensitivity, specificity and acceptable false-positive rate, >50% 2 Risk of nephrogenicfibrosingdermopathy with CKD patient. 3 Very operator dependent and best results with Peak Systolic Velocity

  5. Therapy • Generally Recommended Medical Therapy • Not defined • Aggressive BP control, multiple agents • Statins, consider fixed dose equivalent to pravastatin 40 mg/d • ASA?

  6. Invasive Therapy • Percutaneous Angioplasty with or without stent • PCA with stent: 98% technical success • 17% restenosis 6-29 months of F/U • PCA alone: 77% technical success • 26% restenosis rate • NOT FOR OSTIAL LESIONS • High complication rate • High re-stenosis rate

  7. Surgical Revascularization • Superior patency at 5 years: 82-94% • Mortality 3.1% higher than PCA at 30 d • Patients younger, less ID, and less DM in surgical series compared to PCA • Operative mortality 2-6% • MI/CVA as high as 9%

  8. Surgical vs. Medical Therapy • 52 patients, >75% stenosis <1 renal arteries, CKD (creat 1.5-4) and controlled HTN • Outcomes surgical vs. medical: • >6 year median f/u • No difference in primary end points of • MI, CVA, death, worsening GFR, poorly controlled BP • N=50, either PCA or surgery as determined by doctor. • Surgical mortality 25%, medical 18% at 4 yrs, NS • Differed at baseline, PCA patients older and more with DM, bias surgical group to lower morbidity mortality.

  9. Randomized Medical vs. Endovascular • EMMA, EssaiMulticentrique Medicaments v.sAngioplastie • N=49; HTN; GFR>50mL/min, unilateral ARAS>75% or >60% with confirmatory functional test • Randomized, intention to treat analysis • Primary end point: ambulatory BP at 6 months • Secondary end points: number of meds, complications • Outcomes: no difference in final BP, greater decrease in BP in PCA group (higher baseline BP), fewer meds. • 7/26 went from medical to PCA: re-analysis • Significantreduction in diastolic BP with PCA • Problems: excluded high risk, few stents, high cross-over, few got diastolic<95 mm Hg, median 2 anti-HTN meds

  10. Randomized Medical vs. Endovascular • Newcastle RAS Collaborative • N=50, uni- or bilateral RAS>50% by DSA and “treatment resistant HTN” • Randomized to medical therapy vs. PCA without stent • Bilateral disease: significantly greater BP decrease with PCA at final f/u, NS at 6 mos. • No significant difference in GFR, MI, CVA, death, dialysis • Significant complications with PCA: • Hematoma 20%; AKI dialysis 5%, stroke 5%

  11. Randomized Medical vs. Endovascular • Newcastle RAS • No stents • ACEI not allowed • < 3 anti-HTN meds, not aggressive • Is >75% stenosis a break point?

  12. Randomized Medical vs. Endovascular • Dutch RAS Intervention Cooperative Study • N=106, >50% stenosis, treatment resistant HTN, creatinine<2.3, and affected kidney>8 cm length • Randomized to MT or PCA without stent • Target diastolic<95 • 0-3 months, no crossover • 3-12 months crossover allowed if >3 drugs or worsening creatinine. PCA could be repeated

  13. Randomized Medical vs. Endovascular • DRASTIC • No difference mean BP at 3 and 12 months • PCA group mean 1.9 drugs, MT 2.4 drugs, p=0.002 • PCA creatinine better at 3 mos, NS at 12 months

  14. Randomized Medical vs. Endovascular • Stent Placement RAS: STAR • N=14o, optimal MT vs. PCA with optimal MT • Mean GFR 46, stable BP, >50% stenosis, 1 or 2 art. • MT could crossover if: • Malignant HTN • Pulmonary Edema • Mean BP>160/90 on maximal doses 6 meds. • End point: >20% decrease creatinine clearance x 2

  15. Randomized Medical vs. Endovascular • STAR results: • Intention to treat analysis: MT=PCA • High crossover: no difference • No difference in creatinine clearance, CV morbidity or all-cause mortality • PCA: • 3 died from procedure • 17 groin hematoma • 1 ESRD from MCES

  16. Randomized Medical vs. Endovascular • Angioplasty and Stenting for RAS, ASTRAL • N=806; eligible if uncontrolled or refractory HTN or unexplained loss of renal function • Mean GFR 40, mean BP 150/76, mean RAS 76% • All optimal MT with BP meds, ASA, statins • PCA: 95% got stents • Endpoint: slope of 1/Creatinine(s)/time • Secondary: AKI, ESRD, transplantation, nephrectomy, death from renal failure, CV morbidity or mortality, CABG or Coronary PCA, PAD intervention or amputation, all-cause mortality • More than double power analysis estimate to detect a 20% difference

  17. Randomized Medical vs. Endovascular • ASTRAL Results • 0.00006 L/micromole/year difference favoring PCA, P=0.06 • Mortality: 26% over 5 years • 17% randomized to PCA did not and crossed to MT • 6% randomized to MT crossed to PCA • Intention-to-treat and as-treated no difference on primary or secondary end points • 24h post-PCA: 5% serious complications: MI, MCES, pulmonary edema, femoral aneurysm, renal arterial occlusion or emboli.

  18. Conclusions • 1. Non-invasive DX: • False positive rate: 8-20% • Patients with CKD: risks with CTA, MRA • Invasive angiograpy carries more risk • PCA with or without stent offers NO benefit over MT (aggressive BP control (with ACEI)), ASA, statins (fixed vs. tailored dose) • PCA associated with significant mortality and morbidity risks. • Await CORAl trial: “drive-by” trial • Don’t look for RAS

  19. Membranous Nephropathy • 2d leading cause of NS • Most common age 30-60, men=2x women • 70% present as NS; 50% with hematuria • Thickened GBM around and between immune complex deposits (ICD) underneath podocytes • Methenamine silver “spikes” of GBM between ICD • Granular IgG and C3 glomerular loop deposits • EM electron dense deposits in sub-epithelial portion of GBM

  20. Courtesy University of North Carolina

  21. http://www.med.niigata-u.ac.jp/npa/Lectures/MN.htm

  22. http://www.ndt-educational.org/ferrariomg.asp

  23. http://www.ndt-educational.org/ferrariomg.asp

  24. Membranous Nephropathy • Idiopathic vs. secondary • Secondary: • Autoimmune: SLE, RA, aiThyroid, Sjogren • Infection: Hep B, Hep C, syphilis, malaria, schistosomiasis • Alloimmunization: feto-maternal, GVHD, renal allograft • Drugs/toxins: gold salts, penicillamine, NSAID, mercury, captopril, heavy metals • Malignancy: solid tumors, over age 40

  25. Membranous Nephropathy • Pathogenesis (Heymann nephritis model) • Proximal tubular brush border antigen • Passive or active immunization • Ag is megalin, member of LDL receptor family. • Ab-Ag leads to immune complex deposition • Megalin is on base of podocytes: sub-epithelial space • Complement activated • Since complement activated locally AND on outer portion of GBM: No recruitment of inflammatory cells. • Instead C5b-C9 form membrane attack complex (MAC), inserts into podocyte cell membrane

  26. Membranous Nephropathy • Pathogenesis • Leads to maladaptive cell signaling with podocyte injury but not death • Leads to podocyte fusion and proteinuria • The MAC is shed from the plasma membrane into the GBM. • Thickening occurs over time as MAC shed, incorporated into the GBM.

  27. Membranous Nephropathy • Human glomerulus: No megalin • Alternative: • Neutral endopeptidase expressed on podocytes • Transplacental passage of anti-NEP to infants: MN • Adults with MN: low levels of anti-NEP found • Phospholipase A2 receptor: found on podocytes • Involved in cellular senescence • Major target in MN • Circulating anti-PLA2R found • Levels correlate with disease activity • Not confirmed in animal model

  28. Membranous Nephropathy • PLA2R ab is IgG4 • Weakly activates complement • Co-localizes with PLA2R within IC in idiopathic MN not secondary MN • Other IgG subclasses may be involved • IgG4 may explain the MN seen in SLE • SLE is inflammatory when IgG4 not dominant

  29. Membranous Nephropathy • Other secondary MN • IC may be formed of Ag-Ab complex from infection or tumor, anti-tumor Ab-Ag complexes found. • Initiator or innocent bystander?

  30. Membranous Nephropathy • Natural History • Variable, fluctuating disease course • Impossible to predict • 1/3, 1/3, 1/3 rule. Maybe yes, maybe no. • Spontaneous remission • Young women • Non-NS proteinuria • Schieppati et al: • >33% no NS • partial remission in 65% • 5-year renal survival 88%

  31. Membranous Nephropathy • Pre-ACEI Era • 50% untreated NS lost renal function over 10 yr. • Develop of ESRD takes at least 5 yr. • Definite loss of GFR takes 2.5 yr. • Median time to partial remission: 11-23 months • Mediat time to complete remission: 16-40 months

  32. Membranous Nephropathy • Risk factors for progression: • Older age • Male • NS, especially > 8g/d • Impaired GFR at presentation • Correlates with amount of tubulointerstitialdz • Non-Asian • Renal survival • Complete remission: 100% at 10 yr. • Partial remission: 90% at 10 yr. • No remission: 45% at 10 yr.

  33. Membranous Nephropathy • Treatment • Prevent loss of GFR • Ameliorate complications • HTN, edema • Hyperlipidemia • Thrombophilia

  34. Membranous Nephropathy • General • All: ACEI or ARB, ACEI preferred • Statin • Diuretic, Na+ restriction • If NS after 6 months, or abnormal GFR or worsening GFR: • Immunosuppressive therapy

  35. Membranous Nephropathy • Immunosuppressive Therapy • Alkylating agents: • Given with corticosteroids • Cyclophosphamide or chlorambucil (RCT) • 30-40% complete remission • 30-40% partial remission • 10% progress • Relapse in 25-30 by 5 yr. responds to second course

  36. Membranous Nephropathy • 6 months of alternating corticosteroids and chlorambucil (Ponticelli: Jha) • 88% remission rate (47% for control) • Cyclophosphamide same results, less complications • Calcineurin inhibitors (CNI) • CSA (CSA+steroids x 6 mos. Taper 4 weeks • N=51 with steroid-resistant MN NS • 75% complete or partial remission (22% placebo)

  37. Membranous Nephropathy • Cattran et al: • Similar study: CSA alone vs. CSA/Steroids x 12 mos: • 80% remission both groups • Adjuntive steroid group: lower relapse rate • Tacrolimus • Similar outcomes but more relapse • Taper more slowly for Tacrolimus and CSA

  38. Membranous Nephropathy • Rituximab • Small studies • Equivalent remission to alkylating agents • No long term data • Rituximab could be substitued for long-term CNI • Mycophenolate • Small short term trials. • +/- results: • Myco/steroids inferior to alkylating agent/steroids • ACTH • Short-term small studies • Seems to work as well as established treatments • ACTH used not available in US

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