Why Do Patients Develop the Nephrotic Syndrome? ... Nephrotic Syndrome 7 The nephrotic syndrome is a

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  • One Hundred and Eleventh Series – May 9-10, 2019

    Portland, Oregon

    Why Do Patients Develop the

    Nephrotic Syndrome?

    Ronald J. Falk, MD

    Nan and Hugh Cullman Eminent Professor of Medicine

    Chair, Department of Medicine

    University of North Carolina, Chapel Hill NC USA

  • Scanning Electron Microscopy of Human Glomerulus

    Glomerulus, SEM. Credit: David Gregory & Debbie Marshall. CC BY

  • Normal Glomerulus

  • Normal Glomerulus

  • Normal Glomerulus

  • Nephrotic Syndrome

    7

    The nephrotic syndrome is a clinical syndrome defined by:

    • Leak of protein from blood into urine proteinuria

    • Resulting in a decrease in serum proteins especially albumin

    • Resulting

    • hyperlipidemia,

    • edema,

    • and various other complications

  • Movement of Fluid Between Compartments

    8

    Fluid leaves plasma at arteriolar

    end of capillaries because

    outward force of hydrostatic

    pressure predominates.

    Fluid returns to plasma at

    venular ends of capillaries

    because inward force of colloid

    osmotic pressure predominates.

    Hydrostatic pressure within

    interstitial spaces forces fluid

    into lymph capillaries.

    Interstitial fluid is in equilibrium

    with transcellular and

    intracellular fluids.

    Hole’s Human Anatomy and Physiology 12th Ed. Water,

    Electrolyte and Acid-Base Balance. McGraw Hill, 1994

  • Relative Biopsy Frequency of Causes of Nephrosis n %

    Membranous glomerulopathy 847 28

    Focal segmental glomerulosclerosis 768 25

    Minimal change glomerulopathy 398 13

    Diabetic glomerulosclerosis 246 8

    Type I membranoproliferative glomerulonephritis 190 6

    Mesangioproliferative glomerulonephritis 145 5

    Amyloidosis 108 4

    C1q nephropathy 99 3

    Collapsing focal segmental glomerulosclerosis 86 3

    Glomerular tip lesion focal segmental glomerulosclerosis

    65 2

    Fibrillary glomerulonephritis 59 2

    Light chain deposition disease 26 1

    Type II membranoproliferative glomerulonephritis 14 0.5

    Preeclampsia/eclampsia 6 0.2

    Immunotactoid glomerulopathy 6 0.2

    Collagenofibrotic glomerulopathy 3 0.1

  • Age-adjusted Prevalence of Obesity and Diagnosed Diabetes

    Among US Adults

    Obesity (BMI ≥30 kg/m2)

    Diabetes

    1994

    1994

    2000

    2000

    No Data 26.0%

    No Data 9.0%

    CDC’s Division of Diabetes Translation. United States Surveillance System available at

    http://www.cdc.gov/diabetes/data

    2015

    2015

  • Number and Percentage of US Population with Diagnosed Diabetes (1958-2015)

    http://www.cdc.gov/diabetes/data

  • Diabetic Glomerulosclerosis

  • Diabetic Kidney Disease Variability in Clinical Course

    Micro-

    Albuminuria

    30-299ug/mg

    Overt

    Nephropathy

    ≥300ug/mg

    Increased or

    Normal GFR

    Normoalbuminuria

    Decreased

    GFR

  • Competing Risks in Diabetic Kidney Disease

    ADVANCE.JASN 2009; 20: 1813-1821.

  • RAS blockade of any variety is standard of care

    17

  • Central Role of Hyperglycemia in Development and Progression of Diabetic Nephropathy

    Magee C, Grieve DJ et al. Cardiovasc Drugs Therapy 2017; 31(506):579-92

  • SGLT2 Inhibition: Mechanisms of Protection

    Skrtic M, Cherney DZI. Curr Opin Nephrol Hypertens 2015; 24:96-103

  • Perkovic V et at for the CREDENCE Trial Investigators. N Engl J Med 2019 Apr 14. DOI:10.1056/NEJMoa1811744

  • Perkovic V et at for the CREDENCE Trial Investigators. N Engl J Med 2019 Apr 14. DOI:10.1056/NEJMoa1811744

    Effects on Albuminuria and Estimated GFR

  • Perkovic V et at for the CREDENCE Trial Investigators. N Engl J Med 2019 Apr 14. DOI:10.1056/NEJMoa1811744

    Primary Composite and Renal Outcomes

    Primary composite outcome of ESKD, doubling of serum

    creatinine level or renal cardiovascular death in the

    canagliflozin group and placebo group.

    Renal-specific composite outcome of ESKD, doubling of

    serum creatinine level or renal death.

  • Perkovic V et at for the CREDENCE Trial Investigators. N Engl J Med 2019 Apr 14. DOI:10.1056/NEJMoa1811744

    Subgroup Analysis According to eGFR at Screening and Albuminuria at Baseline

    SGLT2i decrease major kidney outcomes in type 2 diabetes patients with eGFR >30 mL/min/1.73m2 and UACR >300 µg/mg

  • Diabetes is a common cause of the Nephrotic Syndrome

    24

  • How Immune Complexes Deposit in the Kidney

  • Clinical Entities Associated with Membranous Nephropathy

    • Immunologic disorders

    • Neoplasms

    • Infections

    • Medications

    • Miscellaneous

  • Mechanisms of Subepithelial Immune Deposit Formation

    6/4/2019 30 Beck LH Jr., Salant DJ.J Clin Invest. 2014; 124(6):2307-14

  • Anti-PLA2R can be discovered by

    immunohistochemistry and analysis of serum.

    6/4/2019 31 Beck LH Jr., Salant DJ.J Clin Invest. 2014; 124(6):2307-14

  • 32

    Current Classification of MN

    Stahl RA et al. Expert Rev Clin Immunol 2018; Nov 15:1-11. doi: 10.1080/1744666X.2019.1548934. [Epub ahead of print]

  • ELISA-measured anti-PLA2R antibodies predict long- term outcome in idiopathic membranous nephropathy

    • a-PLA2R antibodies were present in 75% of IMN patients with

    active disease

    • a-PLA2R antibodies were higher than in patients in partial or

    complete remission

    • Survival analysis showed that PLA2R antibodies were

    significantly linked with outcome

    • High levels of PLA2R antibodies were linked with active

    disease and a higher risk of declining renal function

    Kanigicherla D et al. Kidney Int 2013; 83:940-8

  • 6/4/2019 34Tomas NM et al. N Engl J Med 2014; 371:2277-87

  • Membranous Nephropathy Therapies

    Ponticelli protocol

    Cyclosporine

    Tacrolimus

    Mycophenolate mofetil

    Rituximab

    ACTH

    Prednisone alone

  • Rituximab in Idiopathic

    Membranous Nephropathy

    Ruggenenti P et al. J Am Soc Nephrol 2012;23(12):1416-25

  • Rituximab in Idiopathic Membranous Nephropathy

    Kaplan–Meier curves for the

    percentages of participants with

    IMN achieving complete remission,

    partial remission, or both.

    Ruggenenti P et al. J Am Soc Nephrol 2012;23(12):1416-25

  • Autoimmune conditions cause of the Nephrotic Syndrome

    38

  • Infections cause the nephrotic syndrome and prevention is the key

  • Nat Rev Nephrol 2015; 11:150-60

    Pathogenesis of HIVAN

  • Int J STD AIDS 2008; 19(11):787-90

    HIVAN Involves all Renal Compartments

    • Glomerular

    o Collapsing glomerulopathy “pseudocrescents”

    • Tubular

    o Microcystic dilatation

    o Atrophied tubular epithelium

    • Immunofluorescence

    o Nonspecific

    • Electron microscopy

    o Podocytopathy

    o Tubuloreticular inclusions

  • Nobakht E. Nat Rev Nephrol 2016; 12(5):291-300

    HIV-Associated Immune Complex Disease

    • Lupus-like GN

    • IgA nephropathy

    • Infection-related GN

    • Membranous nephropathy

    • MPGN cryoglobulinemia

    • Mesangioproliferative GN

    • Immunotactoid/fibrillary GN

  • We rarely see HIV as a cause of the Nephrotic Syndrome in 2019. Kidneys may be damaged by HIV drugs but not from

    the virus

    43

  • Model of Human Hepatitis C Virus

    6/4/2019 44

    © LE Henderson

    © LE Henderson

  • Schematic Depiction of Cryoglobulins in HCV- Associated Mixed Cryoglobulinemia

    6/4/2019

    45 Gupta A, Quigg RJ. Adv Chronic Kid Dis 2015; 22(5):343-51

  • subendothelial immune complex dense deposits

    subendothelial mesangial interposition

    lumen lumen

    Membranoproliferative Glomerulonephritis (I)

  • With anti viral drugs Hepatitis C causing the the Nephrotic Syndrome is remarkably on the decline

    47

  • FSGS is the Most Common Cause of GN Related ESRD in US in Black and White Patients

    Kitiyakara C et al. Am J Kidney Dis 2004; 44(5):815-25

    White

    Black

    Other

  • Perihilar Tip Lesion Collapsing Cellular

  • Causes of FSGS Type of Disease Cause

    Primary (idiopathic) form

    Specific cause unknown; mediated by circulating permeability factors

    Secondary forms

    Familial or genetic Mutations in specific podocyte genes

    Virus-associated Human immunodeficiency virus type 1, parvovirus B19, simian virus 40, cytomegalovirus, Epstein-Barr virus

    Drug-induced Heroin; interferon alfa, beta, and gamma;