why do patients develop the nephrotic syndrome?...nephrotic syndrome 7 the nephrotic syndrome is a...

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 Nephrosisn %

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 <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0%

No Data <4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% >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 DiseaseVariability in Clinical Course

Micro-

Albuminuria

30-299ug/mg

Overt

Nephropathy

≥300ug/mg

Increased or

Normal GFR

Normoalbuminuria

Decreased

GFR

<60ml/min/1.73m2

Diabetes

onset

Time

ESRD

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

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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 30Beck 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 31Beck 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

6/4/201944

© LE Henderson

© LE Henderson

Schematic Depiction of Cryoglobulins in HCV-Associated Mixed Cryoglobulinemia

6/4/2019

45Gupta 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 FSGSType 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; lithium; pamidronate; sirolimus; calcineurin inhibitor nephrotoxicity; anabolic steroids

Adaptive Conditions with reduced renal mass: oligomeganephronia, very low birth weight, unilateral renal agenesis, renal dysplasia, reflux nephropathy, sequela to cortical necrosis, surgical renal ablation, renal allograft, aging kidney, any advanced renal disease with reduced functioning nephrons

Conditions with initially normal renal mass: systemic hypertension, acute or chronic vaso-occlusive processes (atheroembolization, thrombotic microangiography, renal-artery stenosis), elevated body-mass index (obesity, increased lean body mass [e.g., bodybuilding]), cyanotic congenital heart disease, sickle cell anemia

D’Agati VD, Kaskel RJ, Falk RJ N Engl J Med 2011; 365:2398-411

Normal Glomerulus and Glomerular Filtration Barrier

D’Agati VD, Kaskel FJ, Falk RJ. N Engl J Med 2011; 365:2398-411

6/4/2019 52

Genetics of Nephrotic Syndrome and FSGS

Population

Risk allele

MyH9

ApoL1

Familial

Causative

NPHS1

NPHS2

TRPC6

ACTN4

INF2

PLCE1

CD2AP

Sporadic

Causative?

Disease Modifying?

NPHS2

NPHS1

OBESITY is a major cause of perihilar FSGS

When you find proteinuria

Think

Diabetes

Autoimmunity

Infection

Drugs

hypoxemia

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When you find proteinuriaa gram of prevention is worth

a kilogram of cure

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