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
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 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
56
When you find proteinuriaa gram of prevention is worth
a kilogram of cure
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