5/10/22

INFLAMMATORY KIDNEY DISEASES OUTLINE

ì  SESSION ONE:
ì  INTRODUCTION TO GLOMERULAR DISEASE
ì  MECHANISMS OF RENAL INJURY
ì  GLOMERULAR SYNDROMES
Dr. César Toral
ì  SESSION TWO:
Professor of Medicine
ì  NEPHRITIC SYNDROME
Universidad del Azuay ì  NEPHROTIC SYNDROME
Cuenca - Ecuador

INTRODUCTION TO GLOMERULAR
DISEASES
Introduction

ì  GLOMERULUS
Also called Malpiphian TuH

-One million nephrons

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Introduction Glomerular Disease

ì  GLOMERULAR
ì  Is the clinical
FILTRATION
BARRIER consequence of the
increased
Endothelial Cells permeability of the
Glomerular basement glomerular basement
membrane membrane
Podocyte cell
processes – FiltraTon
slits

Gilbert S. et al NKF Primer of Kidney Diseases 2018 Kitching R. et al Glomerular Disease CJASN 2016

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MECHANISMS OF RENAL INJURY Glomerular Injury

ì  Immune mediated
ì  Metabolic mediated
ì  Hemodynamic mediated

Immunological: Histological: PROLIFERATIVE DISEASES

Immune deposits Glomerular cells proliferaTon
Ig – Complement Leukocytes
Extracellular Matrix Expansion
Cell death
Necrosis
GLOMERULAR SCLEROSIS Scarring

“Cellular cross-talk” MESANGIAL CELL ACTIVATION

(autocrine – paracrine loop)
“AcTvated Cells”
Hypertrophy and ProliferaFon
GLOMERULI

Mesangial cells Excessive matrix producFon
GLOMERLAR BASEMENT
Podocyte cells (upregulaFon of PDGF-B)
MEMBRANE DAMAGE
Endothelial cells (FILTRATION BARRIER) Chemokines and Cytokines
ProducFon of oxygen species
Leukocytes


Mesangial Matrix Expansion

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MESANGIAL CELL ACTIVATION MESANGIAL MATRIX EXPANSION

Pe: IgA Nephropathy IntersFFal fibrosis
Immunologic mediated injury:


Glomerular Sclerosis
Pe: Hyperglicemia.

Metabolic and hemodynamic Advanced glycaFon end
products (AGEs) Oxidized
mediated injury: free faPy acids, Decrease GFR
Angiotensin II

GLOMERULAR ENDOTHELIAL CELLS GLOMERULAR ENDOTHELIAL CELLS DAMAGE

Selected Permeability and filtraTon
fenestraTon (50% of the surface area)
60-70nm diameter Proteoglycans with negaFve
charge PROTEINURIA
Covered with GLYCOCALYX:
(regulates permeability) Glycosaminoglycan (GAG)

TUBULAR INTERSTITIAL FIBROSIS
ì  RPGN, ANCA vaculiTs, anT-GBM GN. Types 3
and 4 LN
ì  Pre-eclampsia

ì  HUS
DECREASE GFR

PODOCYTE : PROTEINUIRA GLOMERULAR PARIETAL CELLS:

Damage of the foot processes and Bowman´s capsule parietal cells

filtraTon slits Derived from mesenchymal
Cytoskeletal rearrangement PROGRESSION TO progenitor cells (like podocytes?)
Limited capacity for repair and GLOMERULOSCLEROSIS Responsible for crescents formaTon
regeneraTon

ì  RPGN
ì  MCD DECREASE GFR ì  FSGS
ì  FSGS

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LEUKOCYTES: Leukocytes acFvaFon NEUTROFHILS: Neutrophils acFvaFon

Normally present in the glomeruli First line responders produces
Increase in number in pathologic AcTvated systemically of locally
condiTons Proinflammatory products directly
Recruited by Chemokines and Adhesion damage GBM
Molecules Neutrophils extracellular traps ReacFve oxygen species
Chemokine receptor expressing
leukocytes: Proteasas
ì  GN
ì  CXCL8/IL8 ì  ANCA
Cytokines
ì  CXCR2 chemokines
ì  LN
ì  C3a – C5a

ì  Immunoglobulines



Kitching et al Glomerular Disease CJASN 2016

MONOCYTE / MACROPHAGE: DENDRITIC CELLS:

Pro-inflammatory phenotype (M1) PresenTng anTgen cells

AdapTve immunity response in GN

AcTvaTon of macrophages mainly anT-inflammatory acTon.
Although can act as pro-inflammatory acTvators
AnT-inflammatory phenotype (M2)
MAST CELLS:
ì  AKI: ischemia – reperfusion injury
ì  GN: autoimmune ds (IgG acTvated:
Allergy and anaphylaxis mediators – Histamine and others
Fc-FcyR) Th1 and Th17 acTvate by
cytokines and cell-cell contact. Pro-inflammatory cytokines

Kitching R. et al Glomerular Disease CJASN 2016

T – LYMPHOCYTES: ì  Immune ac>va>on in GN:

CD4+:
AdapTve immunity: cytokines, transcripTon factors,
chemokines receptors
Th1 and Th17 intrinsic anTgen recogniTon
Th17 neutrophil recruitment
CD8+:
Cytotoxic to cells expressing MHC class 1 pepTdes
Secrete cytokines – proinflammatory role

B-LYMPHOCYTES:
ProducTon of anTbodies – deposit in the glomeruli
Humoral immunity

Gilbert S. et al NKF Primer of Kidney Diseases 2018

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GLOMERULAR SYNDROMES

ì  NEPHRITIC SYNDROME

ì  NEPHROTIC SYNDROME

Gilbert S. et al NKF Primer of Kidney Diseases 2018

GLOMERULAR SYNDROMES GLOMERULAR SYNDROMES

ì  NEPHRITIC SYNDROME

ì  NEPHROTIC SYNDROME

NEPHRITIC SYNDROME NEPHRITIC SYNDROME

ì  NEPHRITIC SYNDROME ALSO CALLED ACUTE ì  InfecTon-related GN

GLOMERULONEFRITIS
ì  Azotemia
ì  IgA Nephropathy / IgA VasculiTs
ì  Hypertension
ì  ANCA associated vasculiTs / Pauci-inmmune GN
ì  Edema
ì  Hematuria (gross or microscopic) ì  AnT-GBM GN
ì  Proteinuria (usually under nephroTc range)
ì  Oliguria ì  Membranous ProliferaTve GN

ì  Lupus NephriTs

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Infection-related GN in Children and Adults Infection-related GN

ì  Post infecTous GN in adults:

ì  Usually coexists with the infecTon
ì  Triggers an autoimmune response / RPGN, Lupus,
ANCA vascuTlits, IgA or others.
ì  Commonly presents with renal failure, proteinuria
that can be nephroTc, complement levels are low in
only 30%. High percentage needs dialysis and
mortality up to 20%

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Infection-related GN Infection-related GN

POST STREPTOCOCCAL GN: A.  Diffuse endocapillary

prolifera>ve GN
ì  Most common cause of nephriTc syndrome in childhood
B.  Long standing
ì  Renal lesion develops aHer Group A Beta-hemolyTc infec>on with
streptococci (M1,2,4 and 12) pharyngeal (1-3 weeks) or (M47, 40, 55, subentothelial
57 and 60) cutaneous infecTon (2-4 weeks). immune deposits
ì  High Tters of ASO, anTstreptokinase, anThyaluronidase, anT- C.  ANCA vasculi>s
DNase B and low complement level (C3 90%) lesion + chronic DM
ì  Renal biopsy: diffuse proliferaTve GN. D.  Mesangial nodulos
due to DM and
ì  Self limited course, treatment is supporTve with correcTon of endocapillary
fluid and electrolyte imbalance prolifera>ve GN

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Infection-related GN – Viral Nephropaties Infection-related GN

Hep C associated MPGN (typical HIV – Colapsing FSGN

GBM double contours)

Gilbert S. et al NKF Primer of Kidney Diseases 2018 Gilbert S. et al NKF Primer of Kidney Diseases 2018

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IgA Nephropathy IgA Nephropathy

ì  IGA NEPHROPATY: ì  Also called Berger's disease CLINICAL PRESENTATION:

Proteinuria minimal to nephroTc ì  IgA deposits in the mesangium ì  Episodes of gross glomerular hematuria associated with upper respiratory
range infecTon
ì  Primary or secondary to:
Hematuria: microscopic, gross hepaTc ds, celiac ds, infecTous. ì  AsymptomaTc hematuria – long standing
hematuria common aHer ì  Inheritable suscepTbility
infecTons ì  Acute GN or RPGN less common
ì  The most common glomerular
PosiTve IgA on kidney biopsy ds worldwide- (Asia) ì  NephroTc syndrome rare

ì  Common in young male adults ì  Kidney biopsy: focal GN with meningeal proliferaTon, immunofluorescence
3:1 IgA and C3 deposits.

IgA Nephropathy IgA Nephropathy

1. Mesangial prolifera>on (M), Expansion of the extracellular matrix (S) TREATMENT:

ì  No specific treatment
2. IgA staining
ì  Low risk of progression: monitor

ì  High risk of progression: (HTN, proteinuria greater 1gr/day, decreased GFR:

ACEi and ARB´s, staTn therapy, Omega 3.

ì  In severe cases: glucocorTcoids ? cyclophosphamide could be considered

PROGNOSIS:
ì  One third spontaneous remission

ì  20-40% progress to ESKD: abnormal GFR, proteinuira > 1gr/d, HTN,

tubulointersTTal fibrosis, glomerulosclerosis, crescents.
Gilbert S. et al NKF Primer of Kidney Diseases 2018

IgA vasculitis (Henoch-Shönlein Purpura) ANCA associated Vasculitis

ì  Systemic small-vessel leukocytoclasTc vasculiTs associated with IgA deposits

in vessel walls
ì  Children with infecTons – group A streptococcus

ì  Male predominance

ì  Palpable purpura in lower extremiTes and burock area + arthralgias,

abdominal pain

ì  AKI with acTve sediment

ì  Renal lesions similar to IgA nephropathy

ì  Tretment suporTve. Sever cases Rituximab, glucocorTcoids, plama exchange

Gilbert S. et al NKF Primer of Kidney Diseases 2018

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ANCA associated Vasculitis ANCA associated Vasculitis

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Gilbert S. et al NKF Primer of Kidney Diseases 2018

ANCA associated Vasculitis ANCA associated Vasculitis

ANCA vasculi>s: segmental Microscopic Polyangi>s: renal A.  Immune complex mediated
fibrinoid necrosis and adjacent interlobular artery with fibrinoid B.  Lineas staining in anT-GBM disease
cellular crescent necrosis. C.  No staining in pauci-immne GN

Gilbert S. et al NKF Primer of Kidney Diseases 2018 Gilbert S. et al NKF Primer of Kidney Diseases 2018

ANCA associated Vasculitis Pauci-immune GN (ANCA associated)

ì  ANCA associated small vessels vasculiTs:

ì  Granulomatosis with plyangiiTs (Wegnener granulomatosis)
ì  Microscopic polyangiiTs
ì  Eosinophilic granulomatosis with polyangiiTs (Churg-Strauss
Diseases)

ì  Idiopathic crescenTc glomerulonephriTs (when this is not

systemic involvement)

Gilbert S. et al NKF Primer of Kidney Diseases 2018

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Pauci-immune GN (ANCA associated) Pauci-immune GN (ANCA associated)

ì  ANCA associated small vessels vasculiTs: ì  ANCA associated small vessels vasculiTs:
ì  Citokine-primed neutrophils presenTng cytoplasmic anTgens on ì  Chronic systemic non specific symptoms
their surfaces (proteinase 3 and myeloperoxidase) ì  Hematuria, proteinuria, purpura, mononeuriTs mulTplex, upper
ì  CirculaTng ANCAs bind to these anTgens and acTvate a respiratory symptoms – sinus or lower respiratory tract
neutrophis burst with consequent vascular damage. Also acTvate symptoms with nodular lesions with vacitaTons
the alternaTve complement pathway. ì  Decreased GFR
ì  Immunofluorescence of kidney biopsy lack of immunoglobulin or ì  PR3-ANCA is common in granulomatosis with polyangiiTs
complement deposiTon (pauci-immune)
ì  MPO-ANCA with microscopic polyangiiTs
ì  Renal involvement presents with RPGN.
ì  Kidney biopsy shows necroTzing lesions and crescents with
negaTve immunofluorescence

Pauci-immune GN (ANCA associated) Anti-GBM GN and Goodpasture Syndrome

ì  ANCA associated small vessels vasculiTs: ì  ANTI-GBM:

ì  TREATMENT: ì  Auto-anTbodies to glomerular basement membrane: AnT-GBM
ì  High dose glucocorTcoid GlomerulonefriTs. Concomitant auto-anTbodies to alveolar
ì  Cyclophosphamide or Rituximab basement membrane with pulmonary hemorrhage (Goodpasture
ì  AzaToprine or MMF
Syndrome)
ì  Plasma exchange in severe cases
ì  RPGN

ì  PROGNOSIS: ì  Males in 20´s – 30´s and also 50´s and 60´s (lung involvement)
ì  Poor without treatment ì  Exposure to tabaco, hydrocarbon solvents, HLA-DR2 and HLA-B7.
ì  Clomplete remision in 75%

Anti-GBM GN and Goodpasture Syndrome Membrano Proliferative GN

ì  ANTI-GBM: ì  MPGN:
ì  Pulmonary symptoms: hemoptysis, dyspnea, respiratory failure, ì  Large spectrum of presentaTon: mild hematuria to RPGN:
rapid decrease in GFR, hematuria, proteinuria. ì  Immune complex related
ì  Chest X-ray, anT-GBM anTbodies 90%. ì  Chronic infecTon (HCV) parasiTc, paraproteinemia, Lupus,
ì  Biopsy: crescent formaTon with linear IgG along GBM idiopathic
ì  TREATMENT: ì  Classical complement pathway acTvaTon with immune complex
deposiTon (alternaTve pathway in some cases). C3 low, C4 low.
ì  Plasma exchange, glucocorTcoids, cyclophosphamide, Rituximab,
ì  C3-related disease
dialysis.
ì  Inherited or acquired abnormaliTes in the alternaTve complement
pathway: C3 low.

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Membrano Proliferative GN Membrano Proliferative GN

ì  MPGN: ì  MPGN:
ì  Biopsy: mesangial hypercellularity, endocapillary proliferaTon, ì  TREATMENT: Directed to the underlying condiTon. Idiopathic
capillary wall remodeling resulTng in souble contours of the cases can relay on ACEs, ARB, glucocorTcoides,
GBM (“tram track”) Immunofluorescense: cyclophosphamide, MMF, rituximab.
ì  Immune complex mediated MPGN: C3 and IgG or IgM ì  PROGNOSIS: eventually progress to ESKD. Novel therapies are
ì  C3 glomerulopathy: lack of immunofluorescence or in rare cases being explored.
the presence of dense deposits: “Dense Deposit Diseases”

Lupus Nephritis Lupus Nephritis (classification)

ì  LN:
ì  35-60% renal involvement
ì  Deregulated cellular apoptosis resulTng in autoanTbodies against
nucleosomes, binding to components of the glomerulus to form
immune complex glomerular disease.
ì  From glomerular disease to tubulointersTTal nephriTs and vasculiTs
ì  Several parerns of LN. ( I-VI ). High AnT-DNA, Low C3, C4, CH50.
ì  More common in women than men
ì  Hematuria, proteinuria, decreased GFR, HTN
ì  Kidney biopsy necessary

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Lupus Nephritis Lupus Nephritis

Class IV Lupus Nephri>s Class IV Lupus Nephri>s Class V Lupus Nephri>s (silver)
(hematoxylin and eosin) (trichrome)

Gilbert S. et al NKF Primer of Kidney Diseases 2018 Gilbert S. et al NKF Primer of Kidney Diseases 2018

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Lupus Nephritis Lupus Nephritis (Treatment)

ì  LN:
ì  TREATMENT:
ì  Depends on the class. Class I-II may need monitoring. Class VI does
not need specific treatment.
ì  CorTcosteroids, immunosuppressant agents, cyclophosphamide,
MMF, Rituximab, Belimumab.
ì  Renal disease progression intervenTon
ì  PROGNOSIS:
ì  Depends on the class, (III-IV), degree of renal damage and rate of
progression to ESKD. Remission rates 50-60%. Dialysis quiescence.
Transplant relapse.

Gilbert S. et al NKF Primer of Kidney Diseases 2018

GLOMERULAR SYNDROMES
ì  SUMMARIZES ACUTE GN:

ì  NEPHRITIC SYNDROME

ì  NEPHROTIC SYNDROME

NEPHROTIC SYNDROME NEPHROTIC SYNDROME

ì  NEPHROTIC SYNDROME: ì  NEPHROTIC SYNDROME:

ì  Proteinuria (NephroTc range: > 3gr/day ì  Ranges from proteinuria to full NS

ì  Hipoalbuminemia ì  Most common cause of NS in adults: DiabeTc Nephropathy

ì  Most common cause of NS in children: Minimal Change Diseases
ì  Edema
ì  UA: Proteinuria in 24 hr urine collecTon or P/C raTo on spot urine
ì  Hyperlipidemia
sample, bland sediment, oval fary bodies, protein electrophoresis.
ì  Lipiduria (Oval fat bodies)
ì  BLOOD: Albumin, cholesterol, triglycerides, determine GFR,
complement levels, serology and immunology to rule out systemic
condiTons.
ì  KIDNEY BIOPSY: oHen required in idiopathic nephroTc syndrome. Rare
in classical presentaTon in children (MCD) or in long standing diabetes.

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NEPHROTIC SYNDROME NEPHROTIC SYNDROME

ì  NEPHROTIC SYNDROME: ì  Minimal Change Disease

TREATMENT
ì  Membranous Nephropathy
ì  Proteinuria control: diet, ACEi, ARBs, SGLT2i.
ì  Edema: salt and fluid restricTon, diureTcs
ì  Focal Segmental GN
ì  Hyperlipidemia: staTns, some fibrates, diet, exercise.
ì  Hypercoagulable state: in albumin < 2gr considerer anTcoagulaTon ì  Amyloidosis

ì  DiabeTc Nephropathy

Minimal Change Disease Minimal Change Disease

ì  NephroTc range proteinuria ì  The most common proteinuric disease in children, 80%.

ì  Kidney biopsy shows no ì  In adults 20-25%:

changes on light microscopy
ì  Idiopathic although could be secondary to viral respiratory
ì  Foot process effacement on infecTons, neoplasms, drugs.
electron microscopy
ì  Laboratory findings non specific. Typically: proteinuria,
hypoalbuminemia, dyslipidemia.
ì  Treatment: prednisone.

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Membranous Nephropathy Membranous Nephropathy

ì  Various degrees of ì  MN.

proteinuria
ì  Autoimmune condiTon against podocyte anTgens
ì  Most common cause of ì  Course is variable: spontaneous remission in aprox 30%.
Primary NS in adults Progression to ESKD over 10 years about 40%.
ì  Risk for hypercoagulable ì  Risk of progression: tubulointersTTal compromise, male,
state. decreased GFR at presentaTon, proteinuria greater than 6g/day
ì  PLA2R anTbodies common in primary disease
ì  Biopsy with GBM deposits
ì  Biopsy: capillary wall thickness, spike and dome parern on the
ì  Secondary causes: Hep B, C, GBM, IgG and C3 deposits.
carcinoma

Gilbert S. et al NKF Primer of Kidney Diseases 2018

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Membranous Nephropathy Membranous Nephropathy

ì  MN.
ì  TREATMENT:
ì  If risk factors are not present: conservaTve approach
(spontaneous remission)
ì  ACEi, ARBs. Blood pressure control
ì  Immunosuppression for those with high risk of progression
ì  CorTcosteroids, cyclophosphamide, calcineurin inhibitors, MMF,
Rituximab.

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Membranous Nephropathy Membranous Nephropathy

ì  PLA2R Ab: ì  AnTbody NegaTve:

Gilbert S. et al NKF Primer of Kidney Diseases 2018 Gilbert S. et al NKF Primer of Kidney Diseases 2018

Focal Segmental Glomerulosclerosis Focal Segmental Glomerulosclerosis

ì  FSGS. ì  FSGS.
ì  Podocyte damage ì  Range from nephroTc presentaTon to nephriTc features
ì  Primary or secondary:
colllagen 4 mutaTons, ì  Kidney biopsy: sclerosis of segments of some but not all
polymorphisms in APOL1 glomeruli. IgM, C3 deposits. Podocyte foot process fusion.
gene (african), increased ì  TREATMENT: blood pressure control with ACEi, ARBs. DiureTcs
levels of circulaTng
permeability factor
for edema. Prednisone and immunosuppressants can be
considered in primary disease.
ì  Secondary: obesity, HTN,
HIV, SARS-CoV-2, ì  PROGNOSIS: progression to ESKD is common over Tme,
analgesics, spontaneous remission is rare. High relapse rate aHer
bisphophonates. transplant.

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Focal Segmental Glomerulosclerosis Focal Segmental Glomerulosclerosis

ì  FSGS. ì  FSGS. ì  A. Glomerular segmentally consolidated with

endocapillary foam cells

ì  B. Hypertrophied podocytes

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Focal Segmental Glomerulosclerosis Amyloidosis

ì  TREATMENT: ì  Is a rare cause of NS

ì  Tissue deposiTon of an overproduced and abnormal proteina- amyloid-

ì  Primary amyloidosis (AL) most common: monoclonal Ig light chains

deposits. Plasma cell dyscrasia.
ì  NS, decreased GFR and evidence of organ involvement

ì  Progresses to ESKD.

ì  TREATMENT: melphalan, corTcosteroids, Bortezomib, Daratumumab, stem

cell transplantaTon.
ì  PRGNOSIS: High mortality. Progression to ESKD.

Gilbert S. et al NKF Primer of Kidney Diseases 2018

Amyloidosis Amyloidosis

AL-type amyloidosis (pash stain)

Gilbert S. et al NKF Primer of Kidney Diseases 2018

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Diabetic Nephropathy Diabetic Nephropathy

ì  Evidence of long standing ì  Evidence of long standing Diabetes Mellitus

Diabetes Mellitus
ì  Micro to macro albuminuria
ì  Micro to macro albuminuria
ì  Progressively decline of GFR
ì  Progressively decline of GFR
ì  End organ damage: reTnopathy, peripheral vascular disease,
ì  End organ damage:
coronary diseases.
reTnopathy, peripheral
vascular disease, coronary
diseases.

Diabetic Nephropathy Diabetic Nephropathy

Follow up bx: at
0-5-10 year
intervale:

Diffuse and
nodular
mesangial
expansion and
arteriolar
hialinosis

Gilbert S. et al NKF Primer of Kidney Diseases 2018 Said S et al Silent Nephropathy. KI, 2016

Diabetic Nephropathy
References:
1.  Gilbert S, et al NaTonal Kidney FoundaTon, Primer of Kidney Disease. 2018.

2.  Jameson L, et al. Harrison´s Manual of Medicine. 2020

3.  KDIGO 2021 Clinical PracTce Guidelines for the Management of Glomerular Diseases. KI October 2021

4.  KDIGO 2020 Clinical PracTce Guidelines for Diabetes Management in CKD. KI. October 2020.

5.  Andrade-Oliveira V. et al. InflammaTon in Renal Disease: New and old Players. FronTers in Pharmacology. October 2019.

6.  Stenvinkel P. et al. Chronic InflammaTon in Chronic Kidney Disease Progression: Role of Nrf2. KI reports. 2021.

7.  Cobo G, et al. Chronic InflammaTon in end-stage renal disease and dialysis. NDT 2018.

8.  McWilliam S. et al. The complex interplay between kidney injury and inflammaTon. Clinical Kidney Journal. 2021

9.  Rabb H. et al. InflammaTon in AKI: Current Understanding, key quesTons and knowledge gap. J.Am. Soc. Nephrology. 2016

10.  Kitching A. et al. The players: cells involved in glomerular disease. CJASN. 2016.

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