23/05/2022

DU Reins et Maladies Systémiques

2022

Virus and Kidney

Gabriel Choukroun
Nephrology Internal Medicine Dialysis Transplantation
UFR de Médecine d’Amiens et CHU Amiens Picardie

Liens d’intérêts

o Le CHU Amiens et l’UPJV

o Alnylam
o Amgen
o Astellas
o AstraZeneca
o GSK
o Sanofi

o Takeda
o Vifor

Viral nephropathy

Type of virus Varieties of nephropathies

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Pathogenetic links between viral infection and renal disease

Clinical syndrome
Serological diagnosis
Identification of specific viral antigenemia
Detection in renal structures of viral antigens and host antibodies

Complete cure following eradication of the virus….

Chronic renal disease and viral infections

Hepatitis B Virus
Hepatitis C Virus Chronic glomerulonephritis
HIV Microvascular nephropathy
Parvovirus B19

Parvovirus B19
Hepatitis A virus
Yellow fever Acute glomerulonephritis
Epstein Barr virus

CMV
Polyomavirus (BK virus)
EBV Interstitial nephritis
Hantavirus
Influenza A and Coxsackie B virus

Kidney diseases and viral infection

Hepatitis B Virus

Hepatitis C Virus

HIV

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Kidney diseases and viral infection

Potential mechanisms

o Tropism of the virus for the kidney

o Direct cytopathic effects
o Immune response to the virus and production of immune complexes in the general circulation or in situ
o In tissue, viral proteins inducing necrosis, apoptosis, cells dysfunction, cytokines production, increased
matrix production
o Multiorgan failure

o Nephrotoxicity of antiviral therapy

Non-liver manifestations of HCV infection

o Renal diseases
o Fatigue, depression and cognitive disorders
o Co-infection HIV-HCV
o Cardiovascular complications
o Oncology
o Vasculitis and cryoglobulinemia

Cumulative Incidence of End Stage Renal Disease

Three Diabetic Study Cohorts

HCV+ non treated

Non HCV

HCV+ treated

H su Y C et al., H epatology, 2014

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Hepatitis C-associated Kidney Diseases
Kidney disease
C ryoglobulinem ic
M em branoproliferative G N
N on-cryoglobulinem ic
M em branoproliferative G N
M em branous glom erulopathy
IgA nephropathy
Im m unotactoid glom erulopathy
Fibrillary glom erulonephritis
M esangial proliferative G N
Tubulo-interstitial nephritis
T hrom botic m icroangiopathy
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Cryoglobulinemia is mostly links to HCV infection
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Glomérulonéphrite extracellulaire
Classification selon l’Immunofluorescence
GNC pauci-immunes
(vascularites à ANCA)
Polyangéite
microscopique
Wegener
Churg-Strauss
GN pauci-immune
isolée au rein
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Pathogenesis Clinical manifestations
M esangial deposits of im m une com plexes (H C V A g, Ig,
Nephritic syndrome, nephrotic syndrome
and C fragm ents) - C ryoglobulin deposition
M esangial deposits of im m une com plexes (H C V viral
Nephritic syndrome, nephrotic syndrome
antigens, Ig, and com plem ents fragm ents)
Subepithelial deposits of im m une com plexes (H C V viral
Nephrotic syndrome
antigens, Ig, and com plem ent fragm ents)
M esangial deposits of im m une com plexes (H C V viral
Isolated proteinuria and/or hematuria
antigens, Ig, and com plem ents fragm ents)
M esangial and capillary w all deposition of im m une Nephrotic syndrome, isolated proteinuria and/or
com plexes (H C V viral A g, Ig, and C fragm ents) hematuria
D irect effect of H C V on m esangium by TLR -3 or M M P-2 Isolated proteinuria and/or hematuria
H C V deposition in tubular epithelial and infiltrating cells Proteinuria
Endothelial injury by direct activity of H C V Proteinuria and hematuria
F Fabrizzi et al., A m J K idney D is 2013
Saadoun, A rch Intern M ed, 2006
IgG C3
GNC à Ac anti-MBG GNC à complexes
(Goodpasture) immuns
Endocardite
Dépôts
Linéaires Cryoglobulinémie
d’IgG
Purpura
Dépôts rhumatoïde
IF - GNC granuleux
Lupus
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Cryoglobulinemia-systemic vasculitis

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Features of 250 mixed Cryoglobulinemic patients

Age at disease onset 54 ± 13 (29-72)

Female/Male ratio 3
Purpura 98%
Weakness 98%
Arthralgias 91%
Raynaud's phenomenon 32%
Sicca syndrome 51%
Peripheral neuropathy 81%
Renal involvement 31%
B-cell non-Hodgkin's lymphoma 11%
Hepatocellular carcinoma 3%

Ferri C , M ascia M T, Saadoun D , C acoub P. 2009

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HCV associated Cryoglobulinemic Glomerulonephritis

Membrano-Proliferative Glomerulonephritis (n = 18)

Proteinuria (g/d) 3.1 ! 2.2

Albumin (g/L) 29 ! 5
Microscopic hematuria 53 ! 41
Creatinine (mmol/L) 118 ! 41
Cryoglobulin (II/III) 16 / 2
Cryoglobulin level (g/L) 1.4 ! 1.8
ALT (IU x N/ml) 1.5 ! 1
Genotype 1/ 2/ 3/ 4 11/3/2/2

A lric L et al. A m J K idney D is 2004

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Pathogenesis of HCV-related kidney diseases

HCV bind and penetrate into renal cells via CD81 and SR-B1 receptors
HCV RNA has been found in mesangial cells, tubular epithelial cells and endothelial
cells of glomerular capillaries
HCV is the cause of more than 80% of mixed cryoglobulins

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Therapeutic strategies in HCV-related cryoglobulinemic vasculitis

Harvoni®: Sofosbuvir + Ledipasvir

Viekirax®: Paritaprevir/ritonavir + ombitasvir
Zepatier®: Grazoprevir + Elbasvir

A dapted from F. Fabrizi et al., A m J K idney D is 2013; Saadoun D et al., R heum D is 2015

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Treatment of mixed cryoglobulinemia resistant to interferona with

rituximab

Sansonno D , Z aja F et al, B lood 2003

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Other forms of HCV-associated glomerulopathies

MPGN type 1
MN
FSGN
IgA Nephropathy
Fibrillary – Immunotactotoid glomerulopathy

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Hepatitis B related nephropathy

§ More than 350 millions people word-wide have chronic HBV infection
§ Extrahepatic manifestations of HBV infection rare
Vasculitis (PAN)
Reactive arthritis
Glomerulonephritis (children > adults – men > women)

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Membranous Nephropathy and HBV infection

§ Rare, except in Asia

§ Genotype A and C
§ Genetic predisposition (HLA)
§ Deposition of immune complexes in the glomerulus (IgG and
HBsAg or HBeAg)
§ Histopathology similar than in primitive MN
§ Classically no detection of PLA2R Ab

§ Mostly children (neonatology transmission)

§ Spontaneous remission in children
§ 1/3 adults patients reach ESRD
§ Antiviral therapy (PEG-IFN – nucleos(t)ide analogues)

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Membranous nephropathy
Primary vs secondary diseases using IF microscopy

Primary Secondary to HBV

IgG4 > IgG1, IgG3 Granular IgG1 > IgG4

IgA, IgM absent IgM may be present

Mesangial Ig staining absent Mesangial Ig straining present

C1q negative or weak C1q negative

PLA 2R positive and co-localizes with IgG PLA 2R negative

HBV serology ± HBV DNA PCR must be performed in all patients with MN

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Hepatitis B related nephropathy

Membranoproliferative glomerulonephritis (± Cryo)

FSGS, IgA nephropathy
Polyarteritis nodosa (also described with HCV)

Very very rare

80 % associated with HBV
Blood transmission, IV drug abuse
Antigen-Antibody complex deposition in vessel walls
Arteritis in medium-size vessels (no glomerulonephritis)
Glomerular ischemia – Hypertension - AKI

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Chronic renal disease and HIV infection

• MRC : 3.5% to 30% of HIV patients

• Incidence of CKD ≥ Stage 3: 10 x of non-infected patients
• 2 nd cause of mortality in HIV population
• Causes cumulatives du risque rénal chez ces patients
o Susceptibilité génétique chez le patient Africain (variant G1/G2 ApoL1)
o Infection VIH et déficit immunitaire
o Co-infection VHC
o Troubles métaboliques : diabète, dyslipidémie, obésité
o Risque cardio-vasculaire augmenté
o Exposition tabagique importante
o Exposition aux substances néphrotoxiques

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Renal manifestations in HIV-infected patients

• Non-specific, common
- ARF by ATN
- Toxicity of antiretroviral treatment
• Specific, directly link to viral infection
- HIV-Associated Nephropathy (HIVAN)
- Glomerulonephritis with immune complexes (“Lupus like”)
- IgA nephropathy
- Thrombotic microangiopathy
- Non specific ARF with multiple risk factors

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HIV-Associated Nephropathy (HIVAN)

• Association between HIV and renal disease first reported in 1984

• HIV-1 seropositive patients
• Low CD4 counts (< 200) and/or other criteria for AIDS
• Renal syndrome characterized by progressive renal failure (moderate to severe) and
proteinuria (often in the nephrotic range)
• Peripheral edema is uncommon
• Hypertension is rare
• Renal ultrasound shows echogenic kidneys that are normal-to-large in size
• Most common kidney biopsy finding was FSGS

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HIV-Associated Nephropathy (HIVAN)

• 25 to 70% of glomerulonephritis associated with HIV infection

• 1st cause of ESRD in patients infected with HIV
3ème cause of ESRD in Afro-Americans between 20 and 65 years in the USA
40 - 46% of causes of ESRD in HIV patients in Europe
• Prevalence: 1 % …. to 12%
• Incidence: 0.5 %

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HIV-Associated Nephropathy (HIVAN)

Collapsing focal segmental glomerulosclerosis (FSGS)

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HIV-Associated Nephropathy (HIVAN)

Key histopathologic features

• Collapsing form of Focal segmental glomerulosclerosis (FSGS)

• Microcystic dilatation of renal tubules
• Globally sclerotic glomeruli
• Lymphocytic interstitial infiltrates and interstitial fibrosis
• Podocyte proliferation and loss of podocyte differentiation markers
• Endothelial tubuloreticular inclusions seen on EM

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HIV-Associated Nephropathy (HIVAN)

Key histopathologic features

• Hyalinose segmentaire et focale collapsante

o au moins 1 glomérule avec collapsus/échantillon
o Hyperplasie/dysmorphie podocytaire
o Peu/pas de lésions scléro-hyalines
• Dilatations tubulaires microkystiques
o Anomalies épithéliales tubulaires : atypie nucléaires, atrophie, nécrose

• Lésions interstitielles
o Infiltrats inflammatoires polymorphes : ly T CD8>>CD4,
monocytes, plasmocytes
o Œdème et/ou fibrose interstitielle

• Inclusions tubulo-réticulaires endothéliales (ME)

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HIV-Associated Nephropathy (HIVAN)

Key histopathologic features

C ollapsing FG S Endothelial Tubuloreticular Inclusions

M icrocystic dilatation of the tubules

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Confirmation that HIV-1 infects Renal Epithelial Cells

• A series of 20 HIV-1 seropostive patients with renal disease who underwent renal
biopsy (15 had HIVAN)
• In 11 of the 15 patiens with HIVAN, HIV-1 was detectable in renal epithelial cells by
RNA in situ hybridization
• HIV-1 RNA was detected in renal tubular epithelial cells, glomerular visceral and
parietal epithelial cells, and interstitial leukocytes

n = 20

From B ruggem an et al.

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Confirmation that HIV-1 infects Renal Epithelial Cells

In situ hybridization for HIV-1 mRNA in kidney biopsies.

HIV-1 mRNA in the cytoplasm of tubular epithelial cells and in cellular casts (CC) of the tubular lumen (TL) but not in protein casts
(PC)

C M W yatt et al., C lin J A m Soc N ephrol 2007

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Treatment for HIVAN

• HAART therapy
• ACE-I or Angiotensin Receptor Blockers
• Corticosteroids ?

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Treatment
H IV A N incidence stratified by A ID S status and
T he incidence of H IV A N by calendar period and
antiretroviral use
A ID S status

White bars, no antiretroviral therapy; light grey bars, nucleoside

reverse transcriptase inhibitor therapy; dark gray bars, highly active
antiretroviral therapy

Lucas et al., A ID S 2004

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Néphropathies liées à l’infection VIH

Autres atteintes glomérulaires

U ndeterm ined G N 9% n = 88
Extracapillar GN 1%
G lom erular TM A 3%

D iabetic nephropathy 3%

M inim al change disease 5%

HIVAN
30%
Immune
complex Classic
diseases
FSGS
23%
26%

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Néphrite interstitielle aigue et syndrome de reconstitution immunitaire

CD68

CD3 CD8

Patient 3
Patient 1

Patient 2

D augas E, N at C lin Pract N ephrol. 2006 ; Plaisier E et al, ED TA , G lasgow, 2006

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Hemorrhagic fever with renal syndrome

§ Hantavirus (RNA, 90 – 120 nm)

o All over the world; > 200 000 cases every year

o Natural host: rodent

o Two diseases Hemorrhagic fever with renal syndrome (HFRS)

Hantavirus pulmonary syndrome (HPS)
§ Endemic in
o China, Corea, Europe

o Nord-east of France

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Distribution of HFRS cases in France

Puumala virus

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Hemorrhagic fever with renal syndrome

Clinical presentation

§ Incubation: 7 to 36 days
§ 4 phases Fever during 3 to 5 days – “Flue syndrome” - OPH
Hypotension + purpura + Thrombopenia + Pu and Hu
Oliguria ( J8) + severe AKI
Polyuria (after 2 weeks)
§ Other manifestations Neurologic, cardiac, hematology, etc..
• Biological diagnosis (Elisa, RT-PCR, Immunochromatography)
§ Mortality 5 to 10 %
§ Complete recuperation of renal function
§ No specific treatment

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Histology

Acute Tubulo-Interstitial nephritis

Infiltration mononucléée
Hémorragie et œdème interstitiels
Congestion capillaire

Very rare gomerulonephritis

Mesangial proliferation
IgA nephropathy

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Infections with vBK in renal transplantation

Ø Infection fréquente : 30-40%

Ø Gravité : néphropathie à vBK (N-vBK)

• Prévalence : 5% (1 à 10%)
• perte du greffon : 50 % (10 à 50%)

Ø Traitement au stade de la N-vBK

• efficacité très limitée

Ø Prévention de l’infection à vBK :

• un diagnostic précoce par dépistage virologique
• une diminution précoce de l’immunosuppression

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vBK Nephropathy

§ Prevalence: 5% (1 to 10%)
§ Graft loss: 50% (10 to 80%)
§ Presentation
Increase of serum creatinine (NIT) (PBR)
• Decoy cells (10 cells/lame of centrifugation)
• Viruria (Viral DNA > 10 7 copies/ml)
• Viremia (plasmatic DNA > 10 4 copies/ml)

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Probability of vBK infection and nephropathy

78 renal transplant patients

Viruria : 30%
16 sem (2-69)
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Viremia : 12%
23 23 sem (4-73)

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Nephropathy : 8%
28 sem (8-86)

H irsch H , N E ngl J M ed 2002

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SARS CoV2 and Kidney Diseases

o Acute kidney injury but not specific

o COVAN (Covid-associated glomerular disease) collapsing FSGS (± APOL1)
o COVID-19 Vaccine Associated Glomerular Disease...

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