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Paolo Maggi

Clinica delle Malattie Infettive


Universit degli Studi di Bari

HIV e rene

Prevalence of different non-AIDS related co-morbidities at


different age strata in naive patients
20%
18%

16.6%

16%
Cerebrovascular

14%

Diabetes

12%

Hypertension
Myocardial infarction

10%

Lipodystrophy

8%

eGFR <60

6%
3.4%

4%
2%
0%

1.6%
0.6%
0.5%
0.3%
0.3% 0.1%0

1.5%
1.4%
1.0%
0.2%0

0.8%

4.3%
3.2%
1.1%

Non-AIDS defining malignancies


2.6%

0.6%

Dec 2014

25%

Prevalence of different non-AIDS related comorbidities at different age strata in ART23.2%


treated patients

20%

15%

10%

8.5%

5%

1.3%1.6%
0.4%
0%

5.7%

5.7%
4.9%
1.5%

3.0%
2.5%
0.7%

3.3%

4.0%
2.5%

5.1%

1.8%

0.6%

0.6%

4.6%

3.4%

Cerebrovascular
Myocardial infarction
Non-AIDS defining malignancies

Diabetes
Lipodystrophy

Hypertension
eGFR <60

Dec 2014

Giandomenico Tiepolo (1727-1804): Il mondo nuovo

Proposed mechanism of TDF excretion

Blood
Blood
Tubular Renal
cell

Proximal
tubule
Nucleot
ide
analogu
es

hOATP
hOATP 1-3
1-3

MRP2
MRP2

Nucleotide
Nucleotide analogues
analogues excretion
excretion

tenofov
ir,
adefovir
,
cidofovi
r

Animation based on Izzedine H et al., Nat Rev Nephrol.

Poster # 795
Safety of Tenofovir Alafenamide in
Renal Impairment
Anton Pozniak

Classic risk factors:


age
genetic

high blood pressure


diabetes

25%

Prevalence of different non-AIDS related comorbidities at different age strata in ART23.2%


treated patients

20%

15%

10%

8.5%

5%

1.3%1.6%
0.4%
0%

5.7%

5.7%
4.9%
1.5%

3.0%
2.5%
0.7%

3.3%

4.0%
2.5%

5.1%

1.8%

0.6%

0.6%

4.6%

3.4%

Cerebrovascular
Myocardial infarction
Non-AIDS defining malignancies

Diabetes
Lipodystrophy

Hypertension
eGFR <60

Dec 2014

Virus

Drugs

SMART Study: Short-term CD4+ guided episodic


use of ART is inferior to continuous therapy

CD4+ guided drug conservation (DC) strategy was associated with


significantly greater disease progression or death compared with
continuous viral suppression (VS): RR 2.5 (95% CI: 1.83.6; p<0.001)
Includes increased CVD-, liver- and renal-related deaths and non-fatal
CVD events
Severe complications endpoint and components
Subgroups

Severe complications

No. of patients
with events

31

Non-fatal CVD events

63

Non-fatal hepatic events

14

Non-fatal renal events

1.4
1.5
1.4
2.5

0.1

El-Sadr W, et al. 13th CROI, Denver 2006, #106LB

1.5

114

CVD, liver, renal deaths

Relative Risk
95% CI

Favours DC

Favours VS

10

AIDS October 23, 2014 - Volume 28 - Issue 16

Renal epithelial cells produce and spread HIV1 via T-cell contact
Blasi M et al.
Objectives:Increasing evidence supports the role of the kidney as a reservoir for HIV-1. Invitro co-cultivation of HIV-infected T cells with renal tubule epithelial (RTE) cells results in
virus transfer to the latter, whereas cell-free virus infection is inefficient. We further
characterized the fate of HIV-1 after it is internalized in renal epithelial cells.
Methods:Primary or immortalized CD4+ cells were infected with a green fluorescent protein
(GFP)-expressing replication competent HIV-1. HIV-1 transfer from T cells to RTE cells was
carried out in a co-culture system and evaluated by fluorescence-activated cell sorting
analysis. HIV-1 integration in renal cells was evaluated by Alu-PCR and the production of
infectious particles was assessed by p24-ELISA and TZM-bl assay. HIV-infected renal cells
were used as donor cells in a co-culture system to evaluate their ability to transfer the virus
back to T cells.
Results:Renal cells become productively infected by HIV-1 and multiple copies of HIV-1 can be
transferred from infected T cells to renal cells. Two separate cell populations were identified
among infected renal cells based on reporter gene GFP expression level (low vs. high), only
the high showing sensitivity to azidothymidine and ritonavir. Co-cultivation of HIV-1-infected
renal cells with noninfected T cells resulted in HIV-1 transmission to T cells, supporting
bidirectional exchange of virus between T cells and kidney-derived cells. Persistent
expression and generation of infectious virus in renal cells required HIV integration.

Conclusion:These results support the kidney as a potential reservoir where


virus is exchanged between interstitial T cells and RTE cells

#793
Spectrum of HIV-Associated Kidney Disease in the Era of Combination
Antiretroviral Therapy
John Booth
We reviewed consecutive renal biopsies (1998-2012) of HIV+ patients
attending eight clinics in the UK.
This is the first study to demonstrate a relationship between HIV
replication and ICKD (immune complex kidney disease) .
Compared to HIVAN, ICKD was associated with less advanced
immunodeficiency and a lower rate of progression to ESKD.
The observed association with HIV viraemia for both core ICKD and
HIVAN may imply a pathogenetic role of HIV replication and its associated
immune activation;
it also suggests that suppressive ART may reduce the risk of developing
these types of kidney disease

797. Kidney Dysfunction and Markers


of Inflammation in the Multicenter AIDS
Cohort Study
Alison G. Abraham

Higher circulating levels of


immune activation markers
among treated HIV+ individuals,
despite virologic suppression, may
partially explain their higher burden
of kidney dysfunction compared to
HIV- persons

HCV
I pazienti co-infetti hanno una prognosi renale peggiore.
La presenza di crioglobuline un fattore prognostico di
aumentata mortalit
Fabrizi, F. et al. Hepatitis C virus increases
the risk of kidney disease among HIV-positive
patients: Systematic review and metaanalysis. J Med Virol. 2015. [Epub ahead of
print]

I nuovi farmaci:
Cobicistat
Dolutegravir
(e rilpivirina)

Recettori tubulari e farmaci:


Inibizione passiva
Inibizione attiva

Recettori tubulari e farmaci:


Inibizione passiva
Inibizione attiva

Recettori tubulari e farmaci:


Inibizione passiva
Inibizione attiva

COBI Inhibits Active Tubular Secretion of Creatinine,


Resulting in Increased SCr1,2
Preclinical studies indicate that COBI blocks a transport pathway used for
creatinine secretion from the proximal tubule by inhibiting a transport protein
called MATE1 that is responsible for transporting creatinine into the proximal
tubule1-3
Other drugs have been reported to block tubular secretion of creatinine, such
as ritonavir, cimetidine, and
trimethoprim4-6 Cobicistat
Creatinine
SCr 1.0 mg/dL
SCr 1.14
mg/dL

Proximal Tubule
Cell
m
Frroom
redd F
e
Fiilltteer erruulluuss
C
Crr F lom
e
G
Glom

Blood Vessel

Urinary Space
Forillustrative
illustrative
purposes
only.only.
For
purposes
only.
For illustrative
purposes

Lepist EI, et al. ICAAC 2011. Abstract A1-1724; 2 German P, et al. J Acquir Immune Defic Syndr. 2012;61:32-40; 3 Lepist EI, Ray AS. Expert Opin
Drug Metab Toxicol. 2012;8:433-448; 4 Cohen C, et al. CROI 2010. San Francisco, CA. 58LB; 5 Andreev E, et al. J Intern Med. 1999;246:247-252; 6
Naderer O, et al. Antimicrob Agents Chemother. 1997;41:2466-2470.
1

Anni
120
100

eGFR

80

<5 ml/min 1.73


m2/anno

60

>5 ml/min 1.73


m2/anno

40

>25%

20
0

In ultimo, 3 FAQ:
1) Che fare nella pratica clinica
quotidiana?

La misurazione della funzionalit


renale

Formule per la stima del GFR


III. CKD-EPI

eGFR = 141 * min(SCr/k, 1) * max(SCr/k, 1)-1,209 * 0,993Et * 1,018 (F) * 1,159 (B)
k = 0,7 (F), 0,9 (M)
-0,411 (M)

-0,329 (F),

Valutazione del GFR con metodo di riferimento


Inclusi soggetti con valori normali di GFR
Calcolo basato su creatininemia
Non validata in altre razze
Non accuratezza della misurazione della
creatinina a bassa concentrazione (< 1 mg/dl)

Performance delle formule per


calcolare leGFR

Levey As et al. Ann Intern Med 2009;


150:604-612

Bias di misurazione della Creatinina

Peake & Whiting, Clin Biochem Rev 2006; 173-18

2) Esistono metodiche alternative di


valutazione della funzione renale?

Cistatina C
Pros

Polipeptide di 13 kD
prodotto da tutte le cellule
nucleate
Conc. Plasmatica
indipendente da massa
muscolare, sesso e razza
Filtrata dal glomerulo in
assenza di quota di
secrezione tubulare
Non interferenze nei
metodi analitici

Cons

Aumentata produzione per:


Steroidi ad alte dosi
Neoplasie
Stati infiammatori acuti e
cronici
Ipertiroidismo
Carica virale sistemica
(HIV)
Tabacco

Cistatina C e infezione da
HIV
HIV+
(261)

Controlli
(193)

eGFR (MDRD)

104

93

< 0.001

Cocroft-Gault

118

106

< 0.001

99

120

< 0.001

eGFR (Cys)

Cys vs. HIV mRNA


Cys vs. CD4

0.33

< 0.01

- 0.29

< 0.01

Mauss S et al; Antiv Ther 2008; 13:1091-5

Accuratezza di eGFRcys e
CD4

Gagneux-Brunon A et al; AIDS


2013; 27

Formule per eGFR in HIV

Accuratezza 30%
MDRD
75%
CKD-EPI
82%
CDK-EPICys 80%
CKD-EPImix 81%

Gagneux-Brunon A et al;
AIDS 2013; 27

Monitoraggio clinico della funzione


renale

Valutazione della velocit di


filtrazione glomerulare (GFR)
Misurazione del GFR
Clearance renale della Inulina o
Iotalamato
Clearance plasmatica dello Ioexolo
o 51Cr-EDTA

3) Qual il ruolo della funzione


tubulare?

proteine a basso pm
fosforo
glucosio
acido urico

Valutazione qualitativa della


proteinuria
Proteinuria glomerulare
Danno della MBG (strutturale, funzionale)
Prevalentemente Albumina
Albumina/Proteine urinarie > 0,4

Proteinuria tubulare

Polipeptidi a basso peso molecolare (< 25 kD)


Scarsa quantit di Albumina
Albumina/Proteine urinarie < 0,4
Dosaggio immunometrico di proteine a basso peso molecolare
[Retinol-binding protein, 2-microglobulina, 1-microglobulina,
Cistatina C, NGAL]

Valutazione della proteinuria


Dipstick (Screening) [0 4 +; 0 300
mg/dl]
Proteinuria quantitativa su raccolta urine 24
h [0 0,3 g/24h]
Rapporto Proteine/Creatinina (PCR) [0 0,2
g/g]
Rapporto Albumina/Creatinina (ACR) [0 30
mg/g]

Esame su campioni spot della mattina

Gradi di Proteinuria
Microalbuminuria ACR > 30 < 200
mg/g
Proteinuria franca ACR > 200 mg/g
PCR > 0,2 g/g
Proteinuria lieve:
PCR 0,2 1,0 g/g
Proteinuria moderata: PCR 1,0 3,0
g/g
Proteinuria grave: PCR > 3,0 g/g

Dosaggio immunometrico di proteine a


basso peso molecolare
-Retinol-binding protein
-b2-microglobulina
- a1-microglobulina
- NGAL

Glomerulosclerosi
Tubulo Glomerulo

Sovraccarico tubulare

Grazie per
lattenzione