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Renal Function Overview: The Nephron

F

R

S

E

Filtration: blood to lumen

Reabsorption: lumen to blood

Secretion: blood to lumen

Excretion: lumen to external environment

To renalvein

To bladderand externalenvironment

Bowman’scapsule

Afferentarteriole

Proximaltubule

Efferentarteriole

GlomerulusPeritubularcapillaries

Distaltubule

Collectingduct

Loopof

Henle

l A 26 year old female is admitted in renal failure. Her creatinine is 498 µ mol/l

l She is diagnosed HIV antibody positive

l What are the possible causes of her renal failure?

l Acute v Chronic

l HIV vs non HIV causes

Acute Kidney Injury

Rapid reversible loss of renal functionA medical emergencyOften occurs in the context of multi-organ failureMortality 20-70%

Acute Kidney Injury in HIV

Common in first 3 m of care (14 cases per 100py)Major causes are infectionsDrugs often contribute to AKIAKI is associated with a poor prognosis

Incidence rate of ARF per 100 person-years of follow up

Incidence rate of ARF <3 months (n=54): 13.9 per 100 pyARF >3 months (n=75): 1.1 per 100 py

0%

4%

8%

12%

16%

1 . 0 0

ARF <3 months ARF >3 months

late

AIDS-defining infections

Non-opportunistic infectionsLiver disease

Malignancies

HAART toxicity

ARF - aetiology

ARF <3 months

ARF >3 months

<3 months >3 monthsPre-renal state: 76% 70%NSAIDs: 30% 41%Nephrotoxic agents: 55% 54%

Tuberculosis

Opportunistic Infections

v Tuberculosis

v CMV

v Fungal Infection

v Lymphoma

v Kaposi’s sarcoma

Survival of HIV infected patients who did / did not experience ARF

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8

Years from inception

No RF (n = 2039)

ARF (n = 115)

p<0.0001

Chronic Kidney Disease

KEY CAUSES

1.Diabetes2.Hypertension and Vascular Disease3.Chronic Glomerulonephritis4.Drugs5.HIV-Associated Nephropathy

Prevalence of Diabetes Kenya

0

100000

200000

300000

400000

500000

2000 2030

Characteristics of patients with CRF

CRF (n=36) No CRF (n=1824) P value

Median age 41.5 39.0 0.0008

Female (%) 39 38 0.25

Ethnicity (%)

l Black

l White / Other

64

36

57

43

0.25

HIV risk (%)

l Heterosexual

l MSM

l IVDU

72

28

0

58

37

5

0.08

GFR at HIV diagnosis 47 (30-85) 108 (94-123) <0.0001

Nadir CD4 (med, IQR) 67 (32-148) 214 (100-330) <0.0001

AIDS (%) 53 21 <0.0001

HBsAg pos (%) 8 15* 0.78

HCV Ab pos (%) 3 7* 0.009

Hypertension (%) 56 15* <0.0001

Diabetes (%) 21 3* <0.0001

Survival and dialysis-free survival

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5

Years from inception

p<0.00001

CRF (n=36)

No CRF (n=1824)

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4

Years since CRF diagnosis

CRF / not HIVAN (n=21)

HIVAN (n=15)p<0.0001

Survival free of ESRFOverall patient survival

Years from inception Years since CRF diagnosis

HIV Causes of Renal Disease

1. HIV associated Thrombotic Micro angiopathy

2. HIV associated Immune Mediated Glomerulonephritis

3. HIV associated nephropathy

HIV Associated Thrombotic Microangiography

Pathogenesis - Endothelial cell dysfunction mediated by HIV proteins

- Renal cellular apoptosis

- Inhibition of VWF-cleaving protease

Disease - Fever

Spectrum - Neurological dysfunction

- Microangiopathic haemolytic anaemia

- Renal insufficiency with haematuria

HATM Treatment

v Spontaneous remission may occur

v Steroids

v Immunoglobin infection

v Plasmaphoresis

v Vincristine

v Splenectomy

v HAART

All have variable success

Definition of HIVAN.

l Nephrotic Range Proteinuria

l Bland urine sediment

l Rapidly progressing renal failure

l Absence of edema and hypertension

l Large echogenic kidneys on ultrasound

l Collapsing focal segmental glomerulosclerosis with microcystic tubular dilatation and interstitial infiltrates and fibrosis

Pathology of HIVAN-Glomerular Changes

l Hyperproliferation of renal epithelial cells

l Focal sclerosis of the glomerular tufts

l Glomerular capillary collapse

l Mesangial expansion may be seen early-unclear if it represents precursor lesion or separate process

Tubular changes of HIVAN

l Marked degree of interstitial fibrosis occurs with the focal mononuclear cell infiltrates.

l Cystic tubular degeneration is widespread, with dilated tubular lumens filled with proteinaceous eosinophilic material

Treatment of HIVAN: no controlled randomised trials

l ACE-i/ARB

l Glucocorticoids therapy

l HAART

l Dialysis

l Transplant

D'Agati V et al. J Am Soc Nephrol 1997;138-151 Gupta SK et al. Clin Infect Dis 2005:40:1559-85

Impact of HAART on HIVAN

Before HAART After HAART

Winston JA, et al. N Engl J Med. 2001;344:1979-1984.

0.00

0.25

0.50

0.75

1.00

0 2 4 6 Time from HIVAN diagnosis* (years)

Survival of 60 patients with HIVAN

90% survival at 5 yearsHAART ERA

PRE-HAART ERA

Post et al (King’s College Hospital, London)

Pro

port

ion o

f pati

ents

wit

hout

ESR

DRenal survival in 60 patients with HIVAN

0.00

0.25

0.50

0.75

1.00

0 2 4 6

Time from HIVAN diagnosis (years)

ESRD: n=30 (50%)Never required dialysis: n=24 (40%)

HAART sustains survival but cannot prevent all ESRD

Post et al (King’s College Hospital, London)

HIVAN treatment: ACESurv

ival pro

babilit

y

No ARV

ACE (fosinopril 10 mg/d) treatment

5000 1000 1500

0.00

0.25

0.50

0.75

1.00

Time (days)

Wei A et al Kidney International 2003

44 HIV infected patients :• biopsy-proven HIVAN • serum creatinine ≤2.0 mg/dl• followed 5 years

250 750

Mortality Estimates

In addition: take care of all risk factors for the progression of renal

insufficiency

• Smoking

• Hypertension

• Dyslipidemia

• Anemia

• Diabetes

• Hyperuricemia

• Metabolic syndrome

• Nephrotoxic drugs

Drug-related renal dysfunction in HIV infection

Indinavir

Aciclovir

Foscarnet

Sulfadiazine

Sulfonamides

Atazanavir

Indinavir

Cocaine

Cyclosporine

Valacyclovir

Abacavir

Atazanavir

Indinavir

Ritonavir

Aciclovir

Cephalosporins

Cimetidine

Ciprofloxacin

Cocaine

NSAIDs

Penicillins

Rifampin

Sulfonamides

TMP-SMX

Adefovir

Cidofovir Aminoglycosides

Amphotericin B

Foscarnet

Pentamidine

Tenofovir DF

Didanosine

Abacavir

Lamivudine

Cocaine

ACE inhibitors

Amphotericin B

COX-2 inhibitors

Cyclosporine

Diuretics

Interferon

NSAIDs

ObstructiveTTP-HUSAcute Interstitial Nephritis

Tubule Dysfunction

Prerenal

Guo X, et al. Cleve Clin J Med. 2002;69:289-312.984.

Most Common Grade 4 Events:CPCRA Cohort

0

1

2

3

per

100 P

ers

on

per

100 P

ers

on

-- Years

Years

Reisler RB, et al. JAIDS. 2003;34:379-35:182-189.

LiverLiver2.62.6

NeutropeniaNeutropenia1.51.5

AnemiaAnemia1.11.1 CVDCVD

0.90.9PancreatitisPancreatitis

0.90.9 PsychiatricPsychiatric0.80.8 RenalRenal

0.60.6

IncidenceIncidence

n=2947; CPCRA=Terry Beirn Communityn=2947; CPCRA=Terry Beirn CommunityPrograms for Clinical Research on AIDS.Programs for Clinical Research on AIDS.

Hazard Ratio For Death by Grade 4 Event (95% CI)Hazard Ratio For Death by Grade 4 Event (95% CI)3.493.49

(2.38(2.38--5.12)5.12)PP=0.0001=0.0001

1.021.02(0.61(0.61--1.72)1.72)

PP=0.93=0.93

1.761.76(0.99(0.99--3.09)3.09)

PP=0.051=0.051

7.087.08(4.14(4.14--12.05)12.05)

PP=0.0001=0.0001

3.403.40(1.82(1.82--6.33)6.33)PP=0.0001=0.0001

1.911.91(0.79(0.79--4.63)4.63)

PP=0.15=0.15

4.604.60(2.45(2.45--8.66)8.66)PP=0.0001=0.0001

FRSE

Filtration: blood to lumenReabsorption: lumen to bloodSecretion: blood to lumenExcretion: lumen to external environment

To renal vein

To bladder and externalenvironment

Bowman’scapsule

Afferent arterioleProximaltubule

Efferentarteriole

GlomerulusPeritubularcapillaries

Distaltubule

Collectingduct

Loopof

Henle

The nephron

So what should be done?

• Estimate GFR with either Cockcroft-Gault or MDRD formulae

• Then adjust all drug dosages according to renal function

Serum creatCystatin C

1/Serum creat Formula-based

EstimatedGFR

Plasmaclearance of

Iohexol / EDTA

Measuredcreatinineclearance

(3h collection)

RenalClearance ofInulin/EDTA/iothalamate

Lowest cost & easiness

Accuracy & precision

Adapted from Brenner & Rector, Saunder Ed, 2001

6. Gupta SK et al. Clin Infect Dis 2005:40:1559-85

Cockcroft-Gault5

¢ Derived in 249 hospitalised males

¢ GFR Reference: 24-hour urine creatinine clearance

¢ Adjustment for female gender added later

Equation1:(1.23*(140-age) *weight (kg)* (0.85 if female))/creat (µmol/l)

MDRD6

¢ Derived in 1,628 patients with CKD (GFR 20-60 ml/min/1.73m2)

¢ GFR Reference: iothalamate clearance

¢ 2 variables eliminated (“abbreviated MDRD”)

Equation1:GFR (mL/min/1.73 m2) =

186 x (plasma creatinine/88.1 (µmol/l))-1.154 x (age)- 0.203 (x 0.742 if female) x 1.21 if Afro-Caribbean

Estimating GFR from Serum Creatinine

1. Levy AS et al. Ann Intern Med 1999;130:461-4705. Cockcroft DW, Gault MH Nephron 1976;16(1):31-34

Plasma eGFR vs true GFR

eGFR aMDRD

Measu

red G

FR

Serum creatinine and GFR

Serum creatinine is not the safest way to

determine whether renal function is normal

or not

GFR (inulin clearance) ml/min/1.73 m²

Seru

m c

reatn

ine m

g/d

l

Patients with«normal» creatininemia

Johnson R et al. Comprehensive Clinical Nephrology. 2000. Mosby. St. Louis. 4.15.1–4.15.15.

Abnormal amount of protein in the urine

¢ Glomerular

¢ High in albumin

¢ HIVAN

¢ Hypertension

¢ Diabetic nephropathy

¢ GN

¢ Tubular proteinuria

¢ Not Albumin

¢ Drug-induced tubular damage

Proteinuria

l Dipstick (15p)

l 24 urine collection (always difficult)

l Spot sample –

Urine protein/creatinine ratio (uPCR)

How to assess proteinuria

Trace 150 - 300 mg/l (0.15 - 0.3 g/l)

+ 300 - 1000 mg/l (0.3 - 1.0 g/l)

++ 1.0 - 3.0 g/l

+++ 3.0 - 10 g/l

++++ >10 g/l

Measurement of 300mg/l is equivalent to a 24 hour protein of 600mg if voiding 2L per day

Evaluation of renal function:dipstick evaluation of urine

Skin (UV) Food intake

Adipocyte

Vitamin D3±Temporary storage

Kidney(1a OHase)

Liver(25-OHase)

25-OH Vit D3

Effects of calcitriol on phosphorus:- ­ intestinal absorption- ­ bone uptake- ¯ renal excretion

Lipodystrophy

Renal dysfunction/Fanconi Syndrome

HIV-linked negative impact:

Hepatitis/alcohol

1-25(OH)2Vit D3(Calcitriol)

Phosphorus regulation:A vitamin D story…

44

• Glycosuria with normal blood glucose level

• Proteinuria (not albuminuria)

• Hypophosphatemia

• Acidosis

• Hypokalemia

• Hypouricemia

• Polyuria-polydipsia syndrome

• Bone Pain (if chronic)

Biological features ofFanconi syndrome

Izzedine H et al AIDS 2004;18:1074–1075

-10

-5

0

5

10

15

0 4 48 96

NVP-NORA

ABC-NORA

NVP

TDF

Weeks

Mean GFR change (ml/min/1.73m2)

GFR changefrom baseline

(global p value <0.0001)

Regimen

NVP-N +6.8 +10.1 +8.8

ABC-N +1.2 +6.6 +4.8

NVP +1.1 +3.4 -0.9

TDF -1.2 -2.5 -2.2Reid AJC, et al. XVI IAC (2006). Abst. THAB0105.

DART: Predicted GFR Over Time by Regimen

Routine Screening

l Creatinine and Egfr

l Urinary proteinuria

l Phosphate

l But….

IAS July 2009 48

Trial DesignTrial Design

3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease, CD4<200 cells/mm3 initating ART

Laboratory and ClinicalMonitoring (LCM)

12 weekly biochemistry,FBC & CD4

Other investigations & concomitant medications if

clinically indicated

Switch to second-line for•new/recurrent WHO 4

(or multiple WHO 3)•CD4<100 cells/mm3

Clinically DrivenMonitoring (CDM)

12 weekly biochemistry,FBC & CD4;

FBC & biochemistry only returned if clinically

indicated (or grade 4 toxicity); CD4 never returned

Other investigations & concomitant medications if

clinically indicated

Switch to second-line for•new/recurrent WHO 4

(or multiple WHO 3)

randomise

As per WHO guidelines, switching before 48 weeks discouraged in both arms

IAS July 2009 49

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion e

vent-

free

0 1 2 3 4 5

Years from randomisation (ART initiation)

LCM CDM

Grade 4 AEp=0.18

SAE p=0.20

ART-modifying AEp=0.85

Adverse eventsAdverse events

Grade 3/4 AEp=0.52

IAS July 2009 50

SurvivalSurvival

0.90

0.87

0.92

0.90

0.95

0.94

1494 1445 1395 749CDM1656 1552 1501 1468 1436 796LCM

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion a

live

1660 1542

Years from randomisation (ART initiation)

HR(CDM:LCM) = 1.35 (1.10-1.65) p=0.004

164 eventsLCM: 2.2/100 PYCDM:2.9/100 PY

218 events

Number needed to monitor for 1 year to prevent 1 event =130

IAS July 2009 51

SurvivalSurvival

0.90

0.87

0.08

0.92

0.90

0.18

0.95

0.94

0.55

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion a

live

Years from enrolment

Entebbe Cohort(Uganda):pre-ART 1996-2000, median CD4 75 at enrolment:57.7/100 PY

164 eventsLCM: 2.2/100 PYCDM:2.9/100 PY

218 events

Median Glomerular Filtration Rate (IQR) by Cockcroft-Gault (mL/min) and MDRD

(mL/min/1.73m2) through 6 Years

BL 16 32 48 64 80 96 120 144 168 192 216 240 264 2880

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

Cockcroft-Gault in mL/m in

W EEKS

GLO

ME

RU

LA

RFIL

TR

ATIO

NR

ATE

Modification of Dietin Renal Disease in mL/min/1.73m 2

128 mL/min

117 mL/min/1.73m 2

Baseline CG:116 mL/min; MDRD 112 mL/min/1.73m 2

TDF EAP Risk Factors for Unconfirmed Grade 1 Serum Creatinine Increase

Odds ratio(95% CI)

p-value

Age 1.05 (1.01, 1.09) 0.021

Baseline CD4 – ordinal categories 0.46 (0.30, 0.73) <0.001

Baseline weight 0.94 (0.90, 0.97) <0.001

Nephrotoxic medications taken at baseline

2.40 (1.08, 5.34) 0.032

Nelson M, et al. 13th CROI, 2006; #781.

Multivariant Analysis

-10

-5

0

5

10

15

0 4 48 96

NVP-NORA

ABC-NORA

NVP

TDF

Weeks

Mean GFR change (ml/min/1.73m2)

GFR changefrom baseline

(global p value <0.0001)

Regimen

NVP-N +6.8 +10.1 +8.8

ABC-N +1.2 +6.6 +4.8

NVP +1.1 +3.4 -0.9

TDF -1.2 -2.5 -2.2Reid AJC, et al. XVI IAC (2006). Abst. THAB0105.

DART: Predicted GFR Over Time by Regimen

DART: Changes in eGFR and Incidence of CKD to Week 216

First Line ARVs

Mean Baseline

GFRml/min/1.73

m2 (IQR)

Adjusted mean GFR change to week 216

ml/min/1.73m2 (IQR)*

TDF 90 (75-107) +2 (+1, +3)

NVP 89 (76-103) +7 (+5, +9)

ABC 80 (70-98) +6 (+3, +9)

Reid A, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUPEB184.

CKD= confirmed <60 ml/min/1.73m2 or 25% drop if <60 at baseline. *p<0.001 between TDF and other arms (ANOVA)

Overall 5.0% (4.3-5.8%)

By first-line ART:TDFNVPABC

5.9% (5.0-6.9%)2.1% (1.2-3.7%)3.1% (1.6-5.8%)

p=0.0004

By TDF:Never on TDFEver on TDF

2.0% (1.2-3.4%)5.8% (4.9-6.7%)

p=0.0001

By randomisation:LCMCDM

5.0% (4.0-6.2%)5.0% (4.0-6.2%)

p=0.99

Incidence of CKD (n=162)Changes in eGFR

LipoatrophyDyslipidaemia/CHD Hepatic

GastrointestinalRenal Bone density

HAART: Not Without Toxicity

LipoatrophyDyslipidaemia/CHD Hepatic

GastrointestinalRenal Bone density

HIV: Not Without Toxicity