Tenofovir and kidney

Dr Ameet DravidM.D Medicine, AAHIVS (USA)

Ruby Hall Clinic, Pune

Introduction• India has the second highest population of HIV positive patients in

the world which stands at 2.1 million out of which 600,000 patients are on antiretroviral therapy.

• Tenofovir based antiretroviral therapy is increasingly used for treatment naïve and treatment experienced patients in India over the last 5 years as per recommendation by national guidelines

• It has coincided with availability of generic fixed dose combinations of Tenofovir/emtricitabine(TE), Tenofovir/Emtricitabine/Efavirenz(TEE) and Tenofovir/Lamivudine/Efavirenz(TLE).

• Tenofovir was considered safe and well tolerated due to rarity of side-effects observed in phase 3 clinical registrational trials.

• Structural similarity to adefovir and cidofovir• However the experience in “real world” clinical settings is different

Spectrum of kidney injury

• Proximal renal tubular injury - Fanconi syndrome

• Isolated hypophosphatemia• Reduced bone mineral density• Acute kidney injury• Chronic kidney disease

Fanconi syndrome• With or without reduced GFR• Tubular dysfunction is seen in 17-20% of TDF treated patients• Normal anion gap renal tubular acidosis• Normoglycemic glycosuria• Aminoaciduria• Hypokalemia• Hypophosphatemia• Nephrogenic diabetes insipidus• Calcitriol deficiency• Hypouricemia• Tubular proteinuria : Beta 2 microglobinuria

Diagnosis of Fanconi syndrome

• Dipstick test for spot proteinuria, spot glycosuria

• Protein creatinine ratio > 200 mg/g• Urinary Beta 2 microglobulin estimation• Urinary Retinol binding protein or Cystatin C

estimation

Tenofovir and Acute kidney injury (AKI)

• Tenofovir is associated with small but significant risk of AKI (incidence 1-2.5%)

• Inhibition of mitochondrial DNA polymerase in proximal tubular epithelial cells leads to acute tubular necrosis and tubulointerstitial scarring.

• May be observed even a few months after TDF initiation• Non oliguric renal failure• Incidence of AKI is higher in observational cohort studies as

compared to randomized controlled trials• Renal function recovers on discontinuation atleast partially

Acute kidney injury : Definition

• AKIN criteria : • Rapid time course (less than 48 hours)• Absolute increase in serum creatinine > 0.3 mg/dl• Percentage increase in serum creatinine > 50 %• Decrease in urine output < 0.5 ml/kg/hr for 6 hours• Rifle criteria :• Injury : GFR decrease > 50 %, doubling of serum creatinine or

urine output < 0.5 ml/kg/hr for 12 hours• Failure : GFR decrease > 75 %, tripling of serum creatinine or

urine output < 0.3 ml/kg/hr for 24 hours

Predictors of renal function decline

• Pre-existing renal impairment• Older age• Low body weight• Low CD4 count• Hepatitis C co-infection• Diabetes mellitus• Concomitant use of nephrotoxic drugs• Use of protease inhibitors with Tenofovir

Tenofovir associated acute kidney injury (AKI) in the Indian context

Tenofovir nephrotoxicity in resource limited setting of Western India : Higher rate of renal function decline, acute kidney injury and progression to

chronic kidney disease compared to Western data

A.Dravid1,A.Sadre2,S.Dhande1, A.Borkar1,M.Kulkarni1,M.Dravid3

IAS 2013, Kualalumpur, Malaysia

Study overview• Retrospective observational cohort design• Tenofovir was initiated in patients with Creatinine Clearance (Cr Cl) > 50 ml/min. • Patients started on Tenofovir at baseline Cr Cl < 50 ml/min were excluded.• Annual decline in GFR was calculated by CG formula and MDRD equation for

Tenofovir containing and Tenofovir sparing regimens.• Acute Kidney Injury was defined as Serum creatinine > 2 mg/dl, Cr Cl decrease to

< 50 ml/min or Cr Cl decrease > 50% of baseline (Rifle criteria 2002). • Patients with GFR value < 60 ml/min(MDRD equation), 3 months after Tenofovir

discontinuation were classified as having Chronic kidney disease (CKD). • Presence of co morbidities which increase incidence of renal toxicity like diabetes

mellitus, hypertension, use of concomitant nephrotoxic drugs, obstructive uropathy and urinary tract infecton were recorded.

• Angiotensin converting enzyme inhibitors(ACEI), Non steroidal anti-inflammatory drugs(NSAID’s), Amino glycosides and Amphotericin B were the nephrotoxic drugs studied.

• Obstructive uropathy included conditions like renal calculus disease, urethral stricture and benign prostatic hypertrophy.

Baseline characteristicsTDF containing regimens TDF sparing regimens

Total number 743 340

Age (Mean yrs) 43 yrs 39.5 yrs

Sex (M: F) 68 : 32 62 : 38

Median Baseline CD4 count 168 cells/mm3 121 cells/mm3

Weight (kg) 55.45 kg 52.2 kg

Serum Creatinine 0.85 mg/dl 0.8 mg/dl

GFR (CG) mean 87.7 ml/min 84.51 ml/min

GFR (MDRD equation) mean 96.04 ml/min 100.04 ml/min

Baseline OI 36.6 % 23.2 %

Mean duration of F/U 21 months 33 months

Baseline GFR valuesGFR by CG formula No of patients GFR by MDRD

equationNo of patients

50-70 ml/min 214 30-60 ml/min 22

71-90 ml/min 233 61-90 ml/min 266

91-120 ml/min 218 91-120 ml/min 328

>120 ml/min 78 >120 ml/min 127

TDF containing antiretroviral regimens

247285

56

138

170

50

100

150

200

250

300

No of patients

No of patients

Tenofovir and Acute kidney injury

• Number of patients who developed AKI : 36/743 (4.8%)

• Time to developing AKI• < 6 months : 16• 6 – 12 months : 5• 12 -24 months : 8• > 24 months : 7• Median time to developing AKI : 8.5 months.• Number of patients requiring haemodialysis : 3/36

(8.33 %)• Number of patients who died : 4/36 (11.11 %)

Analysis of risk factors which increase Tenofovir toxicity by multiple logistic regression

Risk factor Number of patients Number of patients developing AKI

P value by multiple logistic regression

Creatinine clearance 50-70 ml/min

214 22 P = 0.01

CD 4 count < 100 cells/mm3

258 22 P = 0.002

Tenofovir with PI 155 17 P = 0.042

Diabetes mellitus 48 9 P = 0.69

Hypertension 65 5 P = 0.105

Concomitant nephrotoxic drugs

56 12 P = 0.031

Obstructive uropathy 37 11 P = 0.001

Tenofovir associated renal dysfunction in clinical practice : an observational cohort from Western India

• Ketan Patel, Atul Patel et al. Indian Journal of Sexually transmitted diseases (IJSTD) 2010.

• Incidence of renal dysfunction in patients on Tenofovir containing ART 6.53 %

• Renal dysfunction more common with TDF + Protease inhibitor (9.44%) as compared to TDF + NNRTI (5.01 %).

• Serum Creatinine normalized in all patients after discontinuing Tenofovir

Tenofovir and chronic kidney disease/ESRD

• In randomised controlled trials , increased risk of chronic kidney disease or end stage renal disease (ESRD) requiring dialysis in patients exposed to Tenofovir as compared to other antiretroviral drugs is not observed.

• However in observational cohort studies Tenofovir is strongly associated with adverse renal outcomes including CKD (eGFR < 60 ml/min/1.73 m2 BSA,MDRD formula)

• Decline in GFR of 7-10 ml/min/year has been described in patients on Tenofovir

• Age related GFR loss is 1 ml/min/year• So in effect, eGFR decline seen in patients taking Tenofovir

based ART cohort studies is similar to that seen in patients suffering from diabetic nephropathy.

Tenofovir nephrotoxicity in resource limited setting of Western India : Higher rate of renal function decline, acute kidney injury and progression to

chronic kidney disease compared to Western data

A.Dravid1,A.Sadre2,S.Dhande1, A.Borkar1,M.Kulkarni1,M.Dravid3

IAS 2013, Kualalumpur, Malaysia

eGFR decline on follow up for entire cohort

Baseline 12 months 24 months 36 months 48 months

Number of patients completing F/U

743 553 274 132 56

Mean GFR by CG formula

87.7 ml/min 91.04 ml/min

91.70 ml/min

92.36 ml/min

92.12 ml/min

Mean GFR by MDRD equation

96.04 ml/min

89.14 ml/min

84.92 ml/min

82.87 ml/min

84.52 ml/min

GFR baseline – GFR F/U by MDRD

equation

6.4 ml/min

5.82 ml/min

4.23 ml/min

-0.22 ml/min

eGFR decline on follow up (TDF + NNRTI vs TDF + PI)

12 months 24 months 36 months 48 months

Number of patients 404 196 90 38

GFR decline in TDF + NNRTI by MDRD equation

(ml/min)

5.5 ml/min 6.3 ml/min 4.19 ml/min 0.9 ml/min

Number of patients 93 55 28 9

GFR decline in TDF + PI by MDRD equation (ml/min)

11.75 ml/min 7.04 ml/min 7.33 ml/min - 2.7 ml/min

Follow up GFR decline

• Mean decline in GFR in Tenofovir exposed cohort : 5.29 ml/min/year

• Mean decline in GFR in patients exposed to TDF + NNRTI only : 4.18 ml/min/year

• Mean decline in GFR in patients exposed to TDF + PI only : 9.19 ml/min/year

• Mean decline in GFR in patients exposed to Tenofovir sparing regimens : 2 ml/min/year

Recovery of renal function post Tenofovir withdrawal and progression to grade 3-5 chronic kidney disease

• Out of 36 patients who developed AKI, 18 patients completed 6 months of follow up post Tenofovir cessation.

• 4 patients died and 2 were lost to follow up.• Only 2 patients had Serum creatinine >2 mg/dl, 6 months

after Tenofovir withdrawal.• None of the patients have required long term renal

replacement therapy as of now.

Increased Risk and Faster Progression of Renal Impairment With TDF-containing Regimens amongst Indian HIV Patients: A Comparative Cohort

Analysis Between Western India and the United Kingdom.Sanjay Pujari et al CROI 2013

Prevention and treatment of Nephrotoxicity

• HIVMA/IDSA guidelines : serum creatinine,creatinine clearance, eGFR, serum phosphorus, proteinuria and glycosuria every 4 months in patients on Tenofovir.

• Urine dipstick assays to identify early tubular damage• Tenofovir withdrawal leads to reversal of toxicity in

majority of patients• Modify the Tenofovir molecule : Tenofovir alefamide

fumarate (TAF)

Conclusions• There is higher incidence of acute kidney injury and amongst our Tenofovir

exposed population compared to that seen in Western resource rich settings.

• This could be attributable to lower baseline creatinine clearance, lower eGFR, lower baseline CD4 count and higher incidence of co-morbidities in our population

• Recovery of eGFR after withdrawal of Tenofovir is incomplete in significant proportion of patients. GFR decline in patients on Tenofovir is higher than those on Tenofovir sparing regimens. This leads to increased risk of progression to stage 3-5 Chronic kidney disease.

• Regular monitoring of all patients exposed to Tenofovir to assess glomerular or tubular dysfunction can help us identify toxicity early and take corrective action

• Finally, management of Tenofovir nephrotoxicity in resource limited settings like India is tough due to limited access to routine laboratory monitoring, renal replacement therapy and alternate antiretroviral drugs like Abacavir.

THANK YOU