1. Kidney and bone disease in HIV
Dr Frank Post
Clinical Senior Lecturer
King’s College London

2. Case 1 (October 2004) 33 yrs old lady – Zimbabwe
New HIV diagnosis; CD4 1 and HIV RNA 530,000
Disseminated tuberculosis
HBV/HCV negative
Creatinine 300; eGFR 20 mL/min; Proteinuria 5 g/24h
Normal sized, echogenic kidneys
HIVAN on biopsy
Commenced cART – current CD4 450, VL<40
Required dialysis for 4 weeks – current eGFR 50 mL/min

3. HIV-Associated Nephropathy (HIVAN)
Black ethnicity
CD4 <250 cells/L
Large, echogenic kidneys
Heavy proteinuria
Associated Focal and Segmental
Glomerulosclerosis in the Acquired
Immunodeficiency Syndrome
T. K. Sreepada Rao et al.
N Engl J Med 1984; 310:
AIDS 2004; 18: 541-6, Nat Genet. 2008; 40:

4. HIVAN in the UK (1998-2004) 16,834 patients Overall survival
HIVAN prevalence in Black patients: 0.93%
HIVAN incidence (in patients without renal disease at BL): 0.61/1000 py
Overall survival
Renal survival
Clin Infect Dis 2008; 46:

5. Natural History of HIVAN
Cohort of 42 patients with HIVAN and 47 patients with renal diseases other than HIVAN
Use of HAART associated with slower progression to RRT
Cohort of 36 patients with HIVAN
Complete suppression of HIV replication may slow progression to RRT
Kidney Int 66: 1145 (2004)
Nephrol Dial Transplant 2006; 21: 2809

6. ESRD>3 months after HIVAN diagnosis (n=20)
Characteristics of HIVAN patients with late onset ESRF / stable renal function
Baseline
ESRD>3 months after HIVAN diagnosis (n=20)
Stable RF
(n=23)
eGFR (mL/min)
28 (12-42)
29 (17-38)
Proteinuria (g/24h)
5.9 ( )
4.9 ( )
CD4 T-cell count
66 (39-140)
77 (34-197)
cART
CD4>200
VL<50
Clin Infect Dis 2008; 46:

7. Renal Disease in HIV infection
77 Renal biopsies
(Johns Hopkins, USA)
(89% African American)
HIVAN %
FS (non-collapsing) GN %
Immune complex GN %
Interstitial nephritis %
Thrombotic % microangiopathy
Amyloidosis (AA) %
Hypertensive nephropathy 1%
99 Renal biopsies
(Baragwanath Hospital, South Africa)
HIVAN %
FS (non-collapsing) GN %
Immune complex GN %
Membranous GN %
Post-infectious/IgA GN %
Other GN’s %
Other %
Haas et al, Kidney Int 67: 1381 (2005)
Gerntholtz et al, Kidney Int 69: 1885 (2006)

8. Case 2 (March 2005) 34 yrs old lady – Finland
New HIV diagnosis; CD4 38 and HIV RNA 120,000
Diabetes mellitus (retinopathy)
HBV/HCV negative
Creatinine 629; eGFR 7 mL/min; Proteinuria 2 g/24h
Normal sized kidneys
Diabetic nephropathy
Commenced cART – current CD4 663, VL<40
Required permanent dialysis – renal transplant 2008
current eGFR 48 mL/min

9. HIV/ESRF in UK CHIC
All patients with permanent RRT in UK CHIC ( )
68 (0.31%) of 21,948 patients had ESRF
AIDS 2009; 23:
Black patients (44)
HIVAN 36
Vascular/HPT 1
Glomerulonephritis
Diabetes
Congenital
Unknown
Confirmed %
White/other patients (24)
Vascular/hypertension 7
Glomerulonephritis 5
Diabetes 4
Amyloid 3
Congenital 2
Unknown 3
Confirmed % 9

10. Patient characteristics (N=21948)
ESRF
No ESRF
P-value1 N 68
21883
Age (years), median (IQR)
36 (31, 41)
34 (30, 40)
0.13
Female, N (%)
20 (29.4)
4707 (21.5)
Black ethnicity, N (%)
44 (64.7)
5418 (24.8)
<0.0001
Prior AIDS diagnosis, N (%)
25 (38.5)
4902 (22.4)
0.005
CD4 nadir (cells/mm3), median (IQR)
72 (27, 157)
179 (71, 300)
HBV+, N (%)
4 (5.9)
1679 (7.7)
0.58
HCV+, N (%)
5 (7.4)
1594 (7.3)
0.98
1 Obtained by Chi-squared and Mann Whitney tests
AIDS 2009; 23: 10

11. Characteristics of those with ESRF by HIVAN status (N=65)
Other
P-value N 35 30 -
Age (years), median (IQR)
35 (29, 39)
42 (37, 48)
0.001
Female, N (%)
15 (42.9)
4 (13.3)
0.01
Black ethnicity, N (%)
35 (100.0)
7 (23.3)
<0.0001
Prior AIDS diagnosis, N (%)
16 (45.7)
9 (30.0)
CD4 nadir (cells/mm3), median (IQR)
70 (29, 144)
72 (25, 190)
0.67
HBV+, N (%)
2 (5.7)
2 (6.7)
0.87
HCV+, N (%)
1 (2.9)
0.11
Baseline eGFR (mL/min), median 11 50
Time HIV-pRRT (days), median (IQR)
196 (0, 1035)
2171 (1574, 3668)
AIDS 2009; 23: 11

12. Prevalence of HIV/ESRF and survival on pRRT
In the UK
The incidence of ESRF was approximately 5-10 fold lower than in the USA
Survival of black patients was markedly better than in the USA (97% v 43% at 2 years)
AIDS 2009; 23:

13. Black ethnicity and low current CD4 cell count are risk factors for HIV/ESRF
AIDS 2009; 23:

14. Case 3 (April 2010) 59 yrs old man – Uganda
HIV diagnosis 1995; CD4 354 and HIV RNA 53,000
HBV/HCV negative
d4T/ddI/NVP
AZT/3TC/NVP
2002 onwards: TFV/3TC/NVP TFV/FTC/NVP
CD , VL<50 (3 blips, 2 rebounds)
2010:
General malaise
Severe acute renal failure (dialysis)
Interstitial nephritis: response to corticosteroids

15. Steroids
Proteinuria 2g/d

16. ARF in a multi-ethnic UK HIV cohort
Associated aetiology
<3 months >3 months
Pre-renal state % %
Nephrotoxic agents % %
NSAIDs % %
Mortality 30%
Clin Infect Dis 2008; 47: 242-9

17. Effects of current CD4 cell count and current eGFR on ARF incidence10 20 30 40
Rate (per 100 person years)
0-50
51-100
>350
Current CD4 cell count 10 20 30
<60
61-74
75-89
≥90
Current eGFR (ml/min/1.73m2)
Ibrahim et al, AIDS 2010

19. Case 4 (April 2006) 28 yrs old man – Portugal
HIV diagnosis 1998; CD4 54 and HIV RNA >500,000
HBV/HCV negative
AZT/3TC/EFV d4T/ddI/IDV/r
2002 onwards: TFV/d4T/LPV/r TFV/d4T/ATV/r
2006:
Painful ribcage, lumbar spine and metatarsal joints
Raised ALP (227), hypophosphatemia (0.47)
Normal creatinine / eGFR
3+ glycosuria (no DM), 1+ proteinuria (PCR 14.7)
Reduced fractional excretion of P (57%)
Normal vitamin D and PTH

20. Fanconi syndrome Prevalence: 1-2% of patients receiving Tenofovir
Bone pain
Phosphate wasting
Osteomalacia
Almost exclusively
when tenofovir is
co-administered with
a (boosted) PI 20

21. Tenofovir-associated renal toxicity
100% of patients had evidence of reduced phosphate re-absorption
HIV8, Glasgow 2006

22. KTD in HIV infected patients
284 consecutive HIV patients
Median creatinine clearance mL/min
22% of 154 on TFV
6% of 49 on cART/no TFV
12% of 81 no cART
AIDS 2009;23:689-96

23. Risk factors for KTD while receiving tenofovir
Role of polymorphisms in genes encoding drug transporters
Curr Opin Infect Dis 2009; 22: 43-48
Clin Infect Dis. 2009;48:e108-16

24. Effects of cART on renal function
AZT/3TC/NVP or AZT/3TC/TFV
Clin Inf Dis 2008;46:
AIDS 2008;22:481-7
Clin Inf Dis 2008;46: , AIDS 2008;22:481-7, AIDS 2009; 23:

25. cART and CKD progression
Mocroft et al. AIDS 2010

26. Proteinuria in the ALLRT cohort (n=2857)
Prevalence 16% (>200 mg/d; 3% > 1 g/d)
Little change in the amount of proteinuria over time
Associated with: older age, HPT, DM, reduced eGFR
reduced CD4, prior ART, HIV viraemia, HCV co-infection
Antivir Ther 2009; 14:

27. Proteinuria as a marker of chronic kidney disease in HIV
Proteinuria in 2057 HIV+ women:
Prevalence (2x dipstix 1+): 32%
Risk factors for proteinuria (OR):
Log HIV RNA 1.05*
CD4 < *
Black ethnicity 2.00*
HCV antibody 1.27*
* p<0.0001
Proteinuria is a risk factor for
Renal failure (doubling serum creatinine)
Death (RHadj = 2.9, p<0.0001)
JAIDS 32: 203 (2003)
Kidney Int 61: 195 (2002)

28. Reduced eGFR, albuminuria, and (cardiovascular) mortality
Lancet 2010; 375: 2073

29. Reduced eGFR, albuminuria, and cardiovascular events in HIV
Case control study (JH cohort)
median eGFR: cases 69 mL/min controls 103 mL/min (p<0.001)
Increased risk of MI with lower eGFR: OR 1.2 ( ), p=0.004 per 10 mL/min reduced
AIDS 2010; 24:
Circulation 2010; 121: 29

30. Factors associated with low BMD
Osteoporosis: HIV+ v -
cART
Brown, AIDS 2006; 20:
Cazanave, AIDS 2008, 22:

31. Fractures in HIV patients
females
males
8525 HIV-infected and
2,208,792 non-HIV-infected patients (1996 – 2008)
Triant, J Clin Endocrinol Metab 2008, 93:

32. Tenofovir, hypophosphatemia, and BMD
Phosphate levels in patients on TDF versus non-TDF HAART
Changes in hip BMD in patients on TDF versus non-TDF HAART 7
Non-TDF-containing HAART 8 6
TDF-containing HAART 6
TDF+3TC+EFV 5 4
d4T+3TC+EFV
Phosphate level, mg/dl 2 4
Mean change, %
P = 0.06 3 –2 –4 2 –6 1
Preliminary clinical evidence for ARV-specific bone toxicity
Some clinical evidence for ARV-specific bone toxicity is presented.
A small reduction in serum phosphate over 24 months was seen in one study in patients on TDF-containing HAART versus those on non TDF-containing HAART [1].
A reduction in BMD was seen in HIV patients during the first year of TDF- versus non-TDF-containing HAART [2].
The mean change in BMD remained at –2.7% in patients on TDF after 5 years, therefore no significant decrease was observed after 1 year [3].
The long-term significance of these reductions in serum phosphate and BMD are not yet known.
References
Buchacz K, et al. HIV Med 2006; 7:451–456.
Gallant JE, et al. JAMA 2004; 292:191–201.
Cassetti I, et al. for the 903 study team. 8th International Workshop on Adverse Drug Reactions and Lipodystrophy. San Francisco, CA. September 24–26, Abstract P152. –8 3 6 9 12 15 18 21 24 BL 24 48 72 96
120
144
Months from baseline
Weeks
Buchacz K, et al. HIV Med 2006; 7:451–456
Gallant JE, et al. JAMA 2004; 292:191–201

33. Tenofovir, PRTD and BMD
In multivariate analysis, neither tenofovir use (OR 1.32 [ ]) nor
PRTD (OR 1.54 [ ]) were associated with reduced BMD
JID 2009; 200:

34. Changes in BMD in patients initiating EFV with ABC/3TC or TFV/FTC
Changes in markers consistent with other drug-induced fanconi-like syndromes, and can progress to full-blown fanconi’s
Tubular Dysfunction
β2-microglobulin is a low molecular weight protein synthesised in all nucleated cells. Very little is found in the urine of healthy subjects, but levels can increase substantially following renal tubular damage caused by disease or exposure to toxic chemicals. Under normal conditions resorption of beta-mic by proximal tubular cells is almost complete (>99.9%), so any increase above normal levels is indicative of tubular damage
Retinol binding protein transports vitamin A in its alcoholic form (retinol) from the liver to epithelial tissues. Most RBP forms a high molecular weight complex with thyroxin-binding prealbumin, preventing filtration by the glomerulus. After delivering retinol to target tissues RBP loses affinity for prealbumin and is feely filtered by the glomerulus. It is absorbed with an efficiency of >99.9% by the proximal tubular cells and normally very little is found in the urine
Tubular Damage
N-Acetyl-(D)-Glucosaminidase is a lysosomal enzyme present in kidney tubule cells. With a molecular weight of Kd, NAG is not normally filtered at the glomerulus, so its presence in urine is indicative of renal tubular cell injury. It has been shown to be a sensitive indicator of renal injury due to a variety of drugs
<100% is a reduction from baseline, >100% is an increase from baseline

35. ART and changes in BMD Hip LS Hip LS 35 Cooper et al, 16th CROI 2009
* -linear regression
No significant interaction of NRTI and NNRTI/PI components (p=0.69)
Mallon, Curr Opin Inf Dis 2010
McComsey, G et al. 17th CROI Abstract 106LB 35

36. DXA is affected by changes in fat

37. STEAL: Effects on DEXA of change to Kivexa or Truvada

38. Vitamin D status in a London cohort: 91.3% <30 g/L (suboptimal)
73.5% <20 g/L (deficient)
34.8% <10 g/L (severely deficient)
Mueller, AIDS 2010; 24: ; Welz, AIDS 2010

39. Summary
Renal dysfunction is common, although severe kidney disease is relatively rare
Renal dysfunction may impact on cardiovascular and bone health
TFV is associated with progression of CKD and renal tubular dysfunction
Vitamin D deficiency and osteopenia are common, but fragility fractures are rare
TFV/FTC is associated with greater initial bone loss compared to ABC/3TC

40. Acknowledgements King's College London:
Lucy Campbell, Fowzia Ibrahim, Lisa Hamzah, Emily Wandolo, Bruce Hendry
King’s College Hospital:
Chris Taylor, Mary Poulton, Claire Naftalin, Emily Cheserem, Jennifer Roe, Tanya Welz, Rashim Salota, Roy Sherwood, Caje Moniz, Paul Donohoe