RenalPhosphate WastingandIncreasedBoneTurnoverin TDF-Treated

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					                                                   Renal Phosphate Wasting and Increased Bone Turnover in TDF-Treated                                                                                                                                                                           Poster 749
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                                                  Patients are not mediated by Low 25(OH) Vitamin D or Hyperparathyroidism
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kl                                             Sebastian Wirz1, Samuel Rubeli1, Anna Christen1, Albrecht Popp2, Carlo Largiadèr3, Nicolas Mueller4, Alexandra Calmy5, Hansjakob Furrer1, Christoph Fux1
                                                                                                           and the Swiss HIV Cohort Study
                                                                                                                                                                                                                                                                                                  Sebastian Wirz, MD
                                                  1University   Clinic for Infectious Diseases, University Hospital Bern and University of Bern, 2Outpatient Clinic for Osteoporosis, University Hospital Bern, 3Department of Laboratory Medicine, University Hospital Bern,                     sebastian.wirz@insel.ch
                                                                                    4University Clinic for Infectious Diseases, University Hospital Zürich and 5University Clinic for Infectious Diseases, University Hospital Geneva, Switzerland




                                • Tenofovir (TDF)-use has been associated with proximal renal                                         Correlations between renal, bone and endocrinologic parameters
                                  tubulopathy (PRT), in particular renal phosphate loss, as well as

     Background                   increased bone turnover with an increase in serum alkaline
                                  phosphatase (sAP) and a reduction in bone mineral density
                                • The link between renal and bone pathologies and the role of key
                                                                                                                                      Hypophosphatemia
                                                                                                                                      n = 32 (15%)
                                                                                                                                                                                          Trend towards lower phosphatemia in TDF-treated patients (multivariable analysis, p=0.06)

                                  regulators of phosphate homoeostasis are unknown
                                                                                                                                      Pathological TmPO4/GFR                              Positive correlation with TDF treatment (p=0.01) and caucasian race (p=0.03) in multivariable analysis
                                                                                                                                      n = 45 (21%)
                                • To correlate phosphatemia, renal phosphate reabsorption and
                                  sAP, a surrogate of obsteoblast activity with regulators of bone                                    sAP                                                 Positve correlation with TDF (p=0.001), IDU (p=0.03) and the time since HIV diagnosis (p=0.04) in
              Aims                metabolism and phosphate (Figure 1) including vitamin D,
                                  parathyroid hormone (PTH) as well as fibroblast growth factor–23                                                                                        multivariable analysis
                                  (FGF-23), the main phosphatonin, in HIV-positive patients.                                                                                              In patients not treated with TDF and/or PIs, there is a positive correlation with PTH levels (p=0.006)

                                                                                                                                      25(OH) vitamin D deficiency                         Positive correlation with caucasian race (p=0.02) and PI use (p=0.009); negative correlation with IDU
                                • We performed a cross-sectional analysis in 215 consecutive                                          (<30 nmol/L)                                        (p=0.002), AIDS (p=0.002) in multivariable analysis. EFV-use associated with lower values as
      Patients &                  HIV-positive patients (Table 1) treated within the Swiss HIV
                                  Cohort Study (SHCS) measuring the parameters cited below.
                                                                                                                                      n=89 (41%)                                          compared to NVP: 31 (14-53) vs 55 (29-77) nmol/L, p=0.01
                                                                                                                                                                                          Negative correlation with phosphatemia (p=0.02) and TmPO4/GFR (p=0.005) (Figure 2)
                                • We correlated laboratory results with patient characteristics, in
       Methods                    particular treatment regimens, to identify risk factors for renal
                                  phosphate wasting and increased bone turnover.                                                      Hyperparathyroidism                                 Positive correlation with age (p=0.03), IDU (p<0.001) and AIDS (p=0.002) in multivariable analysis
                                                                                                                                      n = 13 (6%)                                         Positive correlation with hypophosphatemia (p=0.03), but not with a pathological TmPO4/GFR
                                                                                                                                                                                          negative correlation with phosphatemia and TmPO4/GFR (p=0.02 each) (Figure 3).
                               •   Phosphatemia                           ≥0.8 mmol/L
                               •   TmPO4/GFR (Bijvoet formula)            ≥0.8                                                        FGF – 23                                            No association with baseline characteristics, in particular TDF, in multi-variable analysis
                               •   sAP                                    36-108 IU/L                                                                                                     Trend for lower FGF-23 with pathological TmPO4/GFR (p=0.06)
     Parameters                •
                               •
                                   25(OH) vitamin D
                                   1,25(OH)2 vitamin D
                                                                          30 – 113 nmol/l
                                                                          48 – 160 pmol/l
                                                                                                                                                                                          In PI-treated patients: Significant negative correlation with pathological TmPO4/GFR: FGF-23
                               •   PTH                                    15 – 65 pg/ml                                                                                                   reduction from 25 (17-36) to 14(5-19) vs. 23(11-42) to 21(7-38) (p=0.004)
                               •   FGF–23                                                                                                                                                  In PI-treated patients: Significant negative correlation with hypophosphatemia: FGF-23 reduction
                                                                                                                                                                                          from 24 (16-36) to 14(5-18) vs. 22(8-42) to 22(14-37) (p=0.007)


                                                                                                                                   Figure 2.                                                              Figure 3.                                                   Figure 4.
                                                                                            FGF-23



     Table 1: Patient
     Characteristics (n=215)
Male sex                    140 (65%)
Age in years               46 (39 - 49)
Caucasian                   171 (80%)
BMI (kg/m2)               23.5 (22 - 26.5)
eGFR MDRD (ml/min)        100 (87 - 114)
                                                        Figure 1:
Transmission HET             94 (44%)
                                                        phosphate regulation
                IDU          30 (14%)
                MSM          76 (35%)
                OTHER        13 (6%)                                                                                                                                                                                                                                              Conclusions
                                                     Group       cART       PO4 Serum      PO4 Serum       OR        TmPO4/GFR     TmPO4/GFR        OR          25(OH) Vit. D        OR          Hyper-        OR           sAP IU/L     Linear regression
Years of known HIV        9.2 (4.2 - 15.5)
                                                      (n)                  mmol/L (IQR)   <0.8 mmol/L   (95% CI)       (IQR)          <0.8       (95% CI)        Deficiency       (95% CI)        PTH       (95% CI)          (IQR)       Coeff. (95% CI)
Previous AIDS                50 (23%)
Treated                     176 (82%)                 1 (39)     Naïve          1.05           8%           1            1.07         3%             1              31%               1           3%            1          60 (51–71)            1
                                                                                                                                                                                                                                                               • TDF is associated with PRT and may lead to renal
                                                                            (0.95–1.14)                              (0.92–1.26)
Years of cART             5.3 (1.5 - 11.1)                                                                                                                                                                                                                       phosphate wasting
                                                      2 (40)     TDF+           0.93          23%          3.5           0.85        38%       22.8 (2.8–184)       38%         1.4 (0.5–4.4)     10%     4.2 (0.5–39.6)   87 (71–103)   26.9 (12.1 to 41.6)
VL <50 copies/ml            155 (88%)                           NNRTI+      (0.82–1.07)                 (0.9–14)      (0.73–0.1)
                                                                                                                                                                                                                                                               • TDF-related hyperphosphaturia is neither mediated by
CD4/µl                    460 (334 - 655)             3 (51)     TDF+           0.97          21%           2.6          0.90        25%       13 (1.6–104)         34%         1.5 (0.6–3.5)     7%      2.4 (0.2–23.8)   78 (63–96)    31 (16.8 to 45.2)       25(OH) vitamin D deficiency nor by hyperparathyroidism
                                                                  PI+       (0.85–1.07)                 (0.6–10.2)   (0.79–1.16)
Treatment naive              39 (18%)
                                                      4 (32)     TDF-          0.97           19%           2.2          0.98        22%       10.6 (1.2–91)        41%         1.5 (0.6–4.1)     6%      2.5 (0.2–29.3)   74 (61–85)    14.3 (-0.8 to 29.3)   • The correlation of higher vitamin D / PTH values with
TDF & NNRTI                  40 (19%)                           NNRTI+      (0.84–1.1)                  (0.5–10.1)   (0.81–1.12)                                                                                                                                 lower phosphatemia / higher phosphaturia is physiologic
TDF& PI                      51 (24%)                 5 (34)     TDF-           1.0           17%          2.1           1.01        18%        8.1 (0.9–71)        44%         1.8 (0.7–4.6)     5%      2.4 (0.2–27.4)   69 (60–85)    15.8 (0.2 to 31.3)
                                                                  PI+       (0.9–1.12)                  (0.5–9.4)    (0.88–1.19)                                                                                                                               • PI-treated patients, but not NNRTI/ TDF-treated patients
NNRTI                        32 (15%)
                                                      6 (19)     TDF-           1.11           6%          0.7           1.08        16%        7.1 (0.7–74)        71%         6.3 (1.8–21.5)    5%      2.1 (0.1–35.7)   58 (49–76)    5.3 (-13.0 to 23.6)
                                                                                                                                                                                                                                                                 showed a significant compensatory drop of FGF-23 in
PI                           34 (16%)                           NNRTI-      (0.91–1.17)                 (0.1–6.9)    (0.94–1.26)
                                                                                                                                                                                                                                                                 case of hypophosphatemia or a pathologic TmPO4/GFR
Triple NRTI without TDF      19 (9%)                              PI-

				
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