1. Adynamic Bone Disease Begins before Dialysis The 25 th Annual Dialysis Conference in Tampa Akihide Tokumoto, M.D. San-in Rosai Hospital, Yonago, Japan

2. The prevalence of adynamic bone disease (ABD) has risen alarmingly, especially in the treatment of 2nd HPT by use of Vitamin D agents. On the other hand, the natural occurrence of ABD in the progression of ESRD exists without therapeutic intervention. We investigated the characteristics of ABD with bone biopsies performed at initiation of dialysis in order to gain an insight into the prevalence of ABD in the pre-dialysis stage. Aims 2 nd HPT ABD Vitamin D over-treatment Trade-off hypothesis Skeletal resistance of PTH BMP-7 deficiency ? progression of ESRD

3. From March 1996 to May 2004, 171 dialysis patients (pts) were evaluated with bone histology. 41 pts had received long-term dialysis and 130 pts were biopsied 1 month after start of maintenance dialysis. The last group of pts made up 60% of the total pts who entered maintenance dialysis in the same period. Dialysis modalities were 130 pts on hemodialysis and 41 pts on peritoneal dialysis. Dialysate calcium was 3.0 mEq/l in hemodialysis and 3.5 mEq/l in peritoneal dialysis. Vitamin D and Ca containing phosphate binder were given in 19 and 26 pts on long-term dialysis and 1and 1 pt at the initiation of dialysis, respectively. Within one week of bone biopsy, blood specimens were drawn to determine serum calcium, intact PTH using the Nichols IRMA (the Nichols Advantage intact PTH assay was NOT used), bone alkaline phosphatase (BAP, Metra Biosystems), and Osteocalcin (Mitsubishi, Japan). Bone specimens were obtained at the iliac crest vertically. The histological examination was performed by Dr. Takahashi of the Niigata Bone Science Institute in Japan and histological subtypes were defined according to the classification by Dr. Sherrard (Kidney Int 43:436-442,1993). Methods Fb.V/TVOV/BVBFR/BV adynamic bone (ABD)<0.5%<15%<3.9%/y mild lesion (ML)<0.5%<15%>3.9%/y osteitis fibrosa (OF)>0.5%<15%- mixed type (Mix)>0.5%>15%- osteomalacia (OM)<0.5%>15%- Subjects

4. At initiation of dialysis (n=130) On maintenance dialysis (n=41) OM Mix OF ML ABD Approximately the Same Distribution of Histological Subtypes of Renal Osteodystrophy at Initiation of & After Long Term Dialysis Results

5. Chronic glomerulonephritisDiabetes mellitus In the chronic glomerulonephritis group, bone turnover was prone to decrease over the course of maintenance dialysis. initiation of dialysis (n=43) maintenance dialysis (6) initiation of dialysis (n=55) maintenance dialysis (30) Mix ML ABD OF OM OF OM intact PTH (pg/ml) 290 162 - 480 200 150 - 330 140 28 - 200 145 51 - 261 median Inter quartile range

6. Bone metabolic markers of ABD were not significantly different from those of mild lesion. Total (n=130) ABD (37) ML (60) OF (22) Mix (8) OM (3) Age, years61±1465±1362±1157±1850±1767±4 M/F83/4726/1140/209/136/22/1 Diabetes pts33(28%)17 (46%)21 (35%)3 (15%)0 (0%)2 (67%) HD/PD96/3429/843/1715/76/23/0 Ca, mg/dl9.0±0.8 9.2±0.78.8±0.88.1±0.78.4±0.5 iPTH, pg/ml302±243230±176241±144443±234 b 728±515 b 240±92 BAP, U/l 43±90 (n=88) 29±17 (29) 31±1 (35) 39±20 (14) 167±307 b (7) 51±28 (3) OC, ng/,ml 47±39 (n=95) 29±25 (27) 40±24 (43) 66±35 a (19) 125±107 b (4) 85 (1) a P <0.05 vs. ABD b P <0.01 vs. ABD by Scheffe post hoc test Patient demographics and biochemical profiles according to histological subtypes of renal osteodystrophy at initiation of dialysis

7. At initiation of dialysis On maintenance dialysis Pts with ABD at initiation of dialysis presented with lower serum calcium levels than those pts with ABD who were on long-term maintenance dialysis. * [ * [ ** [ * * * p <0.001 * p <0.05 (Mann-Whitney test) Ca, mg/dl

8. At initiation of dialysis On maintenance dialysis Pts with ABD at initiation of dialysis presented with higher serum intact PTH levels than those pts with ABD who were on long-term maintenance dialysis. * [ Intact PTH, pg/ml * P <0.05 (Mann-Whitney test)

9. ABD patient demographics and biochemical profiles at initiation of dialysis versus long-term maintenance dialysis At initiation of dialysis (n=37) On maintenance dialysis (14) p value (Mann-Whitney or Chi-square test) Age, years65±1357±13ns M/F26/119/5ns Duration, months1±0115±61<0.01 DM17(46%)2 (12%)<0.05 HD/PD29/810/4ns Vitamin D therapy04<0.01 Ca containing P binder15<0.01 Ca, mg/dl9.0±0.8 10.0±1.0 <0.01 iPTH, pg/ml median (interquartile range) 230±176 190 (135-238) 234±402 51 (28-170 ） <0.05 BAP, U/l29±18 (n=29) 26±10 (n=6) ns OC, ng/,ml30±23 (n=22)47±67 (n=10)ns Pts with ABD at initiation of dialysis presented with relatively lower calcium and higher intact PTH than those pts who were on long-term maintenance dialysis.

10. Morphometric parameters of ABD at initiation of versus long-term maintenance dialysis At initiation of dialysis (n=37) On maintenance dialysis (14) p value BV/TV, % 20±5 23±8ns ES/BS, % 21±11 10±90.002 OV/BV, % 5.3±3.6 1.9±1.30.001 N.Oc/BS, /mm 1.9±4.4 0.5±1.30.030 Ob.S/BS, % 3.5±6.93.4±4.4 ns Fb.V/BV, % 0.24±0.660.06±0.16 0.022 BFR/BV, %/yr 0.7±1.21.0±1.1 ns Comparing ABD in pts at initiation of dialysis versus ABD in pts on the long-term maintenance dialysis revealed that pts at initiation of dialysis had increased bone resorption with accumulation of osteoid and marrow fibrosis.

11. The Distribution of Intact PTH for Histological Subtypes of Renal Osteodystrophy <150150~300>300 ABD10216 ML172419 OF1615 Mix026 OM021 In only 42% (55/130) of pts at start of dialysis and 51% (21/41) of pts on long- term maintenance dialysis the bone turnover status was accurately diagnosed by the level of serum intact PTH using the current K/DOQI guideline. <150150~300>300 ABD932 ML983 OF013 Mix011 OM011 At initiation of dialysisOn maintenance dialysis 10/37 =27% =Accuracy for intact PTH to diagnose ABD for pts at initiation of dialysis 9/14 =64% =Accuracy for intact PTH to diagnose ABD for pts on long-term dialysis

12. Area Under Curve (AUC) of ROC Curves for PTH Parameters and Bone Metabolic Markers to Diagnosis of Adynamic Bone From the study of 23 pts biopsied at initiation of dialysis Ratio CAP Intact PTH - CAP CAPOCBAPIntact PTH

13. From the study of 23 patients biopsied at start of dialysis Youden Index of Whole PTH for the Diagnosis of Low Turnover Bone Scantibodies Whole PTH, pg/ml (CAP)

14. From the result of 38 bone biopsies in our facilities (Japan) and Beth Israel Medical Center (Dr. Amerling, New York) Cut-off Values of PTH parameters to Predict Bone Turnover Status Whole PTH LowNormalHigh 110212 pg/ml Total PTH LowNormalHigh 175509 pg/ml Ratio LowNormalHigh 1.471.69

15. Almost the same prevalence of ABD was found at initiation of dialysis versus long-term maintenance dialysis. ABD patients presented at initiation of dialysis with relatively lower calcium and higher intact PTH compared to those on long-term maintenance dialysis. It was difficult to diagnose ABD by conventional bone metabolic markers at the initiation of dialysis. Whole PTH (CAP) and Whole PTH/7-84 PTH ratio were more accurate in identifying ABD at initiation of dialysis. Conclusions