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one Disease in Renal Transplantation and Pleotropic Effects ofitamin D Therapy
.M. Sikgenc, S. Paydas, M. Balal, E. Demir, C. Kurt, Y. Sertdemir, F. Binokay, and U. Erken
ABSTRACT
Osteoporosis, osteopenia, and osteonecrosis are common in renal transplant recipients. Inthis study, we evaluated relationship between bone mineral density (BMD) and posttrans-plant duration; creatinine clearance; serum levels of glucose, calcium, phosphorus, alkalinephosphatase, vitamin D (vitD), parathormone, magnesium, C telopeptide, osteocalcin,lipids, and vit D therapy. Eighty five subjects included in this study had a mean age of36.25 � 10.5 years. At least at 6-month intervals we measured femoral neck (FN) andlumbar vertebra (LV) by DEXA and biochemical parameters. VitD was prescribed in 57patients (vitDG). The mean duration of posttransplantation follow-up was 9.82 � 2.72months. T scores (TS) of FN and LV were normal in 29.4% and 21.2%; osteopenia in56.5% and 49.4%; and osteoporosis in 12.1% and 29.4% of patients, respectively. Uponfollow-up, TS improved significantly from �1.58 to �1.46 in FN and from �1.88 to �1.70in LV (P � .05 for both). In patients receiving vitDG, TS improved significantly from�1.74 to �1.61 on FN and from �2.16 to �1.97 on LV (P � .05 for both). Osteocalcin andvitDG levels decreased in all patients (P � .05 for all). Blood urea nitrogen and serumcreatinine increased (P � .05). In VitDG cohort, triglyceride levels decreased (P � .05)with unchanged blood glucose values; but among the other patients, triglycerides wereunchanged but glucose levels had increased (P � .05). Bone disease including osteopeniaor osteoporosis was observed among 70%. During the follow-up period, BMD increasedsignificantly from baseline at 9.82 � 2.72 months. VitD therapy caused more prominentimprovements in BMD and decreases in serum triglycerides as well as mutigated the
increase in blood glucose.
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STEOPOROSIS, OSTEOPENIA, AND OSTEONE-CROSIS are common complications among renal
ransplant recipients. Besides the bone abnormalities ofhronic kidney disease, persistent hyperparathyroidism, im-unosuppressive drugs such as corticosteroids1 and cal-
ineurin inhibitors,2 renal tubular asidosis, and renal func-ion loss cause skelatal abnormalities after renal transplantation.articularly, loss of bone mineral density (BMD) is evident inhe early posttransplant period.3 Appropriate diagnosis andreatment of bone lesions reduces morbidity and mortalityfter renal transplantation In this study, we evaluatedelationships between BMD and posttransplant duration,reatinine clearance, serum levels of glucose, calcium,hosphorus, alkaline phosphatase, vitamin D (vitD),arathormone, magnesium, C-telopeptide, osteocalcin, to-al cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL C), tryglyc-
rides, and vitD therapy. m
041-1345/10/$–see front matteroi:10.1016/j.transproceed.2010.04.054
518
ATIENTS AND METHODS
mong 101 enrolled subjects we excluded from the study the twoho progressed to chronic renal insufficiency and 14 who discon-
inued follow-up, leaving 85 patients including 57 males. Immuno-uppressive treatment consisted of calcineurin inhibitors (tacroli-us or cyclosporine), mycophenolate mophetil (MMF), andethylprednisolone. The drug dosages were stopulated by proto-
ol. We were only changed MMF to azathioprine and calcineurinnhibitors to mammalian target of rapamycin inhibitors (sirolimusr everolimus) due to gastrointestinal adverse effects, hepatotoxic-
ty, thrombocytopenia, or leukopenia. Angiotensin-converting en-yme inhibitors or angiotensin receptor blockers were the first
From the Department of Nephrology, Cukurova University,edical Faculty, Adana, Turkey.Address reprint requests to Saime Paydas, Cukurova Univer-
ity, Medical Faculty, 1330 Adana, Turkey. E-mail: spaydas@
hoice to target blood pressures less than 130/85 mm Hg if thereere no contraindications. According to the NCEP-ATP III (Theational Cholesterol Education Program Adult Treatment Panel
II criteria4), we used HMG-CoA inhibitors and/or ezetimib (n �each). Active vitD or VitD3 was used in patients free hypercal-
emia (Ca � 9.5 mg/dL). We recorded physical examinations andepeated biochemical tests and femoral neck/lumbar vertebralEXA measurements with at least 6 month intervals. T scores
etween �1 and �1 were accepted as normal; �1 and �2.5 assteopenia; and ��2.5 as osteoporosis. Biochemical tests includearathormone (PTH); osteocalcin; C-telopeptide; thyroid-stimulatingormone; vitamin B12; ferritin (Roche Elecys-170); blood ureaitrogen; creatinine (Cr); sodium; potassium; calcium (Ca); phos-horus (P); magnesium; alkaline phosphatase (ALP); aspartateminotransferase; alanine aminotransferase; albumin; total choles-erol; HDL C; LDL C; tryglyceride; (Roche Moduler DPP instru-ents); complete blood count (Beckman-Coulter); tacrolimus
Architect-Abbott); cyclosporine C2 levels (Cobas-Integra-800);rinary Cr, Ca, P, and protein (Roche Moduler DPP instruments).emoral neck and lumbar vertebra DEXA were evaluated withEXA ODR series X-ray bone densitometers.We excluded patients displaying a serum creatinine value abovemg/dL, active infection, acute rejection episode, diabetes melli-
us, malignant disease, acute or chronic liver disease, bone diseaseelated to other problems.
Data were analyzed using SPSS 16v. Continuous variables ofotal cholesterol, HDL C, DEXA femoral neck, urine Ca, werehown as mean values � standard deviations or medians andin/max values. Discrete variables like gender as well as osteope-
ia and osteoporosis are presented as percentages. Student’s t testr one-way analysis of variance was used to compare normallyistributed data between groups and Mann-Whitney or Kruskallallis test for nonnormally distributed variables. Continuous vari-
bles before and after treatment were compared using the pairedtudent’s t test or Wilcoxon test. The chi-square test was used tovaluate proportions between groups. P values less than .05 wereccepted as statistically significant.
ESULTS
he mean age of the patients was 36.25 � 10.5 (range8–65) years and the durations of prior dialysis and trans-lantation were 24.8 � 23.6 (range � 1–96) and 38.2 � 30.2range � 3–148) months, respectively. The causes ofhronic renal insufficiency were hypertension (24.7%),hronic glomerulonephritis (20%), autosomal-dominantolycystic kidney disease (7.1%), familial Mediterraneanever (5.9%), unknown (32.9%), and other causes (4%).able 1 shows the biochemical parameters. T scores of
emoral neck and lumbal vertebral are presented in Table 2nd Figure I. According to the DEXA results, the inci-ences of normal, osteopenia, and osteoporosis are shown
n Table 3 The relationship between PTH, osteocalcin,-telopeptide, ALP, VitD, body mass index, posttransplan-
ation duration, dialysis duration, age, gender, calcitriolherapy and serum creatinine, and BMD are shown inables 4 and 5. If patients were categorized according to
erum VitD levels (cutoff 26 pg/ml), the femoral neckEXA T scores were �1.21 � 0.688 and �1.76 � 0.951 for
bove versus below, respectively (P � .009). There were no
ignificant differences for lumbar vertebral DEXA T scores. W
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ccording to the serum VitD levels, there was no significantifference for baseline serum lipid levels. The biochemicalesults of patients treated with or without VitD are shownn Table 6. Although fasting blood glucose levels werenchanged in patients treated with VitD, they were signif-
cantly increased from baseline among patients not treatedith VitD (P � .047). Serum osteocalcin levels were
ignificantly decreased among patients treated with VitDP � .006). Daily urinary excretion of creatinine, protein,a, and P did not change with VitD therapy. Interest-
ngly, while total cholesterol and triglyceride levels de-reased significantly among patients treated with VitD,hese parameters were unchanged in the group that didot use VitD (Figs 2–5). HDL C was decreased in allatients. Femoral neck DEXA T score increased from1.74 � 0.911 to �1.61 � 0.880 (P � .038); lumbar
ertebral DEXA T scores, from �2.16 � 0.910 to �1.97 �.949 (P � .021) (Table 7 and Figure 6).
ISCUSSION
lthough kidney transplantation dramatically amelioratesome bone disorders related to chronic renal failure, addi-ional bone damage from glucocorticoids1 and calcineurinnhibitors2 are superimposed on the low-quality substrate toorm varied, complex pathological states.5,6 A decrease inMD occurs rapidly in the early posttransplantion period,specially the first 6 months, which slows thereafter.3 Thencidences of osteopenia and osteoporosis were 68.6% and4.1% in the femoral neck and 78.8% and 78.1% in lumbarertebra at baseline which did not change in incidence
ig 1. DEXA measurement of patients at the beginning and end
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f the study.
uring follow-up. In other studies posttransplant incidencesf osteopenia and osteoporosis were nearly 50%.7,8,9
arcén et al10 reported that the incidences of BMD in theemoral neck of normal, osteopenia, and osteoporosismong 35%, 50%, 15% of subjects, who had normal renalunction at 10 years follow-up, respectively. Lumbal verte-ral BMD incidences of normal, osteopenia, and osteopo-osis were 20%, 52.8%, 27.5%, respectively, in the sameatients. There were no correlations between BMD anderum PTH, age, gender, dialysis, duration or body massndex. In our study, there was also no correlation betweensteoporosis and serum levels of PTH, ALP, and osteocal-in. There was no correlation between body mass index andumbal vertabral osteoporosis, but a lower body mass indexas associated with severe femoral bone lesions (P � .035).he incidences of vertebral osteopenia and osteoporosisere similar for both genders, but femoral osteopenia andsteoporosis were more frequent in females. BMD signifi-antly increased from �1.58 � 0.902 to �1.46 � 0.857 androm �1.88 � 1.08 to �1.70 � 1.08 in femoral (P � .015)nd vertebral studies (P � .003), respectively. Anothertudy showed no further loss of BMD following the firstear.11 BMD increased after renal transplantation withoutny additional therapy upon long-term follow-up as in ourtudy. There was no relationship between osteoporosis andsteopenia with PTH, osteocalain, C-telopeptide, ALP, age,r dialysis and transplantation durations in our study. Onlyt the begining of the study was the relationship betweenemoral BMD and BMI significant (P � .035). Torregrosat al12 reported that BMD did not correlate with age orender. In our patients, the incidence of femoral necksteoporosis was significantly greater in women than menP � .025), but lumbar verebral BMD were similar in malesnd females. Fracture rates have been reported to be asuch as three fold greater in among transplant than similar
ialysis patients, namely, as high as 40% at 3 years amongiabetic transplant recipients.13 We did not observe anyase of fracture among our patients.
Table 3. The Incidence of Normal andOsteopenia/Osteoporosis According to the Bone Mineral
Density at the Beginning and End of Study (After 9.82 � 2.72Months)
Table 4. The Effects of Parahormone, Osteocalcin, C-Telopeptide, Alkaline Phosphatase, Vitamin D Levels, Body Mass Index, Durations of Transplantation and Dialysis andAge on Bone Mineral Density at the Beginning and End of Study
First Femur Measurement First Vertebra Measurement
Normal Mean � SD Osteopenia Mean � SD Osteoporosis Mean � SD P Value Normal Mean � SD Osteopenia Mean � SD Osteoporosis Mean � SD P Value
PTH, Parahormone; ALP, alkaline phosphatase; vitD, vitamin D; BMI, body mass index; Tx, Transplantation.
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The causes of bone disease are use of glucocorticoids andalcineurin inhibitors, persistence of secondary hyperpara-hyroidism, renal tubular acidosis, hypophosphatemia, os-eomalacia, and reduced glomerular filtration rate. Glu-ocorticoids are potent skeletal toxins; even small dosesause significant decreases in bone mass and increases inracture rates of previously healthy bone.1 Bone formations impaired by decreased osteoblast functions, whereassteoclast numbers are increased by the decreased apopto-is.14 Calcineurin inhibitors, especially cyclosporine, inducesteopenia in animal models.15 Persistence of secondaryyperparathyroidism can cause loss of BMD,16 some stud-
es, high PTH levels accompany rapid loss in BMD.17–20
ur patients were not at high risk for elevated serumreatinine and PTH levels. Serum Ca and P levels, whichere within normal levels, did not change over the follow-uperiod. PTH and decreased osteocalcin, which is an osteo-last product and marker of bone formation, may be relatedo resolving secondary hyperparathyroidism with resolutionf high turnover bone disease observed in some patientsr associated with glucocorticoid treatment. However C-elopeptide levels did not change significantly.
In our study group, lumbar vertebra and femoral neckMD improved significantly. In our study patients treatedith or without vitD were similar for age and gender. VitD
herapy resulted in significantly improved lumbar vertebralnd femoral neck BMD. Among patients who did noteceive vitD, BMD did not change significantly. In anothertudy vitD therapy only improved lumbal vertebral BMD.20
ypercalcemia is an important contraindication for vitDherapy. Serum vitD levels and BMD were negatively
Table 5. The Incidence of Normal and Osteopenia/OsteoporoLevels, and Treatment of Vitamin D (VitD) at the Beginni
orrelated. Higher serum levels of vitD accompanied lower w
MD and a higher incidence of osteoporosis. These find-ngs may relate to pretransplant adynamic bone disease;steomalacia or adynamic bone disease have been reportedo be associated with resistance to vitD and low numbers ofitD receptors.21 In our patients, vitD therapy did nothange the serum levels of vitD, Ca, P, and PTH, becausee prescribed low doses to avoid hypercalcemia, although
hese amounts significantly improved BMD. As in ourtudy, no correlation has been reported between 25-OHDevels and BMD.22 In that study 25-OHD was low inirtually all subjects, but its correction may be difficult foratients with hypercalcemia, because hypercalcemia haseen observed in 40% of recently transplanted recipient’snd 25% of them in the long term.22 In a Cochrane analysisreatment with a bisphosphonate, vitD sterol, or calcitoninay protect against immunosuppression-induced reduc-
ions in BMD and prevent fracture after kidney transplan-ation. Adequately powered trials are required to determinehether bisphosphonates are better than vitD sterols for
racture prevention in this population. The optimal route,iming, and duration of administration of these interven-ions remains unknown.23 In a study of bone-fractureealing in an ovariectomized rat model, 1,25(OH)(2)D(3)romoted healing by improving the histomorphometricarameters, mechanical strength, and tendency to increaseransformation of woven bone into lamellar bone.24
We did not observe any correlation between worse renalunction and severe bone disease. But another study dem-nstrated that patients with osteoporosis or osteopeniahowed worse graft function at 1 and 8 years compared withatients displaying normal BMD, a greater number of
Femur (F) and Vertebra (V) According to the Sex, Creatinined End of the Study in Our Renal Transplant Recipients
hom were prescribed vitD (50% vs 23%)10: 1.75 � 0.634
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BONE DISEASE IN RENAL TRANSPLANTATION 2523
ersus 1.32 � 0.33 mg/dL at 1 year (P � .014) and 1.7 � 0.4ersus 1.2 � 0.2 mg/dL at 5 years (P � .01).
Serum vitD levels and vitD therapy were related toetabolic syndrome and serum lipids. In our study, blood
lucose and lipid parameters changed with vitD therapy.hile fasting blood glucose levels were unchanged among
atients treated with VitD, they increased among subjectsot prescribed VitD. However, VitD therapy significantlyecreased total cholesterol and triglyceride levels. But theDL C levels decreased in both groups. It is known that in
ddition to calcium metabolism, vitD has metabolic andmmunologic effects because many cells have vitD recep-ors.25 1,25-dihydroxycholecalciferol activates CYP3A4,hich metabolizes atorvastatin to its main metabolites; vitDoncentrations �30 nmol/L may be required for this effectn patients with acute myocardial infarction.26 In anothertudy, plasma triglyceride levels were inversely associatedith tertiles of plasma 25OHD levels, and changes in
ig 2. Total cholesterol values of the patients according to the
itamin D (VitD) treatment. v
lasma triglyceride levels correlated inversely with seasonalhanges in vitD status. Any pharmacological effect of statinsn vitD status has not been described, but vitD may
nfluence plasma lipid profiles and thus be important toardiovascular health.27 Some authors have reported signif-cant negative correlations of 25(OH)D levels with body
ass index, waist circumference, waist-to-hip ratio, systolicnd diastolic blood pressure, fasting and stimulated glucose,rea under the glucose response curve, fasting insulin,OMA-IR, HOMA-beta, triglycerides, and the quotient
otal cholesterol/HDL C as well as positive correlations of5(OH)D levels with HDL C (P � .05 for all).28 In contrast,itD therapy for Pakistani immigrants did not change totalholesterol, LDL C, HDL C, LDL C/HDL C ratio, veryow-density lipoprotein cholesterol or triacylglycerol.29
igh blood concentrations of parathyroid hormone and lowoncentrations of VitD metabolites 25-hydroxyvitamin D25(OH)D] and calcitriol are considered new cardiovascu-
ig 3. High-density lipoprotein (HDL) values according to the
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ar disease risk markers.30 Renal recipients commonly showigh PTH and low vitD content, which must be corrected.hus vitD therapy should be considered for cardiovascularrophylaxis. However, there is also evidence that calcitriol
ncreases lipogenesis and decreases lipolysis.30 VitD ther-py decreased triglyceride levels but did not change LDL inur patients who showed decreased HDL irrespective ofitD treatment. However, compared with placebo, vitDupplementation increased LDL C concentrations (�5.4%ompared with �2.5%; P � .001) in another study.30
upplementation with reduced-fat calcium-vitD(3) fortifiedilk did not show either a beneficial or detrimental effect
n blood pressure, lipid, or lipoprotein concentrations inealthy community-dwelling older men.31 Can VitD ther-py be harmful for cardiovascular calcification? In anpen-label study of 45 male and female subjects withoronary calcification score (CCS) of �50 without symp-oms of heart disease, treatment with di advice, statins
ig 4. Low-density lipoprotein (LDL) values according to the
itamin D (VitD) treatment. t
iacin, and omega-3 fatty acid achieved LDL C and triglyc-rides values �60 mg/dL; high-density lipoprotein �60g/dL. Vitamin D3 supplementation achieved serum levels50 ng/mL 25(OH) vitamin D. Lipid profiles of subjectsere significantly changed total cholesterol �24%, LDL C41%; triglycerides �42%, HDL C �19%, and mean
erum 25(OH) vitamin D levels �83%. After a mean of 18onths, 20 subjects experienced a decrease in CCS withean change of �14.5% (range � 0% to �64%); 22
ubjects experienced no change or a slow annual rate ofCS increasing �12% (range � 1%–29%). Only three
ubjects experienced annual CCS progression exceeding9% (range � 44%–71%). Despite wide variations inesponses, substantial reduction of CCS was achieved in4% of subjects with slowed plaque growth in 49% ofubjects applying the broad treatment program.32
tinued)
VitD Treatment (�)
PFirst Measurement
Mean � SD (median)Second MeasurementMean � SD (median) P
ig 5. Trygliceride levels according to the vitamin D (VitD)
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BONE DISEASE IN RENAL TRANSPLANTATION 2525
In summary, we observed bone disease including os-eopenia or osteoporosis in 70% of subjects. Duringollow-up BMD increased significantly from baseline after.82 � 2.72 months. VitD therapy produced greater im-rovements in BMD, decrease in serum triglycerides, andrevention of an increased blood glucose. Because of theositive effects of VitD treatment on serum lipids, it coulde useful for prevention of cardiovascular disease amongatients without hypercalcemia or hypercalcuria especiallyuring the first year after renal transplantation.4
EFERENCES
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2526 SIKGENC, PAYDAS, BALAL ET AL
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