Ferreira, A

Guimarães, S

Henriques, AC

Martins, L

Pereira, MC

Queirós, J

Sarmento, AM

Repository of the Hospital Center of Central Lisbon

Renal Osteodystrophy: Histologic Evaluation after Renal Transplantation

Repositório do Centro Hospitalar de Lisboa Central, EPE

Renal Osteodistrophy: Histologic Evaluation AfterRenal TransplantationL. Martins, J. Queiro´s, A. Ferreira, A.C. Henriques, A.M. Sarmento, M.C. Pereira, and S. Guimara˜esSUCCESSFUL RENAL transplantation (RT) is able tosolve most problems of uremic or dialyzed patients(pt). However, renal osteodistrophy (RO) is often a long-lasting problem, and bone disease can even worsen afterRT. In fact, significant changes in bone histology have beenseen up to 5 years after the procedure in more than 80% ofpt with a well-functioning kidney graft.1 Several factors,including age,2,3 sex,4,5 underlying renal disease,3 time ofdialysis,6 type and severity of RO pre-RT,2,6 and alsoimmunosuppressive drugs4,7 may contribute to persistenceor worsening of RO.Therefore, bone disorders still are a relevant morbidityfactor for RT, often difficult to handle. Dual-energy X-rayabsorptiometry (DEXA) is useful to measure bone mineraldensity,5 but mineralized bone biopsy (BB) is the goldstandard to evaluate type and severity of RO. Only a fewhave prospectively evaluated bone histology after RT. Weconducted a prospective study on renal transplant pt toanalyze the histologic evolution of RO after RT.PATIENTS AND METHODSEight pt who completed the study were submitted to a first BB onday 0 and a second BB 6 months after RT. The second BB wasperformed after 500 mg dimethylchlortetracycline/day, double la-beling (3 days on, 10 days off, 3 days on). Transiliac bone biopsiesusing the trephine of Bordier-Meunier with an internal diameter of8 mm were obtained in all pt. The bone specimens were fixed for 24hours in methanol, dehydrated, and embedded in methylmetracry-late. Undecalcified sections of 5-mm thickness were made using amicrotome (Model Leica RM 2155, Germany) equipped with atungsten carbide knife. Three nonconsecutive sections were stainedwith Toluidine blue, acid phosphatase, and von Kossa. Two werestained with a specific histochemical stain for detection of alumi-num in bone (azurin solochrom) and one with a PERLS histochem-ical stain for detection of iron in bone. Each bone section was readtwice by two different persons, without knowledge of clinical orbiochemical information on the pt. All sections were analyzedquantitatively for static parameters of bone formation and bonereabsorption. Histomorphometric measures were carried out usinga semiautomatic image analyzer (Q-Win, Leica, Germany) coupledwith a Leitz microscope. Approximately 40 different fields wereanalyzed for the same bone biopsy. Normal bone histomorphomet-ric values are from Vernejoul et al.8 The bone histomorphometricparameters below, expressed according to the standardized nomen-clature,9 were measured in trabecular bone.All the pt were checked for intact parathyroid hormone (iPTH),total alkaline phosphatase (tAP), serum calcium (Ca), and serumphosphate (P) at time 0 and at 6 months. Serum creatinine was alsochecked at 6 month. No patient received calcium or calcitrioltherapy after kidney transplantation. The immunosuppressive reg-imen used was cyclosporine A (CsA) and prednisone in all pt; onept also had azathioprine; two pt also had antithymocytic globulin;and another two also had micophenolate mofetil. Steroids wereused as three initial bolus of 500 mg methylprednisolone, followedby 0.5 mg/kg per day of prednisone, tapered to 10 mg/d at the endof the third month (our maintenance dose). None experiencedacute rejection episodes, so no further steroid bolus were used.For the statistical analysis, paired t test and Wilcoxon test wereused.RESULTSOur study group was composed of five females and threemales, with a mean age of 50.4 6 9.8 years old (rangingfrom 27 to 57). Their mean time on dialysis (all of themwere on hemodialysis) was 43.4 6 31.3 months (5 to 97months). The underlying renal disease was unknown in twopt, chronic glomerulonephritis in one pt, polycystic kidneydisease in three pt, and chronic interstitial nephritis in twopt.The mean and range of initial iPTH was 348.4 6 440.1pg/mL (38.3 to 1288), and the final iPTH was 76.9 6 45.0pg/mL (19 to 149), with the difference statistically signifi-cant (P 5 .012). The mean initial tAP was 75.5 6 19.7 U/L,and the final tAP was 95.8 6 32.8 U/L, although thisincrement was not significant (P . .05). There was asignificant elevation on Ca during these 6 months (2.12 60.16 vs 2.36 6 0.13 mmol/L; P 5 .001) and a highlysignificant decrease on P between the two measurements(6.40 6 0.95 vs 3.13 6 0.24 mg/dL; P , .001). The meanserum creatinine at month 6 was 1.2 6 0.3 mg/dL.The histologic diagnosis from the initial and the final BBis shown on Table 1. Between the two BB, we verified anFrom the Departments of Nephrology (L.M., J.Q., A.C.H.,A.M.S., S.G.), and Transplant (M.C.P.), Hospital de Santo Anto´-nio, Porto, Portugal and Nephrology (A.F.), Hospital Curry Ca-bral, Lisboa, Portugal.This work was supported by a Portuguese Government grant(Health Ministry).Address reprint requests to Dr L.S. Martins, NephrologyDepartment, Hospital Santo Antonio, 4050 Porto, Portugal.© 2000 by Elsevier Science Inc. 0041-1345/00/$–see front matter655 Avenue of the Americas, New York, NY 10010 PII S0041-1345(00)01802-9Transplantation Proceedings, 32, 2599–2601 (2000) 2599increase in mineralized bone, an increase in osteoblasticand osteoid surfaces, a decrease in osteoclastic surface andosteoclast number, and a decrease in aluminum surface.However, these changes were not statistically significant(see Table 2).DISCUSSIONRT normalizes phosphate urinary excretion and calcitriolproduction,2 two of the most important deficiencies of theuremic state implicated in RO. Also, aluminum overload isefficiently removed by a functioning RT, although this cantake more than 1 year.2 Dialysis-related amyloidosis com-plaints usually rapidly improve, although the cystic lesionspersist.2 However, severe pre-RT hyperparathyroidism(HPTH), especially nodular hyperplasia, may not improveafter RT; indeed this may cause severe hypercalcemia andgraft dysfunction,10 making surgery necessary. Moreover,steroids given for RT have a well-known effect on bone,leading to bone mass loss4 and contributing to avascularbone necrosis. CsA has also been associated with osteope-nia7 and with a disabling bone pain syndrome.11 In addition,adynamic bone disease has increased in the last years,3 andalthough its significance is uncertain, it may contribute toosteopenia observed after RT.As easily understood from our results, some of the pt hadsevere aluminum load pre-RT, which expectedly decreasedon second BB. However, high-turnover bone disease, al-though not extremely severe, was the most frequent causeof RO. These results are in accordance with the litera-ture.2,3 Pre-RT severe osteoporosis was also identified intwo pt. Intact PTH and tAP decreased between the twomeasurements, as previously described,12 and P showed theexpected lowering. On the contrary, Ca significantly in-creased during this time interval, never reaching riskylevels. This increment may be long lasting and probably isdue to nonsolved HPTH.10 All the pt always had a goodgraft function.A significant loss in bone mass early after RT was madeevident by DEXA measurements, predominantly at thelumbar spine. Up to 6.8%12 or even up to 10%2 reductionon bone mass in the first 5 or 6 months has been seen.Fortunately, this extremely high rate of bone loss progres-sively falls: there are studies showing a trend towardimprovement after the sixth month5 and recovery at month12,5 or normalization of bone mass only 2 years after RT.2The less encouraging results show that the loss still existsmore than 8 years after RT, with a bone loss rate of 1.7%per year.13However, there is a lack of studies with histologic analysisclarifying how the dynamic process of bone remodelingreally is functioning after RT. Some of the few publishedworks described a reduction in bone reabsorption, but withlow bone formation rate, as early as 6 months12 and evenseveral months later.14 Our study, with the handicap of onlyeight pt enrolled, showed a trend toward improvement inbone histology. Although the histologic changes betweenTable 1. Bone Histology and Their Evolution Between the Two BBPatient First BB Second BB1 Moderate HPTH; extensive Al deposits; normal mineralization Mild HPTH; decrease in Al deposits; mineralization notsignificantly compromised2 Mild HPTH, severe osteoporosis, extensive Al deposits HPTH persists (predominant bone formation);Al deposits diminished; normal mineralization3 Severe HPTH, without Al deposition; normal mineralization Quite normal histology and normal bone volume4 Moderate HPTH; significant Al deposits; normalmineralizationImproved HPTH, evolving to low-turnover bonedisease; Al deposits decreased; osteoporosis5 Quite normal bone histology; without significant Al deposition Quite normal histology6 Severe HPTH (predominant bone formation); extensive Aldeposits; normal mineralizationModerate HPTH; Al deposits decreased; mineralizationmildly compromised7 HPTH on the past, evolving to adynamic bone disease;extensive Al deposits; osteoporosisNormal bone volume (osteoporosis improved);Al deposits diminished; normal mineralization8 Low-turnover bone disease; normal bone volume; significantAl depositsMild HPTH; important decrease in Al deposits; normalbone volumeHPTH 5 hyperparathyroidism; Al 5 aluminum.Table 2. Bone Histomorphometry and Its Evolution Between the Two BBFirst BB Second BB P valueMineralized surface (%) 32.99 6 15.78 34.46 6 11.08 .780Osteoid surface (%) 4.11 6 2.86 4.73 6 2.68 .676Trabecular surface (%) 37.10 6 16.25 39.20 6 12.02 .699Osteoblastic surface (%) 5.72 6 6.67 6.59 6 5.46 .769Osteoclastic surface (%) 3.05 6 2.34 1.78 6 1.87 .176Trabecular surface with aluminum (%) 39.83 6 35.38 30.98 6 28.73 .228Number of osteoclasts/mm2 3.43 6 2.79 2.45 6 1.96 .3022600 MARTINS, QUEIRO´S, FERREIRA ET ALthe two BB did not reach statistical significance, we ob-served a trend toward improvement in bone formation andmineralization, with reduction of bone reabsorption andalso important aluminum removal.In conclusion, we can say that 6 months after RT there isalready a trend toward improvement in RO, which canprobably be clearly apparent a few months later, accordingto DEXA results. A longer follow-up is needed to confirmthese results.REFERENCES1. Bonomini V, Felleli C, DiFelice A, et al: Adv Exp Med Biol178:207, 19842. Massari PU: Kidney Int 52:1412, 19973. Cannata-Andı´a JB: Kidney Int 54:1000, 19984. Wolpaw T, Deal CL, Fleming-Brooks S, et al: Transplantation58:1186, 19945. Almond MK, Kwan JTC, Evans K, et al: Nephron 66:52, 19946. Nehme D, Rondeau E, Paillard F, et al: Nephrol DialTransplant 4:123, 19897. Movsowitz C, Epstein S, Fallon M, et al: Endocrinology123:2571, 19888. Vernejoul MC, Belenguer R, Halkidou H, et al: Bone 6:15,19859. Parfitt AM, Drezner MK, Glorieux FH, et al: J Bone Min Res2:595, 198710. Julian BA, Quarles LD, Niemann KM: Am J Kidney Dis19:99, 199211. Torregrosa JV, Campistol JM: Nephrol Dial Transplant14:1364, 199912. Julian BA, Laskow DA, Dubovsky J, et al: N Engl J Med325:544, 199113. Pichette V, Bonnardeaux A, Prudhomme L, et al: Am JKidney Dis 28:105, 199614. Velasquez-Forero F, Mondrago´n A, Herrero B, et al: Neph-rol Dial Transplant 11(suppl 3):58, 1996RENAL OSTEODISTROPHY 2601

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Renal Osteodystrophy: Histologic Evaluation after Renal Transplantation

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