A w t Y Z J Med (1976). 6, pp 10-15 ~

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The Use of High Calcium Dialysate in the Treatment of Renal Osteomalacia R. A . Evans" and P. J. Somerville 1 F r o m t h e Renal M e t a b o l i c Unit. R e p a t r i a t i o n General H o s p i t a l S y d n e y

Summary: The use of high calcium dialysate in the treatment of renal osteomalacia. R. A. Evans a n d P. J Somerville. Aust N Z . J Med. 1976, 6, p p 10-15.

Four chronic haemodialysis patients suffering from osteomalacia were treated by increasing their dialysate calcium concentration from 1 ' 4 0 to 2 . 1 5 mM//. Bone biopsies were taken before and after 22 weeks of this treatment and a further biopsy was taken in one patient after 52 weeks. Symptomatic cure occurred in one patient with mild osteomalacia and some improvement occurred in another patient who had mixed osteomalacia and hyperparathyroidism. Bone biopsies showed slight improvement in the patient with mild osteomalacia after 22 weeks, and considerable improvement after 52 weeks. In the patient with mixed histology, the osteitis fibrosa subsided and the osteomalacia became a little worse after 22 weeks. There was no histologic improvement in the two patients with severe osteomalacia after 22 weeks. It is concluded that high calcium dialysis is not an effective treatment for renal osteomalacia. In chronic renal failure bone disease is usually a combination of ostcitis fibrosa and osteomalacia. The osteitis fibrosa appears to be principally a consequence of the attempt by the parathyroid glands to maintain a normal serum calcium in the presence of phosphate retention.' Osteomalacia is thought to be

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*Specialist (Nephrology) tRegistrar Correspondence. Dr P J. Soniervblle. Renal - Metabolic Unit. Repatriation General Hospital Concord, N S W 21 39 Accepted for publication 1 2 August, 1 9 7 5

caused by the kidney's inability to hydroxylate 25-hydroxycholecalcifero12 although the obscrvation by Bordier ef a / . 3 , that eight of nine studied patients with bilateral nephrectomy lacked evidence of osteomalacia casts some doubt on this. Chronic renal disease can also produce osteomalacia by inducing systemic acidosis" and rarely by phosphate dcplction.' In non-dialysed patients it does not appear that calcium loss is of significance, although limitations of calcium balance techniques preclude absolute proof of this.' However, in patients treated by chronic haemodialysis there is evidence that if the usual dialysate calcium concentration of 1.40 mM/1 is used there is significant calcium loss from the body'. and this loss is thought to contribute to "dialytic" bone disease. Osteoporosis, as diagnosed by metacarpal index, has been found to develop if the dialysate calcium is 1. 40 mMj/ but not if it is 1.75 mM//.'O Secondary hyperparathyroidism has been found to be more common if the dialysate calcium is below 1'40 mM,il.' In non-dialysed patients Clarkson et a/." found that a strongly positive calcium and phosphorus balance could be produced by giving large amounts of oral calcium carbonate and calcium phosphate. Such treatment could induce remineralisation of osteoid in osteomalacia, although this remineralisation took place in an abnormal manner.I3 Goldsmith et ~ 1 1 . ~ found ' that, in haemodialysis patients, increasing the dialysate calcium concentration from 1 '40 to 2 mM/l caused secondary hyperparathyroidism to subside ; it was suggested that this treatment might also be effective for osteomalacia. For these reasons high calcium dialysate was given to four haemodialysis patients who suffered from osteomalacia. '8

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MI*2d librow and

ostromalacia

Methods

Four patients ivere studied. after the nature of lhe investigalion had been explained and their consent obtained. Clinical details arc shown in Table 1. The patients were dialysed lor 8~ 10 hours “ice weekly using Travenol twin-coil dialysers for Patients 1 to 3 and a Cordis Dow hollow fibre dialyser for Patient 4. Blood flow through the dialyser was 150--200 ml per minute and dmlysate flow 503 ml per minute. During the period of the study the dialgsatc calcium concentration was incrcased irom 1 . 4 0 to 2.15 mM/i. Patients 2. 3 and 4 wrre given a vitamin D preparation at the conclusion of the study. Iliac crest bone biopsies were obtained before commencing high calcium dialysate and then 22 weeks later. A further biopsy was taken in Patient 1 at post-mortem after 55 weeks of high calcium dialysis. The hiopbics were taken using the technique of Byers and Smith.l4 They were fixed and dehydrated with ethanol, embedded in methyl mcthacrylatc, cut with a Jung K mici-otome at 5 p and stained with toluidine blue. The stained 5ections were asscssed quantitatively using the point-counting technique described by Garner and Ball” to measure total bone and osteoid. The degree of osteitis fibrosa was asscsscd on the semi-quantitative scale described by Ellis and Pearl’” in which the grades range in increasing order of severity from 0-5. Biochemical estimati6na were made using a Technicon auto-analyscr, and in Patients 2. 3 and 4 the skeletal origin of the alkaline phosphatase was confirmed by hcat inactivation.” Results

Clinicul In Patient 1 there was a gradual disappearance of symptoms after approximately eight weeks. Patient 2 did not improve and Patient 3 became worse. Patient 4 had some clinical improvement after approximately eight weeks, but there was still considerable bone pain. In Patients 2, 3 and 4 vitamin D produced relief of symptoms over a period of three to six weeks.

x-rays The results arc summarised in Tablc 1. No patient had pseudo-fractures or bi-concave vertebrae. The high calcium dialysate did not produce any change in the X-rays nor any radiologic metastatic calcification. Biochemical Chunges (Figs. 1-4) The principal biochemical effects of increasing the dialysis calcium concentration arc the fall in plasma phosphorus in all patients, the fall in alkaline phosphatase in Patient 4, and the temporary rise in alkaline phosphatase in Patients 2 and 3.

Bone Biopsies The results are summarised in Table 2. Post Mortem Rrbzilfz Patient 1 died from a pseudomonas empyacma, after 34 years dialysis which included a year of high calcium dialysis. Patient 2 died from a myocardial infarction after three years of dialysis, including 40 weeks of high calcium dialysis. In neither patient was therc macroscopic or microscopic evidence of metastatic calcification at post-mortem. Discussion

The use of high calcium dialysate for the treatment of renal ostcodystrophy was introduced by Goldsmith et ul.” following the observation that osteodystrophy was morc common when the dialysate calcium was below

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LVANS A N D SOMERVILLC

FIGURE 1

I

HIGH

Patient 1 CALCIUI

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FIGURE 2 DIALISATE

Patient 2.

1

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FIGURE 4

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FIGURES 1 4

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Patient 4

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Biochemical dAta relating to variation in treatment of each of the four patients studied, the arrows point to some plasma values immediately post-dialysis

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Normal \slues'

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‘Ellis and Pcart (1972. Rcf. 23).

1.40 mM/l. It was used to treat 10 patients maintained on chronic haemodialysis. After reducing their plasma inorganic phosphorus levels to less than 1.94 mM/I in order to reduce the dangers of metastatic calcification, the dialysate calcium was increased from 1.40 to 2.15 mMjl. The effect of this treatment was to alleviate bone pain (sometimes in as short a period as one week), to increase bone density as assessed by gamma ray densitometry. and to lower the high plasma parathyroid hormone levels over scveral weeks to levels approaching normal. The plasma phosphorus and alkaline phosphatase levels also fell. Their conclusion was that the osteitis fibrosa component of renal osteodystrophy could be prevented or reversed by this treatment and they suggested it “was conceivable that even the osteomalacic component might be reversed”. This study is open to criticism on the grounds that bone histology was not included, and the assumption was made that .because the initial plasma parathyroid hormone levels were high, the bone disease was osteitis fibrosa. Of the four patients described here, only Patient 1 with mild osteomalacia: showed marked improvement and that improvement was histologically slow to occur, although clinical benefit was noted after about eight weeks. Patients 2 and 3 with severe osteomalacia, showed no benefit after 22 weeks.

Patient 4, who appeared histologically to have osteitis fibrosa in addition to osteomalacia, experienced some reduction in bone pain after about eight weeks but there was significant remaining pain ; a second bone biopsy shoived a marked reduction in hyperparathyroid changes but an increase in osteoid. As with Goldsmith’s patients. the plasma inorganic phosphorus fell in all patients and aluminium hydroxide was only required later by Patient 4, and after the administration of vitamin D to Patient 2. However, there was a fall in plasma alkaline phosphatase only in Patient 4; in Patients 2 and 3 there was a temporary rise after commencing high calcium dialysate, and again after giving vitamin D. If the conclusions of both these studies are accepted, there are clear differences in response of renal osteodystrophy to high calcium dialysis depending upon whether it is predominantly osteitis fibrosa or osteomalacia. The hypothesis that osteitis fibrosa will subside if the plasma calcium is elevated appears to be supported in practice. With osteomalacia there are two hypotheses; firstly that it can be healed simply by the administration of calcium (and perhaps phosphorus) and the second that vitamin D does not simply increase gut absorption of calcium and phosphorus, but has a “permissive action” in allowins calcium phosphate to enter the osteoid. It is well known that vitamin D,

13

LVANS A N D SO~l.1CKVILLE

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6,

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if given in sufficient dosage, can heal renal osteomalacia, but there is still doubt as to the efficacy of calcium alone. Snodgrass et 0 1 . ' ~ found a radiologic improvement in renal rickets after treatment with oral calcium carbonate for several months. Eastwood t'r a/.13 found that oral calcium carbonate did produce some remineralisation of osteoid in renal osteomalacia but that it occurred in an abnormal manner. The failure of high calcium dialysate to benefit three of the four patients described here could have three possible explanations; first, that they were not given enough calcium, second that they were depleted of phosphorus, and third that vitamin D is necessary for the calcification of ostcoid. If onc applied the calcium transfer rates given by Goldsmith et ul." it would be likely that more than 60 g of calcium was transferred into the patients during thc 22 week periods. which could be expected to produce considerable osteoid recalcification. Phosphorus depletion is a well recognised cause of osteomalacia, but in published reports of this' the plasma inorganic phosphorus has usually been below 0.646 mM/I. In Patients 2. 3 and 4 it fluctuated between 0.81 and 1 18 mM/ litre; it was not considered justified to add phosphate to the regime in view of the risk of metastatic calcification. It is noteworthy that in Patient 1 the plasma inorganic phosphorus did rise though it is not certain whether this was a cause or effect of healing of the osteomalacia, or simply an incidental finding. Hence the most probable explanation is that vitamin D is important in the calcification of osteoid. The most serious disturbance of calcium metabolism in dialysis patients is rnctastatic calcification, which has greater potential for harm than has an elevated plasma parathyroid hormone level (though the latter in severe form can: of course, cause the former). The use of dialysate with the calcium as high as 3 rnM/'/, particularly in patients with hyperphosphataemia, is known to cause metastatic calcification, sometimes involving the myocardium and causing arrythmias and sudden death.lg As pointed out by Stanbury2" the use of a dialysate calcium as high as 2 mM/1 will produce a positive calcium balance, which in

the long term must increase the likelihood of metastatic calcification. Goldsmith's observation that osteodystrophy is morc frequent when the dialysate calcium is below 1.40 mM!1 suggests that this figure is preferable to the usual 1 .25 mM/I. but until long-term studies. including post-mortem findings have been carried out there is no justificatior, for using a dialysate calcium above 1 .50 mM,I for a patient without 0 s t eod y st r o p h y . If a haemodialysis patient develops osteodystrophy, a bone biopsy should be carried out to determine its type. If it is pure osteitis fibrosa. and if the plasma inorganic phosphorus can be reduced to 1.94 mM/'I, the treatment of choice is high calcium dialysate and this can be effective even if the patient is hypercalcaemic.2' If the serum inorganic phosphorus cannot be reduced to 1.94 mM//, subtotal parathyroidectomy is necessary. Where the histology shows an increase in osteoid in addition to the osteitis fibrosa, vitamin D may be preferable, as dcscribed by Kaye et a1." The chief hazards of vitamin D are its prolonged action and its effect of increasing phosphorus absorption, both of which can be prevented from causing harm by regular observation and administration of aluminium hydroxide (as in Patient 2). Should osteomalacia be the principal histologic lesion, there is no doubt that the correct treatment is vitamin I). Acknowledgement

Thc authors are indebted to the Repatriation Department for a research grant.

I.

2. 3 4.

5. fi. 7.

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E.. KAGLAR.3.. PI:KXI.L~.. J . P.. TAUCART.D. D.. C i r w ~ i . n i i i : ~ J. v . M..Ri.iss. E. and R ~ i c a i : ~ N.. S. ( 1 9 i l ) : On the pathogcncsis of hypcrparathyroid~smi n chronic expcrimciital rcnal Insuficicncy i n ihe dog. J . din. Iitiesr. 36. 492. FaAstm. D. R. and Kiiiiicfi~.E. (1970): Unique biosynrhesis b) thc kidney of a histologically active vitamin D metabolite. .&ariirr 228. 764. BORDER. P J . . 'SllS C:IIOT. S.. FASTWIK)U. J . R.. FOLiiNlER. A. and 01: WARDFNI'R.H. E (1973): Lack of hislologic evidence of vitamin D abnormality in the bones of anephric paticnls. C7in. Sii. 44. 33 RICHARDS. P CHAIIHI.RI.:\I\. M. J . and WROXG. 0.M. (1972): Trcduncnl of osteomalacin of renal tubular acidosis of sodium bwarbondlc alone. I.om ei 2, 994. h ' A G A N T T)C L)I.L.YCHAIRNTS. C . and KRirYr. S. M. (1967) The trcatment Or adult phosphate diaheies and Fanconi Syndrome wiih neutral sodium phosphate. Amcr. J . Mrd. 43. 508. S ~ i r \ ~ KY. i i S. W.(1968:: Bone disease in uremia. Amrr-. .I. :Mvd 44. 714. F0L;K~lER.A. E.. JOHS.W\. W. J.. C A \ % D. R.. BtAu0L.r. J. W.. ARSALI). C . E. and Goi OSMITII. R 5 . 1 I971 I : Aeiiology of hyperparathyroidism and bone d!senrc during chronic haemodialyrii. 1. Aasociation uf bonc d w i w with puwitiaily aetiologic factors. J . d i n . 1 n w . v 50, 592. Fol'R\ii R. A. F... Joiisv)~.W.J.. Cnvrs. D. R.. Llrrnoi 1 . .I. W.. Ansntn. C . E. and Got.iisui1~.R. S. (1971): Aetioloe) of hyperparathyroidism and bonc discane during chronic haemodblyais. 11. Facturr rHccting wrum immuno-reacliw Pardlhormonr. J . d i n I J I V ~50. . ~ 599. ~. SI.AII)I'OLSKI.

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K t C A L OSTEOMAI A C I A .4ND DIALYSATI C 4LC ILM

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14.

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WICG. A. J. (1YhS1 Optiiilum calcium concentration of dialysis auld for mainfenilnce haemodialysi-. Rrir. nitd .I 4. IJC BOYE.1. M.. Dhvrsn~.A M.and RoHsos. .l. S. 119721: Role of dialysis calcium concentration in osteoporosis i n pnt tents o n hacntodialysls. LN~ICFI 1, 1047. t i 0 1 mwtii. R. h.. F i t i v 9 i i ~ J.. . JI)IIXSOY. W. .I . Fot K \ I L R . A. E. and ARSAI:D.C. D. (1971 I: Conlrol of secondar! hyperparaihyloidism during long term dialysis. Anwr. J. . 4 4 d 50. 692. Cr ARKWS. E. M..D K R R O T .C.. Pit11 ti,>. M. E.. Ch)!!rn. P. t.. JI:\VKFS. H. F. a n d o s WAKI)FSER. II. E.(19701:Theeffect oi:i lhlgh intakeofcalclum and phosphate in normal 5ub~ecrzand paticnlr uith chronic renal failure. C h . Sri 39. 693. EASIWCXJU. J. L.. BOHUItR. p. H. and I)I WARDrSlR. H . E.,119711: Cumparison o f the effects of rltamln 1) and calcium carbonale In rcnal osreo1 malacia. Meeting of the Asrociiition of Phyricians Of G e a r Britain and i Ireland. Quurr. .I. .Wed. 40, 569. BYFRS. P. and S Y I I H . R. 119671: Trephine for full thickness iliac-crcst hiopsy. Brir nivd 1.I, 652. Girnxra. A. and 8 ~ 1 . 1J. . (19661: Qusnlilatiw o b ~ c t \ a t i o n ron mincrdliscd and usmineralired hone in chronic reiial azotaemia and intestinal malahsorotion svndromc. J. Pulh. B w r . 91. 543. ELLIS.H. A . and PtAnt. K hl. l 1 9 7 3 l : Arolacnlic rennl 0StCod)srroph). a quanritaiive study on i!~at'b n c . J . clirr. Purl,. 26. 83.

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POSIS.S.. N r ~ r . r .t. C. and CLI tin. J. S. ( I Y b C ] ' Hcat initcli\alioii in 1hP study of human alkaline phnsphaiarc. . 4 m . b r r ~ w r Mvd. 62. 1134. I d . Ssr)oc;RAss. G J. A . 1. and UE WAHI)~\F,R. 11. E. (Karger B a d 1969): Effect of orill calcium on renal rickcra. Abs1ract.r of free cnmmunirarions 4dl Iiir. C n r q r . .Vt.pBrol. Stockholm. p. i X : 9 . TaR\i,\s. D S.. . ~ L I K I Y . A. C . H.an\iozr>. W . S.. Drisstl I\(ICR. P. and HOI.YES.1. H. 119711: Cardiac calcification in uremia. .ivrt>r. J. .l/rd. SO.

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20 S T A S B ~ U Y S . W. (19721: .4loldcmia rcnal osleodptroph\. Chn. B I ~ ,JIcr. I. 167. ?I. VOSIC. W . M . . AFDFRSOK.C. F..STEFIPI:. Hi. P..J o t i z h ~ h .W.J.. ? \ R s * I ~ . C. D. and GOLI~shiIlH.R. S. (19721: Successful medical mdnagemenl of orlcitis fibrora duc 10 tertinn "hyperparpthyroidi,ln". M u w Cliii. Pifu.

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41- 110. ??. KAY~.. M.. CllATTrRIFr. G.. COHFY. Ci. R and SAGtR. S (1970'1:Arrssr of hyperpararhyroid bone discars a i t h dihydrotachysrerol in parientr undergoing chronic haemodialyiis. Asn. rnrt'rn. t4c-d. 73. 22% 13. EL1.15. H. A and P 1 . m ~ .K M. i1972): Quontirarivc ohsenations on mincralired and non mincrali/cd bone in the iliac crest. J . r./bi Purlr. 25, 277. 25. 277.

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Gust. N.Z. J . Med. (1976)- 6 , pp 15 22

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Regional Differences in Lactate Concentration in Experimental Myocardial Infarction" H. J. Smith,

R. M.Norris, B. N. Singh. M. K.

Heng and E. A. Harris

From the Departments of Cardiology, Coronary Care and Clinical P h y s i o l o g y , Gteen Lane Hospital. and the Department of Medicine, Auckland University School of Medicine, Auckland, N e w Zealand

Summary: Regional differences in lactate concentration in experimental myocardial infarction. H. J. Smith, R. M. Norris, B. N. Singh, M. K. Heng and E. A. Harris, Aust. N Z J Med., 1976, 6, pp 15-22. Lactate concentrations were measured in blood from (a) coronary veins within ischaemic myocardium and (b) veins nearer to the coronary sinus, such as the great cardiac vein, for periods of up to 2; hours after ligation of the left anterior descending artery in dogs. Concentrations at (a) were three to fourjimes higher than a t (b), while blood sampled simultaneously from t w o veins at (a) yielded similar concentrations of lactate. At 2; hours after ligation the veno-arterial difference of lactate concentration in blood from (a) was about one half of the difference at 15 minutes. Lactate concentration at (a) was approximately twice as great when the area of ischaemic myocardium drained by the vein was large _ _ ~ . ~ ~

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'Supported by the National Heatt Foundation and the Medical Research Council of New Zealand. Correspondence- Dr R. M Norris, Coronary-Care Unit, Green Lane Hospital. Auckland 3, N e w Zealand Accepted for publication. 7 November, 1975

( 1 8 f l % of heart weight) than when it was small (6&1% of heart weight). No close correlation was apparent between the height of epicardial ST-segment elevation and the level of lactate release. These experiments extend previous observations that changes in lactate concentration at a given site may reflect changes in venous dilution, rather than in the rate of production of lactate, and emphasize that caution is necessary in interpretation of changes in concentrations of metabolites in coronary sinus blood after acute myocardial infarction in man. Changes in coronary venous lactate concentration have been used as a diagnostic guide in clinical coronary artery and have been shown to be helpful in assessing the severity and extent of myocardial ischacrnia in the experimental animal.4 The interpretation in lactate production by the ~ of changes ~ heart is complicated by the heterogeneous nature of ischaemia7-9 however, especially at the edge of ischaemic zones. Lactate is produced by underperfused myocardium, so that the ratios of lactate production to perfusion greatly

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