biochemistry of renal rickets 1

8/7/2019 biochemistry of renal rickets 1

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1926;8:279-291.J Bone Joint Surg Am.G. V. ASHCROFT RENAL RICKETS

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R E N A L R IC K E T S 27 9

RENA L R ICK ETS*B Y G . V . A S H C R O F T , M .D ., C H .B ., D .P .H ., D em on stra to r o f A na tom y,

M an ch es ter U n ive rsityF rom the O rtho paed ic S erv ice and M ed ica l D iv is io n , A ncoa ts H o sp ita l,

Manches t e rR ena l r ick ets is a d isea se n o t m en tioned in m ed ica l tex t-b ook s. The

firs t a sso cia tion of alb um in uria w ith ricke ts w as m ade by C lem en t Lucas,w ho in 1 883 sta ted th at a lbum inuria and late r icke ts w ere too frequ en tlyconn ec ted to be m a tters o f ch ance. Lyon , in 1 901 ; reco rded a case o fin fan tilism assoc ia ted w ith ren al f ib rosis . E x cep t fo r th e se the re is n oreco rd of the cond ition un til 1 911 , since w hen M orley F le tch er , P arson s,M ille r , S u the rland , N aish , W eb er , B a rb er , P ate rson , C am ero n , F eilin gand H olyo ak , and W atso n W em yss h av e w ritten on the sub jec t.

N aish , in 1912 , sum m ariz ing the lite ra tu re at th at tim e, stated tha th e w as aw are o f e igh t ca se s w hich sh ow ed in fan tilism , po ly u ria , p o lyd ipsia ,a lbum en in the u rin e , an d a nega tive W asse rm ann . In five o f these e igh tth ere w as rick ets o f la te o rig in .

B a rbe r,2 in 1 921 , d efined the co nd itio n as one of stu n ted dev elo pm en tassoc iated w ith bon e de fo rm ities o f the la te ricke ts typ e, due to an in sid i-ous ch ron ic in te rstitia l neph ritis o f obscu re etio logy .

S tu dy of the lite ratu re show s th at a c lin ical p ic tu re h as b een fa irlyw e ll recog n ized o f la te yea rs . Th is is o ne o f stun ting assoc iated w ithrach itic d efo rm itie s , u sua lly o f la te on se t, and is repo rted as occu rrin gbo th w ith and w ith ou t d em on strab le k idn ey d isea se.

T he d ea th in A ncoa ts ilo sp ital in 1 921 o f tw o ricke ty pe rson s fromuraem ia focused atten tio n o n th e con d ition , and since the summ er of 1 922all pa tien ts w ith rach itic d efo rm ity , w ho from pa llo r o r o the r reasons w erethou gh t to be su ffer ing from rena l d isea se o r w ho w ere u ndu ly stun tedfo r the ir age , w ere adm itted fo r sp ec ia l in vestiga tion . T hese w ere in them ain ado le scen ts .

T h e m eth od of investiga tion inc lud ed case no te s; g ene ra l roen tgeno -g raph ic exam in atio n of a ll bo nes; b lo od urea estim atio ns; u rea con cen tra -tion te sts ; th e Loew i m yd ria tic te st fo r p an crea tic in su ff iciency ; the G o e tschadren alin in jec tion te st fo r hy pe rth y ro id ism ; th e W asserm ann reac tion ;a pho tog raph , and , w he re po ssib le , exam in a tio n of pos t-m o rtem m ate ria l.

*Read before th e B ritish O rth opaed ic A ssociatio n at M anches ter , O cto ber 2 4 , 192 5 .


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4

F I G . 1Patien t, ag ed 1 8 , w ith renal

rickets.

28 0 G . V. A S HCRO F T

T w en ty -f our c ase s w e re in v e stig ate d .I w ish to rep ort in d etail on e ty p ical case and then b rie f ly to pre sen t

th e re su lts o f the inq u iry .(Fig . 1 .) T h e patien t, ag ed 18 , had had so m e bo w in g o f the legs s incethe ag e o f f our. T h is w as no t v e ry m ark ed and d id no t p rogre ssiv e ly in -

c rease un til th e age o f 1 5 , w hen grow th ceased and th e legs began to b owf urthe r. S he ap peared pale an d stun ted ; the f ace w as o f the larg e w h itety pe , and the re w as f u llne ss roun d the ey e s and a tired ex pres sion . H erhe igh t w as 4 f t. 2 in . ( the no rm al f o r the ag e is 5 f t. 5 in .) . S h ew as w e l lno urished and w e igh ed 5 sto ne , 1 0 p oun ds. T he w e igh t d id no t v arydu ring the f iv e w eek s in h osp ital, A p ril to M ay , 1 923 . G eneral p hy sical


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exam in a tio n w as n ega tive . T he re w as n e ith e r p o lyu ria no r p o lyd ipsia .T he h ead w as sq ua re , w ith fro n ta l p rom in en ce , and the tee th w ere p oor.T he re w as n o rib bead ing . In F igu re 1 m ay be seen th e en la rgem en t a t thelow er ends o f the rad ius and u lna ; th e leg s show an te ro -late ral bow ing ofbo th fem o ra an d o f bo th tib iae and fibu lae , m o re p articu la rly in th e ir low erth ird . T he re w as 30# {176}pe rm anen t flex io n a t th e h ip jo in t and m ovem en tshe re w ere lim ited in range . O n stand ing a w e ll-m arked lum bar lo rdos isw as seen . M u sc le p ow er w as g ood and the re w as n o obv io us w asting .S ensa tion and ref lexes w ere no rm a l. T he ga it w as w add ling . Th e stancew as a little a ton ic an d som e su pport w as needed in tak ing the pho tog raph .

Spec ia l T ests: B lo o d U r ea : = 95 m illig ramm es p er 10 0 c.c.U rea C oncen tra tio n T es t:-

Sp ec im en 1 . B e fo re g iv in g urea 9 0 c.c .= 0 .9% 2 . O n e hour a fte r 80 c.c .= 0 .9% 3 . Tw o hours a fte r 70 c .c .= 1 .0%

Loew i tes t, G o e ts ch te st, and W asserm ann reactio n , nega tive .T he urin e had a spec if ic g rav ity o f 1 010 , w as ac id in reactio n , and

a lbum en w as alw ays p re sen t. N ine m on ths la ter th e u rine w as ac id , hada spec ific g rav ity o f 100 4 , and con ta in ed a lbum en . T he b lo od ureaw as50 .1 m ilh ig ramm es pe r 10 0 c.c .

The u rea co ncen tra tio n tes t g ave:Sp ec im en 1 . B e fo re g iv in g u rea 214 c .c .= 0 .53%

2. O ne hour a f ter 12 4 c .c .= 0 .68% 3 . Tw o hours a fte r 12 9 c.c .= 0 .75%

A s a ro u tine a de ta iled desc rip tion o f the roen tg en ogram s ha s b eenw ritten , co ve rin g in th is ca se som e six p ag es o f ty pe sc rip t. T h is is n o tp resen ted he re , bu t a tten tion is ca lled to som e cha rac te ris tic fea tu res .

In F igu re 2 the sku ll show s gross and un ifo rm th icken ing of th e b oneso f th e vau lt. T he p itu itary fossa is no rm al.

In F ig u re 3 , the sh ou ld er , the re is he re som e ra re fac tion , th e m e taphy -sis is w ide r than norm a l, is b lu rred , and o f co arse , po ro tic app ea ran ce .

In F ig u re 4 , the w rist an d hand , no tice th e rach itic chang es a t the ep i-ph ysea l lin es. The m e tap hyses a re w id er th an no rm a l, hav e a w e ll-m arkedtrab ecu la r app earance, and th e co rtex cann o t b e p ick ed ou t ove r theb lu rred zone w hich imm edia te ly bo und s the ep ip hysea l line . A bou t tw oinches ab ove the low er en d o f the rad ius can be seen th e lin e o f an o ld ob liq uefrac tu re , and the w ho le hand is slig h tly dev ia ted to the inn er side . Th eph alang es show a sem i-cystic po rO tic co nd itio n , and in the firs t and secon dfinge rs the sides o f the b one a re le ss d ense than th e cen te r , p rod uc ing theappea rance o f a co n ta ined ou tlin e.


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F I G . 2Skull o f pat ien t s een in F ig . 1 .

28 2 6. V . A S H C R O F T

FIG. 3Rad iog ram o f shou lde r ofp atien t seen in Fig . 1 .


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1 # { 1 4 9 }

RENAL R ICK ETS 28 3

In F igu re 5 , the tib ia and fib u la , n o te the m arked an te r io r cu rva tu re .O n th e concave sid e the co rtex th ickens and in th e tib ia con densa tiono f bo ne ex tend s rig h t ac ro ss the m edu lla .

T he re is in the tib ia a transve rse frac tu re ex tend in g ha lf w ay acrossth e bo ne and at rig h t ang les to its lo ng ax is .

FIG. 4R ad iogram of hand of pa tien t

seen in F ig . 1.

A s a w hole the roen tg en ogram s show m ild ricke ts w ith gen era l ra re -fac tion an d loca lized m etap hysea l po rosis .

T u rn in g n ow to the re su lts o f the in qu iryFrom the urea tes ts o f th e tw en ty -fou r cases, eig h t w ere fou nd to show

defin ite ev idence of rena l in e ff iciency , abou t 33% , an d to these case s ad iagno sis o f rena l ricke ts has b een app lied . S im ila r ly rena l ine ffic iencyw as susp ec ted in th ir teen , o r 5 4% , and a d iagno sis o f susp ec ted rena lricke ts has been app lied to these .

In rena l r icke ts th e u rin e is p ale , o f a low specif ic g rav ity , u su ally


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F I G . 5

28 4 G . V. ASHCROFT

be low 1010 , and con tain s a lbum en , b u t a lbum en is no t e ssen tia l to thed iagno sis . Su ch a urin e is typ ica l o f ch ron ic in te rstitia l nephritis . E s tab -lish ed po ly u ria and po lyd ip sia, thou gh stres sed by o the rs , w ere n o t co rn -

Ra di ogr am of t i b i a o f pa t i e n t s e e ninF i g. 1 .

mon . Nephri t ic s ymp toms an d o ed em a w ere a ra rity . P a llo rw as presen tin g rea te r o r le ss d eg ree in ev ery case , and it w as a strik ing fea tu re in th osew ith de fin ite rena l ine ffic iency . Th e card io -v ascu la r chang es w hich accom -p an y ch ron ic in te rstitia l nephrit.is w ere n o t p re sen t an d th e b lood pressu rew as norm a l o r be low the norm a l. The L oew i and G oe tsch te sts andWas -


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se rm ann reac tions w ere nega tive . Th e ag e of on se t o f de fo rm ity w assim ilar to tha t o f late r ick ets an d lay ab ou t p ube rty , tho ugh a t th is tim eth ere m ay b e on ly an exacerba tion or rec ru descen ce of p rev io usly ex istingd efo rm ity . O th er observe rs have fo un d the sex inc idence of sim ila r caseso f d efo rm ity asso c ia ted w ith n ep hritis to be ev en ly d iv ided be tw eenm ale s and fem a les . In m y cases th ere w as a g rea t p repo nde ran ce o f fe-m a le s. Th e re w as stun ting w ith ou t in fan tilism and the pa tien ts w ereu sua lly w e ll nou rished . S exu a l deve lopm en t w as p resen t, a lthou gh the rem ay be som e de lay in its deve lopm en t. G ene ra l p hys ica l exam in a tio nw as nega tive . Th e type of d efo rm ity w as tha t o f late r icke ts . In allca se s the re w as a p ro nounced degree o f m uscu lar as then ia . T h is w as no taccom pan ied b y an y m arked degree o f m u sc le w astin g . N o fib r illa rytw itch ing s w ere no ted and th e ref lexes w ere n orm a l. O ne con stan t andcha rac te ris tic fea tu re in co nnec tion w ith th is a sthen ia w as th at w hente sted in b ed the p ow er o f m u scu la r co n trac tion aga inst a resis tan ce w asg ood , bu t ye t the p atien t w as u nab le to stand or w a lk . I t is sugg estedtha t co n trac tile to nus in these case s is no rm al, b u t th at p la stic ton us isde fic ien t. T he p atien ts stand typ ically in an a ton ic postu re , w ith th ek nees an d h ip s flexed , th e sh ou ld ers d roo p ing , the head th rust fo rw ard ,an d the an ter io r ab dom ina l w a ll g roo ved . T he ga it w as o f a w add lingtype , the pa tien ts be in g sca rce ly ab le to lif t the fee t o ff th e g ro und . T heq uadricep s ex ten so r g roup seem ed p articu la rly a ffected and th e p atien tsten ded to th row th e leg from the h ip by a sw in g o f the b ody , m oun tin gsta irs be ing espec ia lly d iff icu lt. S ig ns o f hyp o-thy ro id ism w ere occasion -a lly fou nd . A n odo r as o f stale u rine hu ng abou t cer ta in o f these pa tien ts ,an d ex co ria tion and irite r trig o o f th e ex terna l g en itals w as o f su ffic ien tfrequ en cy to be rem arkab le . In th ree case s the re w as b row n ish p igm en ta -tion of th e sk in , gene ra l in d istr ibu tion .

A roen tgeno gram typ ica l o f rena l ricke ts can b e desc rib ed , the g en era lfeatu re s o f su ch a p ic tu re be ing de fo rm ities o f th e lo ng bones o f the rach iticty pe , a gene ra l ra refactio n , changes at th e ep iph ysea l line s cha rac te ris tico f r icke ts , a tenden cy to excessive d ep ositio n of po orly ca lc ified b one u nde rthe p erio steum , frequen t occu rrence o f sp lit f rac tu res gene ra lly ru nn in ga t rig h t ang le s to the lon g ax is o f th e bon e.

Th e cha rac te ris tic featu re o f th is p ic tu re is tha t th e rach itic chang esa re in th e background and th a t th e ch ie f alte ratio n from the no rm al is ahazy w oo lly porosis in the m e tap hysis .

S ev era l po in ts o f de ta il a re w orth y o f co nside ratio n . In the sk u llth e p itu ita ry fos sa w as a lw ays foun d to b e norm a l: in tw o cases a rem ark -ab le th icken in g o f th e b on es o f the v au lt ha s o ccu rred . In th e w ris t in


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28 6 G . V . A SH C R OFT

sev eral cases o ssif ication has, pro ceeded irregularly and there is apparentfusio n of the w rist bones. (Figure 6 .) In the phalang es a sem i-cy sticporosis w as found, and the degree of alteratio n in the phalang es is a g oodguide as to the severity o f the disease . The pe lv is , scapulae, v ertebrae ,and feet are usually unaffected.

The X -ray pic ture is one w hich is recognizable and may be taken as

FIG. 6Radio gram of w rist epiphyse s typical of

renal rickets . Fusion o f w ris t bones.

charac teris tic , but it does no t appear to be poss ible to c laim that it is aseparate entity . It is that o f a type of ricke ts in w hich one of the patho -log ic e lements-the chang e in the metaphy sis-predominates.

The o rg ans from three cases o f renal ricke ts w ere ex amined. Thekidney s present the changes charac teristic o f chronic inters titial nephritis .In the thyro id g lands the vesic les are large and full o f co llo id and lined bya s ing le lay er o f f lattened cubical cells . From the his to log ic appearancesit is deduced that the ir func tional activ ity is o f a low o rder. The supra-renal g lands show thickening o f the capsule o f the g land and a definite


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RENAL RICKETS 28 7

FIG. 7Suprarenal g land: Zona re ticularis in patient w ith

renal rickets , ag ed 20 .

FIG . 8N ormal suprarenal: Zona reticularis. Same ag e and

se x as Fig . 7 .


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28 8 0 . V . ASHCROF

increase in the connective tissue o fthe organ separating the ce lls from eachother. The change affec ts mainly the zona re ticularis , w hich is broaderthan normal, contains an excess o f g reenish pigm ent, and exhibits an al-tered staining reac tion to M allory s stain. Figure 7 show s the zona re tic -ularis from a patient w ith renal ricke ts , a female aged 20 . Figure 8 show sthe no rmal zona re ticularis for the same age and sex . I am indebted toD r. E. R. A . Cooper fo r permission to photo graph this s lide . It is deducedfrom the histologic chang es pre sent in the suprarenal g lands that there isalteratio n o r de fic iency in the ir secretion. The re st o f the o rgans inc ludingthe pituitary are no rmal.

Considering the patho lo gy of the disease as a w hole there is a chronicinterstitial nephritis , a chronic inflammatory chang e in the suprarenalg land, and an inac tiv e thy ro id. itis sugg es ted that the w hole o f this isdependent on and secondary to an ascending infec tion of the urinary tracto f a long-continued and mild type , also that the inflammation has spreadto the suprarenals from the kidney , and that the inac tiv ity o f the thy ro idg land is due to dim inished secre tio n of the suprarenal g lands.

Passing from such theo riz ing to the results o f observation, the casesin w hich renal func tion is de finite ly pro ved to be de ficient present:-

1 . A typical c linical pic ture.2 . A typical X -ray pic ture .3 . A typical post-mortem picture .

B rie fly to recount the se :The c linical pic ture is one of the onset at puberty of de fo rm itie s o f the

late rickets type , assoc iated w ith a profound muscular asthenia; pallo r;stunting w ithout infantilism ; a low spec ific grav ity urine, pale in co lor andcontaining albumen; a notable absence of o edema and cardio -vascularchang e; a neg ative W assermann; a negative Loew i, and a negative Goe tschtest.

The X -ray pic ture is one of rare fac tion and metaphy seal abnormality ,hazy po ros is , enlargement and lack of cortex , asso ciated w ith some rachiticchanges at the epiphyseal line .

The po st-mortem pic ture is one o f chronic interstitial nephritis asso -c iated w ith fibros is o f the suprarenal g land and an inac tiv e thyro id g land.

The deg ree of renal inv o lvement roughly paralle ls the deg ree of clin-ical and roentgenog raphic abno rmality . It is to the as soc iatio n o f thety pical c linical pic ture , the typical X -ray pic ture , and defic ient renalfunc tion that the term Renal R ickets hasbeen applied.

W hile the kidney le sio n may be responsible for certain o f the findingssuch as albuminuria, nephritic signs and symptoms , and death from urae -


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RENAL R I C K E T S 28 9

mia, the greater part o f the pic ture is due to some cause other than defi-c ient renal func tio n, and I should like to suggest that this o ther cause maybe de fic iency o f the suprarenal g land.

A number o f patients presenting the renal rickets pic ture had had oper-ations, usually som e form o f os teo tomy , and it w as constantly found thatthe results o f these operatio ns w ere bad, and in some cases disastrous. Theleg s, after be ing straight fo r a short tim e, rapidly gave w ay; de fo rm ityw as again produced, and usually w as o f a much gro sser type than had beenpresent be fo re operation. In several cases the history w as obtained thatthe patient had nev er w alked since the operation. A part from this , o per-ation, o r more probably the adm inistration of an anaesthe tic , is attendedw ith considerable immediate risk to life . The literature contains sev eralinstances in w hich operation precipitated an acute attack o f uraem iafrom which the patient died w ithin a few days . A ssuming that osteo tomyis not done w here the roentg enogram show s sig ns o f ac tive ricke ts , the fo l-low ing w ould contra-indicate operatio n :-

(1 ) D efinite or suspec ted renal ineff ic iency .(2 ) A roentg en-ray appearance typical o f renal ricke ts , in particular

the fuzzy metaphy seal po ros is .(3 ) rfhe presence of muscular as thenia.(4 ) A urine of persistently low spec ific grav ity , containing albumen.W here any o f these finding s are present, operatio n is likely to be a

disaster, and at the bes t only a poor result w ill be obtained. The tendencyof the disease to beg in about puberty and the tendency o f operatio n toprec ipitate its onset in a predispo sed person suggest that if there is anyev idence , c linical o r ro entgenographic , o f the renal rickets type, it is ad-v isable to de fer operation fo r som e years, until the time of puberty is pastand the endo crine sy stem not so likely to break dow n, and until the pa-tient has been under observatio n for a considerable period o f time .It isrecommended that during this probation period c linical examination,measurements o f de fo rm itie s , roentgenographic examination, and renale ff ic iency te sts should be perfo rm ed at intervals . The clinical appearanceof this c lass o f case is typical, and the w e ll-deve loped ones are easily pickedout. It is the m ilder cases, w here there is only a sugg es tion o f the renalrickets pic ture, that are like ly to be o verlo oked, and it is for these that aplea is m ade that they should be g iv en v ery great consideratio n be foreo steo tomy is adv ised. It is sugg es ted that be fo re an ado le scent w ith bonedefo rm ity comes to operation renal functiontests should be carried out.

The treatm ent w hich w as g iven tothe cases o f renal rickets and tothose o f sim ilar nature included cod-liv er o il; calc ium lactate in small doses,


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g ly co su ria . H e (the sp eake r) had m et w ith tw o cases o f rena l dw arfs w ith g lycosu ria .The fir st w as reg ard ed a s of pancre atic or ig in , both the p anc rea s an d kid neys being a f-fe cte d b y th e sam e tox ic agen t. In the seco nd h e h ad hadcom ple te exam ina tion s m ade ,an d th ese had proved that the g ly co sur ia w as ren al an d no t p anc reat ic in orig in .Thiss e c o n d p a t i e n t , a girl o f t we l v e , sh owed ric kety ch an ges in the b on es, an d sk iagram s o ft h e s e h e wa s a b l e t oshow . Th e firs t pa tien t w as seen at th e age of six , w ith long , th in ,wa s t e d l i mb s a n d ma r k e d genu va lgum . Th e de form ity w a s cor rected by sp lin ts andsc rew pre ssu re . Tw o y ea rs la te r the pa tie n t w as seenaga in : no grow th wha t so ev e r ha dtak en p lace . T he ch ild show ed m ultip le defo rm itie s resu lting from jux ta -ep iphy sea lf r a c t u r e s , wh i c h i n t h e c ase of the w ris ts w ere ob vio us ly m obile an d ununited . In afew m onths the ch ild d ied . T hese cases d iffe red m arked ly from ord inary ricke ts inth is te nd ency to b end ing and fractu res in the jux ta-ep ip hyseal re g io n . C ou ld an y ex-p lanat ion o f th is b e of fered? H e understo od D r. A shc rof t to say th at ren al insuff ic ie ncyin th ese ca ses w a s accom pan ied b y ricke ty chang es in the b one s. H e h ad m e twithrena l dw arfs w ith de fin ite ren al in su ffic iency w itho u t r icke ty changes in th e bo nes,an d show ed sk iag ram s and a pho tograph of such a pa tien t, a b oy o f s ix , in w hom th eurea c onc en trat ion te st show ed the m ax im um urea excre tion to be 1 .9% ins tead o f thenorm a l 2 .5 to 4% . T here w ere unque stio nab ly va riou s ty pes o f b one af fec tion s second aryto rena l d is ease . H e had seen d efo rm ities associate d w ithrena l d isease in o ld er ch ild renw itho ut dw arfism .

biochemistry of renal rickets 1

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