sign in sign up
<<
Home , Aminoaciduria, Cystinosis, Cystinuria, Fanconi syndrome, Iminoglycinuria, Renal glycosuria

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Kidney International. Vol. 20 (198!), pp.705—7!ó

The and mechanisms of tubular transport dysfunction KARL S. ROTH, JOHN W. FOREMAN, and STANTON SEGAL

Department of Pediatric,sUnimersitv ofPennsvlmaniaSchool of Medicine and theChildrcm'Ho pita! of Philadelphia, Philadelphia. Pennsrlm'ania

Within the past several decades disorders with derangedprocesses of membrane transport. It is the intent of this review transport functions in renal cells have becometo colTelate available knowledge of the transport dysfunction clinically prominent. Every textbook of medicine or pediatricsgathered from clinical studies in and from the investiga- contains a discussion of inherited or acquired involvingtion of animal models. To provide proper perspective with defects in the absorption of specific amino acids, , orregard to present knowledge of normal transport processes for other solutes. The inherited disorders may involve specificvarious substrates, we will discuss the major features of the amino acids, such as in classic with dibasic aminoac-syndrome under the topics of hyperaminoaciduria. . iduria, , and i-Iartnup with neutral ami-and phosphaturia. It is hoped that this review will provide both noaciduria, sugars as in and - insights for the present and stimulation for future investigation. malabsorption, or phosphate as in hypophosphatemic or . Although the exact defect in cell function in these Hyperaminoaciduria disorders has not been delineated, the likely explanation has One of the hallmarks of the Fanconi syndrome is a general- been that they result from a malfunctioning or absent specific ized excessive urinary excretion of amino acids resulting from a carrier mechanism for the transport of the particular substances defect in renal tubular handling. In normal children only I to 6 involved. The renal Fanconi syndrome (Dc Toni-Debré-Fan- mg of amino acids per kilogram of body wt per day are excreted coni syndrome), which has been thoroughly discussed by because over 98% of the filtered load of amino acids (except for Morris et al [I] and by Brodehl [21, on the other hand, is , and where 94 to 98% is reab- characterized by a generalized disorder in proximal renal tubulesorbed) is reabsorbed in the proximal tubule. But, in the transport affecting amino acids, glucose, and phosphate, as well Fanconi syndrome, there is a marked generalized increase in as uric acid, bicarbonate, and other substances. The clinicalthe urinary excretion of amino acids. consequences are , rickets, impaired growth. , Clinical un'estigations. The degree and pattern of this hyper- , and . aminoacidunia in the Fanconi syndrome varies from disease to Besides being manifested by a global dysfunction of renaldisease and even from patient to patient with a particular transport mechanisms, the Fanconi syndrome is associateddisease associated with the Fanconi syndrome. Brodehl found with numerous disease states ranging from rare inherited disor-in 6 patients with the Fanconi syndrome that a pattern of amino ders of to exposure to exogenous toxins. In mostacid excretion tended to mimic that of the normal, that is, those cases, the causation of the abnormal renal function is multifac- amino acids with relatively high excretion rates were affected tonal, with a host of genetic and toxic factors being implicatedmore than those with relatively low excretion rates [31. Manz. in the pathogenesis. Thus, the Fanconi syndrome may be theBremer, and Brodehl [4] also noted that in 6 patients with final common pathway for the phenotypic expression of diverseLowe's syndrome that, although there was a generalized in- inherited and acquired perturbations of renal tubule function. crease in excretion, cystine and dibasic amino acids The diversity of the underlying metabolic derangements, bothwere excreted more than the other amino acids were. We. acute and chronic, suggests there may be a common stephowever, were unable to dicern a clear pattern of amino acid necessary for normal membrane transport upon which manyexcretion in our patients with the Fanconi syndrome associated factors may impinge. In contrast to carrier" abnormalities inwith several diseases (Table I). In all of our patients, histidine specific aminoacidunias, the widespread derangement of renal excretion was within a normal range, but this was one of the tubule function in the Fanconi syndrome could result fronimore affected amino acids in Brodehl's patients. In our patients disordered cell metabolism which is specifically linked to with Lowe's syndrome, the excretion of cystine and the dibasic energy transduction to membranes or to disordered membrane structure as a primary or secondary event. An understanding of the basic underlying mechanism of the Fanconi syndrome is important not only to the clinician who Received for publication April 13, 1981 deals with the consequences in the patient but also to the renal 0085-2538/81/0020-0705 $02.40 physiologist and cell biologist attempting to fathom the cellular © 1981 by the international Society of

705 706 Rotheta!

Table 1.Amino acid excretion in various types of the Fariconi syndrome 24-Hr urinary amino acid excretion Type Normal 2 to 4x 5 to lOx lOx (N =6) SER.GLU ASP,THR PRO.CIT MET,LYS ASN,GLN VAL HIS,TRY GLY ,ALA CYS,ILE TYR,LEU PHE,DRN ARO Lowe's syndrome (N =2)h ASP.THR ASN,GLN PRO S ER ,G LU GLY,ALA CIT MET,ILE VAL,CYS LEU,TYR ORN,LYS PHE,HIS TRY,ARG Lowe's syndrome (N = HIS GLU .CYS SER.GLY THR,ASN MET,ILE ALA,LEU GLN,PRO PHE TYR,ORN CIT,VAL LYSARG (N =1) AS P. PRO GLN,GLU S ER ,AS N THR,MET VAL,ILE CIT,GLY A LA ,PHE TYR LEU,ORN CYS,LYS ARO HIS Idiopathic (N =1) HIS MET,TYR THR,SER LYS GLU,PRO GLY,ALA CYS,VAL LEU,ILE ARG.PHE Headings denote the increase above normal. N denotes the number of patients studied. Abbreviations are defined as follows: ASN—asparagine ASP—aspartic acid ARG— ALA— CYS—cystine CIT—citrulline GLN— GLU— G LY—glycine HIS—histidine ILE— LYS— LEU— MET— PH E— PRO— SER—serine THR—threonine TYR— TRY— VAL— "Three patients with the same disease had two different patterns of amino acid excretion. amino acids was several-fold greater than normal, yet thean interaction of cystine with this system could not be shown excretion of other amino acids was even greater. using renal cortical slices. Neither could defective cystine The nature of the defect underlying this excessive amino acidtransport be demonstrated in patients with cystinuria using excretion remains enigmatic. Amino acid transport in the renal cortical slices [91.But,with the advent of newer in vitro appears to involve specific carriers for groups oftechniques for studying amino acid transport, the isolated renal amino acids, even specific carriers for individuals amino acids.cortical tubule and the renal brushborder membrane vesicle, Evidence for this in the human comes from specific, heritablecystine, and dibasic amino acids were shown to share a defects in amino acid absorption involving several amino acids,common transport system in the rat proximal tubule which was such as iminoglycinuria, , classical cystinuria, not demonstrable using cortical slices [10, II]. This system and hyperdibasic or even involving single aminoprobably also exists in the human and may be defective in acids, such as isolated cystinuria and glucoglycinuria. Furtherclassical cystinuria. evidence for the specificity of these carriers for groups of amino In the Fanconi syndrome, the generalized nature of the acids comes from the infusion of a specific amino acid in normalaminoaciduria militates against a specific defective carrier. A subjects which has reproduced the amino acid excretion patternmore likely explanation would be a disorder of energy genera- observed in several of these aminoacidurias. Examples of thistion or of the coupling of energy generation to the process of are the infusion of lysine, which increased cystine, ornithineamino acid uptake. Amino acid transport in the kidney is and arginine excretion [5, 6], and the infusion of proline, whichdependent on energy since transport in renal cortex slices is increased glycine excretion [7]. Additional support for carrier-sharply curtailed with anaerobiosis or metabolic inhibitors [121. mediated transport comes from studies using renal cortex slicesSome support for a defect in energy production leading to from humans where glycine uptake was shown to he concentra-aminoaciduria comes from the infusion of in patients tive, sodium dependent, and inhibited by proline {8j. Dibasicwith hereditary fructose intolerance which leads rapidly to amino acids were also actively transported by human renalaminoaciduria coincident with accumulation of intracellular cortex and appear to share a common transport system whichfructose-i-phosphate and depletion of intracellular phosphate was thought to be defective in patients with cystinuria, although [I]. Infusion of phosphate concomitant with fructose attenuated Fanconi syndrome and tubular dvsfunction 707

the aminoaciduria, suggesting that the intracellular phosphate newborn cortex. If the major portion of efflux occurs across the depletion with possible reduction in ATP and other high-energy antiluminal surface of the tubule, then influx at the hrushborder phosphate compounds may underlie the renal tubular dysfunc- surface may be slowed in a secondary fashion by the high tion in hereditary fructose intolerance [I]. Another possibleintracellular levels in the newborn [221. This mechanism has explanation for the generalized defect in amino acid handling is also been postulated for the uptake of proline in the prolinuric a primary disorder of the lipid bilayer of the membrane allowing (PRO/Re) mouse kidney [28]. increased efflux of the transported amino acids similar to the Using the neutral amino acid transport analogue, s-aminoiso- Fanconi syndrome induced by the exposure of renal tubule cells butyric acid (AIB), Roth, Goldman, and Segal [16] have investi- to maleic acid both in vivo and in vitro [13—161. There could also gated the in vitro effect of 6 m maleic acid on the neutral be a portion of the carrier or a subunit that is common to all the amino acid uptake system during development of the rat carriers and necessary for insertion or orientation in the mem- kidney. Although maleic acid is known to significantly diminish brane. This could be defective in certain forms of the Fanconi the capacity of mature renal cortical slices and isolated tubules syndrome leading to the renal tubule dysfunction. Also, sodium to concentrate AIB [14], no impairment of newborn uptake has been shown to be important in the transport of many could be demonstrated. But, as the rate of efflux increased as a substrates across the brushborder membrane and a defect in the function of age, so too did the degree of impairment increase in binding of this ion by the carrier or maintenance of properAIB uptake by the tubule. These observations are consistent sodium flux across the cell could lead to the Fanconi syndrome. with those of Bergeron, Scriver, and Mohyuddin [19] obtained Laboratoryini'estigat!ons. Developmental studies in animalwith a microperfusion technique in adult rats treated with models.Just as the human neonatal contains an abun- maleate, which indicated that the aminoaciduria was a conse- dance of various amino acids 1171, so too does the urine ofquence of increased efflux of normally accumulated amino newborns from other species. The pattern, however, of thisacids. Although the basic mechanism by which maleate creates aminoaciduria changes from species to species and varies, as aminoaciduria in animals continues to elude investigators, the well, from one individual to another within a particular species. answer must be found in studying the manner in which maleate Nonetheless, the persistent finding of increased renal clearance affects efflux. of a number of amino acids in the newborn rat, for example, has The developmental approach to renal amino acid transport provided investigators with a physiologic model for study ofhas also been used in the study of cystinuria, in which there is mechanisms for aminoacidurias. Using this model, investiga- increased urinary excretion of cystine and the dibasic amino tors have described many changes in various amino acidacids, arginine, , and lysine. Using renal cortical transport mechanisms which occur with development of theslices, Segal and Smith [29] showed impaired cystine uptake in kidney. newborn slices but they found that lysine uptake was compara- Perhaps the most extensively investigated of the amino acid ble to that in adult slices. In a separate study, the same authors transport systems in the developmental model is the iminogly- also reported that uptake in the newborn was compara- cine system. Particular attention was originally drawn to thisble to that of an adult [301. These observations document the system by the description of an iminoglycinuric syndrome in separate nature of the transport systems for cystine, cysteine. man [181 and by the finding of massive prolinuria and glycinuria and lysine. The relevance of these data to an understanding of in newborn rats [191. Such a finding suggests that the newborn the Fanconi syndrome remains univestigated, although Rosen- renal tubule might be less capable of active accumulation ofberg and Sega! [14] demonstrated a correlation between a glycine and proline than the adult tubule as reflected by massive lysinuria produced in adult rats by injection of maleic decreased intracellular pools of these amino acids in newborn acid and impaired uptake in vitro of lysine by adult rat kidney renal cortex. Recent infusion studies in iminoglycinuric patients slices treated with maleate. support this view [201. To the contrary, however, in vivo Effectsof maleate in animal models. Maleicacid has been glycine pools are significantly higher in newborn cortex while used in a number of ways in attempts to elucidate the mecha- the glycine concentration gradient established by newborn renal nism by which it causes aminoaciduria in animals in vivo and cortex over newborn plasma is 1.3 times higher than in the adult impairs amino acid transport in vitro. Interestingly. Rosenberg [2!]. and Segal [14] were unable to show histologic changes in the In vitro investigations of glycine uptake in rat kidney cortex, kidneys of treated rats within 1, 2, or 4 hours after injection of using both the slice [22, 23] and isolated tubule [24, 25] models, maleate, consistent with a biochemical effect of relatively rapid have shown no impairment ofglycine entry in newborn in onset. The nature of this biochemical effect was suggested by physiologic concentrations. Although it is not possible to differ- earlier reports [31, 32] in which a rapid binding of free sulfhy- entiate brushborder transport events from those occurring atdryl groups by maleic acid had been demonstrated. A subse- the antiluminal surface in the above models, a recent study of quent report by Patrick [331 demonstrated a decrease in the glycine uptake by rat kidney brushborder membrane vesicles activities of SH-dependent enzymes in the livers of cystinotic yielded results very similar to those obtained from intact cell children. The data presented in the same report for renal preparations [26]. Thus, the problem becomes one of explaining enzymes, however, must be interpreted with great care, since the decreased tubular in the newborn where there the end-stage kidney in cystinosis is so scarred and fibrotic as to is strong evidence for normal adult level uptake in vitro.be almost unrecognizable. The applicability of data derived Indeed, the answer may lie in the fact that the loss from the cell from studies in liver to events occurring in the kidney of (efflux) of accumulated material is far slower in newborn tissue children with cystinosis must remain in doubt, because the [22, 271. This finding certainly explains the higher intracellular clinical findings of the disease focus primarily on renal dysfunc- amino acid pool, as well as the greater concentration gradient in tion. Furthermore, Rosenberg and Sega! [14] demonstrated 708 Roth ci a! selective penetration of maleic acid into rat kidney tissue,Deetjen, using microperfusion and free-flow micropuncture in whereas Taggart, Angielski, and Morell [341demonstratedarats treated with maleate, concluded that rnaleate inhibited the relatively rapid rate of metabolic conversion of labeled maleateinflux of glycine via a saturable system and that the passive to carbon dioxide by a rabbit kidney compared to the liver. Thisdiffusion of glycine into the renal tubule cell was unaffected conversion depends on the presence of maleate hydratase[38]. They, however, did not look directly at the efflux of amino which converts the maleate to D( + )malate with further conver-acids from the renal tubule cell. These observations were sion of the latter to fumarate and subsequent entry into theconsistent with the effects of maleic acid exerted on an intracel- Krebs cycle. All of these observations indicate the likelihood oflular site, with the amino acid transport effects considered to be qualitatively and/or quantitatively different effects of maleatesecondary. on liver and kidney. Heavy metal nephrotoxicity nwdel. In an early review of Recent work [35, 36] has implicated an effect of maleate onurinary amino acid excretion by workers exposed to heavy substrate-level oxidations in kidney mitochondria as the under-metals [39], Clarkson and Kench pointed to the frequency of lying biochemical event in the production of the experimentalboth abnormal aminoaciduria and true Fanconi syndrome ap- Fanconi syndrome. The postulated mechanism suggests thatpearing among workers absorbing cadmium. The relationship maleic acid is converted to maleyl-CoA through the action of abetween cadmium exposure and nephropathy was dramatized CoA-transferase on the succinyl-CoA formed through theby the large number of cases of itai-itai disease, caused by Krebs cycle. The maleyl-CoA is thus assumed to react furthercontamination of the soil by cadmium, that appeared in Japan to form a dithioether, a more stable compound than succinyl-after World War II. In addition to severe bony abnormalities CoA, causing a shift in equilibrium toward the former andattributable to osteomalacic changes, affected individuals mani- constituting, in effect, a metabolic "sink." The liver is knownfested glucosuria, aminoaciduria, hyperphosphaturia. hypos- to be deficient in CoA-transferase, thus explaining the resist-thenuria, and —allfeatures of the ance of liver mitochondria to maleate and underscoring theFanconi syndrome. In patients who had advanced disease, the earlier statement about interpretation of renal events fromrenal histology was characterized by tubular atrophy and inter- experiments performed on liver tissue. Anglelski and Szcze-stitial fibrosis. panska [37] have performed in vivo experiments in which they Cadmium intoxication has been studied in a variety of have tested their hypothesis by simultaneously infusing i.v.species, including [40], rabbit [41], rat [42], and mouse [43]. acetoacetate with maleic acid into rats and demonstrate aIn general, there is a correlation between the functional and protective effect of the acetoacetate on renal reabsorption ofmorphologic changes observed and the cadmium concentration bicarbonate and phosphate. This effect they attributed to ain renal cortex, the former appearing only after the cadmium competition between acetoacetate and maleic acid for theconcentration exceeds 100 times normal. In cadmium-intoxicat- transfer ofCoA through the action of the CoA transferase. But,ed [40] and rats [44], Na-K-ATPase of renal cortex was they were unable to show a correlation between maleic acid'sfound to be significantly inhibited. Because this enzyme is effect on renal function and impaired mitochondrial ATP syn-thought to play a role in membrane transport or organic anions, thesis. Their conclusion from this work stated that maleic acidthe inhibition thus demonstrated was considered to represent exerts its inhibitory effects on transport through an action onthe inciting event in creation of glucosuria and aminoaciduria. membrane SH groups involved in the transport process. Thus,Such a postulate had been made earlier for the maleic acid they were unable to clearly demonstrate a link between themodel by Kramer and Gonick [45]. But because the concentra- metabolic and transport inhibition exerted by maleic acid. tions of maleic acid and cadmium used in these studies pro- A parallel approach to an understanding of the maleic acidduced mitochondrial damage at the peak of the functional effect on renal tubular function has been used by other workersabnormalities [40—45], it is difficult to reconcile these studies interested in membrane transport. Rosenberg and Segal [14]with those of Rosenberg and Segal [14] and Roth et al [46], in demonstrated inhibition of uptake of a variety of amino acids bywhich no ultrastructural changes were seen with maleate at the rat kidney cortex slices incubated in 3 ms't maleate. But slicestime of maximum transport inhibition. Furthermore, Roth, made from kidneys of rats treated with maleate did not showGoldmann, and Segal were unable to show Na-K-ATPase such an inhibitory effect. The reason for this discrepancyinhibition by 6 mrvi maleate in isolated renal tubules of either became evident when they restored normal transport in slicesnewborn or adult rats [16]. Any transport process relying on treated with maleate by rinsing them in a fresh buffer, thusoxidative phosphorylation for its energy source will be impaired showing that maleate is a readily reversible inhibitor of mem-if mitochondria are damaged: what remains to he explained is brane transport in vitro. Although thiol group protectors likehow transport processes such as these are inhibited in the mercaptoethanol prevented maleate's inhibitory effect, the easyabsence of such damage. reversibility of transport inhibition by washing treated slices Plumbism has also been reported to induce the Fanconi argued against a covalent link between SH groups and maleicsyndrome in children [47]. Aminoaciduria has been produced acid as the mechanism for this inhibition. Kinetic studies of theby administration of lead salts to rats 1481 and rabbits [49]; once effect of maleate on the uptake of aipha-aminoisohutyric acidagain, ultrastructural damage to mitochondria can be correlated (AIB) showed that although maleate affected influx to a smallwith renal tubular dysfunction, a finding that calls into question degree, the predominant effect was to increase the rate of effluxthe validity of the model for study of physiologic events from the cells. Bergeron, Dubord, and Hausser, using micro-occurring in the human Fanconi syndrome. It seems, therefore. perfusion and stop-flow techniques in the rat, also found thatthat experimental models of the human Fanconi syndrome the major effect of maleate on renal transport was to increaseinvolving administration of heavy metals may not reflect the efflux from the renal tubule cell 151. GUnther, Silbernagl, andactual events in vivo in the human. Fanconi svndrotne and tubular dysfunction 709

Chemical nephrotoxicity. A number of chemical substancestrast to the impaired efflux caused in rat kidney cortical slice in have been reported to cause glucosuria and aminoaciduria onvitro [14—15]. the basis of their direct nephrotoxic action. Perhaps the most Thereport represents a significant advance in our study of thoroughly investigated of these is the clinically relevant com-the biochemical etiology of the human Fanconi syndrome, since pound. . Following Gross's initial report in 1963 ofit documents renal tubular dysfunction as a likely consequence an individual who developed the Fanconi syndrome followingof genetic factors. Such a model would, therefore, allow study ingestion of outdated tetracycline [501. a number of other casesof the actual disease entity, rather than an artificially created appeared in the literature [51. 52]. Three degradation productsmodel in which doubt always remains as to its relationship to of tetracycline were known —4-epi-tetracycline.anhydrotetra-the disease. One can only hope that widespread screening of cycline, and anhydro-4-epi-tetracycline. Benitz and Diermeieranimals seen in veterinary clinics throughout the world will [53] performed a study in rats and dogs designed to determinebecome the rule, in order to elicit more such animals and begin which of these compounds was the inciting agent, showing thata breeding colony. functional derangements of the kidney occurred only after What is known, therefore, about the underlying cellular administration of anhydro-4-epi-tetracycline. Unlike the humanmechanisms that result in renal aminoacidurias does little to cases, however, in which no morphological changes in renalclarify our understanding. The effects of maleic acid on adult rat tissue were demonstrated, the animals in which functionalkidney, the most widely studied experimental model for the changes were seen also showed severe tubular damage up to,human Fanconi syndrome, provide evidence of an accelerated and including, sloughing of the tubules. Similarly, subsequentrate of loss of accumulated substrate [14, 15]. Similar studies in studies have documented these findings [54, 55]. Once again, asnewborn tissue have extended this finding, showing that in in other models, it is known that selectivelyimmature tissue where a slow efflux rate prevails [22,27], localize in mitochondria of hepatic and renal tubular cells. maleateexerts no effect on amino acid uptake [16]. Other inhibiting mitochondrial respiration by a mechanism thought tostudies [35, 36] have shown that maleate forms a CoA "sink" relate to of magnesium [561. Although it is possiblewithin the cell via the succinyl CoA transferase enzyme reac- that doses of anhydro-4-epi-tetracycline might be found whichtion but these observations could not be related to maleate's impair membrane transport events without causing gross mito-membrane transport effects. On the other hand, in vitro studies chondrial and cellular damage, this relationship has gone largely in tissue obtained from dogs with a presumed genetic defect in ignored. Further investigation in this area could provide valu-renal amino acid reabsorption indicate the possibility that the able information on the interaction between oxidative metabo-aminoaciduria derives from impaired luminal uptake in the renal lism and across the membrane barrier of thetubule [66]. Further study of the Fanconi dog model may renal tubule cell. resolve many of these apparent differences. A variety of other chemical compounds have been associated with the appearance of the Fanconi syndrome in humans. These Glucosuria include Lysol (a mixture of cresols) [57]. nitrobenzene [58]. Clinicalinvestigations. Another hallmark of the Fanconi salicylates [591, methyl-3-chromone [601. and streptozotocinsyndrome is glucosuria. seen with normal and even low blood [611. None, however, have been extensively investigated asglucose concentrations, indicating that the renal threshold for animal models for the human Fanconi syndrome. glucose is either very low or nonexistent. Yet, with glucose Fructose-loading in the rat has been shown to affect renalloading there is a rise in the rate of reabsorption indicating that tubular and hepatic cellular metabolism in the fashion postulat-the tubule can respond to increased loads. There are reports of ed for human individuals with hereditary fructose intolerancechildren with the Fanconi syndrome with a reduced renal [1, 62—65].Fructose-loading,however, does not induce a renalthreshold for glucose, but on glucose loading have a normal tubular dysfunction in the rat as it does in the affected humanmaximal glucose reabsorption rate (Tm0) [2, 67]. This normal [I], making it difficult to envision how further study of thismaximal reabsorption rate only occurred at very high plasma animal model might be expected to elucidate the biochemicalglucose concentrations. In adults with the Fanconi syndrome, basis for the Fanconi syndrome. low values for the renal threshold for glucose with normal to Spontaneous anunal model. Recently, Bovée et at [66] re-low values for the Tm0 have also been reported [68]. ported the first known cases of a spontaneous animal model of This glucosuria in the Fanconi syndrome may also play a role the human Fanconi syndrome, occurring in dogs of the Basenjiin the disordered handling of phosphate and amino acids breed. l'he animals presented clinically with andbecause infusions of glucose, fructose, and galactose in normal polyuria, dehydration, weight loss, and weakness. The renalman have resulted in phosphaturia and arninoaciduria [69]. This defect in these animals was represented by increased glucoseeffect was specific for these sugars because a similar infusion of and sodium clearance in the presence of normal blood sugars.xylose did not produce any changes in phosphate or amino acid renal aminoaciduria, and hyperphosphaturia. The urinary p0-handling. These patterns of glucosuria observed in the Fanconi tassium and urate excretion were also elevated. Histologicsyndrome do not easily fit into either of the two groups examination of renal tissue from these animals showed corn-described by Reubi [70] and Bradley et at [71] in patients with pletely normal 1:issue in dogs without renal failure and varyingisolated glucosuria. In these glucosuric patients, one group had degrees of tubular and glomerular damage in the others. Ina reduced renal threshold for glucose, as well as a reduced Tm0 addition, the authors were able to show an in vitro defect of(type A), but the second group had a reduced threshold with lysine and glycine uptake by renal cortical slices made fromexaggerated splay in the titration curve, but a normal Tm0 (type biopsies of affected kidneys. This defect appeared to reside inB). L.ater reports have called into question whether these the processes responsible for substrate entry (influx), in con-patients actually can be separated into two distinct groups, or 710 Rat/i Cf iii whether there is a continuum of tubule glucose reabsorptionexpansion. The absence of volume expansion was an important maxima from low to normal [721. In vitro studies in the humanadvantage in this study since increased volume and decreased using cortical slices [73] and hrushhorder membrane vesiclestubular transit time may. in itself, cause diuresis and naturesis, [74] have shown that glucose transport is an active, sodium-the latter possibly affecting glucose reabsorption since the dependent process mediated by one, possibly two carrierprocess is thought to he sodium-dependent [81, 821. A low-dose systems. With this knowledge of glucose transport, we couldmaleate injection (ISO mg/kg of body wt) was shown to increase explain Reubi's type A pattern of glucosuria by a defectthe fraction of filtered glucose delivered to distal sites but did lowering the maximal glucose transport velocity of the carri-not cause an increase in urinary glucose. On the other hand, a er(s) (Vmax defect), whereas type B could he a defect loweringhigh-dose maleate injection (300 mg/kg of body wt) caused a the affinity of glucose for the carrier (Km defect). distinct glucosuria with fractional glucose excretion reaching Laboratoryinrestigattons: developmentalstudies in aninwiabout 10%. But because the amount of filtered glucose deliv- models.Inasmuchas neither galactose 1751 nor u-methyl-D-ered to distal sites was not increased in this case, it was glucoside [22, 76] could he shown to he actively transported byconcluded that high-dose maleate injection inhibited distal renal cortical slices from newborn rats, little is known about the tubular reabsorption of glucose. The nature of this inhibition in vitro transport mechanisms in immature tissue. But.was not determined, however. concentrative uptake of ctMGbyseparated renal tubules of in a study which combined the use of a number of techniques. newborn rat kidney was subsequently demonstrated by Roth etincluding microperfusion, micropuncture and stop-flow diure- al [22], providing a feasible model for developmental study. Insis, Bergeron et al [15] demonstrated that the basis for the addition to a study of the changes occurring in hexose transportmaleic acid-induced glucosuria in rat kidney was an increased in vilroduringdevelopment of the rat kidney 1771. Roth et alrate of loss from tubular cells. The conclusions reached from have investigated the age-related changes in the effect of maleictheir observations point to a glucosuria resulting from maleic acid on rat kidney hexose transport 1161. These observationsacid-induced effiux of glucose at the proximal tubular site, thus suggest: (1)thata major change takes place in hexose entryincreasing glucose delivery into the distal where it is during development, unlike amino acids in which case thenormally reabsorhed. However. maleic acid induced an in- primary change is in effiux: (2) that hexose transport systemscreased rate of efflux of glucose at the distal tubular site, as are effectively mature by 7 to 14 days in the rat, again unlikewell, thus resulting in failure to correct the defect at the systems for amino acid transport which require 14 to 21 days toproximal site. These conclusions are completely consistent with mature: and (3) that maleic acid creates significant perturba-the observations of Wen 1801 and Silverman and Huang [79]. tions in hexose transport only after niaturation has occurred. Spontaneous animal model. A study of fractional renal These data were thought to point to a genetically-programmedreabsorption of glucose in dogs affected by the spontaneous intracellular change occurring with development which thenFanconi syndrome indicates a mean of 67,3Y reabsorption renders the renal tubular cell susceptible to maleate. compared to controls showing a mean of 99.6% 1821. In vitro Because the primary in vitro effect of maleic acid on hexosestudy of u-MG uptake in slices made from renal biopsies of transport in adult rat kidney has been shown to be an acceler-affected kidneys showed marked impairment compared to con- ated loss of accumulated substrate (effiux) 1461. the postulatedtrols [66]. Furthermore, the significantly slower initial uptake in intracellular change would have to he one which related toaffected tissue was interpreted to indicate that the defect was in cellular retention, rather than to entry. This speculation hasinflux of u-MG into the cells. However, no effiux studies have been extended by the demonstration of Reynolds, McNamara,been published in support of these observations. These, togeth- and Segal [781 that maleic acid does not affect uptake of u-MGer with studies similar to those of Bergeron et al 1151 describing by adult rat renal hrushborder vesicles. distal tubular reabsorption function would be of great interest. Effi'cts of maleate in animal models. Silverman and H uang Thus, although the available data dealing with the mecha- [791 have used a technique known as the multiple-indicatornisms underlying glucosuria are no less voluminous than those dilution method to study the effects of maleate on renal glucosefor aminoaciduria, neither is an elucidation of these mecha- handling in dogs in vivo. The method consists of injection intonisms in the human Fanconi syndrome any closer. There is a the renal artery of the 4C-laheled test substrate and 3H-inulinbasic agreement among all investigators that maleic acid causes and collection of total renal vein effluent. The renal venousan increase in efflux in the nephron, but the evidence from '4C13H ratio is then calculated. A ratio of less than 1 (in thestudy of the spontaneous Fanconi dog suggests quite the absence of 14C uptake by red cells) suggests entry or binding ofopposite, that is, impaired substrate entry. The fundamental the test substance into the renal cell at the antiluminal surtce.difference will require greater future collaboration between Simultaneous collection of urine will permit calculation of ainvestigators for complete understanding of the reasons for the number of parameters including renal clearances, and so forth.discrepancy. The results of this study indicated that maleic acid induces glucosuria by three possible mechanisms: (I) by partial inhibi- tion of D-glucose efflux from cytoplasm into blood at the 1-lyperphosphaturia antiluminal surface: (2) by accelerated efflux of glucose from Clinicalinvestigations. Hypophosphatemiais another major cytoplasm into urine at the luminal brushborder surface: or, (3)feature of the Fanconi syndrome which occurs mainly from a both effects combined. disorder in the renal handling of phosphate. Normally. only 10 In another study, utilizing micropuncture technique, Wento 20% of the filtered load of phosphate is excreted in the final [801 observed the reabsorption of approximately 90% of filteredurine, In the Fanconi syndrome, this fraction is much increased glucose by the canine proximal tubule in the absence of volumeresulting in the reduced plasma levels of phosphate. Diminished Fan(on, VVfl(/JOfl(.' (mdiiibmmhmr(Ir'fii/1(tiOfl 711

phosphate absorption by the does notthe proximal tubule, to leak directly into the urine at the distal appear to play a major role in the [841. tubule site. Thus, phosphate transport appears to be affected by The nature of the detect underlying the disordered renalmaleate in the same fashion as glucose and amino acids, its handling of phosphate remains unknown. The hulk of phos-efflux increasing in the face of relatively normal entry. Fraction- phate reabsorption in the kidney occurs in the proximal tubule. al reabsorption of Pi by the spontaneous Fanconi syndrome dog Uptake of phosphate across the brushhorder membrane ofthe is also decreased by about 30 compared with controls [83], proximal tubule cell of the rat, which is the first step ofalthough the mechanism by which this occurs is unclear. reabsorption, was shown to be carrier-mediated and dependent on a sodium concentration gradient directed into the cell [85-- Other solutes 87]. Transport of phosphate across the basal-lateral membrane, Besides glycosuria, aminoaciduria, and hypophosphatemia, which is the final step for reabsorption, was not dependent on a there are other indicating disorders of' sodium concentration gradient and may be facilitated by thesolute handling by the proximal tubule. A non-delta metabolic favorable negative intracellular electrical potential 185]. Further acidosis is a frequent finding in the Fanconi syndrome. This support for this carrier-mediated model of phosphate reabsorp- metabolic acidosis is usually a proximal renal tubular acidosis tion comes from studies done by Tenenhouse et at [88] whosince an acid urine can be generated, but only in presence of a found a heritable defect of phosphate transport residing at the low serum bicarbonate concentration 11021. In some cases, a level of the hrushborder membrane of the proximal tubule cell defect in distal acidification can also he shown by an inability to in the X-linked hypophosphatemic male mouse, an animalacidify the urine even after severe acidemia 99, 102. 1031. model of vitarnin-D-resistant rickets in man. The phosphaturia is another common finding in the Fanconi syn- in theFanconisyndrome may he related also to a defect of drome, especially in adults [68, 94, 104—107]. Because uric acid phosphate transportat thelevel of the hrushbordermembrane, isboth secretedand reabsorbed in the proximal ttibule. it is Phosphatehandlingby the kidney is also influenced by unclear whether the secretory or reabsorptive steps or both are parathyroidhormone (P'l'H) and possibly vitaminI). It is well affected. Sodium wasting is often seen and at times may be so knownthat raised levels of PTH will causeanincrease in severe as to cause metabolic alkalosis in spite of the lowered phosphate excretion. Morris found in a parathyroidectomized renal threshold for bicarbonate [107, 1(8]. Hypokalemia caused patient with hereditary fructose intolerance that both fructose by exaggerated renal loss of potassium is a constant danger to and PTH were necessary for expression of' phosphaturia and patients with the Fanconi syndrome [103, 108—Il I]. This hypo- other elements of the Fanconi syndrome 89]. Calcium infu- kalemia can be magnified by glucose loading, hence the danger sions, which will suppress PTH secretion, have decreasedin studying maximal glucose reabsorption. 'l'he clearance of phosphate excretion in sonic studies 190—92] and not in others potassium can he as much as twice the glomerular filtration rate [84. 93, 941. Direct measurement of PTH was found to he indicating that net secretion of potassium can occur [112]. normal, however, in the Fanconi syndrome [951. , especially small molecular weight proteins (10,000 administration in Fanconi syndrome patients leads to 50.000 daltons) consisting of enzymes. immunoglobulin light to increased phosphate retention. This is due in part to in- chains, and hormones, is a frequent finding in the Fariconi creased phosphate absorption from the gut [84, 96—99]. Vitamin syndrome [94, 113. 114]. Larger molecular weight proteins, so D, or one of its polar metabolites, may also have an effect on called glomerular proteinuria, can also be found in the later phosphate reabsorption in the kidney by suppressing PTHIstages of cystinosis and chronic intoxications as glomerular secretion either by a direct action on the parathyroid gland or dysfunction becomes more evident 11141. by raising serum calcium, through increased gut absorption of calcium, which will then lead to decreased P'FH secretion [100]. Categories of the F'anconi syndrome Vitamin D, or one of its polar metaholites, may act directly on Patients with theFanconisyndrome can be classified into two the renal tubule to increase phosphate reabsorption 11011. The main categories: acquired and inherited ('I'ahle 2). The major role that PTH and vitamin D play in the phosphaturia and the cause of the acquired form is exogenous intoxications. Numer- excretion of other solutes remains, however, to he defined in ous substances have been described which cause primarily a the Fanconi syndrome. tubular dysfunction, although severe intoxications can lead to Laboratory I/li'estigat!ons.Hyperexcretionof' inorganic- and renal failure. The major groups of phosphorus (Pi) is characteristic of both the human and experi- these toxins are heavy metals, drugs and organic compounds. mental models of the Fanconi syndrome. In the case of maleic Lead [39, 47, 115—1171. cadmium [39, 116, 118]. uranium [39, acid-induced phosphaturia, it is difficult to sort out the underly- 119]. and mercury [39, 99, 1201 have all been associated with ing mechanism, since phosphate transport by brushhorder tubular disorders in both adults and children. Acute lead membranes is sodiLim-dependent 185—871, and naturesis is also poisoning can lead to a complete Fanconi syndrome in children, induced by maleic acid [80]. It is possible that phosphaturia, as as well as the disorders [47, 115, 1171, A well as glucosuria may reflect an alteration in sodium transport mild Fanconi syndrome has been seen in a IS-year-old child created by nialeic acid. On the other hand, if defective sodium following chronic from a teething prepara- transport underlies the other transport defects induced h tion [1201. The use of outdated tetracycline has led to a maleic acid, it is ditlicult to understand the mechanism by which reversible banconi syndrome and the intoxicating substance luminal uptake continues in the face of increased etfiux. be- has been shown to be anhydro-4-epitetracycline farmed from cause entry is, in general, sodium-dependent. tetracycline under the infltience of heat, moisture, and low pH Bergeron et al [IS] have shown that maleate causes Pi. which. [49—521. This substance has been used to experimentally induce like glucose and amino acids, is predominantly reabsorbed in a Fanconi syndrome in dogs and rats [53, 541. Methyl-3- 712 Roth et a!

Table 2. Categories of the Fanconi syndrome metabolism, is also associated with a Fanconi syndrome which Acquired Inherited is reversible with copper chelation by . Other inborn errors of metabolism are associated with the Heavy metals Hereditary fructose intolerance Fanconi syndrome, but the role of a toxin is less clear. Outdated tetracycline Cystinosis, an autosomal recessive disorder associated with the Methyl 3-chromone Tyrosinemia Wilson's disease intracellular accumulation of cystine, initially presents with the Cystinosis Fanconi syndrome at age 3 to 6 months. With time, glomerular Renal transplantation Lowe's syndrome failure overtakes the tubular disorder and results in end-stage Glycogenosis renal failure. It has been proposed that the raised concentra- Idiopathic tions of intracellular cystine cause the renal dysfunction; yet, the concentrations of cystine in fetal tissue are comparable to those found at the time of renal transplantation [139, 140]. The chromone (Diachrome®) has been reported to have produced aFanconi syndrome is a major feature of oculo-cerebro-renal Fanconi syndrome in a 3-year-old child [60]. Maleic acid hassyndrome (Lowe's syndrome), although the pathogenesis of been used experimentally to produce the Fanconi syndromethis disorder remains an enigma. The Fanconi syndrome has [17—19, 38], been associated with a specific type of storage disease Another major cause of the acquired Fanconi syndrome areof which the enzymatic defect remains to be characterized [111, the dysproteinemias, especially multiple myeloma [99, 104,141, 1421. It appears to be inherited as an autosomal recessive 121—125], These disorders are extremely rare in infants andtract. The Fanconi syndrome associated with it is usually children, however. The appearance of tubular dysfunctionsevere, with striking glucosuria. The Fanconi syndrome may seems to be associated with Bence-Jones proteinuria, althougheven precede the appearance of hepatomegaly. Bence-Jones proteinuria can be seen without tubular dysfunc- A primary form of the Fanconi syndrome is the adult or tion [126]. Experimentally, the presence of Bence-Jones pro-idiopathic type [94, 97—99, 104, 137]. As the name implies, this teins in the media inhibited the uptake of PAH by renal cortextype is diagnosed only by exclusion of the known diseases and slices from both rats and rabbits, whereas the presence oftoxins associated with the Fanconi syndrome. Originally, it was proteins from nephrotic urine did not [127, 128]. Injection ofthought to occur only in adults, but it has been well documented kappa-type Bence-Jones proteins into rats induced proximalin children [107, 141. 142]. It usually occurs sporadically but tubular lesions [129]. Besides Bence-Jones proteinuria leadinghas been observed to follow both an autosomal dominant [143] to the Fanconi syndrome, the nephrotic syndrome may, on rareand an autosomal recessive [144] mode of inheritance. It even occasions, be associated with a Fanconi syndrome [130—1341.has appeared to have an X-linked pattern of inheritance [1451. Renal transplantation can be associated with the developmentThe prognosis is uncertain with some patients developing of the Fanconi syndrome either due to ischemia, graft injection,chronic renal insufficiency over a period of 10 to 30 years. hyperparathyroidism, or immunosuppressive therapy [135, 136]Recurrence of the Fanconi syndrome in the patient who had or the recurrence of the Fanconi syndrome in the originalreceived a renal transplant and had no evidence of rejection kidneys [137]. suggests a primary abnormality that was extrarenal [137]. The The inherited forms of the Fanconi syndrome include severalidiopathic Fanconi syndrome may be related to extrarenal inborn errors of metabolism, Lowe's syndrome, and the adultfactors in some patients, but in others it may be related to a form of the Fanconi syndrome. It seems, as mentioned earlier, basic defect in membrane function. although not proven, that the Fanconi syndrome associated In the final analysis we have presented an interim assessment with the inborn errors of metabolism results from either theof our knowledge of the Fanconi syndrome. There are many accumulation of a toxin or a disturbance in energy metabolism. unsolved questions whose answers are basic to a complete The ingestion of fructose in hereditary fructose intolerance, anunderstanding of the syndrome. Clearly the human renal proxi- autosomal recessive disorder associated with deficient activitymal tubule cells perform carrier-mediated transport. In vivo of fructose I-phosphate aldolase, leads to the rapid onset offunction studies in affected patients are difficult to interpret aminoaciduria associated with the accumulation of fructose I-because of the bipolar nature of solute transport carried out by phosphate. Normalization of the aminoaciduria can occur withrenal tubule and the possible directional components abstension from fructose for several weeks. Similarly, theof transport defects. Thus, from a physiologic point of view, we Fanconi syndrome associated with the accumulation of galac-do not yet know whether the human Fanconi syndrome results tose 1-phosphate from deficient activity of galactose I-phos- from (1)defectiveinflux of solutes at the luminal (brushborder) phate uridyltransferase is reversible with a galactose-free diet. surface of the proximal tubule cell, (2)increasedrate of efflux or In contrast, galactosemia from deficient activity of galactoseback diffusion at the luminal surface, or (3) diminished rate of kinase (in which impaired formation of galactose I-phosphatetransport of solutes out of the cells at the antiluminal (basal- occurs) is not associated with renal tubular dysfunction. Tyro-lateral) surface, a process which could result in the back sinemia is another inborn error of metabolism associated withdiffusion mentioned above. From a biochemical and chemical the Fanconi syndrome. The renal tubular dysfunction is revers- viewpoint, it is still unclear whether there is impaired energy ible with dietary phenylalanine and tyrosine restriction again production by the cells or defective energy transduction to raising the possibility of an endogenously produced toxin. membrane transport processes; alternatively, there may be Maleylacetoacetate, an intermediary in tyrosine metabolism, abnormalities in the structure or composition of the renal has been proposed as a possible toxin in tyrosinemia by onemembranes, which result in the observed defects in transport group [138]. Wilson's disease, a familial disorder of copper function. Fancon, svndrone and tubular clvs/unction 713

To skirt the difficulties in obtaining human tissue for study, maleic acid-induced inhibition of and amino acid transport in investigators have used animal models to explore possible the rat renal tubule. PediatrRes 12:1121.1978 mechanisms. Whether these models are indeed representative 17. BRODEHLJ,GELLISSENK:Endogenous renal transport of free amino acids in infancy and childhood. Pediatric,s42:395,1968 of and the experimental observations applicable to the human 18. JOSEPHR,RIBIERREM,JOBIC,GIRAULTM:Maladie familiale Fanconi syndrome cannot be answered at present. The recent associent des convulsions, a debut tres precoce. une hyperalbu- delineation of a spontaneous dog Fanconi syndrome may he minorachie et one hyperaminoacidurie. ArchFr Pediatr 15:374. more helpful than the toxin-induced model in explaining the 1958 19. BAERI.OCHERKE.SCRIVERCR,MOI-IYUDDINF:The ontogeny of syndrome. The basic derangement explaining the global trans- amino acidtransportinrat kidney. I. Effect of distribution ratios port dysfunction of the Fanconi syndrome will be discerned by and intracellular metabolism of proline and glycine. Biochim the application of numerous and varied physiological and Biophvs Ada 249:353.1971 biochemical approaches to the study of renal membrane struc- 20. LASLEYL,SCRIVERCR:Ontogeny of amino acid reabsorption in ture and function. The ability to isolate and study renal brush- human kidney. Infant evidence from the homozygous infant with familial renal iminoglycinuria for multiple proline and glvcine border and basolateral membranes offers great potential for systems. PediatrRes l3:65—7t),1979 solving the present enigma of the Fanconi syndrome. 21. BLAZER-YOSTB,REYNOI.DSR,SEGAL5:Amino acid content of rat renal cortex and the response to in vitro incubation. AmJ Acknowledgments Phvsio/ 236:F398,1979 22. SEGALS.REAC,SMITHI:Separate transport systems for sugars This work was supported in part by Grants AM 10894 and HD 07107 and amino acids in developing rat kidney. P,'ocNatl Acad Sci from the National Institutes of Health. Dr. Roth is the recipient of a USA 68:372,1971 Research Career Development Award K04 HD00257 from the National 23. REYNOLDSR,ROTHKS,HWANGSM,SEGAI.5:On the develop- Institutes of Health. ment of glycine transport systems by rat renal cortex. Biochim Biophv.sActa 511:274,1978 Reprintrequests to Dr. Roth, The Children's Hospital of 24. R0TLI KS, HWANGSM,YUDKOFFM.SEGAL.5:On the transport Philadelphia, One Children's Center, 34th Street and Civic Center of sugars and amino acids by newborn kidney: use of isolated Boulevard, Philadelphia, Pennsylvania /9104, USA proximal tubule. Lif.'Sci 18:1125,1976 25. ROTHKS,HWANGSM,LONDONJW,SEGALS:Ontogeny of References glycine transport in isolated rat renal tubules. AmJ Physiol 233:F24l,1977 I. MORRISRCJR.MCINNES RR.EPSTEINCi.SEBASTIANA. 26. MCNAMARAPD,OzEGovIcB,PEPELM.SEGAL5:Proline and SCRIVERCR:Genetic and metabolic injury ofthekidney, in The glycine uptake by rat kidney cortex brushborder membrane vesi- Kidney, editedby BRENNERBM.RECTORFC.Philadelphia. des. ProcNatI Acad Sci USA 73:4521,1976 Saunders, 1976, p. 1214 27. BAERLOCHERKE,SCRIVERCR,MOHYUDDIN F: Ontogery of 2. BRODEHEJ:The Fanconisyndrome, inPediatricKidney Disease, iminoglycine transport in mammalian kidney. ProcNail Acad Sd editedby EDELMANNCMJR. Little. Brown and Co., 1978, p. 955 USA 65:1009, 1970 3. BRODEHLJ,BICKELH:Aminoaciduria and hyperaminoaciduria in 28. SCRIVERCR,MCINNESRR.MOHYUDDINF:Role of epithelial childhood. C/inNephrol 1:149,1973 architecture and intracellular metabolism in proline uptake and 4. MANZF.BREMERHi.BRODEHLJ:Renal transport of amino acids transtubular reclamation in PRO/Re mouse kidney. ProcNatl in children with oculocerebrorenal syndrome. HelvPaediatr Ada AcadSci USA 72:1431,1975 33:37.1978 29. SEGALS.SMITH1:Delineation of separate transport systems in rat 5. RoRSONEB.ROSEGA:The effects of intravenous lysine on the kidney cortex for L-lysine and L-cystine by developmental pat- renal clearance of cystine, arginine. and ornithine in normal terns. BiochemBiophvs Re,c Common 35:771.1969 subjects in patients with cystinuria and Fanconi syndrome and 30. SEGAL5,SMITHI:Delineation of cystine and cysteine transport their relatives. C/inSci Mol Med 16:75,1957 systems in rat kidney cortex by developmental patterns. ProcNail 6. LESTERFT.CuswoRTH DC: Lysine infusion in cystinuria: theo- Acad Sci USA 63:926,1969 retical renal thresholds for lysine. ClinSci Mol Med 44:991.1973 31. ANGIELSKI5,ROGULSKIJ:Aminoaciduria caused by maleic acid. 7. SciuvCR,EFRONML,SCHAFERIA:Renal tubular transport of Ill. The effect of sult'hydryl compounds. ActciBiochi,n Pot 6:411. proline, . and glycine in health and in familial 1959 . JC/in Invest 43:374.1964 32. ANGIEL5KI5,Roaui.sKiJ,MADONSKAL:Aminoaciduria pro- 8. ROTHKS,I-IOLTZAPPLEP.GENELM,SEGEL5:Uptake ofglycine duced by maleic acid. V. Comparison of maleic acid poisoning by human kidney cortex. Metaholis,n28:677,1979 with intoxications produced by salygran, mercury, chloride. io- 9, Fox M, THIERS.ROSENBERGLE.KISERW,SEGAL5:Evidence doacetate, malonic acid, and phlorhizin. AdaBiochim Pol 7:269. against a single renal transport defect in cystinuria. NFog/f Med 1960 270:556,1964 33. PATRICKAD:Deficiencies of SH-dependent enzymes in cystino- 10. FOREMAN1W.HWANGSM,SEGAL5:Transport interactions of sis. C/inSci Mol Med 28:427,1965 cystine and dibasic amino acids in isolated rat renal tubules. 34. TAGGARTJV.ANGIELSKIS.MORELLH:Complete oxidation of Metaho/is,n29:53.1980 maleicacid via D( +)malatein kidney. Bioc'himBiophvs 4cta II. SEGALS.MCNAMARAPD.PEPELM:Transport interactions of 58:141, 1962 cystine and dibasic amino acids in renal hrushborder vesicles. 35.ROGULSKI J,PACANISA,ADAMONICZW.ANGIELSKIS:On the Science197:169.1977 mechanism of maleate action on rat kidney mitochondria. Effect 12. ROSENBERGLE.BLAIRA,SEGALS:Transport of amino acids by on oxidative metabolism. ActaBiochim Po/ 21:403.1974 slices of rat-kidney cortex. BiochimBiophvs Ada54:479. 1961 36. PACANIS A, R0GuL5KII,LEDOCHOWSKIH,ANGIELSKI5:On the 13. HARRISONHE,HARRISONtIC:Experimental production of renal mechanism of maleate action Oflratkidney mitochondria. Effect glycosuria. phosphaturia. and aminoaciduria by injection of maleic on substrate-level phosphorylation. ActaBiochi,n Polon 22:1. acid. Science120:606.1954 1975 14. ROSENBERGLE,SEGAL5:Maleic acid induced inhibition amino 37. ANGIELSKI5,SZCZEPANSKAM:Effects of acetoacetate onmale- acid transport in rat kidney. BiochemJ 92:345.1964 ate-inducedtubular dysfunction intherat. Abstract. VIlth Inter- 15.BERGERON M.DUBORDL,HAUSSERC:Membrane permeability national Congress of Nephrology, Montreal, 1978, pp. A-l4 as a cause of transport defects in experimental Fanconi syndrome. 38. GUNTHERR,SILBERNAGLS,DEETJENP:Maleic acid induced A new hypothesis. JC/in Invest 57:1181.1976 aminoaciduria, studied by free flow micropuncture and continuous 16. ROTHKS.GOLDMANNDR.SEGAL5:Developmental aspects of microperfusion. Pfli3gersArch 382:109,1979 714 Rothcia!

39. CLARKSON TW, KENCH JE: Urinary excretion of amino acids by 67. BRADLEY SE: Disorders of renal tubular function. AmJ Med men absorbing heavy metals. BiocliemJ 62:361.1956 20:457,1956 40. NECLAY BR, SAUNDERS JP: inhibition of renal adenosine triphos- 68. REEM GH, ISAACS M, VANAMEE F: Renal transport of urate, phatase by cadmium. JPharinacol Exp Ther 200:623,1977 phosphate, and glucose in the Fanconi syndrome. JClin Endo- 41. AXELSSON B, PISCATOR M: Renal damage after prolonged expo- crinolMetab 27:1141,1967 sure to cadmium. An experimental study. ArchEnviron Health 69. Fox M, THIER 5, ROSENBERG L, SEGAL S: Impaired renal tubular 12:360,1966 function induced by sugar infusion in man, JC/in Endocrino/ 42. BONNELL JA, Ross Jl-1, KING E: Renal lesions in experimental Metab 24:1318,1964 cadmium poisoning. BrJ md Med 17:69,1960 70. REUBI FC: Glucose titration in renal glycosuria, in CibaFoi,nda- 43. NORDBERG GF, GOYER RA, NORDBERG M: Comparative toxicity lion Symposium an the Kidney, editedby Lrwis AAG. of cadmium-metallothionein and cadmium chloride on mouse WOLSTENI-IOI.ME GEW, Boston, Little, Brown and Co., 1954, p. kidney. Arc/iPathol Lab Med 99:192.1975 96 44. Gor.ocic HD, INDRAPRASIT S. ROSEN Vi, NEUSTEIN H, VAN DE 71. BRADLEY SE, BRADLEY GP, TYSON Ci, CURRY ii, BLAKE WC: VELDE R, RAGFIAVAN SRV: Experimental Fanconi syndrome. 111. Renal function in renal diseases. AmJ Med 9:766,1950 Effect of cadmium on renal tubular function, the ATP-Na-K- 72. ELSAS U, ROSENBERG LE: Familial renal glycosunia:a genetic ATPase transport system and renal tubular ultrastructure. Mineral reappraisal of hexose transport by kidney and intestine. JC/in Electrolyte Me iab 3:21,1980 Invest 48:1845,1969 45.KRAMERHJ, GorsicK HC: Experimental Fanconi syndrome. 1. 73. SEGAL 5, GENEL M, HOLTZAPPLE P. REA C: Transport of alpha- Effect of maleic acid on renal cortical Na-K-ATPase activity and methyl-D-glucoside by human kidney cortex. Metabolism22:67, ATP levels. JLab C/in Med 76:799,1970 1973 46. ROTH KS, HWANG SM, SEGAL S: Effect of maleate on the kinetics 74. TURNER RJ, SILVERMAN M: Sugar uptake into brushborder vesi- of alpha-methyl-D-glucoside transport by the rat kidney tubule. des from normal human kidney. ProcNat! Acad Sci (ISA 74:2825, BiochirnBiophys Ada 426:675,1976 1977 47. CwsoLM ii, HARRISON HC, EBERLEIN WR, HARRISON HE: 75. BAILEY JM, FISHMAN PH. PENTCHEV PG: Studies on mutaro- Aminoaciduria, hypophosphatemia and rickets in . tases. VI. Enzyme levels and sugar reabsorption in developing rat AmJDis Child 89:159,1955 kidney and intestine. JBiol C/tern 245:559,1970 48. GOYER RA, KRALI. R: Ultrastructural transformation in mitochon- 76. SEGAL 5, ROSENHAGEN M. REA C: Developmental and other dna isolated from kidneys of normal and lead-intoxicated rats. J characteristics of alpha-methyl-D-glucoside transport by rat kid- Cell Biol 41:393, 1969 ney cortex slices. BiochimBiophv.c Acta 291:519, 1973 49. VON STUDNITZ W, HAEGER-ARONSEN B: Urinary excretion of 77. ROTH KS, HWANG SM, YUDKOFF M, SEGAL S: The ontogeny of amino acids in lead-poisoned rabbits. Ac/aPharmacol Tax/cal sugar transport in kidney. PediatrRes 12:1127,1978 (Kobenhavn) 19:36,1962 78. REYNOLDS R, MCNAMARA PD, SEGAL 5: On the maleic acid 50. GROSS iM: Fanconi syndrome (adult type) developing secondary induced Fanconi syndrome: effects on transport by isolated rat to ingestion of out-dated tetracycline. AnnIntern Med 56:523, kidney brushborder membrane vesicles. LifeSci 22:39,1978 1963 79. SILVERMAN M, HUANG L: Mechanism of maleic acid-induced SI. EIJRLIcI-l LI, STEIN WS: Abnormal urinary findings following glucosuria in dog kidney. AmJ Physiol 231:1024,1976 administration of Achnomycin V. Pediatrics31:339,1963 80. WEN SF: Micropuncture studies of glucose transport in the dog: 52. FRIMPTER GW, TIMPANELLI AL, EISENME.NGER Wi, STEIN WS, mechanism of renal glycosunia. AmJ Physiol 231:468,1976 EHRLICH LI: Reversible Fanconi syndrome caused by degraded 81. KINNE R, MURER H, KINNE-SAFFRAN E, THEES M, SACHS G: tetracycline. JAMA184:111,1963 Sugar transport by renal plasma membrane vesicles: characteriza- 53.BENITZKF, DIERMEIR I-IF: Renal toxicity of tetracycline degrada- tion of the systems in the brushborder microvilli and basal-lateral tion products. ProcSoc Exp Bio/ Med115:930, 1964 plasma membranes. JMemb Biol 21:375,1975 54.LINDQUISTRR, FElLERS FX: Degraded tetracycline nephropa- 82. TURNER RJ, StLVERMAN M: Sugar uptake into hrushborder vesi- thy: Functions, morphologic and histochemical observations. Lab des from dog kidney. I. Specificity. Biochi,nBiophvs Actc, Invest 15:864,1966 507:305,1978 55.LOWEMB, TArn' E: Renal damage caused by anhydro-4-epi- 83. B0VEE KC, JOYCE T, BLAZER-YOST B, GOLDSCHMIDr MS. tetracycline. Arc/i PatholLab Med 81:362, 1966 SEGAL 5: Characterization of renal defects in dogs with a syn- 56.DUBUYHG, SHOWACRE IL: Selective localization of tetracycline drome similar to the Fanconi syndrome in man. JAm Vet Med in mitochondnia of living cells. Science 133:196, 1961 Assoc 174:1094, 1979 57.SPENCERAG, FRANGLEN GT: Gross aminoaciduria following a 84. R0DRIGUEz-S0RIAN0 I, HOUSTON IB, B0IcHIs H, EDELMANN lysol burn. Lance!1:190,1952 CM JR: Calcium and phosphorus metabolism in the Fanconi 58.PARKERWE: Acute nitrobenzene poisoning with transient amino- Syndrome. JCl/ti Endc,crinol Merab 28:1555,1968 acidunia.BrMedJ 1:653, 1953 85.HOFFMANN, THEES M. KINNE R: Phosphate transport by isolat- 59. ANDREWS BR, BRUTON OC, KNOBLOCK EC: Aminoacidunia in ed renal brushborder vesicles. IfluegersArc/i 362:147,1976 salicylate intoxication. AmJ Med Sci242:411, 1961 86. STOLL R. KINNE R, MURER H: Effect of dietary phosphate intake 60. OTTEN J, Vs HL: Acute reversible renal tubular dysfunction on phosphate transport by isolated rat renal hrushborder vesicles. following intoxication with melhyl-3-chromone. JPediatr 73:422, BiochemJ 180:465,1979 1968 87. KEMPSON SA, DOUSA TP: Phosphate transport across renal 61. SADOFF L: Nephrotoxicity of streptozolocin (NSC 85998). Cancer cortical brushborder membrane vesicles from rats stabilized on a Treat Rep 54:457, 1970 normal, high or low phosphate diet. LifeSci 24:881.1979 62. MAENPAA PH, RAIVI0 KO, KEKOMAKI P: Liver adenine nucleo- 88. TENENHOUSE HS, SCRIVER CR, MCINNES RR, GI.ORIEUx FH: tides:fructose-induced depletion and its effect on protein synthe- Renal handling of phosphate inviva andin the X-linked sis. Science 1968 vitro by 161:1253, hypophosphatemic male mouse: Evidence for a defect in the 63. BURCH HB, MAX P JR. CHYN K. LOWRY OH: Metabolic interme- brushborder membrane. Kidney 1978 diates in liver of rats given large amounts of fructose and dihy- Int 14:236, droxyacetone. BiochemBiophv.s Res Co,nmun 34:619,1969 89. MoRRts RC JR, MCSHERRY E, SEBASTIAN A: Modulation of 64. MoRRIs RC JR. SEBASTIAN A, MCSHF.RRY F: Renal acidosis. experimental renal dysfunction of hereditary fructose intolerance KidneyIn! 1:322,1972 by circulating parathyroid hormone. ProcNat! Acad Sci USA 65. FROLSCH ER, WOLF HP, BAITSCH H: Hereditary fructose intoler- 68:132,1971 ance: an inborn defect of hepatic fructose-I-phosphate splitting 90. CAI.I.Is L, CASTELLO F, FORTUNY G, VALLO A. BALLABRIGA A: aldolase. AmJ Med 34:151,1963 Effect of hydrochlorothiazide on rickets and on renal tubular 66. BOVEE KC, JOYCE T, REYNOLDS R, SEGAL S: The Fanconi acidosis in two patients with cystinosis. He/vPaediatr Acta syndrome in Basenji dogs: a new model for renal transport 25:602,1970 defects. Science201:1129,1978 91. FELLERS FX, Ko KW, NICOI.AIDOU M: A defect of tubular Fa,uoni ,syndro,ne and tubular dv.v/un(lion 715

secretory function in the de Toni-Fanconi syndrome. AmJ Dis 117. WILSON VK,THOMSONML. DENTCE:Aminoaciduria in lead Child 100:558,1960 poisoning: Acasein childhood. Lc,ncet2:66.1953 92. HAQUANI AH, RAM MM: Renal tubular insufficiency. JPediat'- 118. KAZANTZIS G.FLYNNFV, SPOWAGE iS. 1ROTT DG:Renal 61:242,1962 tubular malfunction and pulmonary emphysema in cadmium pig- 93. FRASERD,LEEMING JM,CERWENKAEA:Uberdie l-Iandhabung ment workers. Q JMed 32:165.1963 von Phosphat durch die Nieren bei hypophosphatamischer vita- 119. ROTHSTEIN A,BERKEHi: Aminoaciduria in uranium poisoning: min D-resistenter Rachitis der einfachen Ast und bei Cystinspei- the use of amino-acidnitrogento ratio in ".pot" cherkrankheit: Reaktion auf verlangerte calciuminfusion. He/i- samples of urine. JPha,-,nacoi Lipher96:179,1949 Paediair Ada 14:497.1959 120. RUTZLER L: Passageres tubuläres Syndrom durch Vergiftung mit 94. Wiisois DR. YENDT ER: Treatment of adult Fanconi syndrome einer organischen Quecksilberverbindung (Glyccromerfcn) bci with oral phosphate supplement and alkali. AmJ Med 35:487,963 einem Ijahrigen Mädchen .Schu'ei:Med Woc'henschr 103:678. 95. FANCONIA,FISCHERJA, PRADERA: Serum parathyroid hormone '973 concentrations in hypophosphataemic vitamin D resistant rickets. 121. KAMM DE, FISCHER MS: Proximal renal tubular acidosis and the He/iPaediatr Ac-to 29:187,1974 Fanconi syndrome in a patient with hypergammaglobulinemia. 96. SALASSA RM: Observation on the metabolic effects of vitamin D in Nephron9:208,1972 Fanconi's syndrome. MayoC/in Proc 29:214,1954 122. MALDONADOJE, VELOSAJA,KYLERA,WAGONERRD.HOLLEY 97. ANDERSON IA, MILLER A, KENNEY AP: and renal KE,SALASSARM:Fanconisyndrome inadults:amanifestationof glycosuria in adults, metabolic investigation of a case with particu- alatentform of myeloma. AmJ Med 58:354,1975 lar reference to the Fanconi Syndrome and to treatment Q JMed 123. HARRISON JF,BLAINEYJD:AdultFanconi syndrome with mono- 21:33,1952 clonal abnormality of immunoglobulin light chain. JC/in Pathol 98. MILNEMD,STANBURY SW, THOMSON AE: Observations on the 20:42,1967 Fanconi syndrome and renal hyperchloraemic acidosis in the 124. SHEARNMA,TuWH: Nephrogenic diabetesinsipidus and other adult. QJMed2I:6l,1952 defects of renal tubularfunctionin Sjogren's syndrome. AmJMed 99.LEE DBN. DRINKARD JP,ROSEN Vi,GONICK HC: The adult 39:312,1965 Franconisyndrome. Medicine(Baltimore) 15:107,1972 125. FINKEL PN, KRONENBERG K,PESCEAJ,POLLAKVE,PIRAN]CC: 100. HAUSSLER MR. MCCAIN TA:Basicclinical concepts related to Adult Fanconi syndrome amyloidosis and marked X-light chain vitamin Dmetabolismand action.N Engi J Med 297:974,1977 proteinuria. Nephron10:1,1973 101.GOLDBERGM,AGus ZA, GOLDFARBS:Renal handlingof phos- 126. KYLE RA, MALDONADO JE, BAYRD ED: Idiopathic Bence-Jones phate calcium and magnesium, inThe Kidney, BRENNERBM, proteinuria—a distinct entity? A,nerJ Med 55:222, 1973 RECTORFC,Philadelphia, W.B.Saunders Co.,1976p. 344 127. PREUSS HG, HAMMACK WJ,MURDAUGHHV: The effect af 102.RODRIGUEZ-SORIANOJ,EDELMANNCMits:Renal tubularacido- Bence-Jones protein on the in vitro function of rabbit renal cortex. sis. AnnuRev Med 20:363,1969 Nephron5:210,1967 103.DAVIES HEF, EVANSB,REESHMN, FOURMANP:The defective 128. PREUSS HG, WEIB FR. IAMMARINO RM,HAMMACKWi. absorption of phosphate and calcium and the effect of vitamin Din MURDAUGH HV: Effects on rat kidney slice function in cilia of the Fanconi syndrome. GuysHosp Rep 107:486,1958 proteins from the of patients with myelomatosis and 104.WALLISLA,ENGLERLJR:Theadult Fanconi syndrome:II. . C/i,,Sci Mo/ Mccl 46:283.1974 Review of eighteen cases. AmJ Med 22:13,1957 129. CLYNE DH, BRENDSTRUP L, FIRST MR: Renal effects ofinti-aperi- 105.WiLsoDR,GOLDSTEINNP:Renalurate excretion in patients toneal kappa chain injection: Induction of crystals in renal tubular withWilson'sdisease. Kidneymt 4:331,1973 cells. LabInvest 31:131,1974 106. BERN AG,YU TT, GUTMANAB:Renal functionin Wilson's 130. DOOLAN PD, MORRIS MD, HARPER HA: Amino aciduria in an disease.J C/in Invest 36:1107, 1957 elderly man with the nephrotic syndrome and a young man with a 107. HOUSTONlB.B0ICHIsH,EDELMANNCM JR: Fanconi syndrome variant of the Fanconi syndrome. AnnIntern Med 56:448,1962 with renal sodiumwastingandmetabolicalkalosis.Am J Med 131. HOOFT C, VERMASSEN A:Syndromede DeToni-Debré-Fanconi 44:638,1968 chez unenfantatteint de nephrose lipoidique. AnnPec/iatr (Ba.sc'/) 108. GODARD C,VALLOTTONMB, BOYER M, ROYER P: A study of the 190:1,1958 inhibition of the renin-angiotensin system in renal potassium 132. ROYER P. DELAITRE R. MATHIEV H, GERBEAUX S. HABIB R. wasting syndromes, including Bartter's syndrome. HeirPoediatr KOEGEL R: Le syndrome nëphrotique avec insuffisance tubulaire Acta 27:495.1972 globale et tetanie recidivante. Ann Pc'c/iatr(Paris) 10:583.1963 109. BICKEL H,HICKMANSEM:Part 7:Some biochemical aspects of 133. STICKLER GB, HAYLES AB, POWER MH. Uits,cti JA: Nephrotic Lignac-Fanconi disease. AdaPaediatr Scand [Suppl 90]42: 137, syndrome complicated by renal tubular dysfunction. AmI Dis 1952 Child98:647,1959 110. CHERRY ID. SURAWICZ B: Unusual effects of potassium deficien- 134. TEGELAERS WHH, TIDDENS HW: Nephrotic-glucosuric-arnino- cy on the heart of a child with cystinosis. Pediatric,s30:414.1962 acuric dwalflsm and electiolyte metabolism. He/c-Pc,ec/icirr Acta Ill. FANCONI G. BICKEI. H: Die chronische Aminoacidurie (Amino- 10:269,1955 sauren- oder nephrotisch-glykosurischer Zwergwuchs) 135. VERTUNO LL, PREUSS HG. ARGY WP, SCHREINER GE: Fanconi bei der Glykogenose und der Cystinkrankheit. He/uPaediatr Act syndrome following homotransplantation - Ais/clate,',,Mc'cI 4:359,1949 133:302,1974 112. BRODEHL I, HAGGE W, GEILISSEN M: Die Veranderungen der 136. MASSRY S, PREUSS HG. MAHER JP. SCHREINER GE: Renal tubular Nierenfunktion bei der Cystinose. Teil I: Die Inulin-. PAI-1-und acidosis after cadaver kidney homotransplantation. AmJ Med Elektrolyt-clearance in verschiedenen Stadien der Erkrankung. 42:248,1967 AnnPaediatr (Basel) 205:131,1965 137. BRIGGS WA.KOMINAMIN,WILSONRE, MERRILLJP:Kidney 113.BARRET TM. CRAWFORD R: Lysozyme excretion as a measure of transplantation in the Fanconi syndrome. NEng/ J Med 286:25, renal tubular dysfunction in children. C/inSci Mo/ Med 39:457, 1972 970 138. LINOBLAD B. LINDSTEDT S. STEEN G:On theenzymatic defects 114. WALDMANN TA,MOGIELNICKI,STROBER W: The proteinuria of in hereditary tyrosinemia. P,-ocNc,t/ Ac'c,d Sc-i USA 74:4641.1977 cystinosis: its pattern and pathogenesis. in Cv,ctino,'is, editedby 139. SCHNEIDER IA, VERROUST FM. KR0I.I, WA. GARVIN AJ. SCHULMAN I, NIH 72-249. Washington, D.C.: Department of HORGER EO 111, WONG VG, SPEAR GS. JACOBSON C. PEI.LET'I Health, Education andWelfare, 1973,p.55 OL. BECKER FLA: Prenatal diagnosis of cystinosis. N Eng/JMed 115. CHISOLM ii: Aminoaciduriaasa manifestation of renal tubular 290:878,1974 injuryin lead intoxication and a comparison with patterns of 140. STATES B, BLAZERB,HARRISD,SEGAL 5: Prenatal diagnosis of aminoaciduria seen in other diseases. JPediatr 6(1:1,1962 cystinosis. JPediatr 87:558,1975 116. GOYER RA, TSUCFIIYA K, LEONARD DL, KAI.Ryo H: Aminoacid- 141. GARTY R, COOPER M, TABACHNIK E: The Fanconi syndrome uria in Japanese workers in the lead and cadmium industries. Am.1 associated with hepatic glycogenosis and abnormal metabolism of C/in Patho/ 57:635, 1972 galactose. JPecliatr 85:821.1974 716 Roth et (II

142. BRODEHL J, GELLISSENK,HAGGEW:The Fanconi syndrome in 144. ILLIG R, PRADERA:Primäre Tubulopathien: 11. Em Fall von hepato-renal , in Progress in Nephrology, idiopathischem Gluko-Amino-Phosphat-Diabetes (DeToni-Debré- edited by PETERS C, ROCH-RAMEL F, Berlin, Springer, 1969, pp. Franconi-Syndrome). Helv Paediatr Acta 16:622, 1961 241 145. NELMANNN,PURSONM,MARCHALC, RAUBER G, GRIGNON G: 143. SHELDON W, LUDER J, Wt BA: A familial tubular absorption Nephropathiefamilial glomerulotubulaire avec syndrome de Toni- defect of glucose and amino acids. Arch Dis Child 36:90. 1961 Debré-Fanconi. Arch Fr Pediatr 25:43, 1968