Clinical Aspects of Renal Tubular Disorders*

WILLIAM F. FALLS, JR. Department of Medicine, Medical College of Virginia, Richmond 23219

When most clinicians consider ificity of defect. Specific defects tion. Generalized defects of tubu­ problems in renal disease, they localized to the proximal tubule in­ lar transport are included under think in terms of levels of blood, clude: renal ; phosphate . The distal tubu­ urea, nitrogen, and creatinine, and diabetes; , which until re­ lar problems to be discussed in­ the presence of red cells, white cently was considered to be solely a clude renal tubular acidosis and cells, or protein in the urine. In es­ defect in dibasic reab­ nephrogenic diabetes insipidus. sence, they think primarily of dis­ sorption; and , Study of patients with these disor­ ease of the glomerular filter or loss which is a defect in monoamino­ ders has shed much light on the of total nephron mass. Indeed, most monocarboxy amino acid reabsorp- normal function of the renal tubule. of the of pa­ tients with commonly recognized renal diseases are related to reten­ ...... ----- ... ;' tion of various noxious materials ~ BICARBONATE which cannot be adequately cleared SODIUM because of the reduced glomerular filtration rate. Despite the overwhelming fre­ AMINO ACIDS quency of diseases involving the PHOSPHATE glomerulus, I would like to discuss a number of interesting clinical renal problems that are primarily characterized by insufficiency of one or more tubular functions in the presence of continuing adequate glomerular operation. These con­ CORTEX ditions are not common but are of ADH great importance, because several are amenable to therapy and be­ cause each is an experiment in na­ ture displaying the profound phys­ iologic consequences of anatomical MEDULLA abnormality or biochemical dys­ SODIUM function of a particular portion of the renal tubule. The diseases that I plan to dis­ cuss are listed in Table 1 and 1200 can be divided into groups ac­ M OSM cording to localization of disorder within the tubule and the spec-

*Presented at the Twenty-First Annual Stoneburner Lecture Series, Fig. I-Schematic representation of a nephron with reabsorptive sites for February 22-23, 1968, Medical Col­ various substances indicated. The water-impermeable portion of the tubule is lege of Virginia, Richmond. indicated by the solid line. The broken line indicates the site of action of ADH.

162 MCV QUARTERLY 4(4): 162-169, 1968 W. F. FALLS, JR .

Review o.f Renal Tubular thick ascending limb of Renie's Since and amino acids Physiology loop. The residual tubular fluid is are reabsorbed by movement from then finally made concentrated by a lower tubular concentration to a It is evident that the renal tubule action of antidiuretic hormone in higher peritubular concentration, profoundly alters the volume and their transport must be considered to composition of the 100 cc of fil­ the collecting duct cell, allowing be "active" and require an energy­ trate entering Bowman's space be­ back diffusion of water into the dependent transport mechanism. It fore it appears in the bladder as 0.5 hypertonic interstitium of the me­ has been learned that the capacity cc of urine (Fig. 1). The filtrate, as dulla. it enters Bowman's space, contains large quantities of glucose, amino 800.--~~~~~~~~~~~~~~~ acids, phosphate, bicarbonate, urate, I sodium, and many other filterable I constituents of plasma. All or most 700 I of these substances are reabsorbed I by the renal tubules. Most reab­ 600 I sorption of these materials and I water occurs in the proximal por­ tion of the nephron with only about I 20% of the isotonic filtrate enter­ I ing the descending limb of Renie's loop. Reabsorption of glucose, amino acids, and filtered protein is virtually complete in the proximal tubule. About 80% of the filtered bicarbonate is reabsorbed there; the remainder is reabsorbed more distally in association with the formation of titratable acid, ammonium and a maximally acid 100 G FR = 125ml ttni urine. It is also in the more distal portion of the tubule that the re­ maining filtrate is initially made 500 600 700 800 hypotonic by sodium extraction PLASMA GLUCOSE (mg%) from the tubular fluid as it passes through the water-impermeable, Fig. 2-Schematic representation of the reabsorptive titration curve for glucose. (From Physiology of the Kidney and Body Fluids, 1st edition, by Robert F. Pitts. TABLE 1 Copyright © 1963, Year Book Medical Publishers, Inc. Used by permission of Disorders of Renal Tubular Year Book Medical Publishers.) Function 1. Specific Disorders of Proximal Tubular Function A. PROXIMAL TUBULE B. Phosphate Diabetes (Vita-. min D-Resistant Rickets) LUMEN CELL C. Cystinuria -¥ - D. Hartnup Disease HCOj + H+ - H+ + HC0-3 -~ B!CARBONATE t C.A. 2. Generalized Disorder of Proxi­ ~ mal Tubular Function (Fanconi RE ABSORPTION H H co3 C02 + H20 Syndrome) -¥ 3. Disorders of Distal Tubular H20 + C02 Function A. Renal Tubular Acidosis B. Nephrogenic Diabetes Tnsipidus Fig. 3-Schematic representation of the mechanism of bicarbonate reabsorption and H+ ion secretion in the proximal tubule.

163 RENAL TUBULAR DISORDERS

of the transport systems for these substances is limited, and that, when DISTA L TUBU LE the reabsorptive load of material in the filtrate reaches a certain value, no more can be reabsorbed, LUMEN CE LL the excess being excreted in the urine. This limiting quantity is HCO~ + W expressed as the tubular maximum BICARBONATE H C03 (Tm) for a given substance. A REABSORPTION :i. typical Tm curve for glucose is H20 + C02 shown in Figure 2. Such a curve is ·········· ····························· ··················· ...... obtained by progressively increas­ FORMATION ing the filtered load of glucose by w [soo J O F raising the plasma level. Reabsorp­ H+ GRADIENT tion is complete until a threshold ········ ·········································· ..... t. .. S. :f.-.·... TITRATABLE HP04 = + H-!- level is reached, at which point a C02 H20 ACID t - little glucose appears in the urine. FORMATION H2 P04 As the load is raised further, the transport mechanism becomes satu­ AMMON IUM H + NH3 ~--+--- rated at the Tm level. The deviation ~ NH3 of the reabsorptive curve from the PRODUCTION N H4 + t line of theoretical complete reab­ G LUTAMI NE sorption is known as the splay of pH 4 .5 the reabsorptive curve. Reabsorption of bicarbonate is also characterized by a Tm limita­ Fig. 4--Schematic representation of the mechanisms of bicarbonate reabsorp­ tion, but its origin is somewhat dif­ tion, H+ ion secretion, bicarbonate regeneration, titratable acid formation, ammo­ ferent. Bicarbonate reabsorption in nia trapping, and H+ ion gradient establishment by the distal tubule. both the proximal and distal tubules is linked to and dependent upon H + ion secretion into the tubular lu­ men. Thus, as seen in Figure 3, bi­ carbonate reabsorption in the proxi­ mal tubule depends on adequate production of H + ion by carbonic anhydrase catalytic hydration of CO, within the cell, followed by movement of H + ion into the lu­ men. Such activity in the proximal 4 .0 tubule represents most of the total H • ion secretory capacity. Bicarbon­ 3.2 ate is regenerated in the distal tubular cell as hydrogen is secreted HC03- 1?£Al3SOIZl3ED into the tubular lumen, where titrat­ 2.4 able acid and ammonium are rn£cr/ 100 ml formed (Fig. 4). It is evident that maximal excretion of these sub­ GFQ 7. 6 stances is dependent on the estab­ lishment of an H• ion gradient 0.8 across the tubule of sufficient mag­ nitude to lower the urine pH and al­ low for formation of titratable acid­ 14 18 22 26 30 34 38 -42 ity and ammonia diffusion from PLASMA HC03- ~ rnEcr:/L the tubule cell. Figure 5 shows a normal Tm curve for bicarbonate. Such a curve is a reflection of the Fig. 5--Schematic representation of the bicarbonate titration curve in normal man total H• ion secretory capacity of (Adapted with permission from J. Clin. Invest. 28:37, 1949).

164 W . F. FALLS, JR . both proximal and distal tubules of Fourth, a -like rash ing of the epiphysis with cupping the kidney. should suggest the possibility of an and ragged mineralization of the abnormality of metab­ metaphyseal plate. Such changes may lead to severe residual de­ Clinical Clues to Diagnosis olism, as seen in Hartnup disease. Fifth, the presence of glycosuria formities in adolescence and adult­ of Tubular Disorders should suggest the possibility of hood. Typical serum chemistries There are seven practical clinical renal glycosuria. When associated include a normal calcium, low phos­ clues to the presence of a renal with an a lkaline urine and phate, and normal or high alkaline tubular disorder (Table 2) . proteinuria in a patient without a phosphatase, depending on the ac­ First, the presence of renal stones family history of diabetes mellitus, tivity of disease. The low serum or nephrocalcinosis should alert one glycosuria should suggest a general­ phosphate is caused by an increased to the possibility of renal tubular ized defect in renal tubular reab­ phosphate clearance. This condition acidosis or cystinuria. sorption, as seen in Fanconi syn­ is inherited as a sex-linked domi­ Second, abnormalities of bone, drome. nant trait with a varying propensity such as rickets, osteomalacia or Sixth, unexplained hyperchlore­ for bone disease in the heterozy­ pseudofractures, may be the first mic acidosis along with an alka­ gous female. Mother-to-son and indication of a defect in tubular se­ line urine should suggest a defect in son-to-daughter transmission but cretion of H • ion or reabsorption bicarbonate reabsorption or H• ion no father-to-son transmission is of phosphate. secretion, as seen in Fanconi syn­ seen, as is characteristic of X-linked Third, visual problems, particu­ drome or renal tubular acidosis. inheritance. larly in infancy or early childhood, Seventh, an unexplained low The etiology of this con ­ should suggest the possible precipi­ serum phosphate in the presence of dition remains doubtful. There is tation of cystine crystals in the adequate food intake and a normal controversy as to whether there is cornea. This, we shall see, may oc­ serum calcium should raise the pos­ a primary defect in calcium absorp­ cur in generalized with sibility of Vitamin D-resistant tion from the gut, with secondary Fanconi syndrome. rickets or F anconi syndrome. hyperparathyroidism and parathy­ roid stimulation of phosphate uri­ Renal Glycosuria nary excretion, or a primary de­ fect in renal tubular reabsorption TABLE 2 Renal glycosuria, depending on of phosphate. Recent evidence of Clinical Clues to Renal Tubular definition, is a relatively common Avioli et al. (1967) suggests that Disorders clinical disorder. When defined in Vitamin D metabolism may be de­ broadest terms, it may be char­ fective with production of water Clue Disorders acterized by an increased splay soluble metabolites which are inef­ 1. Renal Stones Cystinuria or in the Tm titration curve, by a fective in enhancing calcium ab­ or Nephro- Renal Tubular lowered Tm for glucose, or by both. sorption from the gut and have no calcinosis Acidosis It is usually noticed by finding a effect on bone. Whether or not such 2. Rickets, Os- Phosphate Dia- random positive urine . It is metabolites have a renal effect that teomalacia, betes, Fanconi primarily of importance to be dif­ blocks phosphate reabsorption is Pseudofrac- Syndrome, ferentiated from true diabetes mel­ unknown. Recent studies (Wilson tu res Renal Tubular litus in order that hypoglycemic et al., 1965) have suggested that Acidosis agents not be given. Renal glyco­ the bone disease may be healed by 3. Visual Diffi- Fanconi Syn- suria may occur in patients with a vigorous and sustained combina­ culty in drome with true diabetes mellitus, in which Childhood Cystinosis tion of moderate daily doses of case it may make management more Vitamin D (50,000 units) in con­ 4. Pellagra Hartnup Disease difficult, with a tendency to hypo­ junction with frequent administra­ 5. Glycosuria Renal Glyco- glycemic reactions. suria or Fanconi tion of buffered phosphate supple­ Syndrome ments. 6. Hyperchlo- Fanconi Syn- Phosphate Diabetes remic drome or Renal (Vitamin D-Resistant Rickets) Cystinuria Acidosis Tubular Acidosis Phosphate diabetes is a well-de­ Cystinuria is an unusual renal 7. Low Serum Phosphate Dia- fined clinical entity. It characteris­ tubular defect that usually presents Phosphate betes or tically presents in early childhood as with the passage of a renal stone or Fanconi rickets, unresponsive to Vitamin D. gravel. The course is variable, and Syndrome Figure 6 shows the typical bone the first stone may be passed at any changes of rickets including widen- time of life from early childhood

165 RENAL TUBULAR DI SORDERS to old age. Untreated cases may demonstrated that transport of this cyanide-nitroprusside screening test suffer all the complications of renal amino acid is normal in the kidney for cysteine can easily be done in calculi, including urinary tract ob­ and may be so in the bowel. The any lab. Analysis of a stone will struction with the development of high levels of cystine in the urine usually reveal the presence of some hydronephrosis, chronic pyelone­ seem to be a result of intra-urinary cystine, although calcium and phos­ phritis, and progressive renal insuf­ oxidation of abnormally large quan­ phate may be integral parts of the ficiency. tities of excreted cysteine to cystine. calculus. Defective epithelial transport of Because of the limited solubility of Recent studies (Rosenberg et al., the amino acids , ornithine, cystine in the urine, particularly 1966) have indicated that cystinuria and in this condition results when it is acid, precipitation of cys­ is a hereditary disease. Stone for­ in both diminished absorption from tine in characteristic hexagonal­ mation is seen in patients homozy­ the gut and decreased reabsorption shaped crystals occurs. Observation gous for one of three possible genes in the renal tubule, leading to in­ of such crystals should alert the which may or may not be alleles. creased concentrations in the urine. clinician to the possible presence Moderately good 'results with Until very recently, cystine trans­ of this condition. prevention of stone formation have port was also felt to be defective in Cystine crystals are radiopaque, been reported in the past in some both the gut and the kidney, but and cystinuria should be considered cases with a low diet, new data (Thier et al., 1965) have in any stone-forming patient. The chronic alkalinization of the urine, and production of a continuous water diuresis. The therapy of cys­ tinuria has been revolutionized, however, by the introduction of penicillamine, which chelates the urinary cystine, making it more soluble in the urine. In addition, by some unexplained mechanism the penicillamine also decreases total cystine excretion. Thus, optimal therapy in the chronic cystine stone­ former would seem to combine penicillamine with a copious fluid intake, alkalinization of the urine, and low methionine diet to decrease the intake of cystine precursors.

Hartnup Disease

This is an extremely rare but in­ teresting abnormality of mono­ amino-monocarboxy amino acid transport. Clinically, it is charac­ terized by the occurrence of a pel­ lagra-like skin eruption, cerebellar ataxia, and, in some cases, mental deficiency appearing early in life and remitting in late adolescence or adulthood. The basic pathogenic mechanism is considered to be ab­ normal absorption of tryptophan from both the bowel and the renal tubule. As a consequence of these abnormalities, serum tryptophan levels are low, leading to a decreased production of its important metabo­ Fig. 6-Characteristic roentgenographic picture of rickets with widening of the lites and . It epiphysis, associated with ragged, irregular calcification of the developing osteoid. may be a deficiency of these metab­ There is a tendency toward cupping of the ends of the long bones. olites that leads to the integumen-

166 W . F. FAL LS, JR.

tary and central nervous system dis­ tory capacity is reduced and that TABLE 3 orders. Hartnup disease is inherited the acidosis is secondary to a per­ Urinary Amino Acid Excretion in as an autosomal recessive gene. sistent leak of HCOa from the a Patient with Adult Fanconi Therapy is directed to avoidance proximal tubule. When considered Syndrome of sunlight and administration of with evidence of an intact distal large supplements of nicotinamide acidification mechanism, this find­ Patient Normal during the years of rapid growth. ing further supports the suggestion Amino Acid mg/ 24 hr mg/ 24 hr With such measures, improvement that a primary defect in proximal Lysine- has been noted in several patients, tubular function is the basis of the Ornithine 962 7- 100 leading to sustained remission in abnormality observed. 650 I 13-246 adulthood. The causes of Fanconi syndrome 756 68- 200 are outlined in Table 5. It is fre­ Alanine 786 20-70 Serine 766 27- 73 Genera lized Def ects in Proximal quently seen in association with an 2489 Tub ular Function underlying disease process but, in 430 9-31 both children and adults, may be of Threonine- The generalized defects in proxi­ idiopathic origin. Childhood cases 961 9- 77 mal tubular function are usually are most frequently seen in associa­ grouped under the heading of Fan­ tion with a generalized metabolic coni syndrome. This syndrome fre­ disorder ( cystinosis) characterized quently presents clinically by the by deposition of cystine crystals in TABLE 4 occurrence of severe rickets or numerous organs, including the cor­ Results of Glucose Tolerance Test osteomalacia with fractures and nea, liver, spleen, lymph nodes, and in an Adult Patient with Fanconi pseudofractures. Laboratory find­ kidneys. Syndrome ings include the characteristic hy­ Diffuse proximal tubular dys­ perchloremic acidosis with a low function has also been seen in chil­ Blood Urine CO, and high Cl content in the dren with hereditary fructosuria Period Sugar Sugar serum; low serum phosphate; low and and as a part of Fasting 96 3+ serum uric acid; and alkaline urine Lowe's syndrome. Adult cases have 1 Hour 62 3+ with proteinuria, , been described in association with a 2 Hours 107 3+ and glycosuria. Table 3 demon­ variety of conditions including the 3 Hours 87 3+ strates the diffuse aminoaciduria in transplanted renal allograft, Wil­ 4 Hours 95 N.S. a patient with adult Fanconi syn­ 5 Hours 87 N.S. son's disease, multiple myeloma, drome. Determination of the total poisoning from ingestion of out­ amino acid content can be done dated tetracycline, and intoxication by measuring the alpha amino ni­ from heavy metals such as uranium trogen; individual acids must be and bismuth. Experimentally, a TABLE 5 separated by chromatography. A simi lar functional lesion has been Causes of the Fanconi Syndrome typical glucose tolerance test with see n in animals that have been fed 1. Child: persistent glycosuria in the face of maleic acid . A. Cystinosis normal blood is shown in Patients with Fanconi syndrome B. Lowe's Syndrome Table 4. Despite the frequent pres­ must first be carefully evaluated to C. Hereditary ence of an alkaline urine, occur­ determine an underlying etiology, Intolerance rence of renal stones in this syn­ if possible. When an underlying D. Galactosemia drome is distinctly unusual. cause such as multiple myeloma is E. Idiopathic Much evidence points to either found, it should, of course, be 2. Adult : an anatomic or functional defect in treated. Whether or not an under­ A. Heavy Metal Intoxication the proximal tubule as the primary lying cause is determined, several B. Multiple Myeloma and source of difficulty in patients of the metabolic disturbances can Other Tumors with Fanconi syndrome. Microdis­ C. Wilson's Disease be treated. The bone disease may D. Outdated Tetracycline section studies have revealed ana­ respond to oral phosphate supple­ Ingestion tomical damage to the proximal ments, Vitamin D administration, E. Transplanted Renal tubular region in patients with both and large doses of oral bicarbonate Allograft the childhood and adult form of the or Shohl's solution. Hypoglycemia F. Lysol Ingestion disease. Recent work of mine (un­ is not a usual occurrence, despite G. Idiopathic published data) demonstrating a persistent glycosuria. A large pro­ 3. Experimental: Maleic Acid decreased bicarbonate Tm (Fig. 7) tein intake should be encouraged indicates that total H + ion secre- in an attempt to provide for the

167 RENAL TUBULAR DISORDERS

amino acids lost in the urine and distal tubular cell into the urine may occur, however, and, in the the demands of . against a very low H• gradient. questionable case, the response to Recent unpublished data of mine Presumably because of the sys­ an acid load of ammonium chloride suggest that the renal abnormalities temic acidosis, calcium is leached or a sodium sulfate infusion should may be markedly improved by ad­ from the bones as H• ion is buf­ be determined. Under such stimuli, ministration of hydrochlorothiozide fered by the alkaline bone salts. the urinary pH in the patient with and potassium supplements. Osteomalacia develops, and the lib­ renal tubular acidosis will not be erated calcium is excreted in a lowered to the normal range of Renal Tubular Acidosis persistently alkaline urine. Under 5.0 or below. As mentioned in our review of such circumstances calcium phos­ Renal tubular acidosis occurs in renal acidification mechanisms, the phate precipitation occurs, either children without apparent genetic distal tubule reabsorbs the small within the collecting ducts leading cause. An association between adult amount of bicarbonate remaining to nephrocalcinosis (Fig. 8), or in renal tubular acidosis and a num­ in the tubular lumen and estab­ the renal pelvis producing renal ber of disease processes-including lishes a high H • gradient across stones. Most patients with this syn­ a variety of dysglobulinemic states, the tubular wall, allowing for the drome present with either renal cal­ lupus erythematosus, phenacetin formation of titratable acid and culi, bone disease, or progressive nephropathy, and amphotericin tox­ trapping of large quantities of am­ renal insufficiency secondary to icity-has been documented. monia. In the absence of establish­ nephrocalcinosis or pyelonephritis. Treatment is usually effective in ment of such a gradient, neutral Because of the important occur­ the full-blown case and consists of phosphate is excreted, and ammonia rence of renal stones in renal tubu­ the administration of sufficient so­ diffusion into the tubular lumen lar acidosis, it is essential that it be dium bicarbonate orally to correct is limited. Such an abnormality is seriously considered in the patient the systemic acidosis. Under such seen in renal tubular acidosis, with with renal calculi or unexplained circumstances, decalcification is in­ the result that patients with this hematuria. The presence of a urine hibited and hypercalciuria disap­ syndrome are unable to form an pH that is persistently 6.0 or greater pears. The urine remains alkaline, acid urine and, consequently, de­ indicates that investigation of the but further nephrocalcinosis or velop a hyperchloremic metabolic systemic acid-base status should be stone formation usually does not acidosis. Thus, the defect in this dis­ undertaken. The presence of hyper­ occur as long as an adequate water order lies not in the limitation of chloremic acidosis in the absence diuresis is maintained by large oral total H• ion secretion but in the of other tubular abnormalities con­ intake. inability to transfer H• out of the firms the diagnosis. Partial defects Nephrogenic Diabetes lnsipidus

!3!CARf30NAT£ REAf3SORPTION (EXCRETION As we noted previously, a con­ IN THE FANCON! SYNDROME centrated urine is produced by ac­ tion of antidiuretic hormone on the collecting duct cell, allowing back diffusion of water into the intersti­ 4.0 tium. Polyuria unresponsive to vaso­ pressin administration has been de­ 3.2 scribed in a number of clinical sit­

HC03- li!EABSORBEO uations. Infant males may present 2 .4 ...... with severe dehydration and fever rnEcr/ 100 ml • • • .. • oe and, on investigation, be found to G F!2 7. 6 have a persistently hypotonic urine in the face of an elevated serum osmolality. Administration of vaso­ 08 00 pressin does not correct the defect. co°Cll o o o Polyuria with a subnormal ability 0 <:2 0 0 to concentrate the urine Play be 14 18 22 26 30 34 38 42 seen in patients with hypercalcemia, PLASMA HC03- - mE'{/ L hypokalemia, sickle cell disease, or . amyloidosis as well as in patients Fig. 7-Bicarbonate titration curve in a patient with Fanconi syndrome, demon­ with any type of severe chronic strating a decreased Tm for bicarbonate. renal insufficiency.

168 W. F. FALLS, JR.

The male infants mentioned in return of ability to adequately consequent reduction in the amount above are affiicted with an X­ concentrate the urine. In those pa­ of solute presented to the loop of linked genetic defect that causes tients whose nephrogenic diabetes Henle and the distal tubule. As a them to be unresponsive to either insipidus is idiopathic or genetic, result, less dilute urine is formed exogenous or endogenous antidiu­ improvement in the polyuric state and excreted. The patient must retic hormone. If their problem is may be seen following a decreased strictly adhere to a low sodium diet recognized, and adequate hydration dietary solute load or the admin­ while on this regimen in order that is maintained, life can be sustained. istration of hydrochlorothiozide. the glomerular filtration rate not In some older individuals with a After the diuretic produces an ini­ be increased. recognizable cause for vasopressin­ tial saline diuresis, reduction in the fluid volume occurs. unresponsive polyuria, correction of extracellular Summary the underlying disorder, such as This in turn reduces glomerular lowering the serum calcium or rais­ filtration, causing enhanced reab­ I have tried to briefly outline as­ ing the serum potassium, will result sorption in the proximal tubule with pects of the presently recognized disorders of tubular function that are of clinical importance. I would like to stress again that, although such disorders constitute a minute portion of the total health problem in this country, they are of great importance as experiments of na­ ture, study of which is opening the way for a clearer understanding of fundamental transport mechanisms in the renal tubule. Additionally, for those individuals afflicted with any of the disorders I have men­ tioned, the availability of relief is of paramount importance. Such re­ lief can be obtained in some cases by correct diagnosis and proper ap­ plication of physiologically oriented therapy.

References

Av10u, L. v., T. F. WILLIAMS, J. LUND AND H . F. DELUCA. Metab­ olism of Vitamin Da-3H in Vita­ min D-resistant rickets and familial hypophosphatemia. J. Clin. Invest. 46: 1907- 1915, 1967. ROSENBERG, L. E., S. DOWNING, J. L. DURANT AND s. SEGAL. Cystinuria: biochemical evidence for three ge­ netically distinct diseases. J. Clin. Invest. 45: 365-371, 1966. THIER, S. 0., S. SEGAL, M. Fox, A. BLAIR AND L. E. ROSENBE RG. Cys­ tinuria: defective intestinal trans­ port of dibasic amino acids and cystine. J. Cli11. Invest. 44: 442-448, 1965. WILSON, D. R., S. E. YORK, Z. F. JAWORSKI AND E. R. YENDT. Studies in hypopbosphatemic Vitamin D­ Fig. 8-Roentgenogram of the abdomen, showing nephrocalcinosis and renal refractory osteomalacia in adults. calculi. Medicine 44: 99-134, 1965.

169