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The Renal Rickets Syndrome
THE RENAL RICKETS SYNDROME
W.G.HAYWARD Although this disease is by no means common, less than 100 cases having been reported as late as 1938, a not too meager literature has come into existence in the many attempts to record and explain the varied symptoms. As the title implies, rachitic changes are present, assumed to be caused by renal dysfunction. It is a syndrome found in the young, the average age of onset of symptoms being 12½ years in Ellis and Evans series of 20 cases, and slightly higher in the cases histories that I have reviewed. It has occurred about equally in the 2 sexes. In order to have a clearer mental picture of this group of symptoms and signs, a typical case could be described as follows: Nothing abnormal may be noted until the age of 13 is reached except: (a) Smallness of stature. The average height is 24.2 per cent below normal and the average weight is 45.2 per cent below normal, as recorded by Hunt. (b) Signs and symptoms may or may not have lead to an examination of the urinary tract. (c) Mentality is bright. (d) The bony changes develop, genu valgum or knockknees being present in 56 per cent. Other bony changes are less constant. (e) X-rays are quite typical of ordinary rickets. (f) Thirst, polyuria, dryness of skin, loss of appetite, headache, delayed sexual development, etc., are present depending on the severity of the renal involvement. (g) Laboratory studies show poor kidney function, azotemia, but most important of all, a calcium phosphorus reversal. As stated b{:)fore, this is a description of a typical case, and after all, no 2 cases are exactly alike. Of the above, the 3 outstanding points in diagnosis are dwarfism, rachitic changes and calcium-phosphorus reversal. With this picture in mind, we can go on to the etiology. The type of renal impairment is unimportant. Obstructive uropathy, nephritis, cong~nital cystic disease or others can initiate the train of events. Practically all contributors on the subject agree on one thing, and that is that the kidney is unable to excrete phosphorus. This accounts for the high serum phosphorus. The phosphorus is eliminated into the bowel, where it combines with calcium to form insoluble calcium phosphate which the bowel cannot absorb, and thus produces a calcium deficiency. (Experimentally it has been proven that rickets can be produced by a diet low in calcium and high in phosphorus.) However, a lack of calcium absorption is not all there is to it. Controls given a low calcium diet develop osteoporosis only, but in renal rickets the presence of a high serum phosphorus causes a hyperplasia and ov1'l-activity of the parathyroids, which in turn causes diminished density of bones with replacement of fibrous tissue, cysts and hemorrhage, or osteitis fibrosa cystica, Von Recklinghausen's disease. This can be done experimentally by overdoses of parathormone. The presence of large parathyroids has been noted by many observers at autopsy. Drake, Albright, and Sulkowitch s~ate that parathyroid hyperplasia 278
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occurs as a result of long renal deficiency with inability to excrete phosphorus. One of the parathyroid functions is to eliminate phosphorus through the kidney and lower the inorganic level in the blood. Ellsvrorth and Howard showed that injection of parathormone in hypoparathyroidism caused increased phosphorus excretion in urine. This is also seen in normal individuals. Experimentally Drake, Albright and Castleman injected rabbits daily with phosphorus and produced hyperplasia of the parathyroids. So not only is exogenous calcium prevented from entering the .system, but endogenous calcium is being removed by parathyroid action. Mitchell feels that the failure of phosphates to bank up higher in the blood is explained by their excretion into the bowel. You are all familiar with the usual high calcium, low phosphorus ratio that is seen in adenomata of the parathyroid. This has been stressed by Albright et al. Albright postulates, however, that hyperparathyroidism may be associated with normal serum calcium under two circumstances and two only, namely, if there is a low serum protein level or phosphate retention due to renal insufficiency. As has been pointed out earlier in this paper, parathyroid hyperplasia and overactivity are secondary to the phosphatic retention caused by the renal insufficiency in this syndrome. In reviewing a large number of papers and case reports, it was repeatedly obvious that a number of cases reported as renal rickets were not that at all, but instead were primary hyperparathyroidism with secondary renal changes. Vogt states that an imbalance of the calcium phosphorus ratio is more important in the production of rickets than is the total quantity. The daily requirement of calcium during growth is from 0.4 to 1 gm. and more. Calcium phosphate comprises 80 per cent of bone. Bone is the reservoir of both calcium and phosphorus and these salts are constantly being added to or drawn from bone. The acidosis which is present in this syndrome ionizes enough free calcium to keep its level above 3.8 gm. This is above the level at which tetany develops. In a report of 20 cases, only l case of tetany was reported and further than this, I was unable to find any other record of tetany in over 50 articles reviewed. Dwarfism cannot be explained as easily as the calcium-phosphorus reversal and the secondary hyperparathyroidism. Charnock explains it on the pituitarydiencephalon theory. He states, first, that pituitary dysfunction could cause the dwarfism, and that, secondly, an autonomic center in the adjoining diencephalon could cause urinary tract abnormalities in which there is no mechanical block. Davis and Rossen explain it by Thompson's antigrowth factor of the parathyroid. Gardiner-Hill have this to say: "Dwarfism implies a defect in stature below normal standards but does not necessarily signify a pathological state. There may or may not be skeletal disproportions. It may be due to developmental skeletal diseases or acquired skeletal diseases such as rickets, caries or polio. In the type due to rickets, there is softening and deformity due to deficiency, decrease of calcium phosphate and imperfect calcification and ossification in the
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epiphyseal line. Cartilage proliferates excessively. If there is no growth, there is no rickets. Hence, the intensity of the process is directly proportional to the growth rate." The pathology may be quickly passed over by reiterating that any renal lesion so severe as to cause failure of excretion of phosphorus may be present. Albright et al. state that parathyroid cells are not as large in this type of hyperparathyroidism as they are in primary hyperparathyroidism. As for bone changes, Albright and his co-workers clearly explain them to be due to secondary hyperparathyroidism and to consist of swollen metaphyses, bone replacement with fibrous tissue, cysts and hemorrhage. Genu valgum, chest deformity, rosary, a wooly appearance of the skull, and fractures may be present. It must be remembered that abnormal bone changes are found in only 40 per cent of the cases. The signs and symptoms of a typical case were cited earlier in this paper. To quote from Ellis and Evans report of 20 cases: All had lowered renal function; all but one had calcium phosphorus reversal, mental dullness, 3; bright mentality, 1; average mentality, 9; bone changes, 15; dwarfism, 14; infantilism, 7; pigmentation, 14; hypertension and retinitis, 2 each. The symptoms associated with lowered renal function of course varied as would be expected, and consisted of headache, anorexia, nausea, vomiting, increased thirst, etc. Several cases were reported that remained small of stature but without bony deformity until adolescence, when they began to grow rapidly and immediately developed genu valgum. One is indeed fortunate to find a case that can be successfully treated, and it may be postulated that, first, the kidney lesion must be of the obstructive type, and second, that the case must be seen before irreparable renal damage has been done. It is obvious that a nephritis severe enough to cause this syndrome must offer a poor prognosis, as must also polycystic disease. Graham and Oakley report a case ·with an urea nitrogen of 430 which was treated by alkalies. The patient improved when the H-Ion concentration was maintained between 59 and 61 CO 2 volume per cent. Vitamin A and calcium lactate were also given. Albright et al., in the metabolic study of a case, found that the patient did well on a citric acid, sodium citrate mixture. This lowered the pH of the intestine, favoring calcium absorption a~d also produced a blood alkalosis which favored calcium retention. No figures are available, but the seriousness can probably be best brought home to you by stating that of the comparatively large number of cases reviewed, almost all of them included an autopsy report. T. Leon Howard states that the duration of life is only two years after bone changes occur. CASE REPORTS
Case 1. On September 19, 1940, I was called in consultation to see a boy, aged 15, who 9 days previously had been kicked in the right side while playing football. Blood had been seen in the urine at the next voiding, and his physician
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, had kept him in bed. He was in no discomfort and the bleeding stopped after a day or two, to reappear on September 18, or 8 days after the injury. When seen by me he was in a small bed in the Children's Ward, and I thought nothing of it until I was informed that he was 15 years of age. He was mentally alert and co-operative. He was not at all tender in either flank, but it was noted that his abdomen was large, and that there was a feeling of tension or resistance on an attempt to palpate each kidney. An intravenous urogram was advised and this gave shadows in 5, 10, and 15 minutes which consisted of large blobs in either kidney region, with no semblance of normal calyceal shape. The renal pelves were not outlined. It was felt that this finding warranted retrograde cystoscopy, which was done on the following day, September 20, 1940. A tight meatus was incised, after which an infant cystoscope passed without difficulty. In my eager search for posterior urethral valves, I was confident that one was present which closed over the tip of the scope as it was withdrawn. This was incised with the cutting current. The bladder showed no obstructive changes and the ureteral orifices were fairly normal. A catheter passed to the left kidney pelvis without difficulty and a rapid drip of normal appearing urine ensued. This had a pH of 7. On the right side, a catheter met an obstruction judged to be at the uretero-pelvic junction, and no urine could be secured. On September 25, 1940 a cystoscopy was repeated, after urethral dilatation until a Brown-Buerger scope could be passed. It was again noted that the left orifice appeared normal but that the right was considerably nearer the vesical orifice than normal. On this occasion, a No. 4 F. catheter passed to the right pelvis and a rapid hydronephrotic drip of blood tinged urine ensued. Three hundred and fifty cubic centimeters of normal appearing urine was aspirated from the left renal pelvis and 200 cc of bloody urine were aspirated from the right renal pelvis. Neither pelvis was emptied. Following this, 150 cc of 3 per cent sodium iodide were instilled on each side, and the pyelogram showed enormous hydronephroses on each side, with the block apparently at the ureteropelvic junctions, inasmuch as both ureteral shadows appeared normal. I made a note on the record at that time that aberrant lower pole vessels were probably the etiological factor. With these findings at hand, it was apparent that the football injury was not the cause of the pathology, but a fortunate occurrence which had directed attention to the urinary tract. Both the patient and the mother were questioned regarding his past history, and it was learned that he had had the ordinary diseases of childhood and had never felt entirely well. He had frequent headaches, averaging from 4 to 5 a week. He discovered that he felt better after vomiting, and he often forced himself to vomit. His appetite was poor, and his bowels were constipated. No attention had been paid to his smallness of stature. Two months before he was seen by me he began having right lumbar and lower quadrant pain, for which he was taken to the hospital and his appendix removed. Physical examination showed a height of 55 inches, and weight 80 pounds. He was mentally alert and his musculature was firm. Pupillary reflexes and eye-grounds were normal. Teeth were in good condition. The tongue was
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moist, but heavily coated. No thyroid or parathyroid enlargement could be made out. Heart and lungs were normal. Blood pressure was 120 systolic, and 78 diastolic. The abdomen was distended and there was marked tenderness, fullness and muscle spasm over the right kidney. There was also a feeling of fullness and tension over the left kidney, but no tenderness. Pubic hair was making its appearance but was so scanty that its distribution was of no value in diagnosis. The suspensory ligament of the penis was short, otherwise the genitalia appeared normal. The extremities were well formed and symmetrical. There was no beading of the ribs, and no evidence of spina bifida occulta. Culture of the urine showed no growth. The blood urea nitrogen was 35.5 mg. The serum calcium was 7.5 and the serum phosphorus 4.7. Hemoglobin determination on succeeding days averaged around 74 per cent. On September 27, 1940, under gas-oxygen-ether anesthesia, a left lumbar incision was made through a fairly heavy muscle wall. The kidney was easily found and mobilized. The pelvis was huge and as it was being mobilized, a hole was torn in it. At least 1 pint of urine was recovered. An aberrant vessel was coursing across the pelvis to the lower pole and was the cause of the obstruction. A considerable amount of the redundant pelvic wall was excised, and inasmuch as the ureter had been separated from the pelvis at the time of the original tear, it was anastomosed over an indwelling nephrostomy tube which was inserted through one of the upper calyces. This unusual location was used because of the paper thinness of the kidney at this point. When the lower pole aberrant vessel was cut, an area of kidney cortex about ¾" in length was rendered cyanotic. A modification of the Foley Y plastic operation was used in anastomosing the pelvis and ureter, and 000 chromic catgut was employed. A satisfactory funnel shaped pelvis was secured and closure was made in the usual manner, without other drainage. Inspection of the kidney during the operation showed the functioning part of the kidney to be at the lower pole. The upper half of the kidney was of paper thinness and probably functionless. Practically no perinephritis was present. Following the operation intravenous fluids were given and the postoperative recovery was uneventful. Six days after the operation, he was averaging an output of 350 cc of urine a day from this kidney. On October 7, 1940 it was thought safe to operate on the right kidney, and again, with the same anesthetic, a right lumbar incision was made. The upper pole of the kidney was found freely movable, but the lower pole was densely adherent, both to Gerota's fascia and the peritoneum. The peritoneum was accidentally opened twice, but was immediately sutured. By blunt and sharp dissection the ureter was isolated and adherent bands dissected away from it. The pelvis was torn, spilling an enormous amount of purulent urine. No opening could be found between the pelvis and the ureter, and under direct vision the ureter was laid open and the .strictured area between the pelvis and the normal ureter was excised. A nephrostomy tube was introduced through the lower calyx and threaded into the ureter, after which the latter was sutured to the pelvis with 000 chromic catgut. The pelvic wall that was utilized was in poor condition
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but it was all that was available. One cigarette drain was used in closing. Instead of an aberrant vessel causing the obstruction on this side, a ureteral stricture was definitely the cause. This was extensive, so that a mass of firm fibrous and fatty tissue at least 3 cm. in diameter and 4 cm. in length intervened between the pelvis and the ureter of normal calibre. The upper pole or the kidney appeared fairly normal. It was very large and the parenchyma seemed to be in good condition. Intravenous fluid plus intravenous adrenal cortical extract were immediately given, and on the following day 270 cc of urine was recovered through each nephrostomy tube, besides 10 ounces that the patient voided. In spite of all precaution, infection of the left kidney pelvis immediately took place, following insertion of the nephrostomy tube. Daily irrigation of each renal pelvis was made, using a warm saline solution. Methylene blue was instilled through both nephrostomy tubes and appeared faintly in the bladder urine on the following day. On October 22, 1940 it was noted that drainage from the left nephrostomy tube was very slight, and that the patient was voiding more and more each day. Pyelograms were taken, using 3 per cent sodium iodide, through the nephrostomy tubes. The right pelvis was large but tapered down to a perfect funnel at its junction with the ureter. The right ureter could also be outlined and no leak was present. The left pelvis was much smaller but did not taper to a normal uretero-pelvic junction, yet no leak was present. Prontolyn maltocide, 20 per cent, was used experimentally, by instilling it through the nephrostomy tube into the renal pelvis. This apparently had no effect on the infection. By this time the patient was so that he could go home, and it was found that during the day time he voided the greater part of his urinary output, but that at night, while lying down, drainage was through the nephroston;iy tube. On November 4, 1940, indigo carmine appeared in good concentration in 3½ minutes on both sides. On November 6, 1940, under gas-oxygen anesthesia, both nephrostomy tubes were removed. Cystoscopy was then done and both ureters were dilated. Culture of the urine showed B. coli; the infection was treated orally by sulfathiazole. Improvement was rapid, until early in December, when he complained of loss of appetite and pain over the left kidney region. Ureteral dilatation was again done, but it was soon noticed that he lay in bed with his left leg flexed, and complained of more and more pain in the left costo-vertebral angle. On December 26, 1940, under gas-oxygen anesthesia, cystoscopy was again done. A catheter was passed to the left renal pelvis, followed by a rapid hydronephrotic drip. Skiodan was instilled and the pyelogram showed a fairly dense shadmv of the pelvis. which was quite large. A less dense shadow extended laterally and downward which was diagnosed as retroperitoneal leakage. Operation was advised and immediately carried out. A collection of purulent urine was evacuated and drained with a cigarette drain. Recovery was prompt and it was not until Febrnary 22, 1941 that a cystoscopy was again performed. Both ureters were dilated to No. 11 F. The blood chemistry on this date showed a urea nitrogen of 11, serum calcium 7.7 and serum phosphorus 3.3. In March and again in July, 1941 the ureters were dilated.
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At this time it was noticed that the right side dilated easily but that an obstruction was encountered in the upper left ureter which could not be passed. On August 1, 1941 a check-up showed a CO2 of 60.6 per cent, urea nitrogen 17.4, creatinine 2.3, non-protein nitrogen 34, chlorides 596, serum albumin 4.6, serum globulin 2.6, total protein 7.2, phosphorus 4.4, phosphatase 1.5, and calcium 8.3. The urinary calcium was normal by the Sulkowitch test. On December ·30, 1941 examination showed his height to be 57 inches, and weight 85 pounds. His urine was pale, cloudy, specific gravity 1.010, pH 6.5, loaded with pus cells, and a stained smear showed staphylococci. Hemoglobin was 65 per cent, white blood cells 12,000. His blood pressure was 122/90. On May 4, 1942 a cystoscopy was again done, and the ureters dilated. The right ureter dilated easily but again the obstruction was encountered in the upper left ureter. The patient had developed a urinary fistula on the left side, which drained a small amount each day. On September 28, 1942, the chain of his bicycle broke letting him down hard . on the cross-bar. This brought on pain in the left loin and he was again hospitalized. Cystoscopy revealed the fact that the upper left ureter had b~come totally occluded and the left kidney practically functionless as determined by intravenous dye excretion. Blood chemistry findings were as follows: Urea nitrogen 40.9, serum phosphorus 11, urea clearance 59.2 per cent. On October 8, 1942, a left nephrectomy was done followed by immediate improvement. On October 21, 1942 the urea nitrogen was 34.5, calcium 14, and phosphorus 5. On January 20, 1943, he was again examined and found to weigh 100 pounds. His height had increased to 5 ft. His whole general appearance had improved. Case 2. D. C., a male, aged 6, was referred to me on May 3, 1938 because of persistent pyuria. He gave a history of having had congenital club feet for which a corrective operation had been fairly successful. His abdomen had always been very large but this was thought to be due to an enlarged colon. Examination showed a pale, undernourished child who was unable to walk. The eye grounds were not examined. The pupils reacted normally. The teeth were in poor condition. The mucous membranes were pale. The tongue was not coated. There was no cervical adenopathy. The chest wall was thin and the abdomen bulged out below it. Heart and lungs were normal. No definite mass could be identified but the entire abdomen was tense. Genitalia appeared normal. Extremities were tinder-developed. Reflexes were exaggerated. Skin anesthesia was not noted although special care was devoted to eliciting saddle anesthesia. Urine was pale, turbid, with a specific gravity of 1.006, pH 6.5, albumin was 2 plus, sugar negative. It was loaded with pus cells and gram negative bacilli. Red blood cells, 2,360,000; white blood cells 9,650. A differential count showed 51 per cent polymorphonuclears divided into 34 per cent segmented and 17 per cent stabs, lymphocytes 45 per cent, basophiles 1 per cent, and monocytes 3 per cent. The urea nitrogen was 16, blood calcium 9, blood phosphorus 8. X-ray f\Xamination showed no evidence of spina bifida occulta.
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Cystoscopic examination showed a median bar obstruction at the vesical orifice, hypertrophied trigonal muscles, trabeculation and a patchy redness of the bladder mucosa. The ureteral orifices could not be identified. Intravenous injections of Diodrast failed to appear in 30 minutes. A cystogram using 250 cc of sodium iodide showed a reflux up both ureters. The right ureter was as large as the cecum should be and no calyces were visible. The same condition but to a lesser extent was noted on the left side. Catheter drainage was unsuccessful and a suprapubic cystostomy was performed. This allowed removal of obstructing vesical neck tissue by means of a loop electrode. Drainage was maintained suprapubically for 3 weeks. At the end of this period, the urea nitrogen of the blood had risen to 25 but phenolsulphonphthalein was excreted in amounts of 15 per cent each in 1 and 2 hours. Urethral trauma had been sustained at the first cystoscopy and this required frequent urethral dilatation to control. Control of the urethral and anal sphincters was poor but could be maintained if he did not become careless. It was noted on all occasions when the urethra was dilated that there ,vas amost complete anesthesia. The patient was seen on November 18, 1942. He appeared weaker and was still unable to walk. No gross deformities of the extremities were noted but an x-ray report from Dr. Charles "\V. Dodge was as follows: "The skull shows definite findings of osteo-porosis generally distributed. The epiphyses of the long bones of both upper and lower extremities, particularly at the wrist and ankle show evidence of inflammatory change with deformity, bearing out your clinical anticipation." Unfortunately, blood chemistry examination was not done at this time and a month later he died. Autopsy was not obtained.
319 Pine St., Jamestown, N. Y. REFERENCES ALBRIGHT, F. ET AL.: Renal complications of hyperparathyroidism. Am. J. Med. Sci., 187: 49-65, 1934. ALBRIGHT, F., ET AL.: Metabolic studies and therapy in a case of nephrocalcinosis with rickets and dwarfism. Bull. Johns Hopkins Hosp., 66: 7-33, 1940. ALBRIGHT, F., DRAKE, T. G., AND SULKOWITCH, H. W.: Renal osteitis fibrosa cystica. Bull. Johns Hopkins Hosp., 60: 377-399, 1937. BARBER, HUGH: Chronic interstitial nephritis in children. Brit. Med. J., 2: 1204-1205, 1913. - - - : A renal dwarf. Guy's Hosp. Rept., 83: 220-227, 1933. BATES, R. M.: Renal dwarfism. Brit. J. Child. Dis., 36: 34-41, 1939. BOYD, J. D., AND STEARNS, G.: Late rickets resembling the Fanconi syndrome. Am. J. Dis. Child., 61: 1012-1022, 1941. BRAIN, R. T., AND KAY, H. D.: A new test of renal function. Quart. J. Med., 22: 203-216, 1929. BROCKMAN, E. P.: Some observations on the bone changes in renal rickets. Brit. J. Surg., 14: 634-645, 1927. CAMPBELL, M. F.: Pediatric Urology. New York, Macmillan Co., 1937. CHARNOCK, D. A.: Renal rickets. J. Urol., 44: 850-859, 1940. CHOWN, BRUCE: Renal rickets and dwarfism: a pituitary disease. Brit. J. Surg., 23: 552566, 1936. CHOWN, B., AND LEE, M.: Renal rickets and dwarfism as a pituitary disease. Am. J. Dis. Child., 53: 117-127, 1937. DANIS, P. G., AND RossEN, J. A.: Renal rickets. J. Pediat., 18: 103-116, 1941. DEROW, H. A., AND BRODNY, M. L.: Congenital posterior urethral valve causing renal rickets. New England J. Med., 221: 685-690, 1939.
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DRAKE, T. G., ALBRIGHT, F., AND CASTLEMAN, B.: Parathyroid hyperplasia in rabbits produced by parenteral phosphate administration. J. Clin. Investigation, 15: 203206, 1937. ELLIS, A., AND EvANS, H.: Renal dwarfism. A report of 20 cases with special reference to its association with certain dilations of the urinary tract. Quart. J. Med., 26: 231-254, 1933. ELLSWORTH, R., AND HowARD, J.E.: Studies on the physiology of the parathyroid glands. VII. Some responses of normal human kidneys and blood to intravenous parathyroid extract. Bull. Johns Hopkins Hosp., 55: 296-308, 1934. FLETCHER, H. M.: Case of infantilism with polyuria and chronic renal disease. Proc. Roy. Soc. Med., Sect. Study Dis. Child., 4: 95, 1911. GARDINER-HILL, H.: Abnormalities of growth and development: the clinical and pathological aspects. Brit. M. J., 1: 1302-1308, 1937. GITTLEMAN, I. F., AND PINCUS, J.B.: Rickets associated with dwarfism, glycosuria, ketonuria and albuminuria. Am. J. Dis. Child., 60: 1351-1370. 1940. GoLDMAN, F., AND EKSTEIN, G.: Renal dwarfism due to tubular dysfunction. J. Pediat., 15: 53-63, 1939. . GRAHAM, G., AND OAKLEY, W. G.: The treatment of renal rickets. Arch. Dis. Childhood, 13: 1-30, 1938. HowARD, T. L.: Renal rickets or renal dwarfism. Am. J. Surg., 40: 323-348, 1938. HUNT, F. C.: Renal infantilism. Report of a case and a review of the literature. Am. J. Dis. Child., 34: 234-248, 1927. HUNTER, DONALD: The metabolism of calcium and phosphorus and the parathyroids in health and disease. Quart. J. Med., 95: 393-446, 1931. HuTINEL, V.: Sur une dystrophie speciale des adolescents .. Gaz. des H6p., 85: 27-32, 1912. JARRETT, W. A., PETERS, H. L., AND PAPPENHEIMER, A. M.: Parathyroid enlargement in rats following experimental reduction of kidney- substance. Proc. Soc. Exp. Biol. and Med., 32: 1211-1215, 1935. KARSHNER, R. G.: Rickets occurring late in chronic interstitial nephritis. Report of a case. Am. J. Roentgenol., 18: 442-450, 1927. KAY, H. D.: Phosphatase in growth and disease of bone. Physiol. rev., 12: 384-422, 1932. LATHROP, F. W.: Renal dwarfism. Report of a case. Arch. Int. Med., 38: 612-622, 1926. LucAs, R. C.: On a form of late rickets associated with albuminuria, rickets of adolescents. Lancet, 1: 993-994, 1883. MARRIOTT, W. McK., AND HOWLAND, J.: Phosphate retention as a factor in the production of acidosis in nephritis. Arch. Int. Med., 18: 708-711, 1916. MITCHELL, A. G.: Nephrosclerosis (chronic interstitial nephritis) in childhood. Am. J. Dis. Child., 40: 101-145; 345-388, 1930. ORR, W. J. ET AL.: The relation of calcium and phosphorus in the diet to the absorption of these elements from the intestine. Am. J. Dis. Child., 28: 574-581, 1924. PAPPENHEIMER, A. M., AND WILENS, S. L.: Enlargement of the parathyroid glands in renal disease. Am. J. Path., 11: 73-91, 1935. PARSONS, LEONARD: Infantilism associated with chronic interstitial nephritis. Brit. Med. J., 2: 481-482, 1911. PARSONS, L. G.: Bone changes occurring in renal and coeliac infantilism, and their relationship to rickets. Arch. Dis. Childhood, 2: 1-25, 1927. PLATT, R., AND OWEN, T. K.: Renal dwarfism associated with calcification of arteries and skin. Lancet, 2: 135-136, 1934. PRICE, N. L., AND DAVIE, T. B.: Renal rickets. Brit. J. Surg., 24: 548-569, 1937. ROBERTS, J. F.: Renal dwarfism: a case report. Ann. Int. Med., 9: 1729-1736, 1936. SHELLING, D. H., AND REMSEN, D.: Renal rickets. Bull. Johns Hopkins Hosp., 57: 158181, 1935. VoGT, E. C.: Renal rickets. Am. J. Roentgenol., 30: 624-630, 1933.
W.G.HAYWARD Although this disease is by no means common, less than 100 cases having been reported as late as 1938, a not too meager literature has come into existence in the many attempts to record and explain the varied symptoms. As the title implies, rachitic changes are present, assumed to be caused by renal dysfunction. It is a syndrome found in the young, the average age of onset of symptoms being 12½ years in Ellis and Evans series of 20 cases, and slightly higher in the cases histories that I have reviewed. It has occurred about equally in the 2 sexes. In order to have a clearer mental picture of this group of symptoms and signs, a typical case could be described as follows: Nothing abnormal may be noted until the age of 13 is reached except: (a) Smallness of stature. The average height is 24.2 per cent below normal and the average weight is 45.2 per cent below normal, as recorded by Hunt. (b) Signs and symptoms may or may not have lead to an examination of the urinary tract. (c) Mentality is bright. (d) The bony changes develop, genu valgum or knockknees being present in 56 per cent. Other bony changes are less constant. (e) X-rays are quite typical of ordinary rickets. (f) Thirst, polyuria, dryness of skin, loss of appetite, headache, delayed sexual development, etc., are present depending on the severity of the renal involvement. (g) Laboratory studies show poor kidney function, azotemia, but most important of all, a calcium phosphorus reversal. As stated b{:)fore, this is a description of a typical case, and after all, no 2 cases are exactly alike. Of the above, the 3 outstanding points in diagnosis are dwarfism, rachitic changes and calcium-phosphorus reversal. With this picture in mind, we can go on to the etiology. The type of renal impairment is unimportant. Obstructive uropathy, nephritis, cong~nital cystic disease or others can initiate the train of events. Practically all contributors on the subject agree on one thing, and that is that the kidney is unable to excrete phosphorus. This accounts for the high serum phosphorus. The phosphorus is eliminated into the bowel, where it combines with calcium to form insoluble calcium phosphate which the bowel cannot absorb, and thus produces a calcium deficiency. (Experimentally it has been proven that rickets can be produced by a diet low in calcium and high in phosphorus.) However, a lack of calcium absorption is not all there is to it. Controls given a low calcium diet develop osteoporosis only, but in renal rickets the presence of a high serum phosphorus causes a hyperplasia and ov1'l-activity of the parathyroids, which in turn causes diminished density of bones with replacement of fibrous tissue, cysts and hemorrhage, or osteitis fibrosa cystica, Von Recklinghausen's disease. This can be done experimentally by overdoses of parathormone. The presence of large parathyroids has been noted by many observers at autopsy. Drake, Albright, and Sulkowitch s~ate that parathyroid hyperplasia 278
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occurs as a result of long renal deficiency with inability to excrete phosphorus. One of the parathyroid functions is to eliminate phosphorus through the kidney and lower the inorganic level in the blood. Ellsvrorth and Howard showed that injection of parathormone in hypoparathyroidism caused increased phosphorus excretion in urine. This is also seen in normal individuals. Experimentally Drake, Albright and Castleman injected rabbits daily with phosphorus and produced hyperplasia of the parathyroids. So not only is exogenous calcium prevented from entering the .system, but endogenous calcium is being removed by parathyroid action. Mitchell feels that the failure of phosphates to bank up higher in the blood is explained by their excretion into the bowel. You are all familiar with the usual high calcium, low phosphorus ratio that is seen in adenomata of the parathyroid. This has been stressed by Albright et al. Albright postulates, however, that hyperparathyroidism may be associated with normal serum calcium under two circumstances and two only, namely, if there is a low serum protein level or phosphate retention due to renal insufficiency. As has been pointed out earlier in this paper, parathyroid hyperplasia and overactivity are secondary to the phosphatic retention caused by the renal insufficiency in this syndrome. In reviewing a large number of papers and case reports, it was repeatedly obvious that a number of cases reported as renal rickets were not that at all, but instead were primary hyperparathyroidism with secondary renal changes. Vogt states that an imbalance of the calcium phosphorus ratio is more important in the production of rickets than is the total quantity. The daily requirement of calcium during growth is from 0.4 to 1 gm. and more. Calcium phosphate comprises 80 per cent of bone. Bone is the reservoir of both calcium and phosphorus and these salts are constantly being added to or drawn from bone. The acidosis which is present in this syndrome ionizes enough free calcium to keep its level above 3.8 gm. This is above the level at which tetany develops. In a report of 20 cases, only l case of tetany was reported and further than this, I was unable to find any other record of tetany in over 50 articles reviewed. Dwarfism cannot be explained as easily as the calcium-phosphorus reversal and the secondary hyperparathyroidism. Charnock explains it on the pituitarydiencephalon theory. He states, first, that pituitary dysfunction could cause the dwarfism, and that, secondly, an autonomic center in the adjoining diencephalon could cause urinary tract abnormalities in which there is no mechanical block. Davis and Rossen explain it by Thompson's antigrowth factor of the parathyroid. Gardiner-Hill have this to say: "Dwarfism implies a defect in stature below normal standards but does not necessarily signify a pathological state. There may or may not be skeletal disproportions. It may be due to developmental skeletal diseases or acquired skeletal diseases such as rickets, caries or polio. In the type due to rickets, there is softening and deformity due to deficiency, decrease of calcium phosphate and imperfect calcification and ossification in the
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epiphyseal line. Cartilage proliferates excessively. If there is no growth, there is no rickets. Hence, the intensity of the process is directly proportional to the growth rate." The pathology may be quickly passed over by reiterating that any renal lesion so severe as to cause failure of excretion of phosphorus may be present. Albright et al. state that parathyroid cells are not as large in this type of hyperparathyroidism as they are in primary hyperparathyroidism. As for bone changes, Albright and his co-workers clearly explain them to be due to secondary hyperparathyroidism and to consist of swollen metaphyses, bone replacement with fibrous tissue, cysts and hemorrhage. Genu valgum, chest deformity, rosary, a wooly appearance of the skull, and fractures may be present. It must be remembered that abnormal bone changes are found in only 40 per cent of the cases. The signs and symptoms of a typical case were cited earlier in this paper. To quote from Ellis and Evans report of 20 cases: All had lowered renal function; all but one had calcium phosphorus reversal, mental dullness, 3; bright mentality, 1; average mentality, 9; bone changes, 15; dwarfism, 14; infantilism, 7; pigmentation, 14; hypertension and retinitis, 2 each. The symptoms associated with lowered renal function of course varied as would be expected, and consisted of headache, anorexia, nausea, vomiting, increased thirst, etc. Several cases were reported that remained small of stature but without bony deformity until adolescence, when they began to grow rapidly and immediately developed genu valgum. One is indeed fortunate to find a case that can be successfully treated, and it may be postulated that, first, the kidney lesion must be of the obstructive type, and second, that the case must be seen before irreparable renal damage has been done. It is obvious that a nephritis severe enough to cause this syndrome must offer a poor prognosis, as must also polycystic disease. Graham and Oakley report a case ·with an urea nitrogen of 430 which was treated by alkalies. The patient improved when the H-Ion concentration was maintained between 59 and 61 CO 2 volume per cent. Vitamin A and calcium lactate were also given. Albright et al., in the metabolic study of a case, found that the patient did well on a citric acid, sodium citrate mixture. This lowered the pH of the intestine, favoring calcium absorption a~d also produced a blood alkalosis which favored calcium retention. No figures are available, but the seriousness can probably be best brought home to you by stating that of the comparatively large number of cases reviewed, almost all of them included an autopsy report. T. Leon Howard states that the duration of life is only two years after bone changes occur. CASE REPORTS
Case 1. On September 19, 1940, I was called in consultation to see a boy, aged 15, who 9 days previously had been kicked in the right side while playing football. Blood had been seen in the urine at the next voiding, and his physician
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, had kept him in bed. He was in no discomfort and the bleeding stopped after a day or two, to reappear on September 18, or 8 days after the injury. When seen by me he was in a small bed in the Children's Ward, and I thought nothing of it until I was informed that he was 15 years of age. He was mentally alert and co-operative. He was not at all tender in either flank, but it was noted that his abdomen was large, and that there was a feeling of tension or resistance on an attempt to palpate each kidney. An intravenous urogram was advised and this gave shadows in 5, 10, and 15 minutes which consisted of large blobs in either kidney region, with no semblance of normal calyceal shape. The renal pelves were not outlined. It was felt that this finding warranted retrograde cystoscopy, which was done on the following day, September 20, 1940. A tight meatus was incised, after which an infant cystoscope passed without difficulty. In my eager search for posterior urethral valves, I was confident that one was present which closed over the tip of the scope as it was withdrawn. This was incised with the cutting current. The bladder showed no obstructive changes and the ureteral orifices were fairly normal. A catheter passed to the left kidney pelvis without difficulty and a rapid drip of normal appearing urine ensued. This had a pH of 7. On the right side, a catheter met an obstruction judged to be at the uretero-pelvic junction, and no urine could be secured. On September 25, 1940 a cystoscopy was repeated, after urethral dilatation until a Brown-Buerger scope could be passed. It was again noted that the left orifice appeared normal but that the right was considerably nearer the vesical orifice than normal. On this occasion, a No. 4 F. catheter passed to the right pelvis and a rapid hydronephrotic drip of blood tinged urine ensued. Three hundred and fifty cubic centimeters of normal appearing urine was aspirated from the left renal pelvis and 200 cc of bloody urine were aspirated from the right renal pelvis. Neither pelvis was emptied. Following this, 150 cc of 3 per cent sodium iodide were instilled on each side, and the pyelogram showed enormous hydronephroses on each side, with the block apparently at the ureteropelvic junctions, inasmuch as both ureteral shadows appeared normal. I made a note on the record at that time that aberrant lower pole vessels were probably the etiological factor. With these findings at hand, it was apparent that the football injury was not the cause of the pathology, but a fortunate occurrence which had directed attention to the urinary tract. Both the patient and the mother were questioned regarding his past history, and it was learned that he had had the ordinary diseases of childhood and had never felt entirely well. He had frequent headaches, averaging from 4 to 5 a week. He discovered that he felt better after vomiting, and he often forced himself to vomit. His appetite was poor, and his bowels were constipated. No attention had been paid to his smallness of stature. Two months before he was seen by me he began having right lumbar and lower quadrant pain, for which he was taken to the hospital and his appendix removed. Physical examination showed a height of 55 inches, and weight 80 pounds. He was mentally alert and his musculature was firm. Pupillary reflexes and eye-grounds were normal. Teeth were in good condition. The tongue was
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moist, but heavily coated. No thyroid or parathyroid enlargement could be made out. Heart and lungs were normal. Blood pressure was 120 systolic, and 78 diastolic. The abdomen was distended and there was marked tenderness, fullness and muscle spasm over the right kidney. There was also a feeling of fullness and tension over the left kidney, but no tenderness. Pubic hair was making its appearance but was so scanty that its distribution was of no value in diagnosis. The suspensory ligament of the penis was short, otherwise the genitalia appeared normal. The extremities were well formed and symmetrical. There was no beading of the ribs, and no evidence of spina bifida occulta. Culture of the urine showed no growth. The blood urea nitrogen was 35.5 mg. The serum calcium was 7.5 and the serum phosphorus 4.7. Hemoglobin determination on succeeding days averaged around 74 per cent. On September 27, 1940, under gas-oxygen-ether anesthesia, a left lumbar incision was made through a fairly heavy muscle wall. The kidney was easily found and mobilized. The pelvis was huge and as it was being mobilized, a hole was torn in it. At least 1 pint of urine was recovered. An aberrant vessel was coursing across the pelvis to the lower pole and was the cause of the obstruction. A considerable amount of the redundant pelvic wall was excised, and inasmuch as the ureter had been separated from the pelvis at the time of the original tear, it was anastomosed over an indwelling nephrostomy tube which was inserted through one of the upper calyces. This unusual location was used because of the paper thinness of the kidney at this point. When the lower pole aberrant vessel was cut, an area of kidney cortex about ¾" in length was rendered cyanotic. A modification of the Foley Y plastic operation was used in anastomosing the pelvis and ureter, and 000 chromic catgut was employed. A satisfactory funnel shaped pelvis was secured and closure was made in the usual manner, without other drainage. Inspection of the kidney during the operation showed the functioning part of the kidney to be at the lower pole. The upper half of the kidney was of paper thinness and probably functionless. Practically no perinephritis was present. Following the operation intravenous fluids were given and the postoperative recovery was uneventful. Six days after the operation, he was averaging an output of 350 cc of urine a day from this kidney. On October 7, 1940 it was thought safe to operate on the right kidney, and again, with the same anesthetic, a right lumbar incision was made. The upper pole of the kidney was found freely movable, but the lower pole was densely adherent, both to Gerota's fascia and the peritoneum. The peritoneum was accidentally opened twice, but was immediately sutured. By blunt and sharp dissection the ureter was isolated and adherent bands dissected away from it. The pelvis was torn, spilling an enormous amount of purulent urine. No opening could be found between the pelvis and the ureter, and under direct vision the ureter was laid open and the .strictured area between the pelvis and the normal ureter was excised. A nephrostomy tube was introduced through the lower calyx and threaded into the ureter, after which the latter was sutured to the pelvis with 000 chromic catgut. The pelvic wall that was utilized was in poor condition
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but it was all that was available. One cigarette drain was used in closing. Instead of an aberrant vessel causing the obstruction on this side, a ureteral stricture was definitely the cause. This was extensive, so that a mass of firm fibrous and fatty tissue at least 3 cm. in diameter and 4 cm. in length intervened between the pelvis and the ureter of normal calibre. The upper pole or the kidney appeared fairly normal. It was very large and the parenchyma seemed to be in good condition. Intravenous fluid plus intravenous adrenal cortical extract were immediately given, and on the following day 270 cc of urine was recovered through each nephrostomy tube, besides 10 ounces that the patient voided. In spite of all precaution, infection of the left kidney pelvis immediately took place, following insertion of the nephrostomy tube. Daily irrigation of each renal pelvis was made, using a warm saline solution. Methylene blue was instilled through both nephrostomy tubes and appeared faintly in the bladder urine on the following day. On October 22, 1940 it was noted that drainage from the left nephrostomy tube was very slight, and that the patient was voiding more and more each day. Pyelograms were taken, using 3 per cent sodium iodide, through the nephrostomy tubes. The right pelvis was large but tapered down to a perfect funnel at its junction with the ureter. The right ureter could also be outlined and no leak was present. The left pelvis was much smaller but did not taper to a normal uretero-pelvic junction, yet no leak was present. Prontolyn maltocide, 20 per cent, was used experimentally, by instilling it through the nephrostomy tube into the renal pelvis. This apparently had no effect on the infection. By this time the patient was so that he could go home, and it was found that during the day time he voided the greater part of his urinary output, but that at night, while lying down, drainage was through the nephroston;iy tube. On November 4, 1940, indigo carmine appeared in good concentration in 3½ minutes on both sides. On November 6, 1940, under gas-oxygen anesthesia, both nephrostomy tubes were removed. Cystoscopy was then done and both ureters were dilated. Culture of the urine showed B. coli; the infection was treated orally by sulfathiazole. Improvement was rapid, until early in December, when he complained of loss of appetite and pain over the left kidney region. Ureteral dilatation was again done, but it was soon noticed that he lay in bed with his left leg flexed, and complained of more and more pain in the left costo-vertebral angle. On December 26, 1940, under gas-oxygen anesthesia, cystoscopy was again done. A catheter was passed to the left renal pelvis, followed by a rapid hydronephrotic drip. Skiodan was instilled and the pyelogram showed a fairly dense shadmv of the pelvis. which was quite large. A less dense shadow extended laterally and downward which was diagnosed as retroperitoneal leakage. Operation was advised and immediately carried out. A collection of purulent urine was evacuated and drained with a cigarette drain. Recovery was prompt and it was not until Febrnary 22, 1941 that a cystoscopy was again performed. Both ureters were dilated to No. 11 F. The blood chemistry on this date showed a urea nitrogen of 11, serum calcium 7.7 and serum phosphorus 3.3. In March and again in July, 1941 the ureters were dilated.
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At this time it was noticed that the right side dilated easily but that an obstruction was encountered in the upper left ureter which could not be passed. On August 1, 1941 a check-up showed a CO2 of 60.6 per cent, urea nitrogen 17.4, creatinine 2.3, non-protein nitrogen 34, chlorides 596, serum albumin 4.6, serum globulin 2.6, total protein 7.2, phosphorus 4.4, phosphatase 1.5, and calcium 8.3. The urinary calcium was normal by the Sulkowitch test. On December ·30, 1941 examination showed his height to be 57 inches, and weight 85 pounds. His urine was pale, cloudy, specific gravity 1.010, pH 6.5, loaded with pus cells, and a stained smear showed staphylococci. Hemoglobin was 65 per cent, white blood cells 12,000. His blood pressure was 122/90. On May 4, 1942 a cystoscopy was again done, and the ureters dilated. The right ureter dilated easily but again the obstruction was encountered in the upper left ureter. The patient had developed a urinary fistula on the left side, which drained a small amount each day. On September 28, 1942, the chain of his bicycle broke letting him down hard . on the cross-bar. This brought on pain in the left loin and he was again hospitalized. Cystoscopy revealed the fact that the upper left ureter had b~come totally occluded and the left kidney practically functionless as determined by intravenous dye excretion. Blood chemistry findings were as follows: Urea nitrogen 40.9, serum phosphorus 11, urea clearance 59.2 per cent. On October 8, 1942, a left nephrectomy was done followed by immediate improvement. On October 21, 1942 the urea nitrogen was 34.5, calcium 14, and phosphorus 5. On January 20, 1943, he was again examined and found to weigh 100 pounds. His height had increased to 5 ft. His whole general appearance had improved. Case 2. D. C., a male, aged 6, was referred to me on May 3, 1938 because of persistent pyuria. He gave a history of having had congenital club feet for which a corrective operation had been fairly successful. His abdomen had always been very large but this was thought to be due to an enlarged colon. Examination showed a pale, undernourished child who was unable to walk. The eye grounds were not examined. The pupils reacted normally. The teeth were in poor condition. The mucous membranes were pale. The tongue was not coated. There was no cervical adenopathy. The chest wall was thin and the abdomen bulged out below it. Heart and lungs were normal. No definite mass could be identified but the entire abdomen was tense. Genitalia appeared normal. Extremities were tinder-developed. Reflexes were exaggerated. Skin anesthesia was not noted although special care was devoted to eliciting saddle anesthesia. Urine was pale, turbid, with a specific gravity of 1.006, pH 6.5, albumin was 2 plus, sugar negative. It was loaded with pus cells and gram negative bacilli. Red blood cells, 2,360,000; white blood cells 9,650. A differential count showed 51 per cent polymorphonuclears divided into 34 per cent segmented and 17 per cent stabs, lymphocytes 45 per cent, basophiles 1 per cent, and monocytes 3 per cent. The urea nitrogen was 16, blood calcium 9, blood phosphorus 8. X-ray f\Xamination showed no evidence of spina bifida occulta.
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Cystoscopic examination showed a median bar obstruction at the vesical orifice, hypertrophied trigonal muscles, trabeculation and a patchy redness of the bladder mucosa. The ureteral orifices could not be identified. Intravenous injections of Diodrast failed to appear in 30 minutes. A cystogram using 250 cc of sodium iodide showed a reflux up both ureters. The right ureter was as large as the cecum should be and no calyces were visible. The same condition but to a lesser extent was noted on the left side. Catheter drainage was unsuccessful and a suprapubic cystostomy was performed. This allowed removal of obstructing vesical neck tissue by means of a loop electrode. Drainage was maintained suprapubically for 3 weeks. At the end of this period, the urea nitrogen of the blood had risen to 25 but phenolsulphonphthalein was excreted in amounts of 15 per cent each in 1 and 2 hours. Urethral trauma had been sustained at the first cystoscopy and this required frequent urethral dilatation to control. Control of the urethral and anal sphincters was poor but could be maintained if he did not become careless. It was noted on all occasions when the urethra was dilated that there ,vas amost complete anesthesia. The patient was seen on November 18, 1942. He appeared weaker and was still unable to walk. No gross deformities of the extremities were noted but an x-ray report from Dr. Charles "\V. Dodge was as follows: "The skull shows definite findings of osteo-porosis generally distributed. The epiphyses of the long bones of both upper and lower extremities, particularly at the wrist and ankle show evidence of inflammatory change with deformity, bearing out your clinical anticipation." Unfortunately, blood chemistry examination was not done at this time and a month later he died. Autopsy was not obtained.
319 Pine St., Jamestown, N. Y. REFERENCES ALBRIGHT, F. ET AL.: Renal complications of hyperparathyroidism. Am. J. Med. Sci., 187: 49-65, 1934. ALBRIGHT, F., ET AL.: Metabolic studies and therapy in a case of nephrocalcinosis with rickets and dwarfism. Bull. Johns Hopkins Hosp., 66: 7-33, 1940. ALBRIGHT, F., DRAKE, T. G., AND SULKOWITCH, H. W.: Renal osteitis fibrosa cystica. Bull. Johns Hopkins Hosp., 60: 377-399, 1937. BARBER, HUGH: Chronic interstitial nephritis in children. Brit. Med. J., 2: 1204-1205, 1913. - - - : A renal dwarf. Guy's Hosp. Rept., 83: 220-227, 1933. BATES, R. M.: Renal dwarfism. Brit. J. Child. Dis., 36: 34-41, 1939. BOYD, J. D., AND STEARNS, G.: Late rickets resembling the Fanconi syndrome. Am. J. Dis. Child., 61: 1012-1022, 1941. BRAIN, R. T., AND KAY, H. D.: A new test of renal function. Quart. J. Med., 22: 203-216, 1929. BROCKMAN, E. P.: Some observations on the bone changes in renal rickets. Brit. J. Surg., 14: 634-645, 1927. CAMPBELL, M. F.: Pediatric Urology. New York, Macmillan Co., 1937. CHARNOCK, D. A.: Renal rickets. J. Urol., 44: 850-859, 1940. CHOWN, BRUCE: Renal rickets and dwarfism: a pituitary disease. Brit. J. Surg., 23: 552566, 1936. CHOWN, B., AND LEE, M.: Renal rickets and dwarfism as a pituitary disease. Am. J. Dis. Child., 53: 117-127, 1937. DANIS, P. G., AND RossEN, J. A.: Renal rickets. J. Pediat., 18: 103-116, 1941. DEROW, H. A., AND BRODNY, M. L.: Congenital posterior urethral valve causing renal rickets. New England J. Med., 221: 685-690, 1939.
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DRAKE, T. G., ALBRIGHT, F., AND CASTLEMAN, B.: Parathyroid hyperplasia in rabbits produced by parenteral phosphate administration. J. Clin. Investigation, 15: 203206, 1937. ELLIS, A., AND EvANS, H.: Renal dwarfism. A report of 20 cases with special reference to its association with certain dilations of the urinary tract. Quart. J. Med., 26: 231-254, 1933. ELLSWORTH, R., AND HowARD, J.E.: Studies on the physiology of the parathyroid glands. VII. Some responses of normal human kidneys and blood to intravenous parathyroid extract. Bull. Johns Hopkins Hosp., 55: 296-308, 1934. FLETCHER, H. M.: Case of infantilism with polyuria and chronic renal disease. Proc. Roy. Soc. Med., Sect. Study Dis. Child., 4: 95, 1911. GARDINER-HILL, H.: Abnormalities of growth and development: the clinical and pathological aspects. Brit. M. J., 1: 1302-1308, 1937. GITTLEMAN, I. F., AND PINCUS, J.B.: Rickets associated with dwarfism, glycosuria, ketonuria and albuminuria. Am. J. Dis. Child., 60: 1351-1370. 1940. GoLDMAN, F., AND EKSTEIN, G.: Renal dwarfism due to tubular dysfunction. J. Pediat., 15: 53-63, 1939. . GRAHAM, G., AND OAKLEY, W. G.: The treatment of renal rickets. Arch. Dis. Childhood, 13: 1-30, 1938. HowARD, T. L.: Renal rickets or renal dwarfism. Am. J. Surg., 40: 323-348, 1938. HUNT, F. C.: Renal infantilism. Report of a case and a review of the literature. Am. J. Dis. Child., 34: 234-248, 1927. HUNTER, DONALD: The metabolism of calcium and phosphorus and the parathyroids in health and disease. Quart. J. Med., 95: 393-446, 1931. HuTINEL, V.: Sur une dystrophie speciale des adolescents .. Gaz. des H6p., 85: 27-32, 1912. JARRETT, W. A., PETERS, H. L., AND PAPPENHEIMER, A. M.: Parathyroid enlargement in rats following experimental reduction of kidney- substance. Proc. Soc. Exp. Biol. and Med., 32: 1211-1215, 1935. KARSHNER, R. G.: Rickets occurring late in chronic interstitial nephritis. Report of a case. Am. J. Roentgenol., 18: 442-450, 1927. KAY, H. D.: Phosphatase in growth and disease of bone. Physiol. rev., 12: 384-422, 1932. LATHROP, F. W.: Renal dwarfism. Report of a case. Arch. Int. Med., 38: 612-622, 1926. LucAs, R. C.: On a form of late rickets associated with albuminuria, rickets of adolescents. Lancet, 1: 993-994, 1883. MARRIOTT, W. McK., AND HOWLAND, J.: Phosphate retention as a factor in the production of acidosis in nephritis. Arch. Int. Med., 18: 708-711, 1916. MITCHELL, A. G.: Nephrosclerosis (chronic interstitial nephritis) in childhood. Am. J. Dis. Child., 40: 101-145; 345-388, 1930. ORR, W. J. ET AL.: The relation of calcium and phosphorus in the diet to the absorption of these elements from the intestine. Am. J. Dis. Child., 28: 574-581, 1924. PAPPENHEIMER, A. M., AND WILENS, S. L.: Enlargement of the parathyroid glands in renal disease. Am. J. Path., 11: 73-91, 1935. PARSONS, LEONARD: Infantilism associated with chronic interstitial nephritis. Brit. Med. J., 2: 481-482, 1911. PARSONS, L. G.: Bone changes occurring in renal and coeliac infantilism, and their relationship to rickets. Arch. Dis. Childhood, 2: 1-25, 1927. PLATT, R., AND OWEN, T. K.: Renal dwarfism associated with calcification of arteries and skin. Lancet, 2: 135-136, 1934. PRICE, N. L., AND DAVIE, T. B.: Renal rickets. Brit. J. Surg., 24: 548-569, 1937. ROBERTS, J. F.: Renal dwarfism: a case report. Ann. Int. Med., 9: 1729-1736, 1936. SHELLING, D. H., AND REMSEN, D.: Renal rickets. Bull. Johns Hopkins Hosp., 57: 158181, 1935. VoGT, E. C.: Renal rickets. Am. J. Roentgenol., 30: 624-630, 1933.