Postgrad. med. J. (October 1968) 44, 792-798. Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from

Medullary cystic disease of the : its occurrence in two siblings

SATYA PAUL HANDA* ROBERT TENNANT M.B. M.D. The Hartford Hospital, Hartford, Connecticut

Summary Necropsy findings reveal gross or microscopic Two cases of medullary cystic disease of the cysts in the medullary region of the kidney. At kidney in two siblings are presented. In both present there is an ample evidence that medullary siblings there was an insidious onset of azotaemia cystic disease of the kidney and familial juvenile and anaemia at an early age. The urinalyses were represent one and the same dis- normal except for a trace of proteinuria and order (Mongeau & Worthen, 1967; Strauss & persistent low specific gravity. The kidneys were Sommers, 1967). small by radiological studies and this was proved The occurrence of medullary cystic disease in at necropsy. The gross microscopic appearances two siblings prompted the present report. of the kidneys were consistent with medullary cystic disease. The literature on this subject and Case reports current views on the similarities between familial Protected by copyright. juvenile nephronophthisis and this condition are Case 1 discussed. R.B., a 20-year-old white male, was admitted to Hartford Hospital for the first time because of Introduction progressive weakness, headache and epigastric Medullary cystic disease of the kidney, a pro- pain associated with vomiting. gressive renal disorder occuring in children and The patient had had enuresis until the age of young adults, first described by Smith & Graham 7 and nocturia during his entire life. At the age (1945), was reviewed by Strauss in 1962. To date of 13, he experienced increased thirst, polyuria over forty cases of the entity have been reported and fatiguability. A year later daily urine out- in the world literature (Goldman et al., 1966; puts were in the range of 8-10 litres; however, no Herdman, Good & Vernier, 1967). The condition craving for salt was noted. Subsequently he be- is characterized by the insidious onset of uraemia, gan to complain of headache and muscle cramps. anaemia and other features of progressive renal When he was evaluated in 1959 (at the age of 15), disease, but without symptoms of urinary tract he was found to have a blood pressure of 170/ http://pmj.bmj.com/ involvement. On post-mortem examination, the 110 mmHg, congenital ichthyosis and mild kidneys are contracted and scarred, and show azotemia. Intravenous revealed small extensive cyst formation in the medulla or in the kidneys. Over the next 4 years, his renal func- region of the cortico-medullary junction. tion showed a progressive decline (Table 1). Medullary cystic disease of the kidney is He was admitted to another hospital in July thought not to be related to sponge kidney, a 1963 with symptoms of anorexia, weight loss and condition characterized by multiple small cysts itching. The urine output and intensity of thirst on September 26, 2021 by guest. in the medullary region, with little or no evidence had gradually decreased. of impairment of renal functions. Physical examination revealed a pale, muscular The disorder called familial juvenile nephron- boy with ichthyotic and pigmented skin. The ophthisis was described by Fanconi et al. in 1951. pulse was 120, BP 154/100mmHg. The thyroid Since then forty cases have been reported. Clinic- was diffusely enlarged and a slight degree of lid- ally these patients present with features similar lag was present. The heart was enlarged with a to those of medullary cystic disease of the kidney. thrusting apex beat and a presystolic gallop. *Present address: Renal Disease Section, Department of Lungs were clear. Medicine, V.A. Hospital, Washington, D.C. Investigations. PCV 27 5%, WBC 7700/mm3, Reprint requests to Dr Tennant, Hartford Hospital, with a normal differential. Urinalysis; specific- Hartford, Connecticut. gravity, 1 004; 2+ protein and unremarkable sedi- Medullary cystic disease of the kidney 793 Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from ment. Radiological survey of skeletal system was clinical impression was that of renal disease consistent with renal osteodystrophy. Urine rather than adrenal and studies of adrenal func- culture from bladder and both was tion were not done. Despite control of uraemia negative. Cystoscopic examination was unre- by dialysis, the patient developed tinnitus, deaf- markable. ness and Pseudomonas septicemia and he expired The patient was treated with large quantities of on 18 January 1964. salt and fluid intravenously. There was significant Necropsy. The skin showed a brown scaly improvement in his clinical state. The blood urea appearance due to ichthyosis. Fourth toe on each nitrogen (BUN) fell from 230 to 100 mg/ 100 ml. foot was small. Heart weighed 520 g, and showed He was discharged to be followed by his private marked left ventricular hypertrophy. Lungs physician. showed basal congestion. The vertebral marrow In September 1964 he began to complain of was pale. Adrenals and parathyroids were grossly epigastric pain with nausea and was admitted to unremarkable. Thyroid was enlarged. Each Hartford Hospital on 22 November 1964 because kidney weighed 100 g and measured 7 5 x 4 cm. of vomiting. The capsules could be stripped easily, revealing On examination he was dehydrated and sallow. smooth cortical surfaces. On cut section, the Pulse, 84; BP 184/80 mmHg. The remaining phys- parenchyma was firm in consistency; the cortices ical examination was similar to that of 1963, but were atrophic. The medullary areas, especially the fundi showed changes of azotemia and hyper- in the pyramids, showed numerous smooth-walled tension. Hb 82g/lOOml, BUN 295mg/lOOml cysts which varied in size from 0X2 to 1 cm in and serum creatinine 20-7 mg/ 100 ml. The barium diameter (Fig. la). The pelves and calyces were meal showed no abnormality. unremarkable. The ureters were normal. Both The hospital course was that of chronic renal arteries were normal.

azotemia. Large volumes of saline infusions were Histology: Sections of the kidney showed Protected by copyright. given to replace urinary wastage of sodium, rang- ing 84-110mEq/l. In view of the small size of the kidneys with progressive azotaemia, the http://pmj.bmj.com/

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FIG. 1. (a) Case 1. Kidney showing diffuse scarring of FIG. 2. (a) Case 1. (b) Case 2. Shows wall of medullary cortex with numerous medullary cysts. (b) Case 2. cysts with flattened epithelial lining and increase in Kidney section showing medullary cysts. H & E, x 6. fibrous tissue between collecting tubules. H & E, x 60. 794 Satya Paul Handa and Robert Tennant Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from numerous cysts in the medulla. These were lined gravity 1-016, 3 + protein, sediment unremarkable. by low cuboidal epithelium (Fig. 2a). The adja- BUN 187mg/100ml. Subsequently she was cent collecting tubules were compressed and dis- admitted to another hospital with an acute respir- torted. There was a diffuse increase in the inter- atory infection, when she was found to be chron- stitial fibrous tissue in the medulla. The cortex ically ill with a BP 140/90 mmHg. Pulse 104/min. was markedly narrowed and was replaced by The kidneys were seen to be small on flat plate diffuse interstitial fibrous tissue. The convoluted of the abdomen, but could not be visualized in tubules were atrophic and many were encircled the IVP. There was an overall decreased density by bands of collagenized tissue. The glomeruli of the bones. She was put on a low protein diet, showed fibrous thickening of Bowman's capsule calcium lactate and amphogel. With this regimen, and many glomeruli were hyalinized (Fig. 3a). the azotaemia improved and BUN fell to 69 mg/ Many capsular spaces were dilated. There was a 100 ml in 2 months. Other laboratory data scant diffuse infiltration of lymphocytes in the presented in Table 1. Her anaemia was attributed interstitial tissue. Protein casts were present in to azotemia due to hypoplastic kidneys. The many of the tubules. There were also several clinical course remained stable and she was dis- lakes of proteinaceous material present in the charged. interstitium of the cortex (Fig. 4a). This material In November 1955, at the age of 14L she took a strongly positive PAS stain. There was no entered New Britain General Hospital complain- evidence of acute inflammatory reaction present. ing of vomiting, diarrhoea and severe anaemia. Her skin was scaly and pigmented. Pulse 120, Case 2 BP 110/190mmHg. She appeared dehydrated. In J.B., sister of R.B., was first seen in August the hospital she suffered recurrent convulsive 1953, at the age of 12 for the investigation of seizures and died a week after admission. anaemia. Hb 6-7 ml. g /100 Urinalysis; specific Protected by copyright.

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FIG. 4. (a) Case 1. (b) Case 2. Interstitial fibrosis of FIG. 3. (a) Case 1. (b) Case 2. Diffuse interstitial fibrosis cortex with proteinacious material deposited in intersti- with atrophy of tubules and fibrous thicking of glom- tium. Slight diffuse lymphocytic infiltration of stroma. erular capsules present in both cases. H & E, x 60. H & E, x 60. Medullary cystic disease of the kidney 795 Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from

Necropsy. The body was that of a small white multiple cysts present, predominantly in the girl measuring 41 ft in length and weighing 85 lb. medullary region (Fig. lb). The cysts were The heart weighed 250 g and showed moderate unilocular and smooth-walled. There was no hypertrophy of the left ventricle. The kidneys communication between cysts and pelves. They were small: right kidney 70 g and the left 90 g. measured 1-4 cm in diameter. The pelves and The capsules could be stripped with ease; the sur- ureters had pale linings and were normal except faces were slightly granular; the cortex and for slight dilatation of the right pelvis. Lungs medulla could not be differentiated. There were showed right lower lobe hemorrhagic pneumonia

TABLE 1 Laboratory data Haemato- Creat. crit or Blood Alkaline clear- Date Urine haemo- urea Calcium Phos- Sodium Potas- Chloride Carbon phos- ance globin nitrogen phorus sium dioxide phatase (ml/min) (mg/ (mg/ (mg/ (mEq/l) (mEq/1) (mEq/l) (mEq/1) 100 ml) m00ml) 100 ml) R.B. September Alb. 2+ 11-2 g/100 ml 35 9 3 5-2 - _ _ 8-2(KA) 53 1959 WBC 1 -3 HPF RBC 2-5 f July S.G. 1004 12Og/lOOml 40 9-2 4-1 - 1960 Alb. 5 mg/I00 ml

WBC 1-3 HPF Protected by copyright. June S.G. 1006 10 6 g/100 ml 42 ------_ _ 1961 Alb. 15 mg/100 ml October S.G. 1003 30% 59 8-4 4-2 - 1962 Alb. 2 + July S.G. 1004 27-5% and 230 5-6 5-5 135 5-4 100 6-0 3-4(BLU) 1963 pH 6-5 9 3 g/100 ml Alb. 2+ Motile cocci and rods 1 RBC HPF 5 WBC H September - 20-25% 87 109 - - - - - 1964 22 Nov S.G.1007 8 5 g/100 ml 295 8-8 4-7 142 6-9 112 14 11 (KA) 1.9 1964 Alb. 3 + Sugar 3 + http://pmj.bmj.com/ 7 Dec Same but no 260 9-8 6-8 130 6-2 97 19 - 1964 sugar-24 hr urinary protein output 13-1 g After dialysis 29% 44 9 3 6-2 138 5 6 103 21 - - on 13 Dec Terminally - 18% 147 7.4 - 125 7-6 - 18

J.B. (sister) on September 26, 2021 by guest. 1953 S.G.1016 6-7g/lOOml 187 ------Alb. 30 mg/100 ml January - 7g/100ml 69 7 5 2 137 4-2 105*6 17-4 - - 1954 March - - 62-5 6 5*7 141 4-2 104-8 165 - - 1954 August S.G. 1005 7g/lOOml 105 6-4 5-2 133 5.0 99-6 18-5 - - 1954 Alb. 1 + No bacteria November Same 46g/lOOml 215 70 5-4 130 5-0 77 17 - - 1955 796 Satya Paul Handa and Robert Tennant Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from

and the hilar nodes were enlarged. Three para- acquired types, have been well recognized in the thyroid glands were found and were unremark- past few years (Perkoff et al., 1951, 1958; Reyers- able. The right adrenal weighed 9 g and the left bach & Butler 1954; Whalen et al., 1961). In the 11g. usual case of hereditary nephritis, the onset is Histology. Kidneys of normal structural pat- in infancy, with proteinuria, painless haema- tern. Sections showed changes which were strik- turia and pyuria. The severity of the symptoms is ingly similar to those seen in the sibling (Figs. 2b, more pronounced in males and progressive renal 3b and 4b). The same cystic disease was present functional impairment leads to death before the in the medulla with several cysts of large size age of 30. The development of deafness, though present in the pyramids. No cyst was present of a mild type in Case 1, was similar to a common in the cortex. The cortex was thin with marked finding in hereditary nephritis. It was probably interstitial fibrosis present. Most tubules were unrelated to the underlying renal disease. atrophic and the glomeruli were hyalinized. Lakes Familial involvement in polycystic disease of of proteinaceous material were seen in the inter- the kidneys has been well documented (Dalgaard, stitial tissue. In some areas this material appeared 1963; Potter, 1961) and there is ample evidence to have its origin from rupture of over-distended (Ferguson, 1949) that the disease in adults is tubules with discharge of their contents into the inherited as an autosomal dominant trait. stroma. There was scant lymphocytic infiltration Occasional reports of familial medullary sponge present. Some arteries showed fibrous thickening kidney have also been published (Copping, 1967). of their walls, but this was not a prominant Strauss in 1962, in his review of medullary cystic feature. disease, considered a possible occurrence of this disease in siblings. Of the eighteen cases he Family history reviewed, one had a twin brother with impairment The has been reluctant for investi- family any of renal function, and the older brother of theProtected by copyright. gative search in renal disease. We could evaluate second patient had cortical changes in the renal mere historical aspects of thirty-one members in biopsy, similar to those seen in the kidneys of the four generations. There has been no loss of any patient at autopsy; the blood urea nitrogen was member of the family at a younger age and 40 mg/ 100 ml. Since then six families with this deaths in adults were either because of old age or entity have been reported (Gardner et al., 1967; diseases unrelated to the kidney. Both parents are Goldman et al., 1966; Herdman et al., 1967; New- healthy. An intravenous pyelogram done on the ton, 1964; Mongeau & Worthen, 1967). The mother of these siblings was unremarkable. Two family of five generations studied by Goldman et other siblings, both boys, age 15 and 11, are al. (1966) had eleven members afflicted with medul- living and apparently free from renal disease. lary cystic disease. The sex distribution among When possible the other members of this family those patients was four males to seven females and will be studied and reported. its transmission was assumed to be on a dominant gene basis; however, the sporadic occurrence of

Discussion this disease in sibships suggest a recessive form of http://pmj.bmj.com/ Cystic changes in the kidneys are encountered inheritance (Herdman et al., 1967; Mongeau & in a variety of anatomical disorders and patho- Worthen, 1967). logical entities. Each cystic disease is character- Systemic anatomical abnormalities are fre- ized by a relatively uniform clinical picture. quently observed in patients with polycystic There is a large number of published studies on disease of the kidneys (Potter, 1961 ; Melnick, polycystic (Dalgaard, 1963; Rall & Odel 1949; 1955) and occasionally with medullary sponge Simon & Thompson, 1955) and medullary sponge kidney (Morris et al., 1965). Hogness & Burnell kidneys (Ekstrom et al., 1959) and Strauss (1962) (1954) described four patients with medullary on September 26, 2021 by guest. and other observers (Goldman et al., 1966) postu- cystic disease of the kidney and demonstrated an late cystic disease of the medulla as a distinct association of cysts in the pancreas, stenosis of the clinical entity. Clinically this disease is character- renal arteries and in one of them a club-foot. The ized by polyuria, polydipsia, severe anaemia, presence of congenital ichthyosis and short fourth azotaemia and salt-wasting at a young age. There toes on each foot in Case 1 suggest a developmental are no significant urinary abnormalities. Radio- spectrum of anomalies. Congenital ichthyosis has logic studies usually reveal small kidneys. been agreed to be an irregularly inherited disorder The onset of renal disease at an early age in (Ellis, 1951) and endocrine, psychic and neuro- both our cases warrants comments on hereditary logical abnormalities are associated in some of renal disease. Hereditary pyelonephritis and the cases (Aquilera, 1955). The medullary cysts glomerulonephritis, histologically different from co ild be a part of this general phenomenon. Medullary cystic disease of the kidney 797 Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from However, the absence of congenital malformations males, nine females). A history of consanguinity in other reported cases excludes such a hypothesis among parents, an uncommon occurrence in and supports the view that association of develop- medullary cystic disease, was documented in three mental abnormalities may be incidental or a families. In the usual case, the onset is in infancy reflection of multiple gene abnormalities in this with hypotonic polyuria, polydipsia and progres- particular patient. sive renal function impairment with a fatal out- In the early part of this century, the explana- come in 5-10 years. tion of the development of medullary cysts was The kidneys in nephronophthisis are usually based on the theory proposed by Kampmeier contracted and scarred. Cysts are not uniformly (1923). According to that, the first primary seen in the medulla. Mongeau & Worthen (1967) generation of uriniferous tubules developing from in their review of the literature found twenty cases mesonephric mesenchyme come to lie in the with autopsy data and noted macroscopic and medullary region as the subsequent generations microscopic cysts in eight and twelve instances develop and unite with the collecting tubules. respectively. The morphological findings in the The primary or vestigeal tubules normally under- kidneys were well summarized by Ivemark, go cystic degeneration. The persistence and con- Ljungqvist & Barry (1960). The significant tinuing degeneration in the primary uriniferous patho- the logical feature was that of tortuous and lengthy tubules result in development of cystic disease. of Potter (1961) supported this as a cause of the loops Henle with occasional communicating formation of an occasional cyst in the medulla. cyst formation. The basement membrane of these Recent reports allude to the possible role of loops was enormously thickened and they postu- an inborn error of metabolism leading to func- lated that occurrence of cysts and glomerular tional and structural changes in the kidneys alterations were secondary to the defect in the loops of Henle. (Herdman et al., 1967; Mongeau & Worthen, Protected by copyright. 1967). This consideration is based upon studies The gross and microscopic appearance of the of cystic changes in the kidneys of rats experi- kidneys in both our cases are strikingly similar mentally produced by feeding them diphenylam- to those described by Strauss (1962) and others ine (Kime et al., 1962) and observations of clinical (Hogness & Burnell, 1954; Kerlan & Russell and histological similarities of Balkan endemic 1963). The typical microscopic lesions in these toxic nephropathy to those of cystic disease of cases consist of hyalinization of glomeruli, peri- the renal medulla (Hall et al., 1965). Because of glomerular fibrosis and atrophy of the tubules. the familial occurrence of cystic disease, it can On micro-dissection, cysts appear to arise from be surmised that there is a genetically common distal tubules; however no communications with enzyme defect leading to accumulation of collecting tubules are seen. Electron microscopy nephrotoxic material produced endogenously. of renal tissue from such patients demonstrates However, the sporadic occurrence in a family irregular thicking of the basement could be ascribed to exogenous membrane of nephrotoxins the cysts and dilated tubules (Goldman et al., which the body is unable to metabolize. The http://pmj.bmj.com/ nature of these toxins is unknown. 1966). The literature over the past few years reveals In common with other patients described in similarities between medullary cystic disease of the literature both siblings showed clinical the kidney and familial juvenile nephronophthisis features of anaemia and progressive azotaemia. (Mongeau & Worthen, 1967; Strauss & Som- The urinary sediments had been unremarkable. mers, 1967). Clinically both entities are seen at an Case 1 also had a clinical picture of salt-wasting early age; however cases have been reported in similar to patients described by others (five cases older children and young adults. In contrast to by Strauss, 1963; three cases, Goldman et al., on September 26, 2021 by guest. medullary cystic disease where inheritance 1966; one case, Herdman et al., 1967). Clinical demonstrates both dominant and recessive traits symptoms included polyuria, polydipsia and familial juvenile nephronophthisis is usually a muscle cramps. Throughout their clinical course, recessive trait. Von Sydow & Ranstrom (1962) their urine was hypotonic. summarized the data on fifty-one members of thirteen families (tweny-six males and twenty- five females) reported up to 1962. Histological lesions of nephronophthisis were present in thir- Acknowledgment teen instances (six males and seven at We are indebted to Dr Thomas Madden of the Depart- females) ment of Pathology of New Britain General Hospital, New necropsy and a history of renal disease was Britain, Connecticut, who furnished the material on the present in eighteen additional individuals (nine second case. 798 Satya Paul Handa and Robert Tennant Postgrad Med J: first published as 10.1136/pgmj.44.516.792 on 1 October 1968. Downloaded from

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ZIMONJIC, B. & GAON, J. (1965) Investigation of chronic SMITH, C.H. & GRAHAM, J.B. (1945) Congenital medullaryProtected by copyright. endemic nephropathy in Yugoslavia. Amer. J. Med. 39, cysts of kidneys with severe refractory anemia. Amer. J. 210. Dis. Childh. 69, 369. HERDMAN, R.C., GOOD, R.A. & VERNIER, R.L. (1967). Med- STRAUSS, M.B. (1962) Clinical and pathological aspects of ullary cystic disease in two siblings. Amer. J. Med. 43, 335. cystic disease of renal medulla; analysis of eighteen cases. HOGNESS, J.R. & BURNELL, J.M. (1954) Medullary cysts of Ann. intern. Med. 57, 373. kidneys. Arch. intern. Med. 93, 355. STRAUSS, M.B. (1963) Medullary cystic disease. Diseases of IVEMARK, B.I., LJUNGQVIST, A. & BARRY, A. (1960) Juvenile the Kidneys (Ed. by M. B. Strauss and L. G. Welt), p. 938. nephronophthisis. II. A histological and microangio- Little, Brown, Boston. graphic study. Acta paediat. scand. 49, 480. STRAUSS, M.B. & SOMMERS, S.C. (1967) Medullary cystic KAMPMEIER, O.F. (1923) Hitherto unrecognised mode of disease and familial juvenile nephronophthisis. New. origin of congenital renal cysts. Surg. Gynec. Obstet. 36, Engl. J. Med. 277, 863. 208. VON SYDOW, G. & RANSTROM, S. (1962) Familial juvenile KIME, S.W., JR, MCNAMARA, J.J., LUSE, S., FARMER, S., nephronophthisis. Acta paediat. scand. 51, 561. SILBERT, C. & BRICKER, N.S. (1962) Experimental poly- WHALEN, R.E., HUANG, S., PRESCHEL, E. & McINToSH, H.D. cystic renal disease in rats. Electron microscopy, function, (1961) Hereditary nephropathy, deafness and renal foam and susceptibility to pyelonephritis. J. Lab. clin. Med. 60, 64. cells. Amer. J. Med. 31, 171. http://pmj.bmj.com/ on September 26, 2021 by guest.