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Roentgenologic assessment of medullary cysts
Roentgenologic Assessment of Medullary Cysts Erich K. Lang, M.D.
R
ENAL CYSTIC DISEASE comprises a heterogeneous group of disorders on the basis of associated phenomena.2p3 As with other categories, the etiologic entities considered in the group of medullary cysts are attributable to various developmental, heritable, and acquired disorders united by the common denominator of cyst formation in the medulla. 218 The principal entities are : medullary cystic disease or nephronophthisis; meduilary sponge kidney; simple cysts, inflammatory or pyelogenic cysts, and cystic-necrotic tumors located in the medulla; and pyelogenic cysts resultant from medullary necrosis.* Simple cysts, inflammatory or pyelogenic cysts, and cystic-necrotic tumors located in the medulla are identical in pathophysiology and histologic appearance to their more common peer group located in the cortex. Medullary cystic disease, medullary sponge kidney, and pyelogenic cysts secondary to medullary or papillary necrosis, however, are entities specific and exclusive to the renal medulla. MEDULLARY CYSTIC DISEASE AND NEPHRONOPHTHISIS
Medullary cystic disease and nephronophthisis are probably one and the same disease.22 Even though cystic disease of the renal medulla is considered a rare entity, Mongeau and Worthen were able to collect 103 cases from the literature up to 1967. Studies on the inheritance of cystic disease of the medulla suggest a mendelian dominant pattern.9~11*22~30131 However, some cases reported in the European and American literature raise the question of a different type of genetic transmission, nongenetic developmental defect, spontaneously occurring mutation, or possibly homozygosity for a rare recessive gene.31’34
Erich K. Lang, M.D.: Professor and Chairman, Department of Radiology; Louisiana State University School of Medicine in Shreveport, Confederate Memorial Medical Center, Shreveport, La. 71130. Reprint requests should be addressed to: Erich K. Lang, M.D., Louisiana State University School of Medicine in Shreveport, P.O. Box 3932, Shreveport, La. 71130. 0 19 75 by Grune & Stratton, Inc. Seminars
in Roentgenology,
Vol.
X, No.
2 (April),
1975
Clinical Findings The disease has been reported in children, but is predominantly encountered in young adults31 The mean age established from large collected series is 23 yr. l1 However, it has been reported in patients up to the age of 68.32 Uremic medullary cystic disease has been in the limelight as a subgroup because of its distinctive clinical course. Clinically, the disease is characterized by anemia, salt wasting, and progressive azotemia.11y32 Polyuria is another common feature.22 Particularly in the younger age group, renal osteodystrophy (confirmed histologically) and secondary hyperparathyroid&m are relatively common manifestations.5~91’5*30~32The time-honored observation that renal medullary cystic disease appears to be more common in persons with red or blonde hair has been [e-emphasized recently?’ Proteinuria, hematuria, pyuria, and cylindruria are other infrequent manifestations, as is hypertension.” Calcium wasting has been observed and attributed to the same structural abnormalities in the kidney that lead to sodium wasting.’ This phenomenon is particularly noteworthy since it occurs in the presence of very high levels of parathyroid hormone, which would be expected to accelerate tubular reabsorption of calcium.5 The diagnosis is usually suggested by the clinical triad of anemia, azotemia, and salt wasting.’ A high urinary excretion of lysozyme may indicate proximal tubular dysfunction. Similarly, skeletal involvement may be suggested by increased excretion of peptide-bound hydroxyproline and glycosaminoglycans.‘O Pathologic Finditzgs Cysts 50~ to 2 cm in diameter located in the medulla and corticomedullary junction are the pathognomonic pathologic feature (Fig. 1).r13,“~ 22,30*31The multitude of cysts may cause loss of definition of the corticomedullary junction on cut section. The documentation of macroscopically visible cysts in the medulla is not necessary to establish a diagnosis of medullary cystic disease. In 50 postmortem studies, Mongeau and Worthen found macroscopic cysts in 32 patients, but in 18 only microscopic cysts could be identified.22 Ex145
cystic disease. (A) Retrograde pyelogram demonstrated the essentially normal pelvicalyceal system of Fig. 1. Medullary s relatively small left kidney. (6) The cut gross specimen reveals multiple cysts of varying size, all located in the medulla. The kidney is small by measurement and weight. (Cl Detailed photograph of the cross specimen demonstrates cortical atrophy and localizes all of the variably-sized cysts to the medulla. (Courtesy of R. Pfister, M.D., Massachusetts General Hospital, Boston.)
MEDULLARY
147
CYSTS
cept for the tendency to concentrate at the corticomedullary junction, the cysts seen in uremic medullary disease do not differ from those encountered in medullary sponge kidney.1y3S7Y11 The cysts are lined by a single layer of cuboidal epithelium.” The pathognomonic findings on microscopic examination are interstitial fibrosis, periglomerular fibrosis, and proximal tubular dilatation. 1y10Y11~22 The appearance of the glomeruli is variable: hyalinization of some glomeruli, periglomerular fibrosis, or a normal appearance. Many tubules may appear atrophied, whereas others, particularly proximal tubules, may appear hypertrophied.” The hypertrophied tubules of the medulla tend to show a characteristic tortuosity. PAS staining shows thickened hyaline basement membranes of the atrophic tubules, which may be surrounded by connective tissue mantles which stain positive for collagen.’ Electron microscopy demonstrates striking abnormalities in the basement membrane of the cysts and dilated tubules, identifying areas of irregular thickening and loss of distinct boundaries.” There is an obvious histologic resemblance to the changes seen with pyelonephritis. However, bilateral symmetrical involvement and uniform damage throughout both kidneys mitigates against this diagnosis. The microscopic picture is also very similar to that seen with endemic nephropathy occurring in the Balkans. 22 Furthermore, the bilateral occurrence, course of disease, and microscopic features indicate many parallels to the toxic nephropathies2 2129 In view of the familial nature of medullary cystic disease, one might propose toxin accumulation on the basis of an inborn metabolic error as the underlying cause.22 The pathophysiologic deficit of both medullary cystic disease and the toxic nephropathies reflect a glomerulotubular imbalance; simply stated, the filtered sodium load exceeds the reabsorptive capacity of the tubules. 3o Osteitis fibrosa has been described as a prominent histologic feature in children and adolescents.‘5p30 The intravenous urogram does not offer positive diagnostic criteria. However, documentation of relatively small kidneys devoid of calcifications, featuring a normal pelvicalyceal system, and a lack of contrast media pools in the pyramids are important observations for differentiation from adult polycystic disease, chronic pyelonephritis, and medullary sponge kidney (tubular ectasia) (Fig.
1A).273*5V22124S30 High-dosage nephrotomography has a propensity for outlining well-defined corticomedullary lucencies, suggesting the presence of medullary cysts.29>32However, renal arteriography appears to offer the most conclusive diagnostic approach for this purpose (Fig. 2). Mena et al. were able to make the presumptive diagnosis of medullary cystic disease in four of five patients on the basis of the following arteriographic criteria: (1) the cysts do not involve the outer cortex (there are no peak signs); (2) the cortical margins, as seen on the nephrographic phase, are intact and uninterrupted; (3) the cortex is thinned; (4) the kidney size is decreased; (5) interlobar and arcuate arteries are tapered and stretched over larger cysts; (6) there may be a reduction of the caliber of the main renal artery, reflecting a slight to moderate reduction of renal blood flo~.~’ Identification of an intact and uninterrupted, though thin, cortical margin on the nephrographic phase of the arteriogram relegates the cyst to a geographic location other than the outer cortex, and is therefore the single most important differential diagnostic criterion.2r The necessity for detail emphasizes the importance of technically excellent selective renal arteriograms, preferably augmented by enlargement technique. Failure of others to establish the diagnosis by arteriography in three proved and one presumptive case may be attributable to technical factors.5a9 Since macroscopic cysts need not be present, biopsy of the medullary portion of the kidney may become necessary to establish the diagnosis, despite its hazards and technical difficulty.‘T2 2 MEDULLARY
SPONGE
KIDNEY
Medullary sponge kidney of the adult and renal tubular ectasia are the same entity. The condition was first reported by Lenarduzzi in 1939, but has received attention in the English literature only in the last 15 yr.416,7,12,17,18,23,27 Initially, it was considered a very uncommon condition. However, more recent studies have established an overall incidence rate of about 0.5% of all patientsexamined by intravenous urography.25 Medullary sponge kidney is generally discovered in middle age, but has been found in young children and in the aged.4y7J2J3 A predominance of males has been emphasized in the literature.23 The association of hemihypertrophy, ipsilateral to
ERICH
K.
LANG
Fig. 2. Medullary cystic disease. (Al Selective left renal arteriogram shows splaying of interlobar arteries around a small avascular lesion in the medulla (arrows) and many other avascular lesions throughout the medulla. (6) Enlargement arteriogram of the right kidney documents that most of the cysts are located at the corticomedullary junction, and clearly demonstrates that the cortex itself is intact (arrows).
a unilateral medullary sponge kidney has been reported by several observers.6P12y23 Medullary sponge kidney has also been associated with Ehlers-Danlos syndrome and with congenital hypertrophic pyloric stenosis.6g23 Lack of evidence of genetic transmission of medullary sponge kidney has caused some authors to raise the question of whether it may, in fact, reflect more than one disease process.23
In mild cases, symptoms may be absent and the condition disclosed on intravenous urograms. Usually, however, symptoms of recurrent kidney infection, gross and microscopic hematuria, pyuria, renal pain, or ureteral colic bring this condition to the attention of the physician.41’8y23*25
Grossly and microscopically, the changes are limited to the renal pyramids. The most striking cystic involvement occurs in the apex of the pyramid. The cysts vary in size and shape, and may be lined with different types of epithelium.’ The cysts represent dilated collecting tubules and therefore open directly into the renal pelvis and papillary ducts, or interconnect with each other. The connective tissue in the involved area tends to be rich in cells and fibers. The involvement is usually bilateral.7~18 The pathophysiology of this disease is obscure. It has been postulated that the first generation of mesonephric arborization has become cystically dilated. Microdissection has revealed diffuse enlargement of collecting tubules in the papillae; however, the terminal branches are normal?’
Pathologic Findings
RoentgenFindings
Ekstrom et al. presented the classical pathologic description of medullary sponge kidney? The kidneys are normal in size or mildly enlarged.
Whereas symptomatology and clinical findings are nonspecific, the roentgen criteria are considered diagnostic.497318Contrast medium concen-
Clinical Findings
MEDULLARY
CYSTS
tration in ectatic and cystic tubules in the apex of the pyramids with calculi in this same anatomic area are the distinguishing traits of medullary sponge kidney. ‘,18 However, depending on the degree of ectasia of the medullary ducts, the urographic appearance may range from a parameatal blush with normal or enlarged pyramids to ectatic tubules manifested by contrast medium droplets, with or without concretions (Figs. 3 and 4). 25,26 That medullary sponge kidney presents with a spectrum of roentgen changes is supported by the observation that a similar variability of manifestations is seen in different calyces of the same kidney, only some of which exhibit roentgenographically pathognomonic changes.18 Palubinskas offered microscopic proof for this supposition by identifying marked ectasia of collecting tubules of the papillae, with cystlike structures
Fig. 3. Medullary sponge kidney.Note the swollen appearance of the papillae and numerous opacified small cysts in the tip of the pyramid (arrows) _
149
lined by epithelium, in a pyramid which showed on intravenous urogram merely a “sunburst” opacification and parameatal blush.26 To facilitate differentiation of a normal parameatal blush from concentration of contrast medium in ectatic tubules indicative of medullary sponge kidney, magnification radiography and linear nephrotomography have been advocated (Fig. 5).13926 Hayt et al. advocate the use of a 0.3 mm fractional focal spot and a 100 cm targetfilm distance for obtaining a 1.8 : 1 magnification, air gap technique, and par speed screens. To avoid increased parenchymal opacification of parameatal structures which compete with the documentation of ectatic tubules, standardization of the dose of contrast medium to approximately 50 ml of 50% sodium diatrizoate or equivalent is advised.13 The characteristic urographic findings permit
ERICH
K.
LANG
Fig. 4. Medullary sponge kidney. (Al The characteristic ectatic tubules filled with contrast medium in the apex of the pyramids (right arrow) establishes the diagnosis. Displacement and splaying of the superior calyceal group of the left kidney (left arrow1 suggests the presence of a spaceoccupying lesion. (61 Double contrast cyst study moved the lesion to be a solitary simple medullary cyst.
differentiation from most other entities?’ Medullary cystic disease shows cystic changes throughout the medulla of relatively small kidneys, dissimilar to the changes of medullary sponge kidney, which are limited to the tips of the pyramids. Moreover, the mode of clinical presentation is vastly different in the two conditions. The infantile and adult forms of polycystic disease are also readily distinguished from medullary sponge kid-
ney4,W4,33 as indicated in the article by Bosniak and Ambos in this Seminar.
SIMPLE
MEDULLARY
CYSTS
Simple cysts may occur in the medulla, although they are more common in the cortex. The cyst walls are thin or fibrous and are lined by low cuboidal or flattened epithelium. The presence of these usually small medullary cysts is indicated on
MEDULLARY
CYSTS
Fig. 5. Medullary sponge kidney. A parameatal blush of the papillae was notad on the intravenous urogram, and tomography with an elliptok! motion was employed to resolve its nature. Unequivocal small cysts are in evidence in the papillae and apicas of the pyramids (arrows).
the excretory urogram by a deformity of the calyceal system. Infusion nephrotomography will identify them as avascular, with a sharply outlined border against adjacent normally staining renal parenchyma. Ultrasonographic examination indicates a totally echo-free structure with a welldefined interface against adjacent parenchyma. Definitive evaluation usually calls for cyst puncture and aspiration; the latter technique should combine histochemical and cytologic examination of the aspirate with roentgenographic documentation of the cyst by double contrast study (Figs. 4B and 6).” This multidisciplinary approach permits the diagnosis of a benign renal cyst with unusually high confidence level. Moreover, the now widely available SMA-12 profile of the aspirate may yield interesting information relevant to the pathogenesis of such cysts. A vastly different composition of the cyst fluid may reflect a different phylogenetic age and a different prognosis for growth or disappearance. The aspirate from the medullary cyst documented in Fig. 4B revealed glucose 112, chloride
115, calcium 5.6, BUN 41, sodium 148, and potassium 4.7. Histologically, the cyst wall was lined by tubular epithelium with hyperplastic cells similar to the cysts described with the tuberous sclerosis complex.’ As postulated on the basis of the high glucose content, indicative of an “active membrane,” serial intravenous urograms documented progressive enlargement of this cyst.15@ Conversely, the medullary cyst documented in Fig. 6 revealed a glucose level of 22, calcium 2.2, and BUN 54. This cyst likewise had been followed by intravenous urograms for over a year, and the calyceal pattern failed to reflect increasing size but, rather, suggested regression. The low glucose level is felt to infer propensities of the cyst membrane that denote a “stationary” cyst.“J6 OTHER
MEDULLARY
CYSTIC
LESIONS
Cystic necrotic tumors may occur in the medulla.14 This is discussed by Friedenberg and Lilienfield elsewhere in this Seminar. Pyelogenic cyst or calyceal diverticulum, a
152
Fig. 6. Simple medullary cyst. Displacement and splaying of a calyx in the superior calyceal group on urograms suggested a space-occupying lesion in the medullary portion of the kidney. The double contrast cyst study shows a simple medullary cyst. Follow-up urcgrams demonstrated regression in the size of this cyst.
ERICH
K.
LANG
pathologic end-stage that may result from a variety of underlying conditions, is located close to the calyx, and usually communicates with it through a relatively narrow isthmus. Because of this, the cyst fills on intravenous urogram, opacifying best on the later films and often retaining opacification for a prolonged period because of sluggish drainage. This lesion may be congenital, or acquired following the rupture of a small cyst or abscessinto the calyx.’ A pyelogenic cyst may also occur as the end-stage of renal medullary necrosis, an avascular necrosis involving the papilla centrally (Fig. 7). Expulsion of the necrotic tissue into the calyx creates a cystlike cavity communicating with the calyx.82l9 Eventually, the cavity may epithelialize and a classic pyelogenic cyst result (Fig. 8). Rarely, a calyceal diverticulum may lose its communication to the collecting system and then present as a medullary cyst in the pyramid. The inflammatory genesis is recognized on the cyst puncture and aspiration test complex by marked elevation of the lactic acid dehydrogenase and amylase content of the aspirate.14,” A sustained rim stain and dilated rim vessels around an otherwise avascular mass during the early phase of selective arteriography suggests residual inflammatory hyperemia.
Fig. 7. Medullary necrosis. A linear tomographic cut demonstrates characteristic central excavation of the papilla (arrow).
MEDULLARY
153
CYSTS
anemia, azotemia, and salt wasting, establishes the cystic disease or diagnosis of medullary nephronophthisis. Solitary medullary cysts are attributed to many different causes. Histochemical and cytologic information derived from the aspirate of such cysts by cyst puncture and aspiration test complex may prove highly informative as to the etiology and prognosis (enlargement or disappearance) of such cysts. REFERENCES
Fig. 8. Calyceal diverticulum suggests this to be the end-stage this patient.
(arrow). Prior history of medullary necrosis in
DISCUSSION
Medullary cysts of the kidney can be divided into communicating and noncommunicating cysts. Communicating cysts are easily diagnosed by intravenous urography or retrograde pyelography. Etiologically, they reflect a potpourri of different conditions, such as cysts or abscessesthat ruptured into the calyx, and the end-stage of medullary or papillary necrosis resulting in a cavity communicating with the calyx and ultimately healing by re-epithelialization. Medullary sponge kidney (tubular ectasia) is another entity to be grouped with communicating cysts, although the cysts are much smaller. However, once again they tend to opacify on intravenous urography, which demonstrates their communication to the terminal ducts in the apices of the pyramids. Noncommunicating cysts cause problems in roentgen recognition. However, infusion nephrotomography and particularly selective renal angiography augmented by magnification, is capable of identifying the cysts, which are located exclusively in the medulla or corticomedullary junction of the kidneys. Multiplicity of the cysts and exclusive presentation in the renal medulla, together with the classical clinical triad of
1. Axelsson U, Odlund B: Cystic disease of the renal medulla and its possible relation to juvenile nephronophthisis. Acta Med Stand 183:275-280, 1968 2. Bernstein J, Kissane JM: Hereditary disorders of the kidney. I. Parenchymal defects and malformations. Perspect Pediatr Path01 1 :117-146,1973 3. Bernstein, J: The classification of renal cysts. Nephron 11:91-loo,1973 4. Butler MR, Devine HF, O’Flynn JD: Medullary sponge kidney: Review of the literature and presentation of 33 cases.J Irish Med Assoc 66:5-13,1973 5. Castleman B, McNeely BU: Case records of the Massachusetts General Hospital. N Engl J Med 282:799806,197O 6. Eisenberg RL, Pfister RC: Medullary sponge kidney associated with congenital hemihypertrophy (asymmetry). Am J Roentgen01 116:773-777,1972 7. Ekstrom T, Engfeldt B, Lagergren C, et al: Medullary Sponge Kidney. Stockholm, Alurqvist and Wiksell, 1959 8. Elkin M, Bernstein J: Cystic diseasesof the kidneyRadiologic and pathological considerations. Clin Radio1 20:65-82, 1969 9. Gardner KD
Jr: Evolution of clinical signs in adultonset cystic disease of the renal medulla. Ann Intern Med 74:47-54,197 1 10. Giselson N, Heinegard D, Holmberg CC, et al: Renal medullary cystic disease or familial juvenile nephronophthisis: A renal tubular disease. Biochemical findings in two siblings. Am J Med 48:174-184, 1970 11. Goldman SH, Walker SR, Merigan TC, et al: Hereditary occurrence of cystic disease of the renal medulla. N Engl J Med 274:984-992, 1966 12. Harrison AR, Williams JP: Medullary sponge kidney and congenital hemihypertrophy. Br J Urol 43:552-561, 1971 13. Hayt DB, Perez LA, Blatt CJ, et al: Direct magnification intravenous pyelography in the evaluation of medullary sponge kidney. Am J Roentgen01 119:701704,1973 14. Lang
EK: Coexistence of cyst and tumor in the same kidney. Radiology 101:7-16,197l 15. Lang EK: Roentgenographic assessmentof asymptomatic renal lesions. Radiology 109:257-269, 1973 16. Lang EK: Factors influencing disappearance or recurrence of renal cysts following cyst puncture and aspiration. Presentation at Radiolog Sot North Am, 1974
154 17. Lenarduzzi G: Report0 pielografrio poco commune dilatazione delle vie urinarie intrarenali. Radio1 Med (Torino) 26:346-347,1939 18. Lindvall N: Roentgenologic diagnosis of medullary sponge kidney. Acta Radiol. 51:193-206, 1959 19. Lindvall N: Renal papillary necrosis. A roentgenographic study of 155 Cases. Acta Radio1 (Suppl) 192: 1-153, 1960 20. Ljungqvist A, Victorin L, Winberg J: Atypical nephronophthisis. A clinico-pathologic study of juvenile patients without hypotonic polyuria. Acta Paediatr Stand 56: 164-172,1967
21. Mena E, Bookstein JJ, McDonald FD, et al: Angiographic findings in renal medullary cystic disease. Radiology 110:277-281,1974 22. Mongeau JG, Worthen HG: Nephronophthisis and medullary cystic disease. Am J Med 43:345-355, 1967 23. Morris RC, Yamauchi H, Palubinskas AJ, et al: Medullary sponge kidney. Am J Med 38:883-892,1965 24. Norris RF, Herman L: The pathogenesis of polycystic kidneys: Reconstruction of cystic elements in four cases.J Uro144:147-176,194l 25. Palubinskas AJ: Medullary sponge kidney. Radiology 76:911-919, 1961
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K. LANG
26. Palubinskas AJ: Renal pyramidal structure opacification in excretory urography and its relation to medullary sponge kidney. Radiology 81:963-970, 1963 27. Potter EL, Osathanondh V: Medullary sponge kidney: Two cases in young infants. J Pediatr 62:901-907, 1963 28. Rayfield EJ, McDonald FD: Red and blonde hair in renal medullary cystic disease. Arch Intern Med 130: 72-75, 1972
29. Spicer RD, Ogg CS, Saxton HM, et al: Renal medullary cystic disease. Br Med J 1:824-825, 1969 30. Strauss MB: Clinical and pathological aspects of cystic disease of the renal medulla. Ann Intern Med 57: 373-381,1962 31. Strauss MB, Sommers SC: Medullary cystic disease and familial juvenile nephronophthisis. N Engl J Med 277: 863-864,1967
32. Swenson RS, Kempson RL, Friedland GW: Cystic disease of the renal medulla in the elderly. JAMA 228: 1401-1404,1974 33. Vuthibhagdee A, Singleton EB: Infantile polycystic diseaseof the kidney. Am J Dis Child 125:167-170, 1973 34. Wrigley KA, Sherman RL, Ennis FA, et al: Progressive hereditary nephropathy. A variant of medullary cystic disease?Arch Intern Med 131:240-244, 1973
R
ENAL CYSTIC DISEASE comprises a heterogeneous group of disorders on the basis of associated phenomena.2p3 As with other categories, the etiologic entities considered in the group of medullary cysts are attributable to various developmental, heritable, and acquired disorders united by the common denominator of cyst formation in the medulla. 218 The principal entities are : medullary cystic disease or nephronophthisis; meduilary sponge kidney; simple cysts, inflammatory or pyelogenic cysts, and cystic-necrotic tumors located in the medulla; and pyelogenic cysts resultant from medullary necrosis.* Simple cysts, inflammatory or pyelogenic cysts, and cystic-necrotic tumors located in the medulla are identical in pathophysiology and histologic appearance to their more common peer group located in the cortex. Medullary cystic disease, medullary sponge kidney, and pyelogenic cysts secondary to medullary or papillary necrosis, however, are entities specific and exclusive to the renal medulla. MEDULLARY CYSTIC DISEASE AND NEPHRONOPHTHISIS
Medullary cystic disease and nephronophthisis are probably one and the same disease.22 Even though cystic disease of the renal medulla is considered a rare entity, Mongeau and Worthen were able to collect 103 cases from the literature up to 1967. Studies on the inheritance of cystic disease of the medulla suggest a mendelian dominant pattern.9~11*22~30131 However, some cases reported in the European and American literature raise the question of a different type of genetic transmission, nongenetic developmental defect, spontaneously occurring mutation, or possibly homozygosity for a rare recessive gene.31’34
Erich K. Lang, M.D.: Professor and Chairman, Department of Radiology; Louisiana State University School of Medicine in Shreveport, Confederate Memorial Medical Center, Shreveport, La. 71130. Reprint requests should be addressed to: Erich K. Lang, M.D., Louisiana State University School of Medicine in Shreveport, P.O. Box 3932, Shreveport, La. 71130. 0 19 75 by Grune & Stratton, Inc. Seminars
in Roentgenology,
Vol.
X, No.
2 (April),
1975
Clinical Findings The disease has been reported in children, but is predominantly encountered in young adults31 The mean age established from large collected series is 23 yr. l1 However, it has been reported in patients up to the age of 68.32 Uremic medullary cystic disease has been in the limelight as a subgroup because of its distinctive clinical course. Clinically, the disease is characterized by anemia, salt wasting, and progressive azotemia.11y32 Polyuria is another common feature.22 Particularly in the younger age group, renal osteodystrophy (confirmed histologically) and secondary hyperparathyroid&m are relatively common manifestations.5~91’5*30~32The time-honored observation that renal medullary cystic disease appears to be more common in persons with red or blonde hair has been [e-emphasized recently?’ Proteinuria, hematuria, pyuria, and cylindruria are other infrequent manifestations, as is hypertension.” Calcium wasting has been observed and attributed to the same structural abnormalities in the kidney that lead to sodium wasting.’ This phenomenon is particularly noteworthy since it occurs in the presence of very high levels of parathyroid hormone, which would be expected to accelerate tubular reabsorption of calcium.5 The diagnosis is usually suggested by the clinical triad of anemia, azotemia, and salt wasting.’ A high urinary excretion of lysozyme may indicate proximal tubular dysfunction. Similarly, skeletal involvement may be suggested by increased excretion of peptide-bound hydroxyproline and glycosaminoglycans.‘O Pathologic Finditzgs Cysts 50~ to 2 cm in diameter located in the medulla and corticomedullary junction are the pathognomonic pathologic feature (Fig. 1).r13,“~ 22,30*31The multitude of cysts may cause loss of definition of the corticomedullary junction on cut section. The documentation of macroscopically visible cysts in the medulla is not necessary to establish a diagnosis of medullary cystic disease. In 50 postmortem studies, Mongeau and Worthen found macroscopic cysts in 32 patients, but in 18 only microscopic cysts could be identified.22 Ex145
cystic disease. (A) Retrograde pyelogram demonstrated the essentially normal pelvicalyceal system of Fig. 1. Medullary s relatively small left kidney. (6) The cut gross specimen reveals multiple cysts of varying size, all located in the medulla. The kidney is small by measurement and weight. (Cl Detailed photograph of the cross specimen demonstrates cortical atrophy and localizes all of the variably-sized cysts to the medulla. (Courtesy of R. Pfister, M.D., Massachusetts General Hospital, Boston.)
MEDULLARY
147
CYSTS
cept for the tendency to concentrate at the corticomedullary junction, the cysts seen in uremic medullary disease do not differ from those encountered in medullary sponge kidney.1y3S7Y11 The cysts are lined by a single layer of cuboidal epithelium.” The pathognomonic findings on microscopic examination are interstitial fibrosis, periglomerular fibrosis, and proximal tubular dilatation. 1y10Y11~22 The appearance of the glomeruli is variable: hyalinization of some glomeruli, periglomerular fibrosis, or a normal appearance. Many tubules may appear atrophied, whereas others, particularly proximal tubules, may appear hypertrophied.” The hypertrophied tubules of the medulla tend to show a characteristic tortuosity. PAS staining shows thickened hyaline basement membranes of the atrophic tubules, which may be surrounded by connective tissue mantles which stain positive for collagen.’ Electron microscopy demonstrates striking abnormalities in the basement membrane of the cysts and dilated tubules, identifying areas of irregular thickening and loss of distinct boundaries.” There is an obvious histologic resemblance to the changes seen with pyelonephritis. However, bilateral symmetrical involvement and uniform damage throughout both kidneys mitigates against this diagnosis. The microscopic picture is also very similar to that seen with endemic nephropathy occurring in the Balkans. 22 Furthermore, the bilateral occurrence, course of disease, and microscopic features indicate many parallels to the toxic nephropathies2 2129 In view of the familial nature of medullary cystic disease, one might propose toxin accumulation on the basis of an inborn metabolic error as the underlying cause.22 The pathophysiologic deficit of both medullary cystic disease and the toxic nephropathies reflect a glomerulotubular imbalance; simply stated, the filtered sodium load exceeds the reabsorptive capacity of the tubules. 3o Osteitis fibrosa has been described as a prominent histologic feature in children and adolescents.‘5p30 The intravenous urogram does not offer positive diagnostic criteria. However, documentation of relatively small kidneys devoid of calcifications, featuring a normal pelvicalyceal system, and a lack of contrast media pools in the pyramids are important observations for differentiation from adult polycystic disease, chronic pyelonephritis, and medullary sponge kidney (tubular ectasia) (Fig.
1A).273*5V22124S30 High-dosage nephrotomography has a propensity for outlining well-defined corticomedullary lucencies, suggesting the presence of medullary cysts.29>32However, renal arteriography appears to offer the most conclusive diagnostic approach for this purpose (Fig. 2). Mena et al. were able to make the presumptive diagnosis of medullary cystic disease in four of five patients on the basis of the following arteriographic criteria: (1) the cysts do not involve the outer cortex (there are no peak signs); (2) the cortical margins, as seen on the nephrographic phase, are intact and uninterrupted; (3) the cortex is thinned; (4) the kidney size is decreased; (5) interlobar and arcuate arteries are tapered and stretched over larger cysts; (6) there may be a reduction of the caliber of the main renal artery, reflecting a slight to moderate reduction of renal blood flo~.~’ Identification of an intact and uninterrupted, though thin, cortical margin on the nephrographic phase of the arteriogram relegates the cyst to a geographic location other than the outer cortex, and is therefore the single most important differential diagnostic criterion.2r The necessity for detail emphasizes the importance of technically excellent selective renal arteriograms, preferably augmented by enlargement technique. Failure of others to establish the diagnosis by arteriography in three proved and one presumptive case may be attributable to technical factors.5a9 Since macroscopic cysts need not be present, biopsy of the medullary portion of the kidney may become necessary to establish the diagnosis, despite its hazards and technical difficulty.‘T2 2 MEDULLARY
SPONGE
KIDNEY
Medullary sponge kidney of the adult and renal tubular ectasia are the same entity. The condition was first reported by Lenarduzzi in 1939, but has received attention in the English literature only in the last 15 yr.416,7,12,17,18,23,27 Initially, it was considered a very uncommon condition. However, more recent studies have established an overall incidence rate of about 0.5% of all patientsexamined by intravenous urography.25 Medullary sponge kidney is generally discovered in middle age, but has been found in young children and in the aged.4y7J2J3 A predominance of males has been emphasized in the literature.23 The association of hemihypertrophy, ipsilateral to
ERICH
K.
LANG
Fig. 2. Medullary cystic disease. (Al Selective left renal arteriogram shows splaying of interlobar arteries around a small avascular lesion in the medulla (arrows) and many other avascular lesions throughout the medulla. (6) Enlargement arteriogram of the right kidney documents that most of the cysts are located at the corticomedullary junction, and clearly demonstrates that the cortex itself is intact (arrows).
a unilateral medullary sponge kidney has been reported by several observers.6P12y23 Medullary sponge kidney has also been associated with Ehlers-Danlos syndrome and with congenital hypertrophic pyloric stenosis.6g23 Lack of evidence of genetic transmission of medullary sponge kidney has caused some authors to raise the question of whether it may, in fact, reflect more than one disease process.23
In mild cases, symptoms may be absent and the condition disclosed on intravenous urograms. Usually, however, symptoms of recurrent kidney infection, gross and microscopic hematuria, pyuria, renal pain, or ureteral colic bring this condition to the attention of the physician.41’8y23*25
Grossly and microscopically, the changes are limited to the renal pyramids. The most striking cystic involvement occurs in the apex of the pyramid. The cysts vary in size and shape, and may be lined with different types of epithelium.’ The cysts represent dilated collecting tubules and therefore open directly into the renal pelvis and papillary ducts, or interconnect with each other. The connective tissue in the involved area tends to be rich in cells and fibers. The involvement is usually bilateral.7~18 The pathophysiology of this disease is obscure. It has been postulated that the first generation of mesonephric arborization has become cystically dilated. Microdissection has revealed diffuse enlargement of collecting tubules in the papillae; however, the terminal branches are normal?’
Pathologic Findings
RoentgenFindings
Ekstrom et al. presented the classical pathologic description of medullary sponge kidney? The kidneys are normal in size or mildly enlarged.
Whereas symptomatology and clinical findings are nonspecific, the roentgen criteria are considered diagnostic.497318Contrast medium concen-
Clinical Findings
MEDULLARY
CYSTS
tration in ectatic and cystic tubules in the apex of the pyramids with calculi in this same anatomic area are the distinguishing traits of medullary sponge kidney. ‘,18 However, depending on the degree of ectasia of the medullary ducts, the urographic appearance may range from a parameatal blush with normal or enlarged pyramids to ectatic tubules manifested by contrast medium droplets, with or without concretions (Figs. 3 and 4). 25,26 That medullary sponge kidney presents with a spectrum of roentgen changes is supported by the observation that a similar variability of manifestations is seen in different calyces of the same kidney, only some of which exhibit roentgenographically pathognomonic changes.18 Palubinskas offered microscopic proof for this supposition by identifying marked ectasia of collecting tubules of the papillae, with cystlike structures
Fig. 3. Medullary sponge kidney.Note the swollen appearance of the papillae and numerous opacified small cysts in the tip of the pyramid (arrows) _
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lined by epithelium, in a pyramid which showed on intravenous urogram merely a “sunburst” opacification and parameatal blush.26 To facilitate differentiation of a normal parameatal blush from concentration of contrast medium in ectatic tubules indicative of medullary sponge kidney, magnification radiography and linear nephrotomography have been advocated (Fig. 5).13926 Hayt et al. advocate the use of a 0.3 mm fractional focal spot and a 100 cm targetfilm distance for obtaining a 1.8 : 1 magnification, air gap technique, and par speed screens. To avoid increased parenchymal opacification of parameatal structures which compete with the documentation of ectatic tubules, standardization of the dose of contrast medium to approximately 50 ml of 50% sodium diatrizoate or equivalent is advised.13 The characteristic urographic findings permit
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Fig. 4. Medullary sponge kidney. (Al The characteristic ectatic tubules filled with contrast medium in the apex of the pyramids (right arrow) establishes the diagnosis. Displacement and splaying of the superior calyceal group of the left kidney (left arrow1 suggests the presence of a spaceoccupying lesion. (61 Double contrast cyst study moved the lesion to be a solitary simple medullary cyst.
differentiation from most other entities?’ Medullary cystic disease shows cystic changes throughout the medulla of relatively small kidneys, dissimilar to the changes of medullary sponge kidney, which are limited to the tips of the pyramids. Moreover, the mode of clinical presentation is vastly different in the two conditions. The infantile and adult forms of polycystic disease are also readily distinguished from medullary sponge kid-
ney4,W4,33 as indicated in the article by Bosniak and Ambos in this Seminar.
SIMPLE
MEDULLARY
CYSTS
Simple cysts may occur in the medulla, although they are more common in the cortex. The cyst walls are thin or fibrous and are lined by low cuboidal or flattened epithelium. The presence of these usually small medullary cysts is indicated on
MEDULLARY
CYSTS
Fig. 5. Medullary sponge kidney. A parameatal blush of the papillae was notad on the intravenous urogram, and tomography with an elliptok! motion was employed to resolve its nature. Unequivocal small cysts are in evidence in the papillae and apicas of the pyramids (arrows).
the excretory urogram by a deformity of the calyceal system. Infusion nephrotomography will identify them as avascular, with a sharply outlined border against adjacent normally staining renal parenchyma. Ultrasonographic examination indicates a totally echo-free structure with a welldefined interface against adjacent parenchyma. Definitive evaluation usually calls for cyst puncture and aspiration; the latter technique should combine histochemical and cytologic examination of the aspirate with roentgenographic documentation of the cyst by double contrast study (Figs. 4B and 6).” This multidisciplinary approach permits the diagnosis of a benign renal cyst with unusually high confidence level. Moreover, the now widely available SMA-12 profile of the aspirate may yield interesting information relevant to the pathogenesis of such cysts. A vastly different composition of the cyst fluid may reflect a different phylogenetic age and a different prognosis for growth or disappearance. The aspirate from the medullary cyst documented in Fig. 4B revealed glucose 112, chloride
115, calcium 5.6, BUN 41, sodium 148, and potassium 4.7. Histologically, the cyst wall was lined by tubular epithelium with hyperplastic cells similar to the cysts described with the tuberous sclerosis complex.’ As postulated on the basis of the high glucose content, indicative of an “active membrane,” serial intravenous urograms documented progressive enlargement of this cyst.15@ Conversely, the medullary cyst documented in Fig. 6 revealed a glucose level of 22, calcium 2.2, and BUN 54. This cyst likewise had been followed by intravenous urograms for over a year, and the calyceal pattern failed to reflect increasing size but, rather, suggested regression. The low glucose level is felt to infer propensities of the cyst membrane that denote a “stationary” cyst.“J6 OTHER
MEDULLARY
CYSTIC
LESIONS
Cystic necrotic tumors may occur in the medulla.14 This is discussed by Friedenberg and Lilienfield elsewhere in this Seminar. Pyelogenic cyst or calyceal diverticulum, a
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Fig. 6. Simple medullary cyst. Displacement and splaying of a calyx in the superior calyceal group on urograms suggested a space-occupying lesion in the medullary portion of the kidney. The double contrast cyst study shows a simple medullary cyst. Follow-up urcgrams demonstrated regression in the size of this cyst.
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pathologic end-stage that may result from a variety of underlying conditions, is located close to the calyx, and usually communicates with it through a relatively narrow isthmus. Because of this, the cyst fills on intravenous urogram, opacifying best on the later films and often retaining opacification for a prolonged period because of sluggish drainage. This lesion may be congenital, or acquired following the rupture of a small cyst or abscessinto the calyx.’ A pyelogenic cyst may also occur as the end-stage of renal medullary necrosis, an avascular necrosis involving the papilla centrally (Fig. 7). Expulsion of the necrotic tissue into the calyx creates a cystlike cavity communicating with the calyx.82l9 Eventually, the cavity may epithelialize and a classic pyelogenic cyst result (Fig. 8). Rarely, a calyceal diverticulum may lose its communication to the collecting system and then present as a medullary cyst in the pyramid. The inflammatory genesis is recognized on the cyst puncture and aspiration test complex by marked elevation of the lactic acid dehydrogenase and amylase content of the aspirate.14,” A sustained rim stain and dilated rim vessels around an otherwise avascular mass during the early phase of selective arteriography suggests residual inflammatory hyperemia.
Fig. 7. Medullary necrosis. A linear tomographic cut demonstrates characteristic central excavation of the papilla (arrow).
MEDULLARY
153
CYSTS
anemia, azotemia, and salt wasting, establishes the cystic disease or diagnosis of medullary nephronophthisis. Solitary medullary cysts are attributed to many different causes. Histochemical and cytologic information derived from the aspirate of such cysts by cyst puncture and aspiration test complex may prove highly informative as to the etiology and prognosis (enlargement or disappearance) of such cysts. REFERENCES
Fig. 8. Calyceal diverticulum suggests this to be the end-stage this patient.
(arrow). Prior history of medullary necrosis in
DISCUSSION
Medullary cysts of the kidney can be divided into communicating and noncommunicating cysts. Communicating cysts are easily diagnosed by intravenous urography or retrograde pyelography. Etiologically, they reflect a potpourri of different conditions, such as cysts or abscessesthat ruptured into the calyx, and the end-stage of medullary or papillary necrosis resulting in a cavity communicating with the calyx and ultimately healing by re-epithelialization. Medullary sponge kidney (tubular ectasia) is another entity to be grouped with communicating cysts, although the cysts are much smaller. However, once again they tend to opacify on intravenous urography, which demonstrates their communication to the terminal ducts in the apices of the pyramids. Noncommunicating cysts cause problems in roentgen recognition. However, infusion nephrotomography and particularly selective renal angiography augmented by magnification, is capable of identifying the cysts, which are located exclusively in the medulla or corticomedullary junction of the kidneys. Multiplicity of the cysts and exclusive presentation in the renal medulla, together with the classical clinical triad of
1. Axelsson U, Odlund B: Cystic disease of the renal medulla and its possible relation to juvenile nephronophthisis. Acta Med Stand 183:275-280, 1968 2. Bernstein J, Kissane JM: Hereditary disorders of the kidney. I. Parenchymal defects and malformations. Perspect Pediatr Path01 1 :117-146,1973 3. Bernstein, J: The classification of renal cysts. Nephron 11:91-loo,1973 4. Butler MR, Devine HF, O’Flynn JD: Medullary sponge kidney: Review of the literature and presentation of 33 cases.J Irish Med Assoc 66:5-13,1973 5. Castleman B, McNeely BU: Case records of the Massachusetts General Hospital. N Engl J Med 282:799806,197O 6. Eisenberg RL, Pfister RC: Medullary sponge kidney associated with congenital hemihypertrophy (asymmetry). Am J Roentgen01 116:773-777,1972 7. Ekstrom T, Engfeldt B, Lagergren C, et al: Medullary Sponge Kidney. Stockholm, Alurqvist and Wiksell, 1959 8. Elkin M, Bernstein J: Cystic diseasesof the kidneyRadiologic and pathological considerations. Clin Radio1 20:65-82, 1969 9. Gardner KD
Jr: Evolution of clinical signs in adultonset cystic disease of the renal medulla. Ann Intern Med 74:47-54,197 1 10. Giselson N, Heinegard D, Holmberg CC, et al: Renal medullary cystic disease or familial juvenile nephronophthisis: A renal tubular disease. Biochemical findings in two siblings. Am J Med 48:174-184, 1970 11. Goldman SH, Walker SR, Merigan TC, et al: Hereditary occurrence of cystic disease of the renal medulla. N Engl J Med 274:984-992, 1966 12. Harrison AR, Williams JP: Medullary sponge kidney and congenital hemihypertrophy. Br J Urol 43:552-561, 1971 13. Hayt DB, Perez LA, Blatt CJ, et al: Direct magnification intravenous pyelography in the evaluation of medullary sponge kidney. Am J Roentgen01 119:701704,1973 14. Lang
EK: Coexistence of cyst and tumor in the same kidney. Radiology 101:7-16,197l 15. Lang EK: Roentgenographic assessmentof asymptomatic renal lesions. Radiology 109:257-269, 1973 16. Lang EK: Factors influencing disappearance or recurrence of renal cysts following cyst puncture and aspiration. Presentation at Radiolog Sot North Am, 1974
154 17. Lenarduzzi G: Report0 pielografrio poco commune dilatazione delle vie urinarie intrarenali. Radio1 Med (Torino) 26:346-347,1939 18. Lindvall N: Roentgenologic diagnosis of medullary sponge kidney. Acta Radiol. 51:193-206, 1959 19. Lindvall N: Renal papillary necrosis. A roentgenographic study of 155 Cases. Acta Radio1 (Suppl) 192: 1-153, 1960 20. Ljungqvist A, Victorin L, Winberg J: Atypical nephronophthisis. A clinico-pathologic study of juvenile patients without hypotonic polyuria. Acta Paediatr Stand 56: 164-172,1967
21. Mena E, Bookstein JJ, McDonald FD, et al: Angiographic findings in renal medullary cystic disease. Radiology 110:277-281,1974 22. Mongeau JG, Worthen HG: Nephronophthisis and medullary cystic disease. Am J Med 43:345-355, 1967 23. Morris RC, Yamauchi H, Palubinskas AJ, et al: Medullary sponge kidney. Am J Med 38:883-892,1965 24. Norris RF, Herman L: The pathogenesis of polycystic kidneys: Reconstruction of cystic elements in four cases.J Uro144:147-176,194l 25. Palubinskas AJ: Medullary sponge kidney. Radiology 76:911-919, 1961
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26. Palubinskas AJ: Renal pyramidal structure opacification in excretory urography and its relation to medullary sponge kidney. Radiology 81:963-970, 1963 27. Potter EL, Osathanondh V: Medullary sponge kidney: Two cases in young infants. J Pediatr 62:901-907, 1963 28. Rayfield EJ, McDonald FD: Red and blonde hair in renal medullary cystic disease. Arch Intern Med 130: 72-75, 1972
29. Spicer RD, Ogg CS, Saxton HM, et al: Renal medullary cystic disease. Br Med J 1:824-825, 1969 30. Strauss MB: Clinical and pathological aspects of cystic disease of the renal medulla. Ann Intern Med 57: 373-381,1962 31. Strauss MB, Sommers SC: Medullary cystic disease and familial juvenile nephronophthisis. N Engl J Med 277: 863-864,1967
32. Swenson RS, Kempson RL, Friedland GW: Cystic disease of the renal medulla in the elderly. JAMA 228: 1401-1404,1974 33. Vuthibhagdee A, Singleton EB: Infantile polycystic diseaseof the kidney. Am J Dis Child 125:167-170, 1973 34. Wrigley KA, Sherman RL, Ennis FA, et al: Progressive hereditary nephropathy. A variant of medullary cystic disease?Arch Intern Med 131:240-244, 1973