Tuberous Sclerosis and Chronic

Renal Failure*

Potential Confusion with Polycystic Kidney Disease

DANIEL ANDERSON, M.D. and RICHARD L.

Washington, D.C.

TANNEN, M.D. t

The development of chronic renal failure in a nineteen year old girl as a result of tuberous sclerosis is described in detail. Significant features of the clinical course included the discovery of enlarged kidneys at fourteen months of age, the cutaneous and central nervous system manifestations of tuberous sclerosis in the absence of intellectual impairment, the progressive loss of renal function resulting in uremia by the mid-teens, and recurrent episodes of abdominal pain resembling peritonitis. The potential confusion between this entity and polycystic kidney disease and the means of distinguishing between the two is emphasized.

A NGIOMYOLIPOMA, the characteristic patho-

logic renal lesion of tuberous sclerosis,

has been described both as solitary and multi-

ple tumors affecting one or both kidneys; how- ever, the development of chronic renal failure

as a result of this lesion has received little at- tention. This is emphasized by the omission of

tuberous sclerosis from a recent comprehensive

review of hereditary renal disease [I]. Described herein is the clinical course in a

patieat with tuberous sclerosis whose disease progressed to chronic renal failure: the poten- tial confusion of this entity with polycystic

kidney disease is re-emphasized.

CASE HISTORY

This nineteen year old Caucasian girl (A.C., No. WRGH 135104) was seen initially at the Walter Reed General Hospital in October 1949, when she was fourteen months old because of bilateral flank masses. The urinary sediment was unremarkable but 2+ proteinuria was noted. An intravenous pyelogram disclosed bilaterally enlarged kidneys with distorted calyceal patterns and decreased func- tion on the left (Fig. 1).

The cysts in the left kidney were drained surgi- cally in December, 1949; the procedure was com-

plicated by postoperative abcess formation which required surgical drainage. In March 1950 although bilateral function was still demonstrable as deter- mined by intravenous pyelography, a similar pro- cedure was performed on the right kidney. The tis sue obtained from the left kidney was interpreted as fibrous in nature.

Grand ma1 seizures and the recognition of ade- noma sebaceum led to the additional diagnosis of tuberous sclerosis in 1952. At this time the mass in the left flank was no longer palpable, but the left kidney now showed no function on intravenous pyelograms. The blood urea nitrogen ranged be- tween 18 and 25 mg. per cent.

Over the next ten years the patient’s clinical course was relatively uncomplicated. Seizure activity subsided and anticonvulsant medication was not re- quired. The blood pressure remained within nor- mal limits except for transient elevation during 1958 and 1959 to as high as 130 to 150 mm. Hg systolic and 90 to 110 mm. Hg diastolic. Two epi- sodes of abdominal pain and fever occurred which were thought at the time to be due to urinary tract infections; however, unequivocal documentation with cultures was not obtained. None of the many quantitative urine cultures spanning the patient’s entire course revealed significant colony counts. Multiple urinalyses disclosed no significant abnor- malities of the urinary sediment, but 1 to 2+ pro-

* From the Walter Reed General Hospital and Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington, D. C. 20012. Requests for reprints should be addressed to Richard L. Tannen, M.D., c/o Department of Metabolism, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington, D. C. 20012. Manuscript received September 3, 1968.

t Present address: Department of Medicine, University of Vermont CoIlege of Medicine, Burlington, Vermont 05401.

VOL. 47, JULY 1969 163

164 Tuberous Sclerosis and Renal Failure-m/lntlPr.ron, ‘Tnnncn

Mwrer P.lp.ble

Cyst Dr.inogt

Non-functional L.Kidncy (IVP)

Seizures

Chronic Dialyris t FIG. 2. Correlation between renal function, hematocrit and clinical course.

teinuria persisted. There was no evidence of uri- nary tract obstruction on retrograde pyelography, the last examination being performed in 1961. De- spite apparent clinical well being, progressive de- terioration of renal function occurred (Fig. 2) and by October 1963 the blood urea nitrogen was 79 mg. per cent, creatinine 6.5 mg. per cent and hematocrit 23 volumes per cent.

Grand ma1 seizures recurred in July 1965. Eval- uation including a lumbar puncture, electroen- cephalogram and skull films did not disclose any abnormalities that would suggest a brain tumor but

intracranial calcification characteristic of tuberous sclerosis was observed. Dilantin@ therapy was re- sumed with excellent results.

In July 1966 the patient complained of multiple painful subcutaneous nodules over both lower ex- tremities. Koentgenograms showed multiple areas of ectopic calcification, corresponding to the nod- ules. On review of previous roentgenograms it was found that signs of hyperparathyroidism involving the hands, clavicles and skull were present as early as July 1965. Serum calcium was 9.6 mg. per cent, phosphorus 8.3 mg. per cent and alkaline phospha-

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Tuberous Sclerosis and Renal Failure-Anderson, Tannen 165

tase 85 King-Armstrong units. Slit lamp examina- tion of the eyes, kindly performed by Dr. Cheno- weth of the Department of Ophthalmology, showed calcification of the conjunctivas, which was con- firmed by biopsy. After an inadvertent brief course with 50,000 units of vitamin D daily, aluminum hy droxide therapy in an oral dose of 8 to IO gm. per day was instituted. This was followed by resolution of the leg nodules over a period of six weeks, dur- ing which time the serum phosphorus level returned to normal. In addition, the conjunctival calcifica- tion regressed. Treatment with aluminum hydrox- ide in large doses has been continued up to the present and symptoms have not recurred.

Recurrent bouts of abdominal pain constituted the most prominent feature of the patient’s course throughout 1966. The intensity of pain and the duration of these attacks were variable but occa- sionally demanded hospitalization. Most of the milder episodes were associated with tenderness over the mass in the right flank; however, the more severe ones were difficult to differentiate from an acute condition of the abdomen. A particularly se- vere and prolonged attack of pain in the left upper quadrant accompanied by nausea, vomiting and fever caused the patient’s admission in November 1966. Physical examination at the time disclosed an acutely and chronically ill young woman. Tempera- ture was IOI’F., pulse 120 per minute and blood pressure 130/90 mm. Hg. The patient was alert and intelligent. Adenoma sebaceum was prominent, but there were no other skin manifestations of tuberous sclerosis. The lungs were clear. There was no car- diomegaly but a grade 3/6 apical systolic murmur was heard. The abdomen was flat, firm and gener- ally tender, with rebound tenderness in the left up- per quadrant. A mass in the right flank was easily palpated but was not tender. No discrete mass was noted in the left flank. Rectal examination was nor- mal and stool guaiac test was negative. The white blood cell count was 13,200 per cu. mm. and the hematocrit 20.5 per cent. Urinalysis showed a few white blood cells and 2-l- proteinuria; a catheter- ized urine specimen was sterile. The blood urea ni- trogen was 200 mg. per cent and the serum amylase 138 mg. per cent. A chest film was within normal limits. Abdominal films revealed a pattern of mild ileus and multiple radiolucencies as well as diffuse calcification within the mass in the right kidney. Conservative therapy with nasogastric suction and intravenously administered fluids was instituted. On the second hospital day the hematocrit decreased to 16 per cent and 2 units of packed red blood cells were given. Thereafter recovery was uneventful. Milder episodes of pain recurred for the next four weeks, but si,nce then there have been no further bouts of abdominal pain.

The finding of intrarenal lucencies suggested the diagnosis of tuberous sclerosis of the kidney and led

VOL. 47, JULY 1969

FIG. 3. Phototnicrograpb of renal tissue specimen ob- tained at age two demonstrates interstitial infiltration by tumor. The tumor contained fatty, vascular and muscular elements (angiomyolipoma). Original magni- fication, approximately, X 75.

to review of the original pathologic specimens, ob- tained at the time of cyst puncture sixteen years be- fore. Extensive renal involvement by angiomyo- lipomas with diffuse associated cystic changes was found (Fig. 3).

Evaluation to date has revealed no evidence of tuberous sclerosis involving the lungs, liver or heart. As noted, the patient is of normal intelligence, hav- ing completed high school, and is at present attend- ing college. She has one male sibling and neither he, her parents nor any relative is known to have evidence of tuberous sclerosis.

Continuing decline in renal function associated with severe azotemia, loss of muscle mass and fea- tures of uremia resulted in her entrance into a chronic hemodialysis program in July 1967 at the age of nineteen. To date she has done well.

On two occasions, once in June 1967 before hemodialysis had been instituted and once there- after, urine concentrating ability was measured utilizing overnight dehydration and intramuscular Pitressin@ tannate in oil. In both instances, despite these stimuli to maximal concentration, urine os- molality remained 40 to 50 mOsm. per L. lower than plasma osmolality.”

COMMENTS

The basic lesions of tuberous sclerosis are hamartomatous tumors which can involve multiple organ systems including skin, brain, retina, bone, liver, heart, lung and kidney [?I.

* Recently the phenomenon of “Pitressin resistant hyposthenuria” has been noted to occur frequently in subjects with far advanced chronic renal disease. Our patient is included as part of a report dealing with this phenomenon [Z].

1 66 Tuberous Sclerosis and Renal Failure-Anderson, Il;znnen

In the kidney the tumors are angiomyolipomas containing varying degrees of fatty, muscular and vascular components. The triad of con- vulsive seizures, mental retardation and ade- noma sebaceum constitutes the classic clinical presentation of the disease but it recently has been emphasized that mental retardation oc- curs in only approximately 60 per cent of cases [4]_ The multiple potential sites of tumor location can result in extremely protean clini- cal manifestations. Several extensive reviews of tuberous sclerosis are available [?-61 and only the renal aspects of the disease are con- sidered here.

Renal angiomyolipomas have been reported in 50 to 80 per cent of the cases of tuberous sclerosis [5,7,N]; most frequently, they are mul- tiple and bilateral. Solitary renal angiomyo- lipomas also have been reported but they usually have been noted in subjects without other evidence of tuberous sclerosis.

The solitary tumors most often present with abdominal pain and sometimes shock [9] as a result of hemorrha,qe of the vascular tumor but occasionally as a silent renal mass or as pain- less hematuria. The diffuse, bilateral tumors most commonly seen with tuberous sclerosis also usually become symptomatic as a result of hemorrhage from the tumor. However, they may be asymptomatic or present as bilateral abdominal masses which are easy to confuse with polycystic disease [IO]. Surprisingly the development of chronic renal failure as a re- sult of these tumors has rarely been noted [5,6,11-161. To our knowledge this is the first case in which uremia has developed in which the course has been described extensively.

Several features of this case deserve com- ment. Abdominal masses were first noted in early infancy, yet progression to renal failure was slow over the next seventeen years. As shown in Figure 1, blood urea nitrogen and creatinine levels increased slowly and the he- matocrit decreased concomitantly as renal function deteriorated. Proteinuria was never marked, qualitative measurements usually be- ing 1 to 2+, and quantitative determinations varying from 1 to 3 ,gm. per twenty-four hours. The urinary sediment is essentially normal, although microscopic hematuria has been found during episodes of abdominal pain, as has been described in other cases of renal nngiomyolipoma [9]. Mild pyuria has been noted intermittently in our patient, but defi-

nite cultural evidence of urinary tract inlet.- tion was never found. Another interesting aspect has been the lack of hypertension, par- ticularly in the last four years when severe renal failure has been present. No evidence of a salt-losing state has been found to account for the maintenance of generally normal blood pressures.

Recurrent bouts of severe abdominal pain have constituted one of the most prominent features of the patient’s illness, particularly within the recent past. Clinically, tlie more severe episodes closely resembled acute peri- tonitis with abdominal guarding, rebound tenderness, low grade temperature elevation and low <grade leukocytosis. As previously noted, abdominal pain is the most common presenting symptom in both solitary and dif- fuse renal angiomyolipomas and the similarit) of this pain to acute peritonitis has been em- phasized frequently [9,17,18]. Apparently it is a result of hemorrhage into the tmllor and/or retroperitoneal space; the bleeding can be massive enough to lead to death from hemor- rhagic shock. Nephrectomy has been per- formed in most cases, however, conservative therapy has been successful in a few instances [9,19]. Despite seven months of recurrent ab- dominal pain this patient has now gone eighteen months without symptoms. It would seem that a trial of conservative therapy is warranted in those with diffuse bilateral dis- ease, however, such management should pro- ceed with continual awareness on the part of both the patient and the physician of the danger of hemorrhagic shock.

This patient has shown several of the classic bone and laboratory changes of secondary hy- perparathyroidism, with symptomatic meta- static calcification. There was a good response of the metastatic calcification to large doses of aluminum hydroxide.

The differentiation of renal tuberous scle- rosis from polycystic kidney disease is often difficult, and indeed this case was regarded as one of polycystic disease for several years. Similar confusion of these two entities has been reported previously and in fact some in- vestigators have described both entities in the kidneys of the same patient [20,21]. Although this is certainly possible, it seems more likely, since cystic changes are described in conjunc- tion with many renal angiomyolipomas [?,22- 251, that in these instances diffuse tuberous

Tuberous Sclerosis and Renal Failure-Anderson, Tannen 167

sclerosis with marked cystic changes was pres- ent alone.

In addition to possible presentation as bi- laterally enlarged kidneys with similar find- ings on intravenous pyelogram, polycystic dis- ease and tuberous sclerosis have several other features in common. Both can share a domi- nant inheritance pattern [4,26]. Recurrent bouts of abdominal pain are prominent in both disorders, although probably more fre- quent in tuberous sclerosis. Low grade pro- teinuria, occasional hematuria and a generally unremarkable urinary sediment are aspects common to both diseases. Hypertension is quite common in end-stage polycystic disease and it was striking by its absence in this pa- tient.

Several means exist, however, by which the two can be differentiated. The vast majority of cases of diffuse bilateral angiomyolipomas occur in people with other evidence of tuber- ous sclerosis, and a careful search for the dermatologic, retinal and neurologic mani- festations of the disease should allow a proper diagnosis in most instances.

Other than direct microscopic analysis of renal tissue, roentgenographic technics offer the most conclusive way of distinguishing be- tween the two entities. Although the intra- venous pyelogram may be identical in poly- cystic disease and tuberous sclerosis, plain films of the abdomen may show intrarenal lucencies in tuberous sclerosis due to the fatty nature of the tumors [27]. This, of course, is not seen in polycystic disease in which the cysts are filled with urine. Definitive diagnosis is offered by the use of renal arteriography, according to recent reports [8]. Renal angiomyolipomas are high vascular tumors giving a pattern of tumor staining, whereas in polycystic disease, a rela- tively avascular process, little is seen other than vessel displacement.

Insufficient data are available in the few recorded cases of renal failure and tuberous sclerosis to construct a picture of the typical clinical course of this illness; however, the natural history as outlined by our case seems to vary from that of polycystic disease. In polycystic disease two characteristic patterns have been delineated [26]. In the infantile form Ithe course is fulminant and death from renal failure usually occurs within the first few years of life. In the adult form the onset of symptoms is usually delayed until the fourth

VOL. 47. JULY 1969

decade with a moderately protracted course thereafter. Our patient’s time course was clearly different, enlarged kidneys being noted in infancy with progression to severe uremia by the mid-teens. Although both obstructive uropathy and pyelonephritis are certainly po- tential complications of renal tuberous scle- rosis, as emphasized by the case reported by Schnitzer [I(;], neither obstruction nor super- imposed pyelonephritis appeared to be re- sponsible for our patient’s progressive loss of renal function. The influence on her course of the bilateral cyst drainage with postoperative abscess formation on the left side cannot be assessed. The most likely explanation for the slow relentless loss of renal function is progres- sive renal parenchymal displacement by angio- myolipoma, a process in some ways similar to the progressive displacement of renal paren- chyma by the cysts in polycystic renal dis- ease. Extensive renal parenchymal displace- ment with angiomyolipomas does occur [8,10, 16,18,21] even though very few cases of renal failure as a result of tuberous sclerosis have been recorded.

This apparent low incidence of renal failure might seem surprising in view of the 50 to 80 per cent incidence of renal tumors in tuberous sclerosis. One possible explanation might be that patients usually die of some other com- plication of the disease before renal failure supervenes. Indeed, it has been estimated that 75 per cent of the patients afflicted with this illness die before the age of twenty 1161. These figures are probably old and drawn from series of institutionalized patients, but a review of the Armed Forces Institute of Pathology files dating from 1946 to the present seemed to con- firm Ithem. Of the eighteen cases of tuberous sclerosis found at postmortem, 78 per cent of the patients died by the age of twenty-five, and eight of the nine patients with renal tumors died before the age of twenty-five of causes other than uremia. On the other hand a num- ber of patients with well documented bilateral renal involvement have been reported in the third to fifth decades with either mild or no impairment of renal function [8,20,28,29]; we have recently seen one such patient at Walter Reed Army Medical Center. Whether these will progress to renal failure remains to be de- termined. These questions will be resolved by awareness of chronic renal failure as a po- tential complication of tuberous sclerosis, and

168 Tuberous Sclerosis and Renal Failure--Anderson, ‘~nnnen

a search for this entity in patients with a diag- noses of polytystic renal disease.

ADDENDUM

This patient recently died after doing well on chronic hemodialysis therapy for twenty- one months. A massive renal hemorrhage oc- curred as a complication of vigorous treatment with heparin in an attempt to prevent recur- rent clotting of a shunt. A nephrectomy was performed because of persistent bleeding; how- ever, hemorrhage continued and in conjunc- tion with other complications ultimately re- sulted in her death. Pathologic examination of both kidneys revealed extensive displacement of renal parenchyma with angiomyolipomas.

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