Cystic Kidneys: An Enigma Evolves

IN-DEPTH REVIEW

Cystic Kidneys: An Enigma Evolves Kenneth D. Gardner, Jr, MD, and Andrew P. Evan, PhD

I

N 1969 an unsigned editorial appeared in the New England Journal of Medicine. I It was entitled , " The Enigma of Familial Polycystic Kidneys ." It was written , he subsequently told us , by the late Maurice B. Strauss . In that editorial Strauss reaffirmed a then prevailing sentiment of the pathogenesis of adult polycystic kidney disease (APKD): " ... nothing certain is known." In 1984 it still may be that nothing certain is known. However, during the 15 years since Strauss editorialized, substantial contributions have been made to our understanding of the prevalence, the pathogenesis, and the clinical peculiarities of APKD in specific and renal cystic disease (ReD) in general. It is now evident that ReD , primarily APKD , accounts for 10% to 12 %2.3 of all end-stage kidney disease. That figure implies that APKD is responsible for the presence of some 8,000 patients in renal replacement programs across our country. The cost of their care obligates in excess of $200 million per annum, the equivalent of almost $1 from each man , woman , and child in the United States . From their experience in Minnesota , Iglesias and associates estimate that one new case of APKD appears among every 36,000 persons annually, a rate that extrapolates to thousands of newly diagnosed cases each year.4 Given that APKD occurs once in every 1,250 live births, the disorder is more common than sickle cell anemia, cystic fibrosis, Huntington's chorea, and hemophilia. 5 Prevalence, the fact that costs of treatment are mounting , and the fact that third parties appear increasingly reticent to meet them 6 make it imperative that efforts devoted to the prevention, arrest , or control of renal cystic disorders be intensified. No longer merited are the disdainful and fatalistic attitudes with which these disorders have been regarded by some, perhaps because the more common of these diseases often are inherited, are of unknown cause(s), and have no specific tieatment or cure. This review selectively examines recent contributions to the field of ReO in light of their relevance to the diagnosis and treatment of patients. Specific entities are emphasized where appropriAmerican Journal of Kidney Diseases, Vol III, No 6, May 1984

ate. The review begins with brief overviews of the newer techniques for diagnosis of ReD and of models that are enabling ReD to be studied in the laboratory. Discussions follow concerning renal cysts and infection, the acquisition of ReD, and the association of ReD with neoplasia. TECHNIQUES IN THE DIAGNOSIS OF RCD

Prior to 1969, the diagnosis of ReD depended upon four criteria: the positive family history, the discovery of palpable kidneys , the demonstration of advancing azotemia, and the disclosure of renal cysts by intravenous (IV) urography or retrograde pyelography.7 Sonography 8' IO and computer tomography (CT) 1112 have supplanted the latter techniques because of their superior powers of resolution. They can detect cysts down to 0.3 to 0.5 cm in size,1112 and their efficacy does not depend upon the location of cysts in the renal parenchyma. Gray-scale ultrasonography is the preferred screening technique-it is noninvasive, relatively inexpensive, rapid, and reliable . 8 CT scanning is reserved for confirmatory studies or cases in which tumor is suspected. 1112 By sonography and CT scanning, APKD and probably other RCD now can be detected during the early decades of life. 13 At these ages there is still time for effective genetic counseling. The techniques offer greater diagnostic security in the selection of living related donors in families with heritable disease. Often asked, but currently unanswered , are questions of whether, and at what age, negative sonographic and scanning studies can assure that progressive RCD will not develop . To answer these questions we first must know that if cyst development is going to appear, it will always do so From the Department of Medicine, University of New Mexico School of Medicine, Albuquerque; and the Department of Anatomy, Indiana University School of Medicine, Indianapolis. Read in part before the annual meeting of the American Academy of Pediatrics Section on Urology, San Francisco, Calif, October 22, 1983. Address reprint requests to K. D. Gardner, Jr, MD, Departmelll of Medicine. University of New Mexico School of Medicine. Albuquerque, NM 87131. © 1984 by The National Kidn ey Foundation, In c. 02 72-6386/84/060403-11 $03.00/0

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before a specific age. As yet we are not certain of this fact. Caution must be exercised when sonography and scanning fail to disclose renal cysts, especially in the under-30-years-old age group. Present opinion dictates that negative studies in the individual over 30 years old, and almost certainly over 40 years old, mean that APKD will not develop. But this remains as opinion, not fact. MODELS OF ReD

A growing number of models of RCD have been identified. 14 They include both heritable and induced forms. Heritable RCD has been described in rats,15 mice,16 kittens,17 Spring-bok,18 and monkeys. 19 In most of these reports, morphology but not function is detailed . RCD can be induced in rats by the feeding of various cystogenic chemicals, the most popular of which have proven to be antioxidants . 20 Animal models, while sometimes challenged as to their suitability, nonetheless have proven their value in advancing our understanding of RCD. They have demonstrated the susceptibility of the cystic kidney to infection .21 They have given rise to the hypothesis that a circulating cystogenic metabolite may be responsible for some forms of RCD .22 They have shown that RCD can be induced in kidneys that are not genetically predisposed to cyst formation. 23 They have recalled attention to the fact that abnormal cell growth accompanies several forms of human renal cystic disease. 24.25 One model evidences abnormalities in basement membrane composition, a defect that is under current consideration as the lesion primarily responsible for cyst formation in the human kidney. 20 In the study of RCD , models have proven their efficacy. INFECTION AND RCD

In 1957, Thomas et al found that' rats fed the antioxidant diphenylamine developed renal cystS. 23 Kime et al used the model 5 years later to demonstrate that in the laboratory the cystic kidney has an increased susceptibility to infection. 21 In 1975 Werder and co-workers described a fascinating laboratory phenomenon. They reported that the incidence of heritable RCD could be increased from 0 .007 % to 70 % if germ-free CFWw mice were reared in conventional rather than sterile surroundings. 26 Subsequently we have found that chemically induced RCD also can be

enhanced by the conventional rather than the germ-free environmentY Contamination of germfree rats during feeding of the cystogen accelerates renal cyst formation; a feeding period that had required weeks becomes a matter of days. Experimental evidence, therefore, not only highlights the relative ease with which cystic kidneys become infected but also suggests that bacteria may play a role in the formation or enlargement of cysts. Infection of the urinary tract is common among patients with RCD, but the incidence with which cystic kidneys per se become infected is not known. Dalgaard noted that virtually all APKD patients develop pyuria and bacteriuria within 20 years of the onset of symptomatic disease. 28 Sweet and Keane recorded the appearance of symptomatic urinary tract infections in 8 of 24 APKD patients observed for a 42-month interval . 29 (Significantly, five of the eight patients went on to develop perinephric abscesses.) Oppenheimer recorded urinary tract infection among 30 of his 60 APKD patients. 30 De Bono and Evans found it in 35 % of their 65 patients. 31 Therefore, data indicate that infection at least of the lower urinary tract is present at anyone time in 30 % to 50 % of patients with APKD and perhaps ultimately in all. The possibility that infection hastens the decline of renal function is uncertain . Franz and Reubi think not, although in analyzing their data they distinguished between long-term recurring infections and single, one, or short-term recurring infections. 32 They noted that creatinine clearance declined at similar rates between the two groups, which consisted of 15 and 14 patients, respectively. They did not separate and compare renal function simply in infected versus noninfected individuals. Two fragments of evidence favor the possibility that infection could hasten the expression of renal failure in APKD. As mentioned, contamination enhances heritable and acquired RCD in germ-free rodents. 2627 And, bacteria can be grown from cyst fluid aspirates of extirpated polycystic kidneys. Because renal failure evolves slowly in RCD, only carefully controlled long-term studies can establish what , if any, the relationship might be among infection, cyst formation , and renal failure. Clinically the infected polycystic patient is a time bomb that is ticking. Several reports document perinephric abscess, sepsis , and even death among APKD patients with previous lower

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CYSTIC KIDNEYS

urinary tract infections. 29.3335 The occurrence of these complications necessitates consideration of when and how to treat the infected polycystic patient. There are subtopics to the issue. One deals with asymptomatic infection in cysts of the polycystic kidney. The literature, in spite of relatively numerous reports, contains virtually no information on the frequency with which bacteria can be grown from cyst fluid aspirates. Cultures from ten cysts in the kidney described by Schwab et al were negative. 36 Rothermel et al grew Escherichia coli from cyst aspirate obtained at surgery.33 In our laboratory, we have obtained positive cultures in 8 of 69 cysts from the polycystic kidneys of four patients (personal observation). Evidently, the cystic kidney, sometimes at least, can harbor infection in clinical silence. The second SUbtopic spotlights the fact that different kinds of cysts are present in the polycystic kidney. 3738 Analyses of cyst fluid have disclosed two groups. One group of cysts has fluid that contains solute concentrations approximating those of plasma-the proximal cysts. The other group of cysts has fluid containing solute concentrations similar to those in the distal nephron, eg, low sodium, high creatinine, and high hydrogen ion concentrations. These are the distal cysts. Schwab et al have shown a clinical phenomenon relevant to the distinction. 36 High concentrations of clindamycin were achieved in distal but not in proximal cysts. Gentamycin concentrations were low in cysts of both types. These authors suggest that it is the lipid-soluble antibiotics with relatively alkaline pKas that may be useful in the treatment of infected renal cysts. Muther and Bennett found that in addition to gentamycin the concentrations of tobramycin, cephapirin, and tricarcillin were low or nonexistent in cyst fluid from polycystic kidneys. 39 In their study, measurable concentrations of antibiotics were absent from 30 of 31 distal cysts but present in 68 of 70 proximal cysts. Whether cyst fluid pH influences bacterial viability and growth remains to be shown. It may be that antibiotic cures of infected cysts are more often apparent than real; that is, systemic infection is cured, local infection is not. Consequently, even the patient who responds to initial antibiotic therapy must be closely followed for evidence of relapse. It occurs. 34

Persisting or recurring cyst infection may be difficult to diagnose. Pyuria, bacteriuria, pain, fever, and rapidly changing renal contours are helpful signs when present. Several reports laud the gallium scan as a technique of value in the diagnosis of new or persisting cyst infections. 29.33 Cases that are medically nonresponsive require surgical intervention. 2933'35 Infection accounts for the need to operate in about 15 % of APKD patients who must undergo surgery.34 Surgical intervention because of infection is required in about 3 % to 4 % of all patients with APKD. 34 In summary, recent efforts document or confirm five aspects of infection in RCD: (1) Infection is important as a complication of, if not a contributor to, cyst formation in the polycystic kidney. (2) Lower tract infection is a harbinger of upper tract disease. (3) Complacency is unwarranted when antibiotics achieve an apparent clinical "cure" of upper tract infection. (4) The gallium scan has proven efficacious in confirming diagnosis. (5) Surgical intervention is the preferred course of action when treating recalcitrant upper tract infections. ACQUIRED RCD

That RCD can be induced in animals has been an accepted fact for more than a quarter century. 23 Only more recently, however, has it emerged that RCD can be acquired by humans. Three examples (two curious and one increasingly significant) can be cited: (1) Simple (retention) cysts are common in the elderly but rare in the infant. 40 They are acquired during the process of aging. (2) Longterm lithium therapy in humans is associated with renal cyst development,41 a lesion rarely reported since the nephrotoxicity of lithium therapy has been recognized. (3) Patients on long-term hemodialysis may develop renal cysts. 4250 It is this lesion that must be of increasing clinical concern. In 1977 Dunnill and co-workers reported that kidneys from 14 of 30 patients on hemodialysis were cystic. 42 The significance of their report rests in the fact that none of these patients had demonstrable RCD when they started dialysis. By the end of 1981 eight additional reports had appeared. These documented the appearance of cysts in the kidneys of 8 % to 95 % of dialysis populations that ranged in size from 15 to 80 patients. Data from these studies are summarized in Table 1. They indicate that among a total reported population of

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Table 1. Study Dunnill et al 42 Elliot et al 43 Bansal et al 44 Fayemi and Ali4s Krempein and Ritz46 Hughson et al 47 Ishikawa et al 48

Mirahmadi and Viziri 49 Feiner et also Total

Reports of Acquired Renal Cystic Disease Year

Patients

Cysts

Tumors

1977 1977 1978 1979 1980 1980 1980 1980 1981

30 18 60 80 22 66 52 32 15 375

14 5 5 24 21 20 23 15 5 132

6*

8* 4 9 4t 0 2* 33

*One adenocarcinoma. tThree adenocarcinomas.

375 hemodialysis patients , renal cysts have been documented in 132 , an overall incidence rate of 35%. The development of cysts appears to be related to the duration of hemodialysis. Cysts are rare among individuals dialyzed for less than 1 year and common among those dialyzed for more than 3 years.4248 Their cause is unknown. Because of the evidence cited previously that infection may predispose to or accelerate cyst development and the fact that infection of the urinary tract is common in the dialysis population ,5152 bacteria may playa role . The possibility is speculative. Crocker and associates have wondered whether a cystogenic substance, leached from dialysis tubing and analagous in action to the chemicals cystogenic for rats, might be responsible . They report tubular ectasia, in their opinion a forerunner of cyst formation, in the kidneys of rats chronically fed a concentrated eluate of fluid pumped through previously unused dialysis tubing . 53 One group of investigators is skeptical that hemodialysis is involved in the pathogenesis of renal cysts . Bommer and co-workers examined cyst formation among three groups of patients with terminal renal failure. 54 Thirteen had never been dialyzed; 14 were on maintenance dialysis; 4 had undergone transplantation after hemodialysis. Cysts were found in the native kidneys of 6, 11, and 3 patients, respectively. Bommer et al concluded that cyst formation cannot directly result from the dialysis procedure. Had these investigators defined acquired RCD as an entity involving both kidneys with multiple cysts , rather than as few as I to 3 cysts in either kidney, their data might have led them to a different conclusion. Of the 18 patients in their series

who had received hemodialysis at some time, 5 had multiple, bilateral cysts in their native kidneys (28%) . Of 13 patients never dialyzed , none had multiple , bilateral cysts . This difference in incidence is significant at the P = 0 .04 level. The same level of significance is achieved if the transplanted patients are excluded: 4 with multiple cysts among 14 hemodialyzed versus zero of 13 never dialyzed. It remains to be shown, therefore, that hemodialysis does not induce extensive cyst formation in the native kidneys of long-term hemodialysis patients . Geographic as well as hemodialytic factors may playa role in the acquisition of cysts by dialysis patients. In Japan , Ishikawa et al found cysts in 23 of 52 patients (in 79 % of patients who had been hemodialyzed for more than 3 years).48 In Illinois, Bansal and co-workers could find cysts in only 5 of 60 hemodialyzed males,44 a difference in incidence that is lower than the Japanese experience to a highly significant degree (P < 0.0001). Perhaps it is the type of equipment rather than geographic differences that is involved , but in this regard , published data are insufficient at present to permit a conclusion. Acquired RCD has not been described among chronic ambulatory peritoneal dialysis patients. If present, it does not revert after transplantation. 46 It has not appeared in transplanted kidneys. If hemodialysis alone is responsible for acquired RCD and if the data reported to date are representative , over 20,000 American hemodialysis patients have acquired RCD-a veritable epidemic! However, the lesion is not generally recognized to be so prevalent. One only can wonder where it has been. We will reflect on this question later. Whatever its frequency, acquired RCD in the he-

CYSTIC KIDNEYS

modialysis population is a clinically relevant lesion. Acquired cysts are the site of oxalate deposition. The cysts spontaneously rupture and bleed. 54 Surgical intervention has been required. Deaths are reported. Whether these cysts can harbor infection remains to be shown . As is discussed in the following text , they are associated with renal neoplasia. Dialysis personnel should be aware of the entity. Acquired RCD must be considered during the evaluation of any or all of the following symptoms and signs in a chronic dialysis patient: pain, flank or ureteral; gross hematuria , especially recurrent or of recent onset; persisting fever; nephrocalcinosis; and flank masses , renal enlargement, or a change in kidney shape. The fact that neoplastic changes occur in the setting of acquired RCD (Table I) brings us to the last of our topics to be reviewed . NEOPLASIA AND RCD

Neoplasia was among the pathogenetic mechanisms once considered for RCD: If tubular cell growth should outstrip its blood supply, central necrosis could occur and cystic lesions could form in the susceptible kidney. In the early 1940s the idea was laid to rest for lack of evidence. 55 During the 1970s scattered reports appeared that mentioned but did not stress epithelial proliferation in RCD,2256 usually in models. Publications from our laboratory were among them. 5758 We argued that epithelial hyperplasia partially obstructs tubules, restricts outflow , and causes intralumenal pressures to rise, thereby resulting in cystic deformity of the tubulesY·59 When in 1977 Dunnill et al reported the presence of neoplastic growths in 6 of the 14 cystic kidneys in their series,42 bells rang and a search for epithelial proliferation among other forms of RCD was begun. It now is evident that focal proliferation of tubular epithelial cells characterizes heritable , acquired, and induced RCD in animals and in humans.255659 For clinicians, consideration of its occurrence in APKD24 and in acquired RCD4250 is especially relevant: clinicians need to be concerned over a possibility that foci of proliferating cells in the cystic kidney are pre neoplastic . Reports of epithelial proliferation and tumors in association with APKD extend back to the late 1800s. 60 61 Hyperplasia and micropolyps are not invariably found even when they are searched for

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intentionally. 6263 Milutinovic and Agodoa found hyperplasia in a nephrectomy specimen but not in 14 percutaneous renal biopsy specimens,63 either because hyperplasia was not there or because the tissue delivered was inadequately representative of cyst walls and tubules . It is our opinion that focal cellular hyperplasia is a relatively common abnormality in APKD.24 Efforts to document its prevalence in and among polycystic kidneys face an ominous task, analagous to searching for the needle in a haystack. The polycystic kidney is huge. Cellular hyperplasia is focal and only apparent on microscopic examination. To find it and to reliably establish its frequency and location within a single kidney requires a meticulous and methodical search, something not often done by examining pathologists . Large 61 and metastatic tumors, on the other hand, are more readily apparent as a result of either local symptoms or, in cases of distant metastases, the search to locate a primary lesion. As mentioned, epithelial hyperplasia is relatively widespread in APKD .24 At first glance, to judge from published reports, benign and malignant tumors are not. 63-67 The association is so rarely encountered that authors are inspired to expand their case reports with a review of the literature. In 1977 Tan et al reported one case and traced 19 more . 64 That same year Regan et al were able to find reports of 28 cases and to this total added two of their own. 65 In 1980, Ng and Suki added a case report to a total of 49 that they gleaned from the literature. 66 They noted that the frequency of reported cases of renal neoplasm in APKD is increasing. Not all workers agree that APKD is associated with an increased risk of renal malignancy.68 The issue is further complicated by an admixture, especially in earlier literature, of patients with APKD and von Hippel Lindau disease, disorders that are pathologically different. 666970 What brings the possibility that APKD is a premalignant state 7l into focus is the fact that seven case reports describe bilateral renal cell carcinoma. 72 The incidence of bilateral renal carcinoma in APKD is 4 to 14 times greater than is considered to be the case in kidneys without cystic change. 66 Presently, there seems to be no more suitable explanation for this difference than the possibility that one or more of the foci of hyperplastic epithelial cells, which stud cyst walls and impinge on

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Table 2. Frequency of Renal Adenocarcinomas Among Patients Receiving Dialysis Authors

No. of Patients

Slifkin et al 7s Sutherland et al 76 Herr et al 77 Lindner et al 7s

712 88 499 151 1,450

Total

Fig. 1. Scanning electron microscopic view of a cyst wall in human acquired RCD. Hyperplasia and polypoid overgrowth (arrows) of the epithelium that lines the cyst wall are evident. Kidney was removed following spontaneous rupture of cyst with resulting perinephric hematoma. (x 100)

tubular lumens in the polycystic kidney, 24 undergo malignant change. A somewhat different body of information is accumulating regarding neoplasia and malignancy in acquired RCD. In models, hyperplasia of renal tubular cells is present before and after cysts form. 58 Cysts are never found before hyperplasia appears. It is not so easy to ascertain the sequence of epithelial hyperplasia and cyst development in acquired human disease. Hyperplasia occurs 47 (Fig. 1). That a relationship exists appears unequivocal. Tumors, benign and malignant, have been encountered in 33 of 375 (8.8 %) chronic dialysis patients (Table 1). All tumors are found in cystic kidneys. No tumors are described in kidneys that are not cystic. Stated differently, 33 of 132 (25 %) patients with acquired RCD have had renal tumors! In 6 of the 132, or 4.5 %, the tumors have been adenocarcinomas. The frequency of neoplastic change in acquired RCD stands in contrast to the frequencies with which renal cysts and renal tumors exist in other settings. Emmett and associates found tumors and cysts coexisting in 10 of 1,007 kidneys in which either renal cyst or renal tumor qualified the kidney for study. 73 They found tumors in 2.3 % of 428 kidneys in which cysts were present. In the chronic dialysis population (Table 1), the reported association of tumors and cysts is nine times as great. In the setting of renal failure (serum creatinine greater than 2.5 mg/dL), Matas et al noted two

Patients With Renal Adenoca

2

1 5

instances of renal tumor among 646 patients, an incidence of 0.3 %.74 Tumors have been found in 8.8% of chronic dialysis patients (Table 1). According to these figures, the occurrence of benign and malignant renal tumors, therefore, is 29 times more common among the dialysis population than among the azotemic population in general. When subjected to statistical analyses, the difference in the occurrence rates of renal neoplasia in the two populations (Table 1 versus Matas et aF4) is significant to below the 0.03 level. Thus, it can be concluded that tumors occur in the setting of acquired RCD at a significantly increased rate. The same may be said for malignancy. Adenocarcinoma of the kidney was found in 6 of the 375 hemodialysis patients surveyed for acquired RCD. Table 2 lists four additional studies that focused on malignancy in dialysis patients rather than on acquired RCD. Of 1,450 patients, 5 had renal adenocarcinoma. Combining data from Tables 1 and 2, renal adenocarcinomas are described in 11 of 1,825 (0.6%) chronic dialysis patients, an incidence that is more than fourfold above that in the general population. 79 Table 3 compares the frequency at which adenocarcinoma of the kidney has been found among various specified groups of patients or kidneys, based on recent reports in the literature. In the studies surveyed, renal adenocarcinoma is no Table 3. Occurrence of Renal Adenocarcinomas Among Specified Groups of Patients or Kidneys Group

General population Azotemic population Dialysis population Kidneys with cysts Dialysis population with ARCD

Occurrence per 1,000

1.3

Reference

Lakey79

1.5 6.0 22.8*

Matas et al 74 Tables 1 and 2 Emmett et al 73

45.5*

Table 1

*Significantly greater 90 than all but immediately preceding value; P < 0.005.

CYSTIC KIDNEYS

more prevalent among the azotemic population than among the population in general. It is, however, four times as common among dialysis patients, sixteen times as common in cystic kidneys, and over 30 times as common in the dialysis population with acquired RCD (Table 3). The implications of these data are several. One, they provide justification to consider acquired RCD as a premalignant lesion. Two, they raise the question of whether the chronic dialysis population should not be surveyed in an effort to detect adenocarcinoma of the kidney. Three, they suggest that something related to hemodialysis, perhaps the procedure itself, perhaps the post-terminal renal aging that accompanies it, provokes renal malignancy. The possibility that both APKD and acquired renal cystic disease are premalignant lesions has been suggested before.7\.80 It can be supported by animal data. Streptozotocin 81 (Fig. 2) and cisplatinum 82 each provoke cystic disease and tumors in the kidneys of rats. In other models, epithelial hyperplasia, micropolyps, and cysts have been described. 2125 The increased incidence of bilateral renal adenocarcinomas in APKD72 and the increased incidence of adenocarcinoma in kidneys with acquired cystic disease strengthen the argument. In terms of a survey, two issues can be examined. One deals with the how-to, the second with cost-effectiveness. Given that tumors are found only in cystic kidneys (Table 1), the logical first step in a survey would be to establish the presence or absence of acquired RCD. Gray-scale ul-

Fig. 2. Hyperplastic proximal tubular epithelium and micropolyps (arrows) in the kidney of a rat treated with streptozotocin (scanning electron microscopy; x 300).

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trasonography has proven suitable for this purpose. 83 The ability of the CT scan to detect intracystic tumors also has been established,8485 making it, together with its greater cost, the technique of second choice to be used in searching cystic kidneys for tumor. At a list price of $180 per study, an ultrasonographic survey of the chronic dialysis population would cost some $12.6 million, less if the perstudy cost were negotiated downward. Presuming that cysts would be found in 35 % of the patients surveyed (Table 1), and setting the cost of a CT scan at $400 per study, an additional $9.8 million would be required to further evaluate those individuals with cystic kidneys. Given an incidence rate of 4.5% among kidneys with cysts (Table 1), renal adenocarcinoma could be detected among the chronic dialysis population at a cost of $20.8 thousand per case. Whether a survey is cost effective at this rate is a matter for debate. Twenty-one thousand dollars is a large sum of money, but it is the cost of only one year on dialysis. 20 The rates of neoplasia and acquired RCD that are shown in Tables 1 and 2 are impressive-so impressive, in fact, that one must ask where all of these cases have been. Most dialysis centers do not report acquired RCD in one of every three patients, or renal adenocarcinoma in 1 of every 63 hemodialysis patients. Anyone of several explanations are possible. First, regarding the incidence of acquired RCD, it may be that the data are selective-a possibility that seems unlikely. Most, but certainly not all, of the reports listed in Table 1 surveyed general, asymptomatic chronic dialysis populations (eg, Ishikawa et a1 48 ) with striking results. Furthermore, Levine et ai, in a study inspired only by knowledge that acquired RCD occurs in chronic dialysis patients, screened all of their 30 patients. 86 They found cysts in 13. Evidently one has but to look for the lesion and it can be found. A second possibility to explain an "epidemic" of acquired RCD has been alluded to earlier. Environmental factors, in conjunction with hemodialysis, may be involved. Many centers in the United States do not see acquired RCD because, perhaps, they are in the "right" place or use the "right" dialysis equipment. A third possibility is that acquired RCD (and its consequence) is a new entity and one that is growing in prevalence. Before this possibility can be established, more data

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STIMULUS "X" (i nherited)

~

(acqui red)

V

EPITHELIAL HYPERPLASIA

II.

I I I.

STIMULUS "Y"

PARTIAL OBSTRUCTION

TUMOR

V IV.

CYST FORMATION

BENIGN

MALIGNANT

Fig. 3. A conjectural scheme to explain the association of cyst with tumor in induced, acquired, and heritable RCD. An acquired (environmental)23.57·58 or inherited (inborn error of metabollsm)22 cystogen stimulates the growth of renal tubular epithelium, accounting for the presence of epithelial hyperplasia and micropolyps in induced,24.57·58 acquired,42.45·48.5o and inheritedI8.24.6o RCD. When strategically located, hyperplastic foci partially obstruct functioning nephrons, intralumenal hydrostatic pressures rise, and tubules dilate as a consequence.20.58.59.91.82 If the hyperplastic response persists, micropolyps grow to present as adenomas42-48.5o.6o or adenocarcinomas. 44.45.47.48.50 Abnormal basement membrane may be a product of proliferating cells. 22

are needed. To the extent that kidneys , not patients , are surveyed, the incidence rates of neoplasia and of malignancy could be biased upward. It seems unlikely, however, that selection bias is solely responsible for the data summarized in Table 1. Most patients were surveyed because they were on dialysis and not because they presented with signs of benign or malignant neoplasia of their kidneys. A scheme uniting the observations in models and in humans to explain why cysts and tumors are found in the same kidneys with an increased frequency is presented in Fig. 3. Within any kidney in which they appear, cysts and tumors are not invariably found at identical locations. 73 .86 Rapidity of cell growth and location along the nephron or collecting duct may determine whether or not tumor and cyst appear in the same tubule. 24.58.59.91 At the bedside, malignancy in acquired renal disease may show itself in one or more of several ways : hematuria , usually gross and of acute onset ; weight loss; otherwise unexplained fever; flank pain; enlarging flank mass (kidney); changing renal contours; or the discovery of metastatic disease. 87 The occurrence of any of these symptoms or signs in a patient on chronic hemodialysis is justification for study using ultrasonography, CT scanning, and arteriography as appropriate.

MISCELLANEOUS TOPICS

To complete this selective review of advances in RCD , two additional studies should be mentioned. Neither relates to the topics just discussed. In reviewing the clinical signs by which cyst infection and neoplasm might be recognized, mention was made in the preceding text of a change in renal contour or an increase in renal size. Thaysen and Thomsen believe that in the normal course of events the polycystic kidney shrinks during renal replacement therapy. 88 They used computer tomography to derive kidney volume and found that rate of involution to be 0.77% per month of replacement therapy among the polycystic kidneys of six patients followed for 17 to 46 months (P < 0.05) . The observation is intriguing, for its cause is unknown. If true, however, it means that cyst size can be influenced in APKD.In APKD, renal failure has been thought to result from cyst expansion. 2028 Were it possible to delay or reverse cyst expansion by medical means instead of dialysis or transplantation, the evolution of progressive renal failure in APKD might be slowed. More information on this potentially relevant clinical point that polycystic kidneys shrink during replacement therapy is needed. APKD is accompanied by an increased frequency of intracranial aneurysms. 89 Levey and associates have advised against routine arteriography in patients with APKD .89 No gain in survival is achieved unless there is a less than I % rate of surgical complications (unlikely) or the patient is younger than 25 years. SUMMARY

Substantial contributions to the field of RCD have been made over the past 15 years. Most intriguing is a growing awareness of acquired RCD and its complications . Data have been published and are reviewed here in support of a possibility that APKD and RCD acquired during hemodialysis are premalignant lesions. More data are needed before the possibility can be confirmed or denied. The collection of these data is an immediate need in the field of RCD . NOTE

Since this article was submitted for publication, Ishikawa et al 93 have described the involution of acquired cysts in the kidneys of two of seven affected individuals who received renal transplants after 5 or more years on hemodialysis.

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