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Unusual oral lesions in a uremic patient
Unusual oral lesions in a uremic patient Review
of the
UNIVERSITY
OF
literature
MINNESOTA
and
SCHOOL
report
OF
of a case
DENTISTRY
Uremia is defined as the accumulation of nitrogenous waste products in t,he blood Uremia may be caused by either acute or chronic renal failure. Uremic stomatitis represents a relatively uncommon intraoral complication of uremia. Uremic stomatitia has classically been divided into ulcerative and nonulcerative types. Reported here is a pstient with chronic renal failure exhibiting intraoral lesions that persisted despite local treatment but rapidly cleared following renal dialysis. This case represents the first, published report of the microscopic appearance of the nonulcerative type and presents unusual tissue changes heretofore unreported.
T
he intraoral manifestations of renal insuffciency were first described bs Frerichsl in 1851. Soon after, in 1887, Lancereaux2 stated that the oral mucosa “is sometimes thickened, injected” and that occasionally “small superficial erosions” are noted in renal insufficiency states. Bari6,3 in 1889, rendered the first classic description of these intraoral changes. Bar% described two forms : ( 1) an crythemopultaceous form, characterized by red mucosa covered with a thick exudate, a pseudomembrane, and no underlying ulceration and (2) an ulcerative form, characterized by frank ulceration with redness and a “pultaceous coat.” Bar% stated that the oral phenomena were probably a “reverberation” of an “intoxication” of the intestinal canal. The source of this “intoxication” was thought to be the excretion of poisons in saliva, especially urea or ammonium carbonate, which were ordinarily eliminated by the kidneys. BarZ postulated that an added “tissue deficiency” (poor teeth or gingivitis, for example) was necessary for these phenomena, to occur. Only three reports of this condition appeared in the literature in the 50 years following Barik’s publication. Hirtq4 in 1902, reported one of each form. Dalchi: and Claude,” in 1903, described a patient exhibiting exudation and ulceration of the oral mucosa coupled with other ulcerative lesions of the skin, umbilicus, and anal mucosa. The stomatitis differed from that described by Bar% in the associated discomfort, degree of hemorrhage, and ulcer margination.
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In 1926, Abascal and li:cheveri;i’; described gingival and mucosal swelling and ulceration, with no membrane formation mentioned. The microscopic appcarante of the lesions was described; the cpithelium had disappcaretl and the submucosa showed ulceration and leukocytic infiltration. stomatitis; four Meyerson,’ in 1927, reported on five patients exhibiting had the pultaceous variety and OIN had the ulcerative type. ITe noted that, the lesions appeared early or not at all during the course of the uremia. Hempstead and Henchs discussed four patients, three showing the ulcerative and one showing the erythemopultaceous type that represented the only “characteristic” intraoral disease found in 300 patients with uremia. In all of these patients, blood urea nitrogen (BUN) values were greater than 300 mg. per cent. No microscopic description of oral mucosal changes associated with uremia could be found in the literature until 1930. Hempstead and Hench studied two of their patients histologically. They noted that superficial layers of mucosa were destroyed in some instances so tlceply that tops of the papillary bodies were exposed with only tips of rete pegs remaining. There was a moderate lcukocytic migration through vessels of the papillary body to the exudate. Exudate on the surface was noted as being without structure. Cellular remains were indistinct. Bacteria were considered abundant.’ Hempstead and Hench!’ listed four hypotheses as to the cause of this stomatitis. They could add no definite support to any of these hypotheses but believed that “. . . the possible interrelation between excesses of metabolites in the oral tissues, and bacterial infection has bten rightly stressed.” Hempstead and Hen&,! citing earlier experience by Hench and AldrichlO-l* and by Bollman and l\1ann,1:i noted that no stomatitis was observed with cxperimentally induced acute uremia with accompanying BlJK values of 480 mg. per cent and 1,600 mg. per cent. They stated that “Jt is possible that a more chronic type of uremia is necessary to predispose to, or to product, stomatitis” and “. . excess urea, under certain conditions, ma.y act as an irritant or that a.n irritating ammonium compound may be formed from urea . . by the action of bacteria. . .” ?Jaffe and Laing’” conducted an autopsy study of 136 cases of uremia. In twenty-seven csascs they found pseudomembranous and ulcerative changes in the intestinal tract. The authors attacked the so-called ammonia theory. They found that there was practically no difference in tlegrce of retention of urea between two groups, one with and one without necrotic or ulcerative lesions. They noted that the range of variation of the BIJN values was approximately the same in both groups and that the extremely high values wcrc not more cornmon in either of the groups. tJaffce and Laing state that “. . it can be safely stated that there is no parallelism between the severity of the gastrointestinal changes and the retention of urea.” They helievecl that intestinal tracat changes were seconclary to hemorrhages ol’ the intestinal mucosa. “The hcmorrhagcs loosen the cpithelial cover of the mucous membranes ant1 decrease the vitality of the tissue . bacteria infect the hemorrhagic tissue, causing necrosis ant1 altcration. The hemorrhages in the tligcstivc tract arc a part of the hemorrhagic tliathcsis which is common in uremia. . .‘*
Oral Surg. June, 1975
Bliss,‘” in 1937, noted that ulceration of the intraoral mucosa frequently seen in nephritic patients and in experimentally nephrectomized animals ma? be due to local irritation by ammonia. He found that calculus from the teeth of dogs contained urease and, therefore, hypothesized that ammonia is formed by the action of urease on the urea in saliva. This opinion was based on the following observations: Dogs with normal BIT?; values do not show intraoral ulceration, even t,hough the teeth are coated with calculus; in dogs with elevated BUN values, oral ulceration occurred in locations adjacent to teeth only; ulcerations cleared when calculus was rcmovetl, even though the BITN values remained elevated; and calculus from normal as well as nephritic dogs hydrolyzes urea to ammonia, just as urease does. Bliss attempted to show that ammonia actually damages intraoral tissues. In his classic experiment he sealed glass tubes against the oral mucosa of dogs. One tube contained physiologic saline solution, another contained ammonium sulfate, and a third contained ammonium hydroxide (the concentrations of a.mmonium sulfate and ammonium hydroxide wcrc equivalent to the amount of ammonia liberated in the saliva of an animal with a BI‘N value of 300 mg. per cent). Following an X-hour solution-mucosal surface contact, no change was noted under the tube with the saline solution, a slight reddening was noted in the tube containing ammonium sulfate, and sevcr’c mucosal damage was seen in the tube with ammonium hydroxide. The latter abnormality perisistcd at least 1 week following the experiment,. Bliss also demonstrated that when saliva from experimental animals with BUN values of 238 mg. per cent was incubatetl with dog calculus and applied to mucosa, reddening and irritation resulted. In 1941, Bercston and Kcil”; documented the case of a patient exhibiting intraoral gray ulcerations with a membranous covering. These findings were in a patient who had a BUN value of greater than 175 mg. per cent. Smears of showed bacterial contamination but no fungus. Microscopic examination necropsy tissue revealed an acute infammatory reaction with extensive necrosis. Submucosal areas showed similar acute inflammatory exudat,cs. The deeper musculature was also involved because, they supposed, of a “. . reaction to the overlying process, with probable diffusion of ‘toxins’ . . . .” Black,l’ in 1912, reported that an individual patient’s uremic stomatitis rapidly cleared following a dental prophylaxis, utilization of a mouthwash containing 1 per cent hydrochloric acid, and potassium chloride tablets dissolved in the mouth. In 1964, Beaney,l* following a clinical study of seventy-three patients with renal failure, supported the earlier study of Hempstead and Hench with regard to the chronicity of the renal disease and concomitant uremia. Beaney subscribed to the theory that intraoral lesions are caused by the presence of a bacterial urease capable of liberating ammonia which, in turn, produces caustic inflammatory reactions. This mechanism is best illustrated, he thought, in patients with chronic renal insufficiency in whom high BTJN values were present for long periods. Uremic stomatitis was not observed in patients with acute renal failure. Halazonetis and Harlesl,lY in 1967, described a patient with a BUIL’ value
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of approximately 457 mg. per cent. The patient exhibited a painful membranous stomatitis with a thick off-white membrane in most areas of the oral cavity except where the mucosa was “protected” by the patient’s maxillary denture. These intraoral lesions improved markedly following treatment with a 1.5 per cent hydrogen peroxide solution and applications of a triple dye. Halazonetis and Harley regarded uremic stomatitis as “a chemical burn” probably caused by “. . ammonia formed by the action of bacterial urcase associated with calculus on the high concentration of salivary urea in renal failure. ” Carlin and SeldinzO in 1969, reported a patient with a BUN of 200 mg. per cent. This patient exhibited intraoral ulcerations covered with a pseudomembrane. They found that the lesions underwent remission following peritoneal dialysis and the accompanying lower BUN of 28 mg. per cent. Gruskin and associates, 21 in 1970, reported their results following a retrospective study of seventy uremic patients. This study involved ten confirmed and five suspected cases of uremic stomatitis. Both ulcerative and nonulcerative forms were found, often in the same patient. The authors summarized: “The stomatitis seemed to be related to the peak level of the blood urea All but one patient had a blood urea level of more than 300 mg./lOO ml. at the onset of stomatitis, and in most patients the level was greater than 400 mg.” The stomatitis “ . . . tended to disappear with dialysis, and the subsequent lowering of the blood urea level.” Mortensen,22 in 1971, concluded, following a study of forty uremic patients, that ulceromembranous or ulcerative stomatitis apparently does not occur when the blood urea concentration is maintained at a low level through dialysis. Eighty-three per cent of his patients had BUN values of less than 200 mg. per cent for a duration of between 1 month and 7 years. Only two of his patients showed bloody crusting of the lips; these patients had BUN values greater than 300 mg. per cent and were in a terminal stage. CASE REPORT A 37-year-old white man reported to the Renal Transplant Service at the University of Minnesota Hospitals for evaluation on May 18, 1972. Past medical history revealed that the patient had had proteinuria for 15 years and that he had been hypertensive for some time. The patient was taking sodium bicarbonate, 4 Gm. per day, allopurinol, 100 mg. per day, and a probenecid-colchicine compound, 1 Gm. per day. Laboratory studies on May 18, 1972 revealed a HUN value of 96 mg. per cent and a creatinine level of 8.5 mg. per cent. The clinical impression at this time was that the patient had chronic end-stage renal disease, probably due to both gout and hypertension. The patient was placed on methyl dopa, 500 mg. per day. During this initial visit, the patient also complained of oral symptoms, and a clinical intraoral examination revealed x possible mycotic infection. Nystatin ora1 “swish and swallow,” 100,000 units four times a day, was prescribed. On Aug. 17, 1972, the patient returned to the Renal Transplant Service. Laboratory values were as follows: BUN, 158 mg. per cent; creatinine, 11.5 mg. per cent. On August I7 the patient’s oral involvement was more pronounced, and it was thought that the nystatin was not handling it well. At this time it was decided that the patient should come in for a transplantation work-up as soon as possible. On Sept. I, 1972, the patient reported to the Oral Surgery Outpatient Clinic at the
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Oral Burg. June, 197.5
200 mg. per cent. Fig. 1. Predialysis appearance of buccal mucosa; BUN approximately Fig. 2. Predialysis appearance of tongue dorsum. Note the plaques, especially on the lateral borders. Fig. 3. Predialysis appearance of sublingual areas. Note also the gingival plaques in the mandibular anterior region. An intraoral examination at this time revealed superUniversity of Minnesota Hospitals. ficial white patches which could be scraped off, producing no hemorrhage or ulceration. Thesr patches were located in the right and left buccal areas and the lateral borders as well as the dorsal and lingual aspects of the tongue (Figs. 1 and 2). The floor of the mouth and loner anterior vestibular area were also involved (Fig. 3). The dental hygiene of the patient was noted to be good. .Some calculus was noted on the lingual aspects of the lo\Ter anterior teeth. No cervical lymph nodes mere palpable. The patient was still using the nystatin “swish and swallow,” reported that the intraoral white 100,000 units four times a day. The patient Since then, they had propatches began in April, 1972, in the buccal areas bilaterally. gressed to involve other areas despite the use of the nystatin. The clinical appearance at this time was consistent with the previous diagnosis of candidiasis. The patient was advised to continue the nystatin mouthwashes, and Negatol was applied topically to the lesions. On Sept. 7, 1972, the patient returned to the Outpatient Oral Surgery Clinic. He reported that the condition had improved slightly. The pain had lessened, and the buccal areas were involved to a lesser degree. It was noted, however, that the sublingual areas had become more involved since the previous visit. The patient was instructed to continue the nystatin mouthwashes. On Sept. 14, 1972, the patient again returned to the Outpatient Oral Surgery Clinic. At this time the intraoral condition had worsened considerably. Lesions now appeared in the sublingual area, in the buccal area, and on all surfaces of the tongue and had spread to the huccnl vestibular areas. The patient’s medications at this time consisted of a spironolactone-
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[j~~j~sunl ornl
lesio,ls i)L uremic
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hydrochlorothiazide compound, 100 mg. per day; furosemide, 20 mg. per day; allopurinol, 100 250 mg. mg. per day; a probenecid-colchicine compound, 1 Gm. per day; aluminum hydroxide, per day; and methyl dopa, 250 mg. per day. The patient was still using the nystatin with a possible mouthwashes. At this time a tentative diagnosis of uremic stomatitis secondary infection of Can&& albicms was considered. On September 14 :I tissue biopsy specimen of the left buccal mueosa was taken. This tissue was submitted for routine histopathologic examination as well as for determination of fungal content. The patient was examination also taken off the nystatin mouth rinse. The results of the histopathologic were consistent with the tentative diagnosis of uremic stomatitis. It was noted, however, that the underlying lamina propria area was only minimally and nonspecifically inflamed. The results of the test for fungal contamination were negative. On Oct. 5, 1972, the patient again reported to the Outpatient Oral Surgery Clinic. The patient’s condition was noted to be relatively unchanged. It was decided to begin palliative treatment, using :I thorough prophylaxis, intraoral rinses of 1.5 per cent hydrogen peroxide, topical application of a triple dye solution (brilliant green 2.29 mg. per cubic centimeter, gentian violet, 2.29 mg. per cubic centimeter, proflavine, 1.14 mg. per cubic centimeter), and an oral suspension of tetracycline-nystatin compound, 1 teaspoon every 6 hours, with home care instructions. This oral treatment program had just begun when, later that day, the all medications and arrangements were Renal Transplant Service elected to discontinue made for dialysis. on the Renal Transplant On Oct. 9, 1972, the patient was admitted as an inpatient service. Laboratory values upon admission were as follows: HUN, 200 mg. per cent ; creatinine, 13.3 mg. per cent. On Oct. 10, 1972, renal dialysis was instituted. Six days later, on Oct. 16, 1972, following three dialysis machine runs, the patient’s laboratory values were as follows: RUN, 98 mg. per cent; creatinine, 9.2 mg. per cent. The patient’s intraoral lesions were noted to be almost completely resolved. On Oct. 18, 1972, the patient’s intraoral lesions had completely disappeared. His laboratory values on that day were as follows: RUN, 53 mg. per cent; creatinine, 7.3 mg. per cent (Figs. 4, 5 and 6). The patient was continued on the dialysis machine until a suitable kidney donor was located. Sometime later a renal transplant was performed. No complications followed, and the patient was subsequently discharged.
COMMENTS
Intraoral lesions that had persisted for 6 months in a patient with chronic renal failure, despite long-term anti-fungal treatment, rapidly cleared following diminution of the patient’s blood urea nitrogen level. This rapid remission was apparently related to the removal of nitrogenous waste products through kidney dialysis, therefore effecting a decrease in toxic products which had been secreted in the patient’s saliva. This remission is similar to that published by Carlin and Seldin”’ in which a rapid improvement of intraoral lesions was reported in a renal-failure patient following peritoneal dialysis. Palliative treatment consisting of dental prophylaxis, hydrogen peroxide mouth rinses, topical application of a triple dye, and an antibiotic was instituted, but evaluation of this treatment was rendered impossible by the patient’s admission orders. Previously publishecl cases in which biopsies of affected tissue were pcrformed”, *, lB all seem to be examples of Bar%% ulcerative type. In these cases there was clinical ulceration substantiated by microscopic confirmation of ulceration coupled with moderate to gross inflammatory reactions.
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Jaspers
Fig. 4. Postdialysis Fig. 5. Postdialysis Fig. 6. Postdialysis disappeared.
53 mg. per cent. appearance of buccal mucosa; BUN approximately view of tongue dorsum; no plaque is evident. appearance of sublingual areas; all evidence of whitish plaques has
Fig. 7. Photomicrograph of biopsy sample from and the pronounced parakeratin layer. (Magnification,
left buccal mucosa. Note the hyperplasia x31.)
Ti~~usunl ornl lesio?ls ix uremic patient
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Fig. 8. Photomicrograph cation, x125.) Fig. 9. Photomicrograph x500.)
of parakeratin of microbial
layer
showing
contamination
bacterial
contamination.
of parakeratin
layer.
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(Magnifi-
(Magnification,
The case presented here, however, apparently represents the first report on the microscopic appearance of Barie’s erythropultaceous type of oral change. The pathologist’s report markedly differs from those previously published : No ulceration and minimal underlying inflammation were noted. The mucosal specimen was covered with a stratified squamous epithelium that was hyperplastic and unusually and extensively hyperparakeratinized (Fig. 7). There is evidence of microbial contamination, especially superficially (Figs. 8 and 9). The basal and prickle cells reflect reasonably regular patterns of differentiation and maturation without mitotic or cytologic irregularities (Fig. 10). Rounded, fragmentary bodies probably arising through nuclear changes are noteworthy in superficial epithelial portions. (Figs. 11 and 12). The intraoral lesions in this case were fully manifested at a BIJN value of 158 mg. per cent. There was some hint of this condition in its early stages, when t.he patient’s BUN value was 96 mg. per cent. These BUN values are
Fig. 20. Photomicrograph of epithelial layer. Note the m:rrk(vl lack of inflammatory exudate. (Magnification, xl 25.)
acanthosis
ant1 the wlatiw
interesting, since in twenty of the previously rcportetl patient histories,“, 11’,“I, 22 the patients manifested intraoral changes onl- after the B‘IJX values had risen to greater than 300 mg. per cent. In at least two additional previous cases,‘“, L0 the patients exhibited intraoral changes at BUN values of no less than 175 mg. per cent. Jaffe and LangI asserted that there was no correlation between the digestive tract changes and the blood urea 1~~~1. It should be noted, howeTTer, that Jaffe and Lang dealt only with digcstivc tract changes occurring below the midesophageal region. Xo mention is made in their study concerning the intrahowcvcr, state that the intraoral changes oral lesions. (:ruskin and associates” they observed “ . . . seemed to bc related to the peak level of the blood urea.” This case, t,hen, rcprcscnts a very early manifestation ot’ intraoral changes at a BUN value of 96 mg. per cent. Thcsc intraoral vhangrs reached their peak at a BUN value of 158 mg. per cent, somewhat lower than ally previously reported instance. A rcvie\\: of previously reported casts revcaletl an apparent lack of eorrelation between t.he BlJN value and thr form (erpthropultaeeous or ulcerative) of- intraoral changes produced. lntlividual tissue deficiencies may be a factor; however, at least one case, that of (iruskin and colleaguts,” cxhihitetl both types of lesions in the same person at the same time. Previous reports of uremic stomatitis mention intraoral bacterial growth’“1i, I9 or “abundant” bacterial contamination.” The tissue examined from this cast showed very obvious bacterial contamination in the parakeratin and superficial epithelial layers. The etiologic significance of this bacterial contamination is an interesting question; these bacteria may have been urease producing and, if such was the case, were probably contributing to the protluction of the a.mmonium compound and the subsequent tissue rcartion. Gross fungal contamination in previous cases was not noted.l”x Ii, EL “‘) This ease showed no response to long-term antifungal therapy, and the tissue specimen
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Pig. 21. Photomicrograph (Magnification, x125.) Fig. 12. Photomicrograph the epidermis. (Magnification,
li~~~w~nl ornl lesio?ls in uremic patient
of epithelial-
parakeratin
of the fragmentary x500.)
bodies
junction. within
Note
the nuclear
the superficial
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changes.
portions
of
showed no evidence of fungal contamination. Apparently, the tissue changes and the pH change-induced alteration of the normal bacterial flora which Beaney18 reported as predisposing to colonization of yeastlike organisms in the oropharynx are not operative within the oral cavity proper. The most striking aspect of this case is the epithelial hyperplasia and overlying heavy layer of parakeratin coupled with the minimal, nonspecific inflammation in the lamina propria. The relative absence of this inflammatory reaction leads one to question the suitability of the term stomutitis in the present instance. The mechanism by which the cpithelial changes were induced with little evidence of an inflammatory reaction remains obscure and worthy of further study. I wish to acknowledge the assistance of Dr. Robert A. Vickers, Professor, Division of Oral Pathology, University of Minnesota Dental School, for his invaluable assistance during the preparation of this manusript.
944
Oral Surg. .Tune, 1975
Jtrspers
REFERENCES
F. T.: Die Brightsche Nicrenkrankheit Bmunschweig, 1851. (Cited by Mortensen.22) Mctl. S.‘(* 44’ . Lr~nwrcwus : Anntomie pathologique cat c~omplications tic l’urbmifx, llniou 865-869, 1887. (Cited by Hempstead and Hencl1.h) Harib, E. : DC la stomntite uremique, Arch Gen. Med. 2: 415-432, 690-702, 1889. (Cited by Hempstead and Hench.s) Hirtz. E.: Les stomatitra urGmiauc%s et leur (&gnostic:, Sem. Med. 22: 109-I 10, 1902. iCite; tw Hcmstead and Hench.sj& i):,lchC, P., and Claude, H.: &rations hbmorrhagiques de In peau et, tles muquenses tlans l’urfimie, Bull. M6m. Sot. MBd. H6p. Paris 20: 75-81, 1903. (Cited by Hempstead and 1-lench.s) Abawal, hi.’ P., and Echeveria, B. J. I.: Urrmic: Stomatitis, Rev. Med. IJruguay 29: l-13, 1926. (Cited by Hempstead and Hmch.s) Mvyvrson, M. C.: A Manifestation of Uremia in Pharynx, Larynx, Trachea, and Bronchi, J.A.M.A. 89: 685-687, 1927. Trans. Am. Laryngol Rhinol. Hempsiteatl, B. E., and Hen&, P. S.: lJrrrnic Htomatitis, Otol. Sot. 36: 510-522, 1930. Ilemnstca~l. B. E.. and Hen&. P. R.: Uremic Htomntitis. Proe. Mayo (Yin. Staff Mevt: 5: liO-112, 1430. The Concrntrxtion of Ur~:r in Saliva, J.A.M.A. 79: Hen&. P. S.. and Aldrich. Martha: 1409-1~12, lh2. Hcnch, P. S., and Aldrich, Martha: A Salivary Index to Renal Function, J.A.M.A. 81: 1997-2003, 1923. Hench, P. S.: Urea Retention: A Simple Met,hod for Its Estimation by the Mercury Combining Power of Blood, Arch. Int. Med. 38: 474-488, 1926. Constituents of the Blood Following Bollman, J. L., and Mann, F. C.: The Nitrogrnous Differcwt Lrwls of the Intestine, Experimcntnl Transplantation of the Ureters lnto Proc. Staff Meet. Mayo Clin. 2: 134-135, 1927. Jaffc, R. II., and Laing, 1). R.: Changes of the Digestive Tract in Uremia, Arch. Int. Med. 53: 851-864, 1934.~ Bliss. S.: The Cause of Sore Mouth in Neuhritis. J. Biol. Chem. 121: 425427. 1937. Here&on, E. S., and Keil, H.: Meml,rano’us Stbmatitis Assoriatcd With Debilitation With Uremia, Arch Dermatol. 44: 562-570, 1941. Black, 1). R. :‘Nephritic Stomntitis, IJrol. &tan. Rev. 46: i3-74, 1942. Brwney, CT. P. E.: Otolaryngeal Problems Arising T)uring Management of Severe Renal Failure, *J. Laryngol. 78: 507-515, 7964. Hnlazonetis, J., and Harley, A.: TJremic Stomntitis: Report of a Case, ORAL SJURG.23: 573-577, 1967. Cnrlin, K. T., and Seldin, R.: Oral Ulcerations Associatwl \Vith IJremin, N. Y. State Dent. J. 35: 211.214, 1969. Gruskin, S. E., Tolman, D. E., and Wngorwr, R.D.: Oral Manifestations of Uremia, Minn. Med. 53: 49.5499, 1970. Mortenscn, FT. : Oral? Forandringrr vrd uraemi, Txndlaegel~ladet 75: 461-470, 1971.
1. Frcrichs, 2. 3. -4. 5.
6. 7. 8. 9. IO.
11. 12. 13. 14. 15. 16. Ii. 18. 19. 20. 21. 22.
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Dr. Mark T. Jnsprrs 7-174a Health Sciences Bldg. Uniwrsity of Minnesota School of Dentistry Minneapolis, Minn. 55421
of the
UNIVERSITY
OF
literature
MINNESOTA
and
SCHOOL
report
OF
of a case
DENTISTRY
Uremia is defined as the accumulation of nitrogenous waste products in t,he blood Uremia may be caused by either acute or chronic renal failure. Uremic stomatitis represents a relatively uncommon intraoral complication of uremia. Uremic stomatitia has classically been divided into ulcerative and nonulcerative types. Reported here is a pstient with chronic renal failure exhibiting intraoral lesions that persisted despite local treatment but rapidly cleared following renal dialysis. This case represents the first, published report of the microscopic appearance of the nonulcerative type and presents unusual tissue changes heretofore unreported.
T
he intraoral manifestations of renal insuffciency were first described bs Frerichsl in 1851. Soon after, in 1887, Lancereaux2 stated that the oral mucosa “is sometimes thickened, injected” and that occasionally “small superficial erosions” are noted in renal insufficiency states. Bari6,3 in 1889, rendered the first classic description of these intraoral changes. Bar% described two forms : ( 1) an crythemopultaceous form, characterized by red mucosa covered with a thick exudate, a pseudomembrane, and no underlying ulceration and (2) an ulcerative form, characterized by frank ulceration with redness and a “pultaceous coat.” Bar% stated that the oral phenomena were probably a “reverberation” of an “intoxication” of the intestinal canal. The source of this “intoxication” was thought to be the excretion of poisons in saliva, especially urea or ammonium carbonate, which were ordinarily eliminated by the kidneys. BarZ postulated that an added “tissue deficiency” (poor teeth or gingivitis, for example) was necessary for these phenomena, to occur. Only three reports of this condition appeared in the literature in the 50 years following Barik’s publication. Hirtq4 in 1902, reported one of each form. Dalchi: and Claude,” in 1903, described a patient exhibiting exudation and ulceration of the oral mucosa coupled with other ulcerative lesions of the skin, umbilicus, and anal mucosa. The stomatitis differed from that described by Bar% in the associated discomfort, degree of hemorrhage, and ulcer margination.
934
In 1926, Abascal and li:cheveri;i’; described gingival and mucosal swelling and ulceration, with no membrane formation mentioned. The microscopic appcarante of the lesions was described; the cpithelium had disappcaretl and the submucosa showed ulceration and leukocytic infiltration. stomatitis; four Meyerson,’ in 1927, reported on five patients exhibiting had the pultaceous variety and OIN had the ulcerative type. ITe noted that, the lesions appeared early or not at all during the course of the uremia. Hempstead and Henchs discussed four patients, three showing the ulcerative and one showing the erythemopultaceous type that represented the only “characteristic” intraoral disease found in 300 patients with uremia. In all of these patients, blood urea nitrogen (BUN) values were greater than 300 mg. per cent. No microscopic description of oral mucosal changes associated with uremia could be found in the literature until 1930. Hempstead and Hench studied two of their patients histologically. They noted that superficial layers of mucosa were destroyed in some instances so tlceply that tops of the papillary bodies were exposed with only tips of rete pegs remaining. There was a moderate lcukocytic migration through vessels of the papillary body to the exudate. Exudate on the surface was noted as being without structure. Cellular remains were indistinct. Bacteria were considered abundant.’ Hempstead and Hench!’ listed four hypotheses as to the cause of this stomatitis. They could add no definite support to any of these hypotheses but believed that “. . . the possible interrelation between excesses of metabolites in the oral tissues, and bacterial infection has bten rightly stressed.” Hempstead and Hen&,! citing earlier experience by Hench and AldrichlO-l* and by Bollman and l\1ann,1:i noted that no stomatitis was observed with cxperimentally induced acute uremia with accompanying BlJK values of 480 mg. per cent and 1,600 mg. per cent. They stated that “Jt is possible that a more chronic type of uremia is necessary to predispose to, or to product, stomatitis” and “. . excess urea, under certain conditions, ma.y act as an irritant or that a.n irritating ammonium compound may be formed from urea . . by the action of bacteria. . .” ?Jaffe and Laing’” conducted an autopsy study of 136 cases of uremia. In twenty-seven csascs they found pseudomembranous and ulcerative changes in the intestinal tract. The authors attacked the so-called ammonia theory. They found that there was practically no difference in tlegrce of retention of urea between two groups, one with and one without necrotic or ulcerative lesions. They noted that the range of variation of the BIJN values was approximately the same in both groups and that the extremely high values wcrc not more cornmon in either of the groups. tJaffce and Laing state that “. . it can be safely stated that there is no parallelism between the severity of the gastrointestinal changes and the retention of urea.” They helievecl that intestinal tracat changes were seconclary to hemorrhages ol’ the intestinal mucosa. “The hcmorrhagcs loosen the cpithelial cover of the mucous membranes ant1 decrease the vitality of the tissue . bacteria infect the hemorrhagic tissue, causing necrosis ant1 altcration. The hemorrhages in the tligcstivc tract arc a part of the hemorrhagic tliathcsis which is common in uremia. . .‘*
Oral Surg. June, 1975
Bliss,‘” in 1937, noted that ulceration of the intraoral mucosa frequently seen in nephritic patients and in experimentally nephrectomized animals ma? be due to local irritation by ammonia. He found that calculus from the teeth of dogs contained urease and, therefore, hypothesized that ammonia is formed by the action of urease on the urea in saliva. This opinion was based on the following observations: Dogs with normal BIT?; values do not show intraoral ulceration, even t,hough the teeth are coated with calculus; in dogs with elevated BUN values, oral ulceration occurred in locations adjacent to teeth only; ulcerations cleared when calculus was rcmovetl, even though the BITN values remained elevated; and calculus from normal as well as nephritic dogs hydrolyzes urea to ammonia, just as urease does. Bliss attempted to show that ammonia actually damages intraoral tissues. In his classic experiment he sealed glass tubes against the oral mucosa of dogs. One tube contained physiologic saline solution, another contained ammonium sulfate, and a third contained ammonium hydroxide (the concentrations of a.mmonium sulfate and ammonium hydroxide wcrc equivalent to the amount of ammonia liberated in the saliva of an animal with a BI‘N value of 300 mg. per cent). Following an X-hour solution-mucosal surface contact, no change was noted under the tube with the saline solution, a slight reddening was noted in the tube containing ammonium sulfate, and sevcr’c mucosal damage was seen in the tube with ammonium hydroxide. The latter abnormality perisistcd at least 1 week following the experiment,. Bliss also demonstrated that when saliva from experimental animals with BUN values of 238 mg. per cent was incubatetl with dog calculus and applied to mucosa, reddening and irritation resulted. In 1941, Bercston and Kcil”; documented the case of a patient exhibiting intraoral gray ulcerations with a membranous covering. These findings were in a patient who had a BUN value of greater than 175 mg. per cent. Smears of showed bacterial contamination but no fungus. Microscopic examination necropsy tissue revealed an acute infammatory reaction with extensive necrosis. Submucosal areas showed similar acute inflammatory exudat,cs. The deeper musculature was also involved because, they supposed, of a “. . reaction to the overlying process, with probable diffusion of ‘toxins’ . . . .” Black,l’ in 1912, reported that an individual patient’s uremic stomatitis rapidly cleared following a dental prophylaxis, utilization of a mouthwash containing 1 per cent hydrochloric acid, and potassium chloride tablets dissolved in the mouth. In 1964, Beaney,l* following a clinical study of seventy-three patients with renal failure, supported the earlier study of Hempstead and Hench with regard to the chronicity of the renal disease and concomitant uremia. Beaney subscribed to the theory that intraoral lesions are caused by the presence of a bacterial urease capable of liberating ammonia which, in turn, produces caustic inflammatory reactions. This mechanism is best illustrated, he thought, in patients with chronic renal insufficiency in whom high BTJN values were present for long periods. Uremic stomatitis was not observed in patients with acute renal failure. Halazonetis and Harlesl,lY in 1967, described a patient with a BUIL’ value
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of approximately 457 mg. per cent. The patient exhibited a painful membranous stomatitis with a thick off-white membrane in most areas of the oral cavity except where the mucosa was “protected” by the patient’s maxillary denture. These intraoral lesions improved markedly following treatment with a 1.5 per cent hydrogen peroxide solution and applications of a triple dye. Halazonetis and Harley regarded uremic stomatitis as “a chemical burn” probably caused by “. . ammonia formed by the action of bacterial urcase associated with calculus on the high concentration of salivary urea in renal failure. ” Carlin and SeldinzO in 1969, reported a patient with a BUN of 200 mg. per cent. This patient exhibited intraoral ulcerations covered with a pseudomembrane. They found that the lesions underwent remission following peritoneal dialysis and the accompanying lower BUN of 28 mg. per cent. Gruskin and associates, 21 in 1970, reported their results following a retrospective study of seventy uremic patients. This study involved ten confirmed and five suspected cases of uremic stomatitis. Both ulcerative and nonulcerative forms were found, often in the same patient. The authors summarized: “The stomatitis seemed to be related to the peak level of the blood urea All but one patient had a blood urea level of more than 300 mg./lOO ml. at the onset of stomatitis, and in most patients the level was greater than 400 mg.” The stomatitis “ . . . tended to disappear with dialysis, and the subsequent lowering of the blood urea level.” Mortensen,22 in 1971, concluded, following a study of forty uremic patients, that ulceromembranous or ulcerative stomatitis apparently does not occur when the blood urea concentration is maintained at a low level through dialysis. Eighty-three per cent of his patients had BUN values of less than 200 mg. per cent for a duration of between 1 month and 7 years. Only two of his patients showed bloody crusting of the lips; these patients had BUN values greater than 300 mg. per cent and were in a terminal stage. CASE REPORT A 37-year-old white man reported to the Renal Transplant Service at the University of Minnesota Hospitals for evaluation on May 18, 1972. Past medical history revealed that the patient had had proteinuria for 15 years and that he had been hypertensive for some time. The patient was taking sodium bicarbonate, 4 Gm. per day, allopurinol, 100 mg. per day, and a probenecid-colchicine compound, 1 Gm. per day. Laboratory studies on May 18, 1972 revealed a HUN value of 96 mg. per cent and a creatinine level of 8.5 mg. per cent. The clinical impression at this time was that the patient had chronic end-stage renal disease, probably due to both gout and hypertension. The patient was placed on methyl dopa, 500 mg. per day. During this initial visit, the patient also complained of oral symptoms, and a clinical intraoral examination revealed x possible mycotic infection. Nystatin ora1 “swish and swallow,” 100,000 units four times a day, was prescribed. On Aug. 17, 1972, the patient returned to the Renal Transplant Service. Laboratory values were as follows: BUN, 158 mg. per cent; creatinine, 11.5 mg. per cent. On August I7 the patient’s oral involvement was more pronounced, and it was thought that the nystatin was not handling it well. At this time it was decided that the patient should come in for a transplantation work-up as soon as possible. On Sept. I, 1972, the patient reported to the Oral Surgery Outpatient Clinic at the
938
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Oral Burg. June, 197.5
200 mg. per cent. Fig. 1. Predialysis appearance of buccal mucosa; BUN approximately Fig. 2. Predialysis appearance of tongue dorsum. Note the plaques, especially on the lateral borders. Fig. 3. Predialysis appearance of sublingual areas. Note also the gingival plaques in the mandibular anterior region. An intraoral examination at this time revealed superUniversity of Minnesota Hospitals. ficial white patches which could be scraped off, producing no hemorrhage or ulceration. Thesr patches were located in the right and left buccal areas and the lateral borders as well as the dorsal and lingual aspects of the tongue (Figs. 1 and 2). The floor of the mouth and loner anterior vestibular area were also involved (Fig. 3). The dental hygiene of the patient was noted to be good. .Some calculus was noted on the lingual aspects of the lo\Ter anterior teeth. No cervical lymph nodes mere palpable. The patient was still using the nystatin “swish and swallow,” reported that the intraoral white 100,000 units four times a day. The patient Since then, they had propatches began in April, 1972, in the buccal areas bilaterally. gressed to involve other areas despite the use of the nystatin. The clinical appearance at this time was consistent with the previous diagnosis of candidiasis. The patient was advised to continue the nystatin mouthwashes, and Negatol was applied topically to the lesions. On Sept. 7, 1972, the patient returned to the Outpatient Oral Surgery Clinic. He reported that the condition had improved slightly. The pain had lessened, and the buccal areas were involved to a lesser degree. It was noted, however, that the sublingual areas had become more involved since the previous visit. The patient was instructed to continue the nystatin mouthwashes. On Sept. 14, 1972, the patient again returned to the Outpatient Oral Surgery Clinic. At this time the intraoral condition had worsened considerably. Lesions now appeared in the sublingual area, in the buccal area, and on all surfaces of the tongue and had spread to the huccnl vestibular areas. The patient’s medications at this time consisted of a spironolactone-
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hydrochlorothiazide compound, 100 mg. per day; furosemide, 20 mg. per day; allopurinol, 100 250 mg. mg. per day; a probenecid-colchicine compound, 1 Gm. per day; aluminum hydroxide, per day; and methyl dopa, 250 mg. per day. The patient was still using the nystatin with a possible mouthwashes. At this time a tentative diagnosis of uremic stomatitis secondary infection of Can&& albicms was considered. On September 14 :I tissue biopsy specimen of the left buccal mueosa was taken. This tissue was submitted for routine histopathologic examination as well as for determination of fungal content. The patient was examination also taken off the nystatin mouth rinse. The results of the histopathologic were consistent with the tentative diagnosis of uremic stomatitis. It was noted, however, that the underlying lamina propria area was only minimally and nonspecifically inflamed. The results of the test for fungal contamination were negative. On Oct. 5, 1972, the patient again reported to the Outpatient Oral Surgery Clinic. The patient’s condition was noted to be relatively unchanged. It was decided to begin palliative treatment, using :I thorough prophylaxis, intraoral rinses of 1.5 per cent hydrogen peroxide, topical application of a triple dye solution (brilliant green 2.29 mg. per cubic centimeter, gentian violet, 2.29 mg. per cubic centimeter, proflavine, 1.14 mg. per cubic centimeter), and an oral suspension of tetracycline-nystatin compound, 1 teaspoon every 6 hours, with home care instructions. This oral treatment program had just begun when, later that day, the all medications and arrangements were Renal Transplant Service elected to discontinue made for dialysis. on the Renal Transplant On Oct. 9, 1972, the patient was admitted as an inpatient service. Laboratory values upon admission were as follows: HUN, 200 mg. per cent ; creatinine, 13.3 mg. per cent. On Oct. 10, 1972, renal dialysis was instituted. Six days later, on Oct. 16, 1972, following three dialysis machine runs, the patient’s laboratory values were as follows: RUN, 98 mg. per cent; creatinine, 9.2 mg. per cent. The patient’s intraoral lesions were noted to be almost completely resolved. On Oct. 18, 1972, the patient’s intraoral lesions had completely disappeared. His laboratory values on that day were as follows: RUN, 53 mg. per cent; creatinine, 7.3 mg. per cent (Figs. 4, 5 and 6). The patient was continued on the dialysis machine until a suitable kidney donor was located. Sometime later a renal transplant was performed. No complications followed, and the patient was subsequently discharged.
COMMENTS
Intraoral lesions that had persisted for 6 months in a patient with chronic renal failure, despite long-term anti-fungal treatment, rapidly cleared following diminution of the patient’s blood urea nitrogen level. This rapid remission was apparently related to the removal of nitrogenous waste products through kidney dialysis, therefore effecting a decrease in toxic products which had been secreted in the patient’s saliva. This remission is similar to that published by Carlin and Seldin”’ in which a rapid improvement of intraoral lesions was reported in a renal-failure patient following peritoneal dialysis. Palliative treatment consisting of dental prophylaxis, hydrogen peroxide mouth rinses, topical application of a triple dye, and an antibiotic was instituted, but evaluation of this treatment was rendered impossible by the patient’s admission orders. Previously publishecl cases in which biopsies of affected tissue were pcrformed”, *, lB all seem to be examples of Bar%% ulcerative type. In these cases there was clinical ulceration substantiated by microscopic confirmation of ulceration coupled with moderate to gross inflammatory reactions.
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Jaspers
Fig. 4. Postdialysis Fig. 5. Postdialysis Fig. 6. Postdialysis disappeared.
53 mg. per cent. appearance of buccal mucosa; BUN approximately view of tongue dorsum; no plaque is evident. appearance of sublingual areas; all evidence of whitish plaques has
Fig. 7. Photomicrograph of biopsy sample from and the pronounced parakeratin layer. (Magnification,
left buccal mucosa. Note the hyperplasia x31.)
Ti~~usunl ornl lesio?ls ix uremic patient
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Fig. 8. Photomicrograph cation, x125.) Fig. 9. Photomicrograph x500.)
of parakeratin of microbial
layer
showing
contamination
bacterial
contamination.
of parakeratin
layer.
941
(Magnifi-
(Magnification,
The case presented here, however, apparently represents the first report on the microscopic appearance of Barie’s erythropultaceous type of oral change. The pathologist’s report markedly differs from those previously published : No ulceration and minimal underlying inflammation were noted. The mucosal specimen was covered with a stratified squamous epithelium that was hyperplastic and unusually and extensively hyperparakeratinized (Fig. 7). There is evidence of microbial contamination, especially superficially (Figs. 8 and 9). The basal and prickle cells reflect reasonably regular patterns of differentiation and maturation without mitotic or cytologic irregularities (Fig. 10). Rounded, fragmentary bodies probably arising through nuclear changes are noteworthy in superficial epithelial portions. (Figs. 11 and 12). The intraoral lesions in this case were fully manifested at a BIJN value of 158 mg. per cent. There was some hint of this condition in its early stages, when t.he patient’s BUN value was 96 mg. per cent. These BUN values are
Fig. 20. Photomicrograph of epithelial layer. Note the m:rrk(vl lack of inflammatory exudate. (Magnification, xl 25.)
acanthosis
ant1 the wlatiw
interesting, since in twenty of the previously rcportetl patient histories,“, 11’,“I, 22 the patients manifested intraoral changes onl- after the B‘IJX values had risen to greater than 300 mg. per cent. In at least two additional previous cases,‘“, L0 the patients exhibited intraoral changes at BUN values of no less than 175 mg. per cent. Jaffe and LangI asserted that there was no correlation between the digestive tract changes and the blood urea 1~~~1. It should be noted, howeTTer, that Jaffe and Lang dealt only with digcstivc tract changes occurring below the midesophageal region. Xo mention is made in their study concerning the intrahowcvcr, state that the intraoral changes oral lesions. (:ruskin and associates” they observed “ . . . seemed to bc related to the peak level of the blood urea.” This case, t,hen, rcprcscnts a very early manifestation ot’ intraoral changes at a BUN value of 96 mg. per cent. Thcsc intraoral vhangrs reached their peak at a BUN value of 158 mg. per cent, somewhat lower than ally previously reported instance. A rcvie\\: of previously reported casts revcaletl an apparent lack of eorrelation between t.he BlJN value and thr form (erpthropultaeeous or ulcerative) of- intraoral changes produced. lntlividual tissue deficiencies may be a factor; however, at least one case, that of (iruskin and colleaguts,” cxhihitetl both types of lesions in the same person at the same time. Previous reports of uremic stomatitis mention intraoral bacterial growth’“1i, I9 or “abundant” bacterial contamination.” The tissue examined from this cast showed very obvious bacterial contamination in the parakeratin and superficial epithelial layers. The etiologic significance of this bacterial contamination is an interesting question; these bacteria may have been urease producing and, if such was the case, were probably contributing to the protluction of the a.mmonium compound and the subsequent tissue rcartion. Gross fungal contamination in previous cases was not noted.l”x Ii, EL “‘) This ease showed no response to long-term antifungal therapy, and the tissue specimen
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Pig. 21. Photomicrograph (Magnification, x125.) Fig. 12. Photomicrograph the epidermis. (Magnification,
li~~~w~nl ornl lesio?ls in uremic patient
of epithelial-
parakeratin
of the fragmentary x500.)
bodies
junction. within
Note
the nuclear
the superficial
943
changes.
portions
of
showed no evidence of fungal contamination. Apparently, the tissue changes and the pH change-induced alteration of the normal bacterial flora which Beaney18 reported as predisposing to colonization of yeastlike organisms in the oropharynx are not operative within the oral cavity proper. The most striking aspect of this case is the epithelial hyperplasia and overlying heavy layer of parakeratin coupled with the minimal, nonspecific inflammation in the lamina propria. The relative absence of this inflammatory reaction leads one to question the suitability of the term stomutitis in the present instance. The mechanism by which the cpithelial changes were induced with little evidence of an inflammatory reaction remains obscure and worthy of further study. I wish to acknowledge the assistance of Dr. Robert A. Vickers, Professor, Division of Oral Pathology, University of Minnesota Dental School, for his invaluable assistance during the preparation of this manusript.
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Jtrspers
REFERENCES
F. T.: Die Brightsche Nicrenkrankheit Bmunschweig, 1851. (Cited by Mortensen.22) Mctl. S.‘(* 44’ . Lr~nwrcwus : Anntomie pathologique cat c~omplications tic l’urbmifx, llniou 865-869, 1887. (Cited by Hempstead and Hencl1.h) Harib, E. : DC la stomntite uremique, Arch Gen. Med. 2: 415-432, 690-702, 1889. (Cited by Hempstead and Hench.s) Hirtz. E.: Les stomatitra urGmiauc%s et leur (&gnostic:, Sem. Med. 22: 109-I 10, 1902. iCite; tw Hcmstead and Hench.sj& i):,lchC, P., and Claude, H.: &rations hbmorrhagiques de In peau et, tles muquenses tlans l’urfimie, Bull. M6m. Sot. MBd. H6p. Paris 20: 75-81, 1903. (Cited by Hempstead and 1-lench.s) Abawal, hi.’ P., and Echeveria, B. J. I.: Urrmic: Stomatitis, Rev. Med. IJruguay 29: l-13, 1926. (Cited by Hempstead and Hmch.s) Mvyvrson, M. C.: A Manifestation of Uremia in Pharynx, Larynx, Trachea, and Bronchi, J.A.M.A. 89: 685-687, 1927. Trans. Am. Laryngol Rhinol. Hempsiteatl, B. E., and Hen&, P. S.: lJrrrnic Htomatitis, Otol. Sot. 36: 510-522, 1930. Ilemnstca~l. B. E.. and Hen&. P. R.: Uremic Htomntitis. Proe. Mayo (Yin. Staff Mevt: 5: liO-112, 1430. The Concrntrxtion of Ur~:r in Saliva, J.A.M.A. 79: Hen&. P. S.. and Aldrich. Martha: 1409-1~12, lh2. Hcnch, P. S., and Aldrich, Martha: A Salivary Index to Renal Function, J.A.M.A. 81: 1997-2003, 1923. Hench, P. S.: Urea Retention: A Simple Met,hod for Its Estimation by the Mercury Combining Power of Blood, Arch. Int. Med. 38: 474-488, 1926. Constituents of the Blood Following Bollman, J. L., and Mann, F. C.: The Nitrogrnous Differcwt Lrwls of the Intestine, Experimcntnl Transplantation of the Ureters lnto Proc. Staff Meet. Mayo Clin. 2: 134-135, 1927. Jaffc, R. II., and Laing, 1). R.: Changes of the Digestive Tract in Uremia, Arch. Int. Med. 53: 851-864, 1934.~ Bliss. S.: The Cause of Sore Mouth in Neuhritis. J. Biol. Chem. 121: 425427. 1937. Here&on, E. S., and Keil, H.: Meml,rano’us Stbmatitis Assoriatcd With Debilitation With Uremia, Arch Dermatol. 44: 562-570, 1941. Black, 1). R. :‘Nephritic Stomntitis, IJrol. &tan. Rev. 46: i3-74, 1942. Brwney, CT. P. E.: Otolaryngeal Problems Arising T)uring Management of Severe Renal Failure, *J. Laryngol. 78: 507-515, 7964. Hnlazonetis, J., and Harley, A.: TJremic Stomntitis: Report of a Case, ORAL SJURG.23: 573-577, 1967. Cnrlin, K. T., and Seldin, R.: Oral Ulcerations Associatwl \Vith IJremin, N. Y. State Dent. J. 35: 211.214, 1969. Gruskin, S. E., Tolman, D. E., and Wngorwr, R.D.: Oral Manifestations of Uremia, Minn. Med. 53: 49.5499, 1970. Mortenscn, FT. : Oral? Forandringrr vrd uraemi, Txndlaegel~ladet 75: 461-470, 1971.
1. Frcrichs, 2. 3. -4. 5.
6. 7. 8. 9. IO.
11. 12. 13. 14. 15. 16. Ii. 18. 19. 20. 21. 22.
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Dr. Mark T. Jnsprrs 7-174a Health Sciences Bldg. Uniwrsity of Minnesota School of Dentistry Minneapolis, Minn. 55421