Acute Idiopathic Tubulointerstitial Nephritis: Report of Two Cases and Review of the Literature

CASE REPORTS

Acute Idiopathic Tubulointerstitial Nephritis: Report of Two Cases and Review of the Literature Aaron Spital, MD, Bernard J. Panner, MD, and Richard H. Sterns, MD • Two patients who presented with severe renal failure and evidence of generalized proximal tubular dysfunction were found to have severe diffuse acute tubulointerstitial nephritis on renal biopsy. No etiology could be found in either case. Both patients had dramatic improvement in renal function following steroid therapy. In the first reported case of its kind, one patient relapsed when steroids were withdrawn, but improved again with reinstitution of steroid therapy. These cases, as well as others in the literature, show that steroids are effective and may be necessary to improve renal function in some patients with acute idiopathic tubulointerstitial nephritis. Evidence of proximal tubular dysfunction is a clue to the presence of this disorder. © 1987 by the National Kidney Foundation, Inc. INDEX WORDS: Interstitial nephritis; Fanconi syndrome.

A

CUTE tubulointerstitial nephritis is characterized histologically by inflammation of the renal interstitium, with relative sparing of glomeruli.1.2 This lesion may account for 10% to 15 % of cases of unexplained acute renal failure investigated with renal biopsy.3.4 Acute tubulointerstitial nephritis may be caused by drugs, infections, or systemic disease, but sometimes no cause is found. 2.5-24 Because cases of acute idiopathic tubulointerstitial nephritis are rarely diagnosed, clinical experience with them is limited and optimal therapy is unknown. In particular, while steroid therapy has been used with apparent success,6-8.11.12.19-22.24 its true value remains unproven. This report will review the clinical and pathologic features of acute idiopathic tubulointerstitial nephritis and report two additional cases. Our patients presented with severe azotemia and evidence of generalized proximal tubular dysfunction. Both patients responded dramatically to steroid therapy. CASE REPORTS

Case 1 A 15-year-old white male, previously in excellent health except for obesity, developed malaise, anorexia, nausea, and vomiting. Other family members had similar symptoms that resolved spontaneously. The patient remained ill and subsequently developed thirst, frequency, nocturia, and weight loss. There was no fever, skin rash, exposure to medications or toxins, nor other symptoms of systemic disease. The serum creatinine level was found to be 9.8 mg/dL and the patient was admitted to the hospital. On admission, the patient was afebrile and his BP was 150/ 90. Other than obesity, the physical examination was unremarkable. There was no skin rash. Admitting laboratory data were BUN 86 mg/dL, creatinine 10.9 mg/dL, uric acid 4.8 mg/

dL, phosphorus 5.4 mg/dL, albumin 4.1 g/dL, glueose 134 mg/dL, sodium 137 mEq/L, potassium 3.3 mEq/L, CO 2 14 mmol/L, chloride 104 mEq/L, hematocrit 31 %, WBC count 6,500 with 2% eosinophils, and the ESR (Wintrobe) was 59 mm/h. Urinalysis revealed a sp gr of 1.007, pH 5.5, 1 + glucose, I + protein, renal tubular epithelial cells, WBCs, and many granular casts. A renal ultrasound and diethylenetriaminepentaacetic acid (DTPA) scan showed normal-sized unobstructed kidneys. A trial of volume expansion failed to improve renal function. Due to the obscure origin of the renal failure, a percutaneous renal biopsy was performed and processed by routine methods for light, immunofluorescent, and electron microscopy. There were ten glomeruli that were essentially normal, except for a slight increase in mesangial matrix. The striking finding was diffuse marked cellular infiltration of the interstitium, with lymphocytes, plasma cells, and occasional eosinophils (Fig I). There was also prominent interstitial edema and tubular necrosis. In some tubules, lymphocytes were seen between the tubular basement membrane and the tubular epithelial cells-socalled tubulitis. Immunofluorescence revealed only minor nonspecific staining for IgG and C3. Immunoperoxidase failed to stain lymphocytes invading tubular epithelium for IgG, IgM, and muramidase, suggesting that these were T lymphocytes. Electron microscopy confirmed marked tubulointerstitial inflammation and tubular necrosis, and there were no deposits. No cause could be found for the tubulointerstitial nephritis. The following tests were negative or normal: chest x-ray, blood and urine cultures, cold agglutinins, heterophile, cytomegalovirus (CMV), toxoplasmosis and leptospiral antibodies, hepatitis B profile, antistreptolysin-O titer (ASOT), serum protein electrophoresis, IgE level, heavy metal screen, ANA, and complement levels. A 24-hour urine contained 2, 122 mg pro-

From the Departments of Medicine and Pathology, Rochester General Hospital ad Strong Memorial Hospital, University of Rochester School of Medicine, New York. Address reprint requests to Aaron Spital, MD, Rochester General Hospital, 1425 Portand Ave, Rochester, NY 14621. © 1987 by the National Kidney Foundation, Inc. 0272-6386/87/cnOl-00Il $03.00/0

American Journal of Kidney Diseases, Vol IX, No 1 (January), 1987: pp 71-78

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72

SPITAL, PANNER, AND STERNS

Fig 1. Case 1. Section shows essentially normal glomerulus. A necrotic tubule near the center of the field is filled with cellular debris and shows disruption of tubular basement membrane (arrow). There is extensive mononuclear cell infiltration in the edematous interstitium. Two lymphocytes surrounded by clear spaces are invading epithelial cells of a tubule (asterisk). (H & E, original magnification x 132.)

tein, 937 mg uric acid, 639 mg phosphorus, 17 g glucose, and generalized aminoaciduria. The fractional excretions of phosphorus, uric acid, and glucose were 76%, 113 %, and 60%, respectively. Urine protein electrophoresis showed only a trace of albumin, with no monoclonal protein. Prednisone , 60 mg daily was begun and renal function improved dramatically. Within 1 week, the creatinine had decreased to 6.0 mg/dL, and by 1 month decreased to 1.8 mg/dL. Steroids were gradually tapered over the next 2 months, at which time the creatinine was 1.4 mg/dL. Approximately 21/2 months following hospitalization, the patient complained of redness and discomfort in the right eye. An opthalmologist diagnosed right episcleritis and mild bilateral uveitis. He was treated with topical steroids and experienced complete resolution. Now, more than 2 years after presentation, the patient's serum creatinine is I. 1 mg/ dL. The urine sediment shows five to ten WBCs per high-power-field. A 24-hour urine contains 98 mg protein, 343 mg glucose, 1,127 mg phosphorus, and 1,004 mg uric acid. The fractional excretions of uric acid, phosphorus, and glucose are 10.4%,13.5%, and 0.18%, respectively. Aminoaciduria is no longer present, and first-morning urine osmolality is 758 mosm/kg.

Case 2 A 71-year-old white man presented to a urologist with symptoms of bladder outlet obstruction. An intravenous pyelogram (IVP) revealed a faint nephrogram bilaterally, but no visualization of the collecting system. A renal ultrasound showed normal-sized kidneys, without hydronephrosis. Cystoscopy revealed only a mildly enlarged prostate. The patient was admitted for further evaluation. There was no history of prior renal disease. He was taking no medications and denied exposure to heavy metals or other toxins. There was no fever, rash, nor other manifestations of systemic disease. On physical examination, his BP was 1601100 and he was afebrile. There was no skin rash. Admitting laboratory data were creatinine 11.4 mg/dL, BUN 118 mg/dL, uric acid 9.7 mg/dL, phosphorus 7.7 mg/dL , glucose 197 mg/dL, albumin 3.5 g/dL, sodium 138 mEq/L, potassium 3.9 mEq/L, CO 2 16 mmollL, chloride 102 mEq/L, hematocrit 32% WBC count 7,100 with 2 % eosinophils, and the ESR was 75 mm/h. The first urinalysis (which was not obtained until immediately following cystoscopy) showed a sp gr of 1.014, pH 7, 2 + protein, many RBCs, few WBCs, and several granular casts. A renal biopsy was performed and processed by routine

ACUTE IDIOPATHIC INTERSTITIAL NEPHRITIS

73

Fig 2. Case 2. Severe disruption of tubules is accompanied by loss of tubular basement membranes (arrow), lymphocytic invasion of tubular epithelium (arrow head shows lymphocyte adjacent to tubular epithelial cell in mitosis), and interstitial infiltration by lymphocytes, monocytes, and plasma cells. (H & E, original magnification x 132.) methods. The ten glomeruli present were essentially normal , with the exception of a slight increase in mesangial matrix. The striking finding was a diffuse inflammatory process of the insterstitium with marked cellular infiltration, with lymphocytes , plasma cells, and eosinophils (Fig 2). There was also interstitial edema and fibrosis . Some of the tubules appeared flattened , with evidence of regeneration, and areas of tubulitis were seen. In several areas, the tubular basement membrane was absent. There was also moderate arteriosclerosis. Immunofluorescence was negative, except for minor faint staining of the tubular basement membrane for fibrinogen and focal vascular staining for C3. Lymphocytes invading the tubular epithelium did not stain for IgG or IgM by the immunoperoxidase method. Electron microscopy revealed no electron-dense deposits and confirmed the marked tubulointerstitial inflammatory process. Further evaluation included a chest x-ray, which showed a small right pleural effusion. Serum protein electrophoresis and complement levels were normal. Cryoglobulins, ANA, hepatitis B surface antigen , VDRL, and blood cultures were all negative. The streptozyme screen was < 100 units. A PPD skin test was negative, with a positive control. The 24-hour urine contained 1,174 mg protein, 377 mg phosphorus, 590 mg uric acid , and 6,740 mg glucose, but no generalized aminoaciduria. The fractional excretions of phosphorus, uric acid , and glucose

were 80% , 117% , and 105 %, respectively. The urine protein electrophoresis showed no monoclonal protein. An ophthalmology evaluation showed no evidence of uveitis. Prednisone, 60 mg daily, was begun and renal function improved dramatically (Fig 3). Within four days , the creatinine, which had peaked at 12.6 mg/dL, decreased to 8.9 mg/dL. Within 2 weeks , it had decreased to 4.9 mg/dL , and by I month further decreased to I. 9 mg/dL. Prednisone was tapered and discontinued after a course of 3 months. Two months after discontinuing prednisone, the serum creatinine increased to 3.9 mg/dL (Fig 3). The uric acid was 2.3 mg/dL , phosphorus 2.0 mg/dL , glucose 111 mg/dL , sodium 138 mEq/L, potassium 3.2 mEq/L, CO 2 16 mmollL, and chloride 112 mEq/L. A repeat serum protein electrophoresis and immunoelectrophoresis of the serum were both normal. Circulating immune complexes were normal by Clq. Urine protein excretion was 1.6 g/24 hours, with no monoclonal protein. The fractional excretions of phosphorus, uric acid, and glucose were 80 %, 85 %, and 15 %, respectively. Generalized aminoaciduria was present. Renal ultrasound showed no hydronephrosis. The hematocrit was 37%, WBC count 6,900 with 5 % eosinophils, and there were no urinary eosinophils. After the patient refused a repeat renal biopsy, a second course of steroids, beginning with 60 mg of prednisone daily,

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DISCUSSION

These two patients remind us that acute idiopathic tubulointerstitial nephritis must be con-

sidered in the differential diagnosis of nonhospital-acquired acute renal failure. These two cases were seen in 1 year at a general medical hospital, which suggests that this disease may be more common than generally appreciated. The clinical features may be derived from a review of our patients and other cases in the literature (Table 1). Cases of chronic interstitial nephritis,2S and those possibly due to systemic disease 26 or having insufficient data,2.s.916.1819 have been excluded from Table 1. Although there is a predominance of females, both sexes and all ages are affected. In the majority of cases, there is a prodrome consisting of nonspecific constitutional symptoms, and a few patients experience flank or abdominal pain. Unlike drug-induced acute interstitial nephritis, fever and skin rash are usually absent. There is no history of preceding drug or toxin exposure, nor are there signs or symptoms of

14/F 11/F

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Yes Yes Yes Yes Yes Yes No

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Yes No No Yes No No No No No

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Reported Cases of Acute Idiopathic Tubulointerstitial Nephritis

Abbreviations: PD, peritoneal dialysis; HD, hemodialysis; Eos, eosinophilia; NI, normal. 'Two cases possibly due to drugs have been excluded. tBaseline creatinine 3. :j:500 mg methylprednisolone IV for first three days. §Methylprednisolone.

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a specific systemic disease. However, some cases have been associated with uveitis and bone marrow and lymph node granulomas. 6,8,15,16,19,20,22 The patients present with moderate to severe renal failure, which is usually nonoliguric. BP is almost always normal. There is usually mild anemia, and the ESR is almost always elevated, but routine cultures and serologic markers of rheumatologic and infectious disease are negative. Complement levels are usually normal. Eosinophilia is seen only in a minority of patients, and IgE levels, when measured, have been either normal or increased. Proteinuria is generally < 2 g124 h, and only occasional RBCs, WBCs, and granular casts are seen on urinalysis. Only four patients with heavy proteinuria have been reported, and all had glomerular involvement on biopsy.5,9 The kidneys are of normal size and are not obstructed. Our patients presented with severe renal failure and evidence of generalized proximal tubular dysfunction, with impaired reabsorption of glucose, amino acids, uric acid, and phosphorus.27 The recognition of proximal tubular dysfunction is more difficult when the glomerular filtration rate is reduced 28 ; however, renal failure alone cannot explain all the findings in our patients. Both patients had marked elevations of the fractional excretion of uric acid, much greater than that associated with renal failure alone. 29 Moreover, both patients had marked renal glycosuria and generalized aminoaciduria, useful markers of proximal tubular dysfunction, which are not features of renal failure alone. 28 During an exacerbation, case 2 demonstrated the full Fanconi syndrome, including a hypokalemia hyperchloremic acidosis, hypophosphatemia, hypouricemia, renal glycosuria, and generalized aminoaciduria. While there are only two previous reports of generalized proximal tubular dysfunction 6 and Fanconi syndrome 10 in acute idiopathic tubulointerstitial nephritis, many other cases have had glycosuria on routine urinalysis. 8,1 \.1320,22,23 We suspect that many of these patients would have manifested other features of the Fanconi syndrome had these been sought. As previously suggested ,6 the finding of glycosuria in the presence of a normal blood glucose is an important clue to the diagnosis of acute tubulointerstitial nephritis, but its absence does not exclude the diagnosis. 18 Histologically, an intense inflammatory interstitial infiltrate is seen, with relative sparing of the glomeruli. The majority of infiltrating cells are

SPITAL, PANNER, AND STERNS

lymphocytes and plasma cells-eosinophils are prominent only occasionally. Lymphocytes may be seen between the basement membrane and tubular cells, so-called tubulitis. 30 There may be tubular necrosis, loss of tubular basement membrane, and varying degrees of interstitial edema and fibrosis. In most cases, immunofluorescence has been negative or has shown only nonspecific staining, and electron microscopy confirms tubular injury and has usually not revealed deposits. 1 The prognosis of acute idiopathic tubulointerstitial nephritis has generally been favorable with or without steroid therapy. Only one patient has been described who required permanent dialysis,14 although several patients have required dialysis during the acute illness. Many patients reported were left with some degree of renal impairment. However, their ultimate outcome is unclear because follow-up was short. The etiology of this condition is unknown. Its frequent prodrome raises the possibility of an infectious origin. In fact, in our first case other family members had similar symptoms. However, attempts to demonstrate viral, bacterial, and fungal infections have been unsuccessful in all reported cases. Similarly, no systemic disease has emerged during follow-up of these patients. The lack of specific immunofluorescence and the demonstration that the majority of infiltrating cells are T-lymphocytes 513 ,21 suggest a role for cell-mediated immunity in this disorder. If cellmediated immunity is responsible for the injury pattern, then steroids would be rational therapy.19,31 In several cases, steroids were used and led to dramatic improvements of renal function 6-8,11,12,19-22,24 usually within 1 to 2 months. However, since there have been reports of spontaneous recovery6-8,15,23 the value of steroids remains open to question. Our two cases shed further light on this issue. Both patients' renal function improved dramatically after steroid therapy was begun. Moreover, our second case is the first reported in which renal function initially improved on steroids, deteriorated when steroids were withdrawn, and then improved a second time with reinstitution of steroid therapy (Fig 3). This leaves little doubt that steroids were both effective and instrumental in reversing the tubulointerstitial nephritis in this patient. Similarly, Frommer et al 12 described a patient who was on dialysis for 3 1h months before a renal biopsy demonstrated interstitial nephritis;

ACUTE IDIOPATHIC INTERSTITIAL NEPHRITIS

77

the creatinine decreased to 2 mg/100 mL after the institution of steroid therapy. Thus, while the prognosis of acute idiopathic tubulointerstitial nephritis is generally good with or without therapy, steroids are effective and may be necessary to improve renal functi c: '1 in some patients. Therefore, in the absence of contraindications, we believe a short course of high-dose steroid therapy is indicated in patients with severe renal failure . During follow-up, markers of proximal tubular dysfunction should be monitored in addition to the serum creatinine. In our second case, despite near normalization of serum creatinine, glycosuria persisted after the first course of steroid therapy; such findings signal the need for close observation and perhaps continued therapy.

Finally, we emphasize that such cases demonstrate the value of renal biopsy in acute renal failure of obscure origin. Although gallium scanning may be suggestive, 24 only through biopsy can acute tubulointerstitial nephritis be diagnosed definitively. Left undetected, this potentially treatable lesion can lead to end-stage renal disease. 12

ADDENDUM Since preparation of this manuscript, we have become aware of three more reports of acute idiopathic tubulointerstitial nephritis. 32- 34

ACKNOWLEDGMENT The authors wish to thank Carolyn Guerrera for her excellent preparation of the manuscript.

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Idiopathic acute interstitial nephritis , in Cotran RS, Brenner BM , Stein JH (eds): Tubulo-interstitial Nephropathies. New York, Churchill Livingstone , 1983 , pp 176-178 2. Heptinstall RH: Interstitial nephritis, in Heptinstall RH (ed): Pathology of the Kidney. Boston , Little, Brown, 1983, pp 1149-1193 3. Linton AL, Clark WF, Driedger AA, et a1: Acute interstitial nephritis'due to drugs. Review of the literature with a report of nine cases. Ann Intern Med 93:735-741, 1980 4. Wilson DM, Turner DR, Cameron JS, et al: Value of renal biopsy in acute intrinsic renal failure. Br Med J 2:459-461, 1976 5. Bender WL , Whelton A, Beschorner WE, et al: Interstitial nephritis, proteinuria, and renal failure caused by nonsteroidal anti-inflammatory drugs. Am J Med 76:1006-1012, 1984 6. Burghard R, Brandis M, Hoyer PF, et al: Acute interstitial nephritis in childhood. Eur J Pediatr 142: 103-110, 1984 7. Chazan JA, Garella S, Esparza A: Acute interstitial nephritis. A distinct clinico-pathological entity? Nephron 9: 1026, 1972 8. Dobrin RS , Vernier RL , Fish AJ: Acute eosinohilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. Am J Med 59:325-333, 1975 9. Ellis D, Fried WA , Yunis EJ, et al: Acute interstitial nephritis in children: A report of 13 cases and review of the literature. Pediatrics 67:862-870, 1981 10. Glassock RJ, Malluche HH , Tate M, et a1: Recurrent fractures, hypophosphatemia , and renal insufficiency in an elderly woman. Am J Nephrol 4:329-335, 1984 11. Graber ML, Cogan MG, Connor DG: Idioipathic acute interstitial nephritis. West J Med 129:72-76, 1978 12. Frommer P, Vldall R, Fay Wp, et al: A case of acute interstitial nephritis successfully treated after delayed diagnosis. Can Med Assoc J 121 :585-591 , 1979 13. Husby G, Tung KSK , Williams RC Jr: Characterization of renal tissue lymphocytes in patients with interstitial nephritis. Am J Med 70:31-38, 1981 14. Hyun J , Galen MA: Acute interstitial nephritis. A case characterized by increase in serum IgG, IgM, and IgE concen-

!rations. Eosinophilia, and IgE deposition in renal tubules. Arch Intern Med 141:679-681 , 1981 15. Iida H, Terada Y, Nishino A, et al: Acute interstitial nephritis with bone marrow granulomas and uveitis. Nephron 40: 108-110, 1985 16. Kida H, Abe T, Tomosugi N, et al: Prediction of longterm outcome in acute interstitial nephritis. Clin Nephrol 22:55-60, 1984 17. Klassen J, Andres GA, Brennan JC , et al: An immunologic renal tubular lesion in man. Clin Immunol Immunopathol \: 69-83, 1972 18. Laberke HG, Bohle A: Acute interstitial nephritis: Correlations between clinical and morphological findings. Clin Nephrol 14:263-273, 1980 19. Levy P, Guesry P, Loirat C: Immunologically mediated tubulo-interstitial nephritis in children. Contrib Nephrol 16: 132-140, 1979 20. Nakamoto Y, Kida H, Mizumura Y: Acute eosinophilic interstitial nephritis with bone marrow granulomas. Clin Immunollmmunopathol 14:379-383, 1979 21. Pamukcu R, Moorthy AV, Singer JR , et al: Idiopathic acute interstitial nephritis: Characterization of the infiltrating cells in the renal interstitium as T helper lymphocytes. Am J Kidney Dis 4:24-29, 1984 22. Steinman TI, Silva P: Acute interstitial nephritis and iritis. Renal-ocular syndrome. Am J M ed 77 : 189-191 , 1984 23 . Wilkinson DG, Boyd DHA: Recovery from acute interstitial nephritis. Br Med J 1:827-828, 1978 24. Wood BC, Sharma IN, Germann DR, et al: Gallium citrate Ga 67 imaging in noninfectious interstitial nephritis. Arch Intern Med 138: 1665-1666, 1978 25. Bergstein J, Litman N: Interstitial nephritis with antitubular-basement-membrane antibody. N Engl J Med 292:875878, 1975 26. Kikkawa Y, Sakurai M, Mano T, et al: Interstitial nephritis with concomitant uveitis. Contrib Nephrol 4: 1-11, 1977 27 . Roth KS , Foreman JW, Segal S: The Fanconi syndrome and mechanisms of tubular transport dysfunction . Kidney Int 20:705-716, 1981 28. Lee DBN, Drinkard Jp, Rosen VN , et al: The adult Fan-

78 coni syndrome. Observations on etiology, morphology, renal function and mineral metabolism in three patients. Medicine 51:107-138, 1972 29 . Steele TH, Rieselbach RE: The contribution of residual nephrons within the chronically diseased kidney to urate homeostasis in man. Am J Med 43 :876-886, 1967 30. Ooi BS , Jao W, First MR, et al : Acute interstitial nephritis. Aclinical and pathologic study based on renal biopsies. Am J Med 59:614-629, 1975 31. Laberke HG: Treatment of acute interstitial nephritis . Klin Wochenschr 58:531-532 , 1980

SPITAL, PANNER, AND STERNS

32. Burnier M, Jaeger P, Campiche M, et al: Idiopathic acute interstitial nephritis and uveitis in the adult. Am J Nephrol 6:312-315, 1986 33. Gafter U, Ben-Basat M, Zevin D, e t la: Anterior uveitis, a presenting symptom in acute interstitial nephritis. Nephron 42 :249-251 , 1986 34 . Vanhaesebrouck P, Carton D, De Bel C, et al: Acute tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) . Nephron 40:418-422, 1985