Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Tubulointerstitial Nephritis Workup

  • Author: A Brent Alper, Jr, MD, MPH; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Jan 23, 2015
 

Approach Considerations

In general, proteinuria is usually absent or modest in acute tubulointerstitial nephritis. Urinalysis may show microscopic hematuria and/or sterile pyuria (with or without eosinophils). Although the clinical presentation is often sufficient to make the diagnosis, renal biopsy is required to make a definitive diagnosis.

Patients with acute tubulointerstitial nephritis caused by nonsteroidal anti-inflammatory drugs (NSAIDs) typically present with heavy proteinuria, often in the nephrotic range. Findings on gallium scanning have been reported to be confirmatory in the diagnosis of acute interstitial nephritis.[11, 12] Thus, a negative finding helps to rule out this diagnosis. However, findings on this test have proved to be too nonspecific, except as a confirmatory tool in suspected cases.

Clinical investigations in chronic tubulointerstitial nephritis may show modest elevation in serum creatinine, evidence of tubular dysfunction (ie, renal tubular acidosis), or Fanconi syndrome (ie, aminoaciduria, glycosuria, hypophosphatemia, hypouricemia). Proteinuria is usually mild, often less than 1 g/d. In contrast to glomerular disease, a significant fraction of the protein is low molecular weight (eg, immunoglobulin light chains, beta2 microglobulin, lysozyme, peptide hormones). These proteins are normally taken up by the proximal tubules and broken down there. Thus, in diseases predominantly involving tubular structures, decreased endocytosis of filtered proteins leads to the characteristic tubular proteinuria.

In patients with suspected lead exposure, an ethylenediaminetetraacetic acid (EDTA) lead mobilization test or determination of tibial bone lead by radiographic fluorescence can confirm lead etiology.

The diagnosis of atherosclerotic kidney disease can usually be made clinically, and radiologic investigations, such as duplex scanning of the renal arteries, digital subtraction angiography, or magnetic resonance imaging (MRI), reveal atherosclerotic stenosis of the renal arteries. Kidney biopsy is seldom necessary and, if performed, shows nonspecific changes of chronic tubulointerstitial nephritis (ie, tubular atrophy, fibrosis, and arterial or arteriolar sclerosis with paucity of cellular infiltration). Because these patients tend to have atherosclerotic complications, they are likely to experience multiple contrast procedures and hence are at risk for acute recurrent contrast nephropathy, which can accelerate progression to end-stage renal disease.

Patients with Balkan endemic nephropathy are identified easily in endemic regions by checking for tubular proteinuria. Beta2 microglobulinuria has proved particularly useful in identifying cases and has been proposed and used as a marker of the disease.

Next

CBC With Differential

Eosinophilia, when present, can be very helpful in the evaluation of tubulointerstitial nephritis. However, this finding is neither specific nor sensitive enough to establish the diagnosis. Although the true incidence of eosinophilia in acute tubulointerstitial nephritis is unknown, it is estimated to be present in approximately half of patients. Typically, eosinophilia is absent in acute tubulointerstitial nephritis that is induced by nonsteroidal anti-inflammatory drugs (NSAIDs).

Previous
Next

Chemistry Panel

A complete set of chemistries, including blood urea nitrogen (BUN) and serum creatinine, provides information on whether renal insufficiency exists. A low bicarbonate level (total carbon dioxide < 24-23 mEq/L) may indicate acidosis. Low serum potassium levels may indicate a proximal tubular disorder, and elevated serum potassium levels with a low bicarbonate level may indicate type 4 renal tubular acidosis, which can be observed with lead nephropathy and nonsteroidal anti-inflammatory drug (NSAID)–induced analgesic nephropathy, among other conditions.

Previous
Next

Urine Studies

Urinalysis may reveal proteinuria, hematuria, and the presence of white blood cells (WBCs), with or without bacteria. A microscopic analysis of urine sediment may reveal casts, WBCs, eosinophils, and crystals. If allergic interstitial nephritis is suspected, send a cytospin specimen to determine if eosinophils are in the urine. Unfortunately, the absence of eosinophiluria does not rule out the diagnosis, and it can be observed in other diseases, including cholesterol microembolism, urinary tract infections, parasitic disorders, and glomerulonephritis. In nonsteroidal anti-inflammatory drug (NSAID)–induced acute tubulointerstitial nephritis, eosinophiluria is usually absent.

Quantitative determination of urine protein may also be helpful. Low-molecular weight proteins, such as beta-2 microglobulin, retinol binding protein (RBP), alpha-1 microglobulin, and immunoglobulin light chains, are increased in chronic tubulointerstitial nephritides. Beta-2 microglobulinuria has been found helpful in the diagnosis of Balkan endemic nephropathy and cadmium nephropathy.

Hettinga and colleagues, in a prospective cohort study of 45 young patients with uveitis, found that urinary β2-microglobulin (β2M), urinary protein, and serum creatinine had predictive value for detecting tubulointerstitial nephritis and uveitis (TINU) syndrome. The positive predictive value of increased β2M levels combined with increased serum creatinine was 100% for detecting patients with definitive and/or probable TINU syndrome.[13]

Urinary N-acetyl-β-D-glucosaminidase (NAG) and matrix metalloproteinases (MMPs) 2 and 9 were significantly inversely correlated with the rate of decline in estimated glomerular filtration rate (GFR) over a period of 11 to 54 months in a study of 54 patients with drug-induced chronic tubulointerstitial nephritis, 10 patients with IgA nephropathy, and 20 healthy controls. These biomarkers may be able to predict deterioration in drug-induced chronic tubulointerstitial nephritis. The areas under the receiver operating characteristic curve for urinary NAG, MMP-9, MMP-2 and α1-microglobulin for predicting decline in estimated GFR were 0.879, 0.867, 0.735 and 0.709, respectively (all P < 0.05).[14]

Previous
Next

Ultrasonography and Radiography

Ultrasonography is noninvasive imaging technique that is extremely helpful in identifying hydronephrosis in obstructive disease as well as calculi in stone disease. Both radiolucent and radiopaque stones can be visualized with this modality. A combination of ultrasonography and flat plate kidney, ureter, and bladder (KUB) radiography is helpful in the workup and identification of radiopaque versus radiolucent stones.

Normal kidney size by ultrasonographic examination generally favors but does not prove a diagnosis of acute (thus potentially reversible) kidney disease. In contrast, small (shrunken) kidneys with increased echogenicity indicate chronic and irreversible kidney disease.

Once widely used, intravenous pyelography seldom plays a role in the workup of kidney diseases in modern medicine. In many instances, similar information can be obtained by ultrasonography without exposing the patient to potentially nephrotoxic contrast dye.

Previous
Next

CT Scanning

Computed tomography (CT) scanning provides information similar to ultrasonographic scanning in the workup of kidney disease, generally with greater resolution. However, an ultrasonographic examination is sufficient in most kidney diseases. A high-resolution scan showing microcalcifications in renal papillary tips can be very helpful in diagnosis of analgesic nephropathy. The kidneys may be very small in Balkan endemic nephropathy and aristolochic acid nephropathy.

Previous
Next

EDTA Lead Mobilization Test

Consider the possibility of lead nephropathy in patients presenting with chronic renal insufficiency, hypertension, and gout. In the absence of documented episodes of acute symptomatic lead poisoning, the medical history is not reliable in ascertaining the lead etiology in patients presenting with chronic tubulointerstitial nephritis.

Diagnosis of lead nephropathy requires an estimation of the cumulative body stores of lead by either ethylenediaminetetraacetic acid (EDTA) lead mobilization test or by determination of bone lead content by radiographic fluorescence.

The EDTA lead mobilization test is performed by measuring 24-hour urine lead excretion after intravenous or intramuscular administration of 2 g EDTA (calcium disodium versenate). Excretion of more than 0.6 g of lead per 24 hours is considered an abnormal finding.

Blood lead levels, although elevated during acute or recent exposure, are not very helpful in the evaluation of chronic lead poisoning. During acute exposure, lead is concentrated in the red blood cells (RBCs) and later extracted to tissues and bone as the RBCs senesce.

Previous
Next

Kidney Biopsy and Histologic Features

Kidney biopsy is the definitive test for diagnosing acute allergic interstitial nephritis, particularly in cases in which the clinical diagnosis is difficult. Because the differential diagnosis of acute tubulointerstitial nephritis encompasses multiple etiologies, consider kidney biopsy when the diagnosis is not obvious.

Kidney biopsy shows mononuclear and often eosinophilic cellular infiltration of the renal parenchyma with sparing of the glomeruli (see the following images). Sometimes, interstitial changes such as fibrosis and atrophy are also present (eg, Renal biopsies have shown severe interstitial fibrosis in patients with Chinese herb/aristolochic acid nephropathy).

Kidney biopsy. This is an example of acute interst Kidney biopsy. This is an example of acute interstitial nephritis. The renal cortex shows a diffuse interstitial, predominantly mononuclear, inflammatory infiltrate with no changes to the glomerulus. Tubules in the center of the field are separated by inflammation and edema, as compared with the more normal architecture in the right lower area (periodic acid-Schiff, 40 X).
Kidney biopsy. Shown here is an example of acute i Kidney biopsy. Shown here is an example of acute interstitial nephritis. The diagnosis is based on the active inflammatory infiltrate on the right with unaffected glomeruli. Interstitial edema and fibrosis are present on the left side of the field, where some tubules show thickened basement membrane (hematoxylin and eosin, 20 X).
Kidney biopsy. This image shows acute interstitial Kidney biopsy. This image shows acute interstitial nephritis. The mononuclear inflammatory infiltrate contains abundant eosinophils, suggesting an allergic etiology. Severe tubular damage is observed (hematoxylin and eosin, 40 X).
Kidney biopsy. This image shows acute interstitial Kidney biopsy. This image shows acute interstitial nephritis. The inflammatory infiltrate forms an ill-defined granuloma, suggesting allergic or infectious etiologies. A partially destroyed tubule is present (periodic acid-Schiff, 40 X).

Findings on kidney biopsy in chronic tubulointerstitial nephritis usually show varying degrees of interstitial fibrosis, tubular atrophy, fibrosis, arteriolar sclerosis, and, occasionally, patchy mononuclear cell infiltration (see the image below). Often, the findings are nonspecific and the etiology is not discernible from the biopsy; some diseases, such as sarcoidosis, show noncaseating granulomas, and, in viral diseases, immunostaining can yield clues to the cause.

Kidney biopsy. This image shows chronic tubulointe Kidney biopsy. This image shows chronic tubulointerstitial nephritis. The interstitium is expanded by fibrosis, with distortion of tubules and periglomerular fibrosis. Glomeruli do not show pathologic changes (hematoxylin and eosin, 20 X).

Kidney biopsy during the acute phase of cholesterol microembolism shows the characteristic needle-shaped clefts caused by the cholesterol crystals within the small- and medium-sized arterioles accompanied by patchy tubulointerstitial nephritis with mild mononuclear cellular infiltration. (Eyeground examination may also reveal the characteristic cholesterol crystals, also termed Hollenhorst plaques, in retinal vessels, which can support the diagnosis.)

Kidney biopsy in interstitial nephritis. This imag Kidney biopsy in interstitial nephritis. This image shows a cholesterol microembolism. The 2 arterioles in the center are occluded by elongated crystals (hematoxylin and eosin, 20 X).
Kidney biopsy in interstitial nephritis. This imag Kidney biopsy in interstitial nephritis. This image shows a cholesterol microembolism. The arteriole in the center of the field has a thickened wall. The lumen is occluded by elongated spaces, corresponding to dissolved crystals surrounded by cellular reaction. The 2 glomeruli flanking the arteriole are sclerotic and hardly recognizable (hematoxylin and eosin, 40 X).

Kidney biopsy is not diagnostic of lead etiology for chronic lead poisoning and shows nonspecific changes such as interstitial fibrosis, tubular atrophy, and vascular sclerosis, findings common to tubulointerstitial nephritides of other etiologies.

Previous
 
 
Contributor Information and Disclosures
Author

A Brent Alper, Jr, MD, MPH Associate Professor of Medicine, Section of Nephrology and Hypertension, Department of Medicine, Tulane University School of Medicine

A Brent Alper, Jr, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Hypertension, American Society of Nephrology, National Kidney Foundation, Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ajay K Singh, MB, MRCP, MBA Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Additional Contributors

F John Gennari, MD Associate Chair for Academic Affairs, Robert F and Genevieve B Patrick Professor, Department of Medicine, University of Vermont College of Medicine

F John Gennari, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Acknowledgements

We wish to thank Suzanne Meleg-Smith, MD, for her previous contributions to this article.

References
  1. Harris RC, Neilson EG. Toward a unified theory of renal progression. Annu Rev Med. 2006. 57:365-80. [Medline].

  2. Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006 Jan. 69(2):213-7. [Medline]. [Full Text].

  3. Rangan GK, Wang Y, Tay YC, Harris DC. Inhibition of nuclear factor-kappaB activation reduces cortical tubulointerstitial injury in proteinuric rats. Kidney Int. 1999 Jul. 56(1):118-34. [Medline].

  4. De Broe ME, Elseviers MM. Over-the-counter analgesic use. J Am Soc Nephrol. 2009 May 7. [Medline].

  5. Slade N, Moll UM, Brdar B, et al. p53 mutations as fingerprints for aristolochic acid: an environmental carcinogen in endemic (Balkan) nephropathy. Mutat Res. 2009 Apr 26. 663(1-2):1-6. [Medline]. [Full Text].

  6. Karmaus W, Dimitrov P, Simeonov V, et al. Offspring of parents with Balkan Endemic Nephropathy have higher C-reactive protein levels suggestive of inflammatory processes: a longitudinal study. BMC Nephrol. 2009 Apr 28. 10:10. [Medline]. [Full Text].

  7. Maripuri S, Grande JP, Osborn TG, et al. Renal involvement in primary Sjögren''s syndrome: a clinicopathologic study. Clin J Am Soc Nephrol. 2009 Sep. 4(9):1423-31. [Medline]. [Full Text].

  8. De Broe ME. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy. Kidney Int. 2012 Mar. 81(6):513-5. [Medline].

  9. Saeki T, Nishi S, Imai N, Ito T, Yamazaki H, Kawano M, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int. 2010 Nov. 78(10):1016-23. [Medline].

  10. Mackensen F, Billing H. Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol. 2009 Sep 11. [Medline].

  11. Border WA, Holbrook JH, Peterson MC. Gallium citrate Ga 67 scanning in acute renal failure. West J Med. 1995 May. 162(5):477-8. [Medline].

  12. Linton AL, Richmond JM, Clark WF, Lindsay RM, Driedger AA, Lamki LM. Gallium67 scintigraphy in the diagnosis of acute renal disease. Clin Nephrol. 1985 Aug. 24(2):84-7. [Medline].

  13. Hettinga YM, Scheerlinck LM, Lilien MR, Rothova A, de Boer JH. The Value of Measuring Urinary ß2-Microglobulin and Serum Creatinine for Detecting Tubulointerstitial Nephritis and Uveitis Syndrome in Young Patients With Uveitis. JAMA Ophthalmol. 2014 Oct 30. [Medline].

  14. Shi Y, Su T, Qu L, Wang C, Li X, Yang L. Evaluation of urinary biomarkers for the prognosis of drug-associated chronic tubulointerstitial nephritis. Am J Med Sci. 2013 Oct. 346(4):283-8. [Medline].

  15. Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med. 2003 Jan 23. 348(4):277-86. [Medline].

  16. Lin JL, Lin-Tan DT, Yu CC, Li YJ, Huang YY, Li KL. Environmental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes. Kidney Int. 2006 Jun. 69(11):2049-56. [Medline].

 
Previous
Next
 
Kidney biopsy. This is an example of acute interstitial nephritis. The renal cortex shows a diffuse interstitial, predominantly mononuclear, inflammatory infiltrate with no changes to the glomerulus. Tubules in the center of the field are separated by inflammation and edema, as compared with the more normal architecture in the right lower area (periodic acid-Schiff, 40 X).
Kidney biopsy. Shown here is an example of acute interstitial nephritis. The diagnosis is based on the active inflammatory infiltrate on the right with unaffected glomeruli. Interstitial edema and fibrosis are present on the left side of the field, where some tubules show thickened basement membrane (hematoxylin and eosin, 20 X).
Kidney biopsy. This image shows acute interstitial nephritis. The interstitium is expanded by mononuclear inflammatory infiltrate and edema. Acute tubular damage is present; some tubules are distended and contain granular casts (hematoxylin and eosin, 40 X).
Kidney biopsy in interstitial nephritis. Acute crescentic glomerulonephritis. The glomerular tuft is compressed by the proliferation of epithelial cells, forming a crescent. The interstitium shows mononuclear inflammatory infiltrate and edema (periodic acid-Schiff, 40 X).
Kidney biopsy. This image shows acute interstitial nephritis. The mononuclear inflammatory infiltrate contains abundant eosinophils, suggesting an allergic etiology. Severe tubular damage is observed (hematoxylin and eosin, 40 X).
Kidney biopsy. This image shows acute interstitial nephritis. The inflammatory infiltrate forms an ill-defined granuloma, suggesting allergic or infectious etiologies. A partially destroyed tubule is present (periodic acid-Schiff, 40 X).
Kidney biopsy. This image shows chronic tubulointerstitial nephritis. The interstitium is expanded by fibrosis, with distortion of tubules and periglomerular fibrosis. Glomeruli do not show pathologic changes (hematoxylin and eosin, 20 X).
Kidney biopsy in interstitial nephritis. This image shows a cholesterol microembolism. The 2 arterioles in the center are occluded by elongated crystals (hematoxylin and eosin, 20 X).
Kidney biopsy in interstitial nephritis. This image shows a cholesterol microembolism. The arteriole in the center of the field has a thickened wall. The lumen is occluded by elongated spaces, corresponding to dissolved crystals surrounded by cellular reaction. The 2 glomeruli flanking the arteriole are sclerotic and hardly recognizable (hematoxylin and eosin, 40 X).
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.