Acute and Chronic Tubulointerstitial Nephritis

Acute and Chronic Tubulointerstitial Nephritis

Sergey V. Brodsky

Tibor Nadasdy


Cellular and fluid exudation in the interstitial tissue was noted by Councilman in 1898, while he studied kidneys of patients who died of scarlet fever and diphtheria (1). Councilman also determined that these kidneys did not contain bacteria (they were sterile). He called the condition acute interstitial nephritis (AIN). The term interstitial nephritis connotes predominant involvement of the renal interstitium and tubules by inflammatory cells, often with edema or fibrosis and tubular atrophy. Because interstitial nephritis is commonly accompanied by variable tubular damage, the term tubulointerstitial nephritis (TIN), or tubulointerstitial nephropathy, is preferable and is often used interchangeably with interstitial nephritis. TIN has two common clinical presentations: sudden onset and rapid decline in renal function—acute TIN—and protracted onset with slow decline in renal function—chronic TIN. Because chronic TIN may present with prominent fibrosis and few inflammatory cells, the term chronic tubulointerstitial fibrosis, or chronic tubulointerstitial nephropathy, is used by some. Tubulitis refers to infiltration of the tubular epithelium by leukocytes, usually mononuclear cells. Acute TIN, with time, can evolve into chronic TIN; therefore, overlaps between these two entities often exist.

The term primary TIN refers to cases where the inflammation is essentially limited to the tubules and interstitium; glomeruli and vessels are uninvolved or show minor changes. Secondary TIN implies tubulointerstitial inflammation associated with a primary glomerular, vascular, or systemic disease. Idiopathic TIN is a primary TIN whose etiologic agent or cause is unknown.

Reactive TIN connotes tubulointerstitial inflammation from the effects of systemic infections; the kidneys usually are sterile. Infectious TIN denotes tubulointerstitial inflammation from the effects of localization of live microorganisms in the kidney, where they can be identified and from which they often can be cultured.

Interstitial nephritis is commonly secondary to infection. These include acute and chronic pyelonephritis by bacteria or fungus, viral infection, and protozoal infections. Infectionassociated interstitial nephritis is discussed in Chapter 24.


The exact incidence of TIN is unknown. Available figures vary by geographical area, entry criteria, and mode of diagnosis. While renal biopsy remains the gold standard for diagnosis of TIN, nephrologists are less likely to biopsy patients with clinical signs and symptoms of TIN than patients with glomerular diseases. Therefore, the diagnosis of TIN is often based on epidemiologic, clinical, and laboratory evaluations rather than renal biopsy findings (2). Also, mild forms of TIN may be overlooked, because of the absence or vagueness of clinical symptoms. Acute TIN accounts for approximately 3% of kidney biopsies, but this figure may be as high as 25% to 27% in adult patients with acute kidney injury (AKI) (3). In children, acute TIN may account for up to 7% of patients with AKI (4).

It is important to establish the diagnosis of TIN through kidney biopsy for the following reasons: (a) Clinical and laboratory data alone often do not differentiate between TIN and other renal diseases attended by renal insufficiency or renal failure; (b) most acute tubulointerstitial nephritides can be successfully treated; (c) untreated acute TIN may result in interstitial fibrosis and irreversible renal injury; and (d) the use of molecular and other techniques discloses possible genetic abnormalities and the underlying mechanisms of tissue injury (5).


TIN is best classified according to the underlying etiology. The classification that we follow in our outline has been modified from those of Churg et al. (6) and Colvin and Fang (7). Some causes of TIN, including infectious etiologies, are covered in other chapters. TIN is often multifactorial, and several etiologic agents or causes, such as concurrent infection and obstruction, may contribute to tubulointerstitial renal disease in the same patient. Drug-induced TIN is the most common type determined by kidney biopsy, accounting for more than two thirds of the cases. Infection-related TIN may account for up to 15% of cases, whereas idiopathic forms of TIN represent approximately 10% of cases (3,8,9,10). The etiologic agents and causes of TIN are varied but can be grouped into broad categories. Baker and Pusey (8) pooled their data with two series from the literature (11,12). They found that the most frequent etiology of interstitial nephritis is drug related (71.1%), with antibiotics accounting for about a third of these cases. Infection caused 15.6% of interstitial nephritis cases, and 7.8% were idiopathic. TIN and uveitis syndrome (TINU) was responsible for 4.7% of cases, and only 0.8% of the biopsies were due to sarcoidosis. Similar data were observed by other authors as well (9). Among autoimmune interstitial nephritis, more and more attention is paid to IgG4-related TIN (13). The exact incidence of autoimmune interstitial nephritis, including IgG4-related TIN, is unknown, but it is likely that many of the so-called idiopathic interstitial nephritides represent a form of autoimmune interstitial nephritis.

TABLE 25.1 Main etiologic and pathogenetic factors responsible for TIN

Drug toxicity

Heavy metals

Metabolic disorders

Hereditary disorders

Miscellaneous disorders


Immunologic mechanisms

Anti-TBM antibodies

Immune complexes

Cellular mechanisms


The main etiologic/pathogenetic factors responsible for TIN are shown on Table 25.1.


Various nonspecific clinical and laboratory findings may occur depending, in part, on the underlying cause or portion of the nephron that is affected. AIN may develop at any age and may be associated with variable degrees of acute renal insufficiency. Acute renal failure tends to be more prominent in the elderly. Systemic manifestations of hypersensitivity, such as erythema, maculopapular skin rash, arthralgias, fever, and peripheral eosinophilia, may occur primarily in drug-induced AIN, but these findings are frequently absent. Urinalysis usually reveals microscopic hematuria. Very rarely, gross hematuria or red blood cell (RBC) casts may be seen. Typically, these patients have white blood cells (WBCs) in the urine, and urine cultures are negative (sterile pyuria). Eosinophils in the urine, particularly if this number is greater than 1% of the cells, are thought to be a very characteristic finding in AIN. However, recent publications suggest that the specificity of urine eosinophils may be overestimated. Thus, out of 62 patients with eosinophiluria, only 13 patients had acute TIN, with the sensitivity of 25% and positive predictive value of 3% (14). Ruffing et al. (15) addressed the diagnostic accuracy of this test. In a selected group of patients, in which the diagnosis of AIN was suspected by the nephrologist, the sensitivity of eosinophiluria was 40% and the specificity was 72% with a positive predictive
value of only 38%. The same authors also examined consecutive patients with WBC in the urine who did not have interstitial nephritis. Four of these patients had urinary eosinophils greater than 1%. Eosinophiluria is not uncommon in secondary forms of interstitial nephritis, particularly in those that are associated with crescentic glomerulonephritis (vasculitis).

Mild proteinuria, usually less than 1 g/24 hours, is frequently seen, but nephrotic-range proteinuria is rare. Nephrotic syndrome may occur if interstitial nephritis is associated with minimal change disease secondary to nonsteroidal anti-inflammatory drugs (NSAIDs). If the inflammation affects primarily the proximal tubule, it may result in renal glucosuria, aminoaciduria, phosphaturia, and uricosuria. If the distal tubule is primarily damaged, potassium secretion and sodium balance regulation suffer. Renal tubular acidosis may follow the damage of both distal and proximal tubules. It is worth noting that in many instances both the proximal and distal tubules are equally undergoing injury. Medullary inflammation may be associated with inappropriate urinary concentration and polyuria.


The details of gross and histologic features underlying the pathology of tubulointerstitial nephritides associated with various agents or conditions are provided in the following sections. In this section, we present an overview of the pathology of primary TIN. Pyelonephritis and other infection-related interstitial nephritides are discussed in Chapter 24.

FIGURE 25.1 Interstitial nephritis in a 66-year-old patient who did not have any identifiable underlying etiology but had peripheral eosinophilia. A: Interstitial mononuclear cell infiltrate with edema. (PAS, ×100.) B: Focally large numbers of eosinophils were present in the interstitium. (H&E, ×400.) C: In several foci, the inflammatory cells infiltrated the tubular epithelium (tubulitis). (PAS, ×600.)

Acute Tubulointerstitial Nephritis

Grossly, the kidneys are pale, edematous, and enlarged, with the degree of enlargement proportional to the extent of involvement. The external surface is smooth.

Microscopically, the cellular infiltration and edema are multifocal and vary in intensity. Although neutrophils are common in acute TIN, mononuclear cells, including lymphocytes and macrophages, also participate in inflammation and are usually the predominant cell types (Fig. 25.1). Drug reactions, such as those to antibiotics, are often associated with mononuclear cell infiltrates, including lymphocytes and frequently eosinophils. Most mononuclear cells in the inflammatory infiltrate are T cells (Fig. 25.2) (16,17). Overall, CD4+ T cells predominate relative to CD8+ T cells (17). However, in the report of Bender et al. (16), nine patients with drug-induced TIN had nephrotic-range proteinuria and predominance of CD8+ T cells in the interstitial infiltrate. Similarly, in the report of D’Agati et al. (18), CD8+ T cells outnumber CD4+ T cells in the interstitium in 22 of 26 biopsies of patients with lupus nephritis. It appears that CD8+ T cells are effectors of injury, whereas CD4+ cells play a predominantly regulatory role (19). In later stages of progressive tubulointerstitial disease, monocytes/macrophages tend to predominate (20). Eosinophils are
common in drug-induced cases, but their absence does not exclude a drug-induced form of interstitial nephritis (21). After a few days or weeks have elapsed, a variable accumulation of plasma cells and histiocytes may be present (Fig. 25.3). Although not a common component of acute TIN, granuloma formation may occur in drug reactions, sarcoidosis, and idiopathic forms (Fig. 25.4) (3). If many plasma cells are seen, the diagnosis of IgG4-related interstitial nephritis should be considered, and an immunostain for IgG4 should be performed (13) (Fig. 25.5).

FIGURE 25.2 Immunohistochemistry reveals many T cells in the interstitial inflammatory cell infiltrate in this biopsy from a patient with Sjögren syndrome. (Immunoperoxidase with an anti-CD3 antibody, ×400.)

Tubular injury includes tubulitis (see Fig. 25.1C), breaks of tubular basement membrane (TBM), necrosis of tubular cells, and, later, atrophy and loss of tubules, depending on the stage of the disease. According to Ivanyi et al. (22), tubulitis more often involves the distal nephron. Biopsies taken several days after the initial insult show features of tubular cell regeneration, manifesting as flattening of the epithelial lining, cytoplasmic basophilia, and enlarged nuclei with frequent and prominent nucleoli. Nuclear changes may also be observed due to direct drug toxicity or in association with viral infections. Although not a common component of acute TIN, some interstitial fibrosis, as a part of the reparative process, may be seen in late biopsies. The presence of monocytes/macrophages and granulomas and some degree of fibrosis, encountered in some forms of acute TIN, emphasizes the overlap that exists between acute and chronic TIN (Figs. 25.4 and 25.6). Tamm-Horsfall protein (THP) may find its way into the interstitium following tubular rupture (Fig. 25.7). Interstitial THP is commonly found in nephron obstruction, but it is not exclusive to obstructive nephropathy.

FIGURE 25.3 Many plasma cells in an acute and chronic interstitial nephritis, in a patient with Sjögren syndrome. (H&E, ×600.)

FIGURE 25.4 Granulomatous interstitial nephritis. Well-defined epithelioid granuloma with giant cells in the renal biopsy of a patient with sarcoidosis. (H&E, ×100.)

Immunofluorescence and immunohistochemical techniques may be helpful in the determination of the underlying etiology. Linear deposits of an immunoglobulin (usually IgG) and complement along the TBM suggest an antibody directed to or cross-reactive with the TBM. Granular deposits of an immunoglobulin and complement in the TBM, interstitium, or both suggest an immune complex pathogenesis. This is common in systemic lupus erythematosus (SLE) and IgG4-related interstitial nephritis (13,23). However, granular or linear TBM staining for complement (particularly C3) is a frequent nonspecific finding, especially in the basement membrane of atrophic tubules.

Electron microscopy is also of limited value in the diagnosis of interstitial nephritis. Ultrastructural examination may occasionally reveal electron-dense immune-type deposits along the TBM or in the interstitium, particularly if there is underlying SLE or IgG4-related disease. Crystalline inclusions in tubular epithelial cells or finely granular electron-dense deposits along the TBM indicate monoclonal immunoglobulin deposition. Crystalline inclusions may also be seen with cystinosis. Rarely, electron microscopy may be helpful in detecting viral particles in infected tubular epithelial cells.

In acute TIN, the glomeruli are mostly spared. Arterial and arteriolar changes are usually absent. When present in
older persons, they are unrelated to the primary tubulointerstitial process and reflect aging, associated hypertension, or both.

FIGURE 25.5 IgG4-related interstitial nephritis. A: Numerous plasma cells are seen in interstitial inflammatory cell infiltrates. (H&E, ×200.) B: Immunohistochemistry shows multiple IgG4-positive plasma cells. (Immunoperoxidase, ×200.)

The morphology of AIN is nonspecific, and only in rare instances is it possible to define the exact etiology. If typical viral inclusions are present or other microorganisms can be identified or if characteristic immune complex deposits are present, an etiologic diagnosis may be possible. A more detailed description of the morphologic findings will be given in this chapter in the section describing the different forms of AIN.

Chronic Tubulointerstitial Nephritis

Common causes of chronic TIN are infections, drug reactions (e.g., analgesics, lithium), urinary tract obstruction, sterile reflux of urine, some forms of immune-mediated TIN, plasma cell dyscrasias, metabolic disorders, exposure to heavy metals, hereditary diseases, and various chronic nephropathies, including idiopathic TIN. Chronic TIN always develops if a progressive chronic primary glomerular disease is present. It is also a common finding in systemic disorders involving the kidney, including systemic autoimmune diseases, monoclonal gammopathies, and metabolic diseases. Vascular diseases are also frequently associated with chronic TIN, particularly vasculitis and chronic forms of thrombotic microangiopathies, but also ischemia secondary to atherosclerosis and hypertension can induce chronic tubulointerstitial injury with some degree of inflammation.

FIGURE 25.6 Active appearing interstitial inflammatory cell infiltrate with eosinophils in the background of interstitial fibrosis and tubular atrophy in a patient with a long history of gout and multiple medication use. (H&E, ×200.)

Grossly, kidneys with chronic TIN appear small, contracted, and pale. Variable papillary involvement, including papillary necrosis, sclerosis, and calcification, may be evident. The external surface is usually scarred, or finely granular from small vessel disease, compensatory hypertrophy of residual nephrons, or both. The corticomedullary junction is usually poorly demarcated. The intrarenal vessels are prominent and may have thickened walls.

FIGURE 25.7 Tubular rupture with expulsion of Tamm-Horsfall protein from the tubule into the interstitium. Note the interstitial inflammatory cell infiltrate around the Tamm-Horsfall protein. This is a nonspecific finding that can occur in any renal injury with tubular disruption and secondary interstitial Tamm-Horsfall protein deposits. (PAS, ×400.)

FIGURE 25.8 Different histologic appearances of atrophic tubules. A: Prominent thickening of the TBM in “classic” atrophic tubules highlighted by double PAS-trichrome stain (28). Note violet appearance of the TBM and blue interstitial collagen between the atrophic tubules. (PAS-trichrome double stain, ×200.) B: Endocrine-type atrophic tubules surrounding a sclerotic glomerulus. In this type of atrophic tubule, the basement membrane is thin and the epithelium is simplified with no or only very narrow lumen. These tubules resemble endocrine glands. (PAS, ×400.) C: Thyroidization of tubules in a scarred area of the renal cortex. Thyroid-type atrophic tubules have flattened epithelium and PAS-positive proteinaceous filling the lumen, resembling thyroid follicles. (H&E, ×100.)

Microscopically, the inflammatory cell infiltrates are made up of variable numbers of lymphocytes, monocytes/macrophages, and plasma cells. Granulomas may be seen in TIN associated with drugs; infections with mycobacteria, fungi, and parasites; sarcoidosis; and vasculitis. Some are idiopathic (24,25,26). Tubular atrophy and interstitial fibrosis are the histologic hallmarks of chronic interstitial nephritis, usually associated with some degree of interstitial mononuclear cell infiltrate. Tubular atrophy has different morphologic subtypes (27) (Fig. 25.8). The most common type is the “classic” type: atrophic tubule with prominently thickened, frequently wrinkled, and lamellated basement membrane (see Fig. 25.8A). The “endocrine”-type atrophic tubule has a narrow lumen or no lumen at all, is usually prominently reduced in diameter, and has simplified epithelium and a thin basement membrane (see Fig. 25.8B). These “endocrine”-type atrophic tubules usually occur in clusters. The “thyroid”-type atrophic tubule has only mildly thickened basement membrane, a simplified flattened epithelium, and a lumen filled with eosinophilic Periodic acid-Schiff (PAS)-positive homogenous proteinaceous material; therefore, the tubule resembles a thyroid follicle (see Fig. 25.8C). These “thyroid”-type atrophic tubules also occur in clusters, and, in occasional cases of renal scarring, the parenchyma resembles thyroid gland. The diagnostic significance of these different types of atrophic tubules is somewhat limited. The endocrine-type atrophic tubule is frequently seen in chronic ischemia, including renal artery stenosis. The thyroid-type atrophic tubule is a common finding in chronic pyelonephritic scars, but we have also frequently observed thyroidization of tubules in ischemic scars, including kidneys with interstitial fibrosis secondary to antiphospholipid antibodies.

In chronic tubulointerstitial injury, tubules frequently undergo compensatory hypertrophy, whatever the etiology. These hypertrophic tubules are lined usually with tall proximal-appearing tubular epithelial cells. The lumen is dilated and commonly irregular (Fig. 25.9). Microcystic dilation of tubules in scarred interstitial areas may also occur. These microcystic tubules usually have a thin simplified epithelium and are filled by proteinaceous homogeneous material. Sometimes, the microcysts may have a scalloped outline (Fig. 25.10).

Interstitial fibrosis, a characteristic feature of chronic TIN, must be considered according to location. In the cortex, the interstitial volume is uniform and composes approximately 7% of the cortical volume (29), whereas in the medulla, the interstitial space increases from the outer stripe of the inner medulla to the tip of the renal papilla. For example, in the rat kidney, the interstitial space at the base of the inner medulla is about 10% of the medullary space but attains 30% of the interstitial space at the tip of the papilla (30). Interstitial fibrosis may be multifocal or diffuse, and the deposited extracellular matrix is a combination of various types of collagens, including types I, III, and V, derived from interstitial fibroblasts. Other cells,
including tubular epithelial cells and endothelial cells, also contribute to the extracellular matrix deposition by producing fibronectin, type IV collagen, and a variety of other matrix proteins (31). Interstitial fibrosis and tubular atrophy are cardinal features for the diagnosis of chronic TIN because inflammatory cells may be scarce or absent.

FIGURE 25.9 It is common to see large hypertrophic tubules with thick, hypertrophic epithelial lining in any type of advanced chronic renal injury. (H&E, ×100.)

Immunofluorescence and immunohistochemical techniques may be helpful in delineation of the pathogenic mechanisms in a few cases, in a manner similar to that already described for acute TIN. Granular deposits of immunoglobulin and complement along the TBM and interstitium may indicate tubulointerstitial injury mediated by immune complexes. But one has to remember that C3 deposition is a very common nonspecific finding in the basement membrane of atrophic tubules. Immunohistochemical techniques also can be used to identify the segment of the nephron that is involved (32) to develop functional correlates of tissue injury. For example, when TIN involves predominantly the proximal tubules, proximal renal tubular acidosis (type II) develops owing to loss of proximal tubule resorbate (e.g., glucose, phosphate, uric acid, organic acids, low molecular weight proteins), with or without Fanconi syndrome. When distal tubules are predominantly involved, distal renal tubular acidosis (type I) develops, caused by failure of lowering the urinary pH, with or without hyperkalemia and salt wasting. When collecting ducts and papillary involvement predominate, water conservation is compromised by the decreased ability to concentrate urine. Molecular techniques have enabled the detection of deletions of genetic material as a possible cause of certain tubulointerstitial nephritides, such as the defect in the tubulointerstitial antigen gene in some children with progressive TIN (see later section in this chapter) (33).

FIGURE 25.10 Microcystic dilation of tubules with scalloped outline. Such tubules can be seen in any kind of chronic tubulointerstitial injury. (PAS, ×100.)

FIGURE 25.11 Thickened lamellated basement membrane of an atrophic tubule. (Uranyl acetate and lead citrate, ×3000.)

Electron microscopy in chronic TIN has limited diagnostic value, as indicated above in the discussion of AIN. The basement membrane of atrophic tubules is not only thickened on ultrastructural examination but is frequently also lamellated. This lamellation is probably the result of repeated tubular epithelial injury and regeneration. The regenerating renal epithelium probably creates newer and newer thin layers of basement membrane material, which will lend a lamellated pattern to the thickened TBM (Fig. 25.11). Aggregates of granular to microspherical material in the thickened basement membranes of atrophic tubules are not uncommon (Fig. 25.12). This material should not be misinterpreted as immune complex deposition.

In contrast to acute TIN, in which glomeruli are usually spared, glomeruli in chronic TIN often show changes. These glomerular changes are frequently secondary to poor glomerular blood perfusion and include tuft wrinkling and collapse, thickening of the Bowman capsule, periglomerular fibrosis, and glomerular obsolescence. Glomeruli with periglomerular fibrosis are frequently, but not always, atubular (34). Occasionally, segmental glomerulosclerosis may develop. Arterial and arteriolar changes, such as intimal thickening and medial hyperplasia, are usually present and reflect aging and associated hypertension.

FIGURE 25.12 Deposits of granular to microspherical material in the TBM is a common finding in atrophic tubules. Under low magnification, these structures may be misinterpreted as electron-dense immune-type deposits in the TBM. (Uranyl acetate and lead citrate, ×20,000.)


The pathogenic mechanisms operative in tubulointerstitial nephritides associated with various agents or conditions are provided in the sections to follow. In this section, we present a brief overview of pathogenic mechanisms that are specific for certain tubulointerstitial nephropathies and that are common to most forms of chronic tubulointerstitial nephropathies.

Reactive TIN appears to result from systemic release of lymphokines that are filtered and reabsorbed by the kidneys, thereby promoting chemoattraction and activation of mononuclear cells in the kidneys (1,7,35,36). Infectious TIN results from three basic mechanisms of tissue injury (37): microbial release of degradative enzymes and toxic molecules, direct contact or penetration of host cells by the microbe, and the inflammatory response mediated by antibodies, T cells, or both. The pathogenesis of infectious TIN and vesicoureteral reflux is covered in Chapter 24. Drug-induced TIN is most likely immunologically mediated. The most widely accepted theory is that drugs behave as haptens after binding to extrarenal proteins that later will be planted in the kidney or to renal proteins (38). This will be discussed in detail in the following section of this chapter. Drug-induced AIN occurs in only a small percentage of patients taking a medication and is not dose dependent, and exacerbation occurs after reexposure to the drug. Also, systemic signs of hypersensitivity may be evident.

TIN owing to anti-TBM antibodies involves predominantly IgG antibodies directed against different autoantigens in basement membranes, including a 54-kDa protein called TIN antigen, localized to chromosome 6p11.2-12 whose molecular composition has been cloned and sequenced (39). However, in our experience, true anti-TBM antibody-mediated interstitial nephritis is extremely rare, and we believe that the anti-TBM antibodies may form secondary to the tubular damage rather than causing it.

TIN owing to immune complexes involves predominantly IgG antibodies, which probably are generated against a variety of tubular antigens. It is possible that antibodies may form against THP or megalin (a protein, localized in the brush border of proximal tubular epithelial cells), because immunization of rabbits or rats with those proteins resulted in AIN (40). IgG4-containing immune complexes are present along the TBM in IgG4-related interstitial nephritis; the pathologic role of these immune complexes is unclear (41). Tubulointerstitial injury may depend on complement activation by antibody (42), release of chemoattractants, and activation of leukocytes with release of chemokines, cytokines, proteases, and toxic oxygen radicals (36). In many forms of interstitial nephritis, eosinophils are prominent in the interstitium, which may be related to a chemotactic cytokine, eotaxin, produced locally by renal parenchymal cells (43).

TIN due to cell-mediated mechanisms encompasses two types of reactions. First, delayed-type hypersensitivity reaction, which requires prior sensitization and is caused by CD4+ T cells and macrophages, results in production of various lymphokines and may induce a granulomatous reaction. Second, cytotoxic T-cell injury, which requires no prior sensitization, is mediated by CD4+ and CD8+ T cells (26).

Tubulointerstitial inflammation, fibrosis, and tubular atrophy, common to most chronic tubulointerstitial nephropathies, can be induced by various agents and causes. If the underlying etiology is persistent and cannot be eliminated, eventually all etiologic agents will cause chronic tubulointerstitial injury. Various pathogenetic factors are involved in the generation of interstitial fibrosis and tubular atrophy, including ischemia, reactive oxygen species, toxic agents, or immunologic injury (44). It is likely that an important role in the common final pathway leading to fibrosis can be attributed to the transforming growth factor beta (TGF-β)/Smad3 signaling pathway (45,46,47). TGF-β is up-regulated in response to injurious stimuli by angiotensin II (47). This accounts, at least in part, for the beneficial effect of angiotensin convertase inhibition slowing the progression of chronic renal injury. TGF-β transmembrane receptors transduce downstream signals via cytoplasmic latent transcription factors called Smad proteins. Smad 2 and 3 are phosphorylated, and they bind to Smad 4 and translocate to the nucleus, where they act as transcriptional regulators of target genes. Disruption of the TGF-β/Smad signaling pathway inhibits interstitial fibrosis in experimental animals (45). Connective tissue growth factor (CTGF) is a downstream mediator of the profibrotic effects of TGF-β. Recent data indicate that CTGF may play a pivotal role in the pathogenesis of TGF-β-dependent interstitial fibrosis (48). There is growing evidence that TGF-β is also capable of inducing epithelial to mesenchymal transdifferentiation of renal tubular epithelial cells (Fig. 25.13) (49,50). The theory is that during tubular injury, activated, injured tubular epithelial cells migrate through TBM ruptures into the interstitium, where they lose their epithelial characteristics and gain mesenchymal markers, such as smooth muscle specific actin, and turn into myofibroblasts. This transdifferentiation process of the injured tubular epithelial cells may be a key pathogenetic step in the development of chronic interstitial nephritis; however, convincing in vivo evidence for tubular epithelial cell to mesenchymal transdifferentiation is still missing (50,51,52). Based on lineage analysis of mesenchymal cells during nephrogenesis in a mouse model, Humphreys et al. (52) recently proposed that expansion of pericytes is primarily responsible for the development of interstitial fibrosis.

FIGURE 25.13 Scattered cytokeratin-positive cells are commonly found in the fibrotic renal interstitium. It is theoretically possible that these cytokeratin-positive cells represent cells undergoing epithelial-tomesenchymal transformation. (Immunoperoxidase, ×600.)


The kidney is adversely affected by a wide variety of therapeutic and diagnostic agents and toxic compounds. However, there are only a limited number of patterns of injury produced in the kidney. These may affect any of the compartments of the kidney including tubulointerstitial, glomerular, and vascular pathology (53,54). In the following section, we will focus only on acute and chronic TIN induced by drugs. Other patterns of renal injury associated with drug reaction, including acute tubular necrosis (ATN) and glomerular and vascular changes, will be discussed in other chapters.

It should be recognized that it is often difficult to establish a pathogenetic link between a pathologic lesion and a particular drug or toxin. Several factors contribute to this uncertainty, including concurrent factors that may produce renal injury, such as administration of several potentially nephrotoxic drugs at the same time, lack of or inadequacy of morphologic data in reported cases of drug toxicity, and the fact that some drugs may have multiple effects. Moreover, experimental models of toxicity may not be relevant to a particular clinical context because of interspecies variation and markedly different dosing of drugs in these models. In general, we limit our discussion to those drugs for which toxicity has been well documented in humans by disappearance of toxic effects when the drug is withdrawn, reoccurrence of symptoms on rechallenge, or both.

As pointed out earlier, today the most common form of interstitial nephritis is drug induced. Many drugs, including a range of widely used therapeutic agents, produce unpredictable idiosyncratic systemic reactions that may manifest in the kidney primarily as TIN.

Clinical Features

TIN caused by drug or toxin exposure develops in a few patients who receive the drug; reactions can sometimes be predicted if the patient has had a reaction to the same or a similar agent. The reaction is generally unrelated to the cumulative dose of the drug. Exposure to the offending agent typically occurs days to a few weeks before the clinical presentation (10). Patients may show signs of a systemic syndrome that include fever, skin rash, eosinophilia, and arthralgias. However, only a few patients will have this classic constellation of symptoms (12). Affected individuals may note fluid retention or a fall in urine output, and occasionally, patients may experience back or flank pain (55). Many patients show symptoms of AKI.

Analysis of the urine typically reveals pyuria with numerous mononuclear cells, including lymphocytes and monocytes. There may also be eosinophils, which researchers have touted as a specific marker for allergic interstitial nephritis (56). However, eosinophiluria is not specific for drug-induced interstitial nephritis (14). Eosinophils may best be detected by the use of special stains, such as the Hansel stain (57). Hematuria is not uncommon and is usually microscopic. Mild proteinuria may also be detected, and proteinuria may occasionally be in the nephrotic range, especially in those cases caused by drugs that also produce minimal change disease in the glomeruli. NSAIDs most commonly cause this constellation of symptoms. Urine cultures are routinely negative.

Because the interstitial inflammatory process can result in tubular injury, there may be evidence of tubular dysfunction. Patients may have glycosuria, aminoaciduria, and phosphaturia; occasionally, Fanconi syndrome has been described (58). In addition, tubular acidosis, electrolyte losses, or concentrating defects may be documented. On ultrasound, the kidneys are seen to be of normal size or enlarged. The parenchyma is typically echogenic—a finding that has been correlated with the extent of inflammatory infiltrate (and with the development of long-term changes in the interstitium).

Patients may have renal dysfunction without other accompanying symptoms. Because drug-induced interstitial nephritis is eminently reversible in the early stages, it is important to recognize the etiologic agent, so that long-term damage can be avoided. Some drugs produce more insidious changes, resulting in protracted injury without an obvious acute phase. Classic examples are lithium and analgesic compounds. These patients may show initial signs of salt wasting or acid-base imbalances and evidence of progressive tubular injury.


Gross Findings

In acute TIN, the kidney is usually pale and swollen. Areas of congestion and hyperemia may be seen at the corticomedullary junction. In chronic TIN, the kidney is smaller with thinning of the cortex. The surface of the kidney may become granular. Parenchymal cysts may develop as interstitial fibrosis progresses. The cortex may become pale due to a combination of fibrosis and inflammatory cells.

Light Microscopy


Glomeruli are typically spared. Occasionally, the interstitial inflammatory infiltrate may breach the Bowman capsule. In later stages of chronic interstitial nephritis, glomeruli may show nonspecific ischemic collapse and sclerosing changes. Periglomerular fibrosis is common in chronic cases.


In AIN, there are patchy or diffuse edema and inflammatory infiltrates. The infiltrate is predominantly mononuclear (see Fig. 25.1). Both CD4+ and CD8+ T cells have been detected in varying proportions. B cells and monocyte/macrophages can also be found. Eosinophils typically make up to 10% or less of the infiltrating cells. The eosinophils in the infiltrate may be focal and, rarely, they form clusters resembling a microabscess (see Fig. 25.1B) (56). Eosinophils are typically seen in reactions to antibiotics, especially penicillins, sulfonamides, and rifampicin, more than in response to various other drugs. Neutrophils are usually rare. Mast cells, which are difficult to detect without special stains, have been reported to constitute 1% to 2% of infiltrating cells (59). There is correlation between the number of interstitial mast cells and the degree of interstitial fibrosis in interstitial nephritis (60). Steroid treatment may reduce the severity of the inflammation and, in particular, lessen accompanying edema.

Granulomatous features are seen in the inflammatory reaction to many drugs (Table 25.2) (see Fig. 25.4). Granulomas, typically noncaseating and composed of epithelioid histiocytes, lymphocytes, and giant cells, may be scattered in the interstitium. They resemble the epithelioid granulomas of sarcoidosis, but the granulomas in drug-induced granulomatous interstitial nephritis are frequently less well defined than in sarcoidosis.

TABLE 25.2 Causes of granulomatous interstitial nephritis

Infection (see Chapter 24)


Fungal infections




Sulfonamides Penicillins










Nonsteroidal anti-inflammatory drugs (NSAIDs)

Bisphosphonates (alendronate)





Tubulointerstitial nephritis and uveitis syndrome (TINU)

Granulomatous vasculitis (Wegener’s)

Oxalosis (see Chapter 27)

Gout (see Chapter 27)

Cholesterol granuloma


In chronic drug-induced interstitial nephritis, the defining feature is interstitial fibrosis. An interstitial inflammatory infiltrate often persists, but it is usually mild and composed largely of nonactivated lymphocytes, plasma cells, and macrophages. These infiltrates are often nodular and localized to fibrotic areas. Although drug-induced acute TIN occasionally may persist and lead to chronic interstitial nephritis, some drugs have a propensity to produce subclinical progression to chronic renal failure. These drugs include analgesics, lithium, and calcineurin inhibitors.


Accompanying acute TIN, there may be evidence of tubular cell injury, which may include vacuolation, loss of brush border, and exfoliation and loss of tubular cells. The tubular epithelium is often infiltrated by inflammatory cells, usually lymphocytes (tubulitis) (see Fig. 25.1C). Although these characteristics are often described in the proximal nephron, a few investigators have reported that tubular injury and tubulitis may be more severe in the distal nephron (21,22). With a severe inflammatory reaction, the TBM may be disrupted. In the circumstance of chronic interstitial nephritis, tubular atrophy is typically seen to be associated with fibrosis in the interstitium.


Vessels are usually uninvolved, though a few drugs may produce vasculitis or thrombotic microangiopathy (see Chapters 16 and 18).


Fibrin is often detected in the interstitium by immunofluorescence, reflecting interstitial edema. IgG and C3 have been reported to be deposited in a linear pattern along the TBM in some cases of apparent drug-induced interstitial nephritis, including cases induced by penicillins (56,61,62,63) and rifampicin (64). Such linear TBM staining may be nonspecific. Minetti et al. have also reported granular peritubular IgG in one case due to rifampicin (65). In cases of methicillin-induced AIN, a drug antigen has been immunolocalized along the TBM as well (61,62).

Electron Microscopy

Ultrastructural examination is usually of limited informative value in drug-induced interstitial nephritis. Electron microscopy of the interstitium in cases of drug-induced interstitial nephritis reveals edema, infiltrating inflammatory cells, and tubulitis. Olsen et al. (66) have described severe reduction of the proximal tubular brush border and proximal and distal tubular basolateral infoldings in this context, reflecting tubular injury. In some areas, there may be thinning or disruption of the TBM. Electron-dense immune-type deposits are usually not present in TBMs.

Etiology and Pathogenesis

Three major types of immune mechanisms may lead to TIN in response to drugs. These include hypersensitivity/allergic, immune complex, and cell-mediated reactions. Each of these types is discussed in turn. In a few individual cases, mechanisms of action are clearly defined, but for others, pathogenetic mechanisms are assumed, often based on morphologic
and clinical findings. It is possible that several mechanisms of action are at work in an individual patient.

Allergic-type hypersensitivity reactions are idiosyncratic and not related to dose. The reaction to the agent is presumably caused by previous sensitization, and, indeed, patients may give a history of exposure to the ingested drug or a similar compound. The reaction in the kidney is often part of a systemic hypersensitivity reaction, which may include fever, arthralgias, and skin rash. Eosinophils are often a significant component of cells in the inflammatory infiltrate, and, as noted earlier, there is often a peripheral eosinophilia as well.

Reactions involving immune complex deposition are of two types: those with formation of immune complexes that are deposited around tubules and those due to formation of antibodies directed against antigens at or in the TBM. In a few cases, antigens from the drug have been immunolocalized to the TBM. The inciting drug may serve as a hapten, leading to antibody formation. Thus, granular TBM IgG and C3 deposits were reported in a patient after NSAID treatment (67). In a few patients, anti-TBM antibodies have been found; Colvin and Fang (7) reported that these antibodies are frequently found in patients with different forms of AIN if they are sought. In many cases, however, it is unclear whether these antibodies are of clinical significance, and the specificity of the methodologies to detect these antibodies is not always high. The finding of linear staining for IgG along the TBM is not a specific test to detect anti-TBM antibodies; proof of presence of anti-TBM antibodies requires demonstration of the antibody in the serum or renal eluates. Complexing of antibody to antigen may lead to complement binding and activation, triggering a cascade of events that result in inflammatory infiltrates and tissue injury.

Cell-mediated immunity has also been implicated in the genesis of drug-induced interstitial nephritis. The presence of granulomas in the kidney, in a number of cases of interstitial inflammatory reaction to drugs, is consistent with the delayed-type hypersensitivity. Recent data indicate that drug-specific T cells may be activated locally in the kidneys, and this T-cell activation may mediate a local inflammation via secretion of various cytokines, the type of which depends on the cytokine pattern secreted. This T-cell-mediated inflammation may be responsible for the renal damage (17). Cytotoxic lymphocytes, which were reactive against autologous renal cell line, have been isolated from one patient being treated with recombinant interleukin-2 (IL2) (68).

Chronic interstitial nephritis with fibrosis resulting from a prolonged inflammatory process is likely mediated by inflammatory cells and the cytokines released by them. It appears that interstitial mast cells facilitate the development of interstitial fibrosis (60). Some drugs appear to produce persistent tubulointerstitial damage without an acute injury phase. They include analgesics and lithium. Persistent changes produced by analgesics presumably result in part from ischemia produced by imbalances in the vasodilatory versus vasoconstrictor prostaglandins (PGs) over a prolonged period (see later section on “Analgesics and Nonsteroidal Antiinflammatory Drugs”). Chronic TIN is associated with prominent loss of the peritubular capillaries, which may further aggravate the ischemic injury (69). As pointed out earlier, certain cytokines, such as TGF-β, enhance production and release of matrix from epithelial and mesenchymal cells and likely also play a role in bringing about interstitial fibrosis through promoting epithelial-mesenchymal transdifferentiation of renal tubular epithelial cells (6,7).

Clinical Course

Drug-induced interstitial nephritis is generally reversible by withdrawal of the offending agent. Steroid therapy may enhance the rate of recovery and is frequently given along with withdrawal of the drug. A typical and diagnostic feature of drug-induced interstitial nephritis is its recurrence on reexposure to the drug or a related compound. Although recovery of renal function is the rule if the drug is withdrawn immediately, a study from Germany indicates that permanent renal insufficiency remained in 88% of drug-induced acute TIN cases if the suspected drug was taken for more than a month before the diagnosis of drug-induced interstitial nephritis was made (70). Also, the same authors suggest that NSAID-induced interstitial nephritis has a worse outcome as compared to other drug-induced forms.

Specific Agents

Antimicrobial Agents


The cephalosporin group of antibiotics comprises several “generations” of these useful agents, defined on the basis of antimicrobial activity. The first generation includes cefazolin, cephalothin, and cephalexin. Cefamandole, cefonicid, cefuroxime, cefaclor, cefoxitin, and cefotetan are second generation, whereas the third generation includes ceftazidime, cefotaxime, and ceftriaxone. Cefepime is a fourth-generation cephalosporin more resistant to beta-lactamases than the previous agents. The newest, fifth generation of cephalosporins includes ceftobiprole (with stronger anti-Pseudomonas activity) and ceftaroline. These drugs may be nephrotoxic, particularly in patients with preexisting renal insufficiency. Cephaloridine, the most toxic of the group, is no longer available in the United States but is used experimentally for toxicity studies.

Clinical Presentation The cephalosporins are most likely to produce renal failure in patients with preexisting renal insufficiency (71,72), in those with drug overdose (73), and in those receiving other antibiotics (73,74). Patients simultaneously receiving furosemide (73) are also at increased risk, which is probably related to the ability of furosemide to prolong the half-life of the cephalosporins (75). Many of the patients reported to have nephrotoxicity due to cephalosporins are elderly and acutely ill with severe infections.

Cephaloridine has been reported to cause AKI, often as the result of oliguria (75,76). Cephalothin given alone (72) or with gentamicin, tobramycin (76,77), or other substances (78) can cause AKI in humans or can worsen preexisting renal insufficiency (71). The AKI is usually reversible. Cephalexin is less likely to cause nephrotoxicity than cephaloridine or cephalothin, but hematuria, eosinophilia, and a transient rise in BUN have been reported (79). Clinical features suggest an immunologic basis. Hypersensitivity reactions have been reported in patients treated with cephalothin as well (77,80). Rare cases of skin rash, eosinophilia, fever, and renal insufficiency with ceftriaxone have been reported (81).

Pathology Renal biopsies have been obtained in relatively few cases of cephalosporin-induced renal injury, usually in those in which the older cephalosporins were given. Biopsies
have shown a picture of interstitial edema with variable numbers of mononuclear cells, accompanied by variable degree of acute tubular injury (76,82,83). Granulomas may be seen in some cases (84). No immunoglobulins or complement have been seen with immunofluorescence techniques.

Pathogenesis Cephalosporins appear to be capable of producing direct toxic injury to tubular cells. Tune and Hsu (85) have shown that cephalosporins interfere with mitochondrial function in the renal tubule. Cephaloridine has structural homology to carnitine, and it has toxic effects on carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria; in vivo/in vitro effects on pyruvate metabolism have been seen, albeit at very high concentrations (85). Cephaloridine also produces lipid peroxidation and acylation and inactivation of some tubular cell proteins. Other cephalosporins, which lack cephaloridine’s side group constituents, largely affect tubular cell proteins and especially mitochondrial anionic substrate transporters (85). In vitro, proximal tubular cells show evidence of cytotoxicity on exposure to cephaloridine, cephalexin, and cephalothin, whereas distal tubules do not. These studies provide evidence of the role of oxidative stress, cytochrome P450 activation, and mitochondrial dysfunction in tubular cell toxicity (86). It is important to note that preexisting chronic renal failure (the degree of which is not accurately represented by serum creatinine [Scr] levels alone) is a very important risk factor for the development of progressive renal failure following the use of nephrotoxic medications.

In addition, cephalosporins are known to cause hypersensitivity reactions. In some cases, there has been resolution with drug withdrawal and, in a few cases, recurrence on rechallenge (82). The cephalosporins are structurally similar to the penicillins, which produce similar reactions (see later), and cross-reactivity may occur in 1% to 20% of patients (87). No specific cephalosporin is more likely than others to cause such a reaction.


Clinical Presentation Fluoroquinolones belong to a family of synthetic broad-spectrum antibiotics. Ciprofloxacin, the most widely used of these drugs, has been reported to produce AKI with interstitial nephritis. Levofloxacin, norfloxacin, tosufloxacin, and moxifloxacin have also been associated with interstitial nephritis (88,89,90,91). There is typically fever, eosinophilia, and skin rash (92,93,94,95,96), but systemic manifestations may not be present (97). Onset of symptoms is generally within 2 to 12 days of beginning either oral or intravenous therapy. Patients have responded to withdrawal of the drug and, generally, concomitant treatment with immunosuppressive agents.

Pathology Renal biopsies in cases of fluoroquinolone-associated renal dysfunction have revealed interstitial nephritis. In a few cases, there were granulomatous features in the interstitial inflammatory infiltrate (69,96,98). Shih et al. have reported a necrotizing vasculitis in the kidney in two patients being treated with ciprofloxacin (96). An interesting case from Japan was reported in which a patient developed crystal-forming chronic interstitial nephritis following long-term exposure to tosufloxacin (90). The crystals were present in interstitial macrophages, but the crystals did not contain immunoglobulin. The patient’s renal function improved following discontinuation of the drug.

Pathogenesis The mechanism of pathogenesis appears to be a hypersensitivity reaction, with evidence of a cell-mediated process in the few cases with granulomatous features. As with many drug reactions, the possibility that another drug or underlying disease process may have produced the renal effects cannot be ruled out in several of these cases.


In the following section, adverse reactions to ampicillin, methicillin, and penicillin are discussed in detail. AIN has been reported with other penicillins as well, including cloxacillin (99) and piperacillin (100,101).

Clinical Presentation Several cases are recorded in which ampicillin appears to have provoked renal dysfunction (102,103,104,105). Fever, skin rash, and eosinophilia may be found and may antedate renal symptoms. Renal manifestations may be mild, with hematuria and a small amount of proteinuria, or severe, with acute oliguric renal failure. Rapid recovery is the rule. Time to onset varies, but renal symptoms generally appear within a few days of administration of ampicillin; other manifestations, such as fever and skin rash, develop within 24 hours. In several cases, there had been prior treatment with penicillin, methicillin, or tetracycline.

There are many reports of renal damage caused by methicillin. Nephrotoxicity with methicillin is not dose dependent. Onset of toxic reactions usually begins within 5 weeks after initiation of the drug. Patients typically manifest fever and skin rash, and 73% of patients in a review of 68 patients were male (106). Patients of all ages are at risk, though renal failure appears to be more common in older patients. Eosinophilia is a typical feature and may reach very high levels (56). Hematuria may occur; it is often the first sign of renal involvement. Proteinuria is seen in some cases but is generally mild. WBCs are frequently found in the urine, which is usually sterile, and eosinophils are present in the urine in a high proportion of patients (56,106). Azotemia occurs in over half of patients and oliguria in one third. Complete recovery of renal function is the rule, though azotemia may persist in less than 10% of patients (107).

Penicillin has been widely used for more than 50 years, and there have been several reports of nephrotoxicity ascribed to the drug. Appel and Neu (108) summarized the reported adverse reactions to penicillin under three main headings: various vascular and glomerular lesions, acute anuric renal failure after a single injection, and AIN. In a number of cases, there is fever, skin rash, and eosinophilia, suggesting a hypersensitivity reaction. The patients have hematuria with varying degrees of proteinuria, and renal failure may ensue.

Pathology Histologic changes in interstitial nephritis associated with penicillin and its derivatives do not differ from other forms of drug-induced interstitial nephritis. Eosinophils, however, are frequently abundant. Occasionally, granulomas (63,109) and vasculitis lesions (56,110) were recorded, but these are rare. Immunofluorescence is usually nonspecific; however, occasional investigators describe linear staining along the TBM for IgG (61,62,111,112). Such staining, in many instances, is probably nonspecific; however, antibodies to TBM antigens were reported in a few cases (62). Ultrastructural examination is also usually noncontributory. Association of minimal change disease with penicillin-induced interstitial nephritis has been
reported (113). A few investigators described fibrillar deposits along distal convoluted tubules and in glomerular epithelial cells (102,105), but the relevance of these fibrils is unclear, and they may merely represent procollagen.

Morphologic examination cannot differentiate between interstitial nephritides caused by different penicillins. In fact, the histology does not even indicate whether the interstitial nephritis is secondary to penicillin or some other drug or injurious agent. Pirani et al. (114) compared beta-lactam-induced interstitial nephritis with NSAID-induced interstitial nephritis and found that the beta-lactam-induced cases contained more eosinophils. Both types contained primarily mononuclear cells with some plasma cells in the infiltrate. Still, these are histologic findings of low specificity.

Pathogenesis Nephrotoxicity of the penicillins is not dose dependent, and the clinical picture overall is that of a hypersensitivity reaction. In several studies, immunofluorescence microscopy raises the possibility that anti-TBM antibodies may play a role in the pathogenesis of TIN, but the evidence is weak (61,62,111). Cell-mediated mechanisms may also be involved in some cases, based on the nature of the inflammatory infiltrate, and the absence of antibody and complement deposition. Gilbert et al. (102) have reported exacerbation of the reaction to methicillin by inadvertent exposure to ampicillin, a closely related drug. In addition, some case histories suggest that ampicillin can trigger a hypersensitivity reaction in patients who might have been sensitized to other penicillins. In one of these cases, antibodies against ampicillin were detected in the patient’s serum (104). In some studies, hypocomplementemia provided additional evidence of an immune reaction (102).


Clinical Presentation Rifampicin is a drug used in the treatment of tuberculosis. When it is given intermittently, it causes various adverse reactions, including fever, chills, dizziness, nausea, and diarrhea (115,116). There have been several reports of acute oliguric renal failure during intermittent rifampicin therapy (115,116,117,118). The most common clinical scenario is AKI following a single dose of rifampicin. The average time between the initiation of therapy and clinical presentation is less than 3 weeks (119). Clinical manifestations may include gastrointestinal symptoms. Usually, no skin rashes are observed. Hematuria without any significant proteinuria is common. Anemia is often present, sometimes with associated thrombocytopenia (119). Most patients recover when the drug is withdrawn (116), a few cases have been reported to result in permanent renal damage (119,120).

Pathology Renal biopsies in cases of rifampicin toxicity typically show interstitial edema with variable numbers of mononuclear cells, and eosinophils have also been found (64). Rarely, granulomas may be seen (121). There may be patchy necrosis of the tubular epithelium. Even patchy cortical necrosis has been described (120); in that case, there was residual renal dysfunction. However, the degree of tubular necrosis is often not severe, and in one case, the tubules were described as unaffected (115). In addition, pigmented casts may be evident. Although glomeruli and vessels are usually normal, rarely glomerulonephritis, including crescentic and necrotizing glomerulonephritis, has been noted (64,116). On immunofluorescence microscopy, it has usually not been possible to establish the presence of immunoglobulins or complement (117,118), although C3 has been found in the mesangium and in the TBM (64,122) (common nonspecific findings).

Pathogenesis Antibodies to rifampicin have been detected in patients (123,124); in one study, they were present in one third of 49 patients (123). The various adverse reactions reported in this series, including renal dysfunction, were found more commonly in patients with antibodies than in patients without them. These authors suggest that the drug acts as a hapten, which, after it has become bound to macromolecules in the plasma, becomes antigenic with the formation of antibodies. The antibodies are considered to be directed against the drug, with formation of hapten-antibody complexes when the drug is given again.


The sulfonamides have been widely used, with relatively few renal complications. Alleged hypersensitivity reactions in the early days of their use were associated with polyarteritis or AIN (125,126). However, AIN secondary to sulfonamides has become a rare event, and only a few cases have been reported (127,128). In one case, acute oliguric renal failure developed in a patient being treated with sulfadiazine. The patient recovered after 6 weeks of oliguria (128). Cotrimoxazole (sulfamethoxazole and trimethoprim) has occasionally been found to cause deterioration of renal function (129,130). A case of delayed acute TIN in a patient who developed “drug rash” with eosinophilia and systemic symptoms (DRESS syndrome) secondary to sulfasalazine was described (131).

Patients in whom crystalline precipitates develop with the use of sulfonamides have microscopic or gross hematuria, crystalluria, and renal colic, and in some cases, they become oliguric or anuric (108,132). Occasionally, urolithiasis may evolve. In one series of 40 patients, the urinary bladder was the most common location of stones (133). Sulfasalazine (a combination of 5-amino salicylic acid and sulfapyridine) has been reported to cause obstructive uropathy secondary to calculi (134). Less soluble forms, including sulfapyridine, sulfathiazole, and sulfadiazine, are most frequently associated with crystalline obstruction (135). Fortunately, this complication became rarer when sulfonamides of greater solubility became available. Rapid improvement may take place with discontinuation of the drug, fluid administration, and alkalinization of the urine.

The typical pathologic finding is interstitial nephritis. Eosinophils are a typical component of the infiltrate (127,130,136). Granulomas have occasionally been described (136). In patients with crystallization of sulfonamide in the kidney, some pathologic changes are due to obstruction as a consequence of crystal formation.


Vancomycin is a glycopeptide antibiotic used increasingly to treat infections caused by organisms resistant to other antibiotics such as methicillin-resistant Staphylococcus aureus (MRSA). With the growing number of MRSA infection, the cases of vancomycin-associated TIN have been reported more frequently (137,138,139). Nephrotoxicity is a known complication of the drugs when given alone or in combination with other drugs, especially aminoglycosides (140,141) or cephalosporins (74). Pediatric patients may be less susceptible to the toxic effects of
vancomycin combination therapy (142). Some patients have an associated rash and eosinophilia, suggesting a hypersensitivity reaction. In addition to these adverse renal effects, in some cases, patients have an anaphylactoid reaction to the drug, with generalized flushing—the so-called red man syndrome.

Pathologic findings in kidney biopsies obtained from patients with vancomycin-associated AKI may include TIN with many eosinophils (137,143). Several case reports described ATN in patients after vancomycin treatment without relevant interstitial inflammation, predominantly in pediatric patients (144,145,146). Rarely, vancomycin-associated kidney injury may be manifest as granulomatous interstitial nephritis (139). In the last 8 years, we have seen over 50 biopsies with ATN and interstitial nephritis following vancomycin administration. Most of these patients had high vancomycin trough levels and underlying preexisting chronic renal injury. Interestingly, in our experience, the ATN is the predominant finding associated with relatively mild but active interstitial inflammatory cell infiltrate with interstitial edema. In these cases, the lesions are usually reversible unless patients have severe systemic disease, sepsis, or other prominent chronic renal injury such as diabetic nephropathy.

The pathogenesis of renal toxicity is not well defined clinically, but experimental studies suggest that it stems from tubular cell injury. In some patients, the constellation of clinical symptoms and pathologic features indicate a hypersensitivity reaction (147), but many patients do not develop such a syndrome. The potentiation of toxic reactions when vancomycin is used with aminoglycosides may be due, at least in part, to enhancement of aminoglycoside binding to brush border and, presumably, its uptake into tubular cells, with subsequent cellular injury (148).

Analgesic Nephropathy

Analgesic nephropathy is a chronic progressive tubulointerstitial disease induced by the prolonged use (abuse) of analgesics and potentially addictive substances, such as caffeine or codeine. Analgesic nephropathy was first described in the 1950s (197) and was further characterized in the following decades (198,199,200,201,202). It became apparent that the chronic use of analgesics, primarily phenacetin, might be associated with the development of renal failure. However, after the withdrawal of phenacetin from the market, the incidence of analgesic nephropathy did not decrease subsequently; therefore, the scientific advisory board of the National Kidney Foundation formed an ad hoc committee who redefined analgesic nephropathy as a disease resulting from the habitual consumption over several years of a mixture containing at least two antipyretic analgesics and usually codeine and caffeine (203).

The definition of analgesic abuse is quite variable and arbitrary in the different studies, but the consumption of daily analgesics for ≥1 year or a cumulative intake above 1000 units (tablets) is the minimum criterion required by most investigators. However, true analgesic abuse and subsequent nephropathy are associated with higher cumulative intake (usually above 5000 units).


The incidence varies greatly from study to study, depending primarily on the timing of the study and on the region or country where the investigation was performed. In Europe, the percentage of analgesic nephropathy among patients with ESRD undergoing long-term dialysis varied widely, from only 0.1% in Ireland, Norway, Poland, and Hungary to 18.1% in Switzerland (204). According to the Analgesic Nephropathy Network of Europe study, the average European incidence of analgesic nephropathy among patients who were started on renal replacement therapy in 1991-1992 was 6.4% (199). In Australia and Canada, 11% and 2.5% incidence rates have been reported, respectively (205,206). In the United States, 1.7% to 10% of the ESRD cases are thought to be the result of analgesic nephropathy in various regions (200,207). These large geographic differences may be explained by differences in local habits, psychosocial factors, availability of these drugs, and the frequency of correct diagnosis and reporting.

The removal of phenacetin from the market as well as other regulations (restricting over-the-counter sales and marketing smaller packages) resulted in a decline of the proportion of patients requiring dialysis therapy for analgesic nephropathy in Australia, Sweden, and Germany (206,208,209). Still, the incidence remains high in many countries, indicating that drugs other than phenacetin, such as acetaminophen and NSAIDs, are responsible for the development of the disease (160,198,208). Some authors believe that combination analgesics (acetaminophen and salicylates or aspirin) are more likely to induce analgesic nephropathy than single drug usage (198). Data on analgesic nephropathy in two highly endemic regions, Belgium and New South Wales, Australia, demonstrated that the downward trend and prevalence of analgesic nephropathy were very similar, despite the fact that the sale of only phenacetin was banned in Belgium, while other combined analgesics remained on the market, and in New South Wales not only phenacetin but all combined analgesics were prohibited. Still, the downward trend and prevalence of analgesic nephropathy were very similar during the follow-up period indicating that nonphenacetin mixed analgesics probably do not play a significant role in the development of analgesic nephropathy (210). Because of the relevance of the cumulative dose of analgesics, the effects of restrictions in the sale of combined analgesic medications show only with a delay. Studies from Australia and Belgium (211,212) indicate a recent decline in the incidence of analgesic nephropathy, particularly in the younger population. The cumulative dose of analgesics appears to be an important factor. Perneger et al. (200) have shown that the odds ratio of ESRD is 2 in patients with a cumulative dose of greater than 1000 pills and 2.4 in patients taking greater than 5000 pills of acetaminophen, compared with that in persons taking less than 1000 pills. They also found that the use of NSAIDs is associated with an increased risk of ESRD in patients taking greater than 5000 pills of NSAIDs (odds ratio 8.8), whereas the use of aspirin is not. It appears that the absolute risk of developing ESRD in analgesic abusers is approximately 1.6 to 1.7/1000 per year (198). However, the true incidence of analgesic nephropathy is quite difficult to determine. An Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy critically reviewed the available data of the association between NSAID and renal disease (213). They found that many studies on analgesic nephropathy are inconclusive because of sparse information and substantial methodologic problems. Also, they emphasized that the diagnosis of analgesic nephropathy in different studies can vary and, in many cases, the diagnosis is based primarily on information about drug ingestion without any specific imaging or histologic studies. Therefore, the committee decided that there is no convincing evidence that
nonphenacetin combined analgesics are truly associated with nephropathy (213).

A large autopsy study performed on 616 patients in Switzerland indicates that the autopsy prevalence of analgesic nephropathy decreased from 3% in 1980 to 0.2% in 2000. Similarly, capillary sclerosis of the urinary tract, the initiating event in the pathophysiology of papillary necrosis and analgesic nephropathy and the histologic hallmark of the effect of toxic metabolites of phenacetin in analgesic abusers, decreased from 4% of autopsy cases in 1980 to a 0.2% in 2000. Thus, the classic analgesic nephropathy has practically disappeared some 20 years after the removal of phenacetin from the analgesic market despite the fact that mixed analgesics containing paracetamol, the main metabolite of phenacetin, have continued to be popular and widely used drugs (214). This study later received some critique because it was supported by pharmaceutical companies and the ad hoc committee consisted mainly of researchers from Germany, Switzerland, and Austria. Still, later studies from these three countries further indicate that analgesic nephropathy is disappearing and that non-phenacetin-containing analgesics do not cause analgesic nephropathy (214,215,216). However, as mentioned above, studies from Belgium and Australia contradict these findings, and, in spite of the declining prevalence of analgesic nephropathy, they state that the continuing use of non-phenacetin-containing analgesics (including paracetamol/phenacetin combined with NSAID, codeine, caffeine) is still associated with the development of analgesic nephropathy (211,212,217). Data from the Physicians’ Health Study indicated that analgesic use in healthy male patients is not associated with the risk of subsequent renal failure (218). The study involved 4772 healthy male physicians with normal Scr levels in 1982. During a follow-up period of 14 years, there was no evidence of renal impairment in these patients, not even in those who consumed more than 7000 analgesic pills (218). The studies somewhat contradict previous data, but they emphasize that a preexisting underlying renal condition or other coexisting aggravating pathogenetic factors (such as hypertension, diabetes, obesity) may be important in the pathogenesis of analgesic nephropathy and analgesic intake by itself may not be deleterious to the kidney if no other coexistent or preexistent pathologic factors are present (219). In spite of these contradictory data, considering the widespread use and abuse of analgesics, analgesic nephropathy must be considered an important public health issue.


The typical patient is a middle-aged woman with a variety of symptoms, frequently including headaches and some degree of acute and/or chronic renal failure. The decline in the GFR may be due to vasoconstriction, vascular damage, or tubular obstruction (220). Tubular damage is reflected in defects of urinary concentration, acidification, and sodium retention. Microscopic hematuria occurs in 40% of patients (220). Gross hematuria with loin pain and AKI is suggestive of papillary necrosis (221). Occasionally, full-blown papillary necrosis occurs. If the necrotic papilla is sloughed into the renal pelvis, fragments of necrotic papilla segments may cause obstruction or be voided in the urine. Significant proteinuria (greater than 0.3 g/24 hours) is present in half of the patients, but nephrotic-range proteinuria is uncommon (220). Hypertension develops in a substantial number of patients.

The diagnosis of analgesic nephropathy should not be solely based on renal biopsy. Renal imaging techniques, such as sonography and particularly computed tomography, are the best methods for diagnosis in the appropriate clinical context (199). The Analgesic Nephropathy Network of Europe study showed that shrinkage of renal mass (sensitivity 96%, specificity 37%), bumpy renal contours (sensitivity 57%, specificity 92%), and the presence of papillary calcifications (sensitivity 85%, specificity 93%) are the most useful criteria in diagnosing analgesic nephropathy. The combination of these three criteria resulted in a sensitivity of 85% and a specificity of 93% (199). Radiocontrast examinations may be helpful in the diagnosis of papillary necrosis. The specificity and sensitivity of diagnostic imaging studies have been reviewed by De Broe and Elseviers (222).


Gross Appearance In the full-blown form, both kidneys are somewhat contracted, and the subcapsular surface shows irregularly alternating depressed areas and raised nodules, the latter sometimes assuming a characteristic ridged form (223,224). The depressed areas correspond to atrophic, scarred portions of the cortex above a necrotic papilla. The nodular areas correspond to the hypertrophic areas of the cortex above the columns of Bertin. The papillae are shrunken and withered and may be pale or brown. Calcification may be present, primarily in the medulla. In early-stage papillary necrosis, yellow stripes radiating outward from the tip of the medulla may be seen, separated by dark zones. This appearance may be confined to the tip or may extend through the entire papilla. Later, the yellow appearance becomes confluent and extends to the border of the inner and outer medullae. In some cases, only the tip of the papilla becomes necrotic. In others, the necrosis is found only in the central part of the papilla. Occasionally, the necrotic papillae become sequestered and may be found lying free in the pelvis. Soft phosphate stones may also be noted in the pelvis in association with papillary necrosis. A characteristic brown pigmentation of the pelvic mucosa may be observed, which is thought to be the result of lipid deposition (225,226).

Light Microscopy The earliest change is the sclerosis (basement membrane thickening) of capillaries beneath the urothelial mucosa (Fig. 25.15) (224,226,227). This suburothelial capillary calcification was demonstrated in phenacetin
abuse-associated analgesic nephropathy, and it is not entirely clear whether non-phenacetin-related cases have the same capillary calcification. This capillary sclerosis increases in intensity toward the pelvic-ureteric junction, is most prominent in the proximal ureter, and then gradually decreases (224). At a more advanced stage (in early stages of papillary necrosis), the capillary sclerosis involves the peritubular capillaries in the papilla and inner medulla. The ascending loop of Henle also exhibits a substantially thickened basement membrane, but the basement membranes of the collecting ducts, descending loop of Henle, and vasa recta are not affected or are only mildly affected. The thickened basement membranes are PAS positive and contain lipid as well as calcium deposits (Fig. 25.16). Ultrastructurally, this basement membrane thickening consists of numerous thin layers of basement membrane material (Fig. 25.17), which probably forms as the result of repeated injury of the capillary endothelium and the epithelium of the thin limb of Henle (224,228). Early on, these changes are confined to the central part of the inner medulla, but as the disease progresses, the affected small foci become confluent and may involve the entire inner medulla.

FIGURE 25.15 Portion of a kidney with advanced analgesic nephropathy. Note the pale gray-white papilla, representing papillary sclerosis/necrosis.

FIGURE 25.16 Calcium deposits in the basement membranes of the vasa recta in the renal papilla in analgesic nephropathy. (Von Kossa, ×200.)

FIGURE 25.17 Electron micrograph of a capillary obtained by biopsy of the renal pelvis of a patient who had abused analgesics. Numerous new basement membrane lamellae have been formed. (×7050.) (From Mihatsch MJ, et al. The morphologic diagnosis of analgesic (phenacetin) abuse. Pathol Res Pract 1979;164:68.)

As full-blown papillary necrosis develops, the collecting ducts and the vasa recta become necrotic as well, and a ghost outline of the original structure is present (Fig. 25.18). Renal papillary necrosis is not associated with an influx of neutrophils into the necrotic areas or the bordering preserved renal parenchyma. There may be focal collections of lymphocytes and macrophages. If the necrotic portion of the papilla sloughs into the lumen of the renal pelvis, the resulting cavity will reepithelialize. The necrotic material may also remain in place, and in such cases, calcification of the necrotic papilla is common, with possible bone formation (Fig. 25.19).

The cortical changes are thought to stem from the alterations in the papilla (229,230). The cortex may be normal in the
early and intermediate forms. The cortical changes consist of tubular loss and tubular atrophy with interstitial fibrosis and a varying degree of interstitial infiltration of chronic inflammatory cells (Fig. 25.20). Lipofuscin accumulation is frequently noted in the epithelium of atrophic tubules. These are nonspecific changes and cannot be reliably differentiated from other forms of chronic tubulointerstitial injury. It appears that the necrotic papilla, in some ways analogous to obstructive nephropathy, is responsible for the cortical changes. This is also supported by the fact that the columns of Bertin are often spared.

FIGURE 25.18 Low-magnification picture taken from the specimen shown in Figure 25.15. In analgesic nephropathy, typically there is no inflammatory reaction around a necrotic/sclerotic papilla. The ghost structure of the renal papilla is still recognizable. (H&E, ×10.)

The glomerular changes are presumably the result of the tubulointerstitial changes and are quite nonspecific as well. In the atrophic suprapapillary cortex, periglomerular fibrosis, glomerular ischemia, obsolescence, and sclerosis may occur. In the columns of Bertin, where compensatory hypertrophy is common, some glomeruli may undergo segmental hyalinosis and sclerosis (224,231). Zollinger (231) called this change “overload glomerulitis,” which is in fact identical to glomerular hyperperfusion injury. Except for the medullary and pelvic capillary sclerosis, there are no vascular changes characteristic of analgesic nephropathy. Arteriolar hyalinosis and varying degrees of arterial intimal fibrosis may develop, particularly in older patients and in patients with arterial hypertension.

FIGURE 25.19 Bone formation in a necrotic papilla from a patient who had used analgesics for many years. (H&E, ×140.)

FIGURE 25.20 Interstitial fibrosis and tubular atrophy in the cortex of a kidney with analgesic nephropathy. Note that most glomeruli in this section are preserved; only scattered sclerotic glomeruli are seen. (H&E, ×40.)


One theory is that the papillary changes are caused by insufficient blood supply (232,233). Lagergren and Ljungqvist (234) were unable to demonstrate the postglomerular vessels of juxtamedullary glomeruli, indicating decreased blood supply of the papilla. A reduction in number and dimension of the vasa recta in a rat model of analgesic nephropathy was noted by Kincaid-Smith et al. (232) as well. Molland (233) suggested that the reduced medullary blood flow in analgesic nephropathy is the consequence of disturbed autoregulation.

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Jun 21, 2016 | Posted by in UROLOGY | Comments Off on Acute and Chronic Tubulointerstitial Nephritis

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