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.

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).

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).

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.

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.

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.

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.