4.2.1 Acute interstitial nephritis (AIN) without granulomas

Definition: Acute interstitial inflammation with tubulitis (without destruction of the parenchyma)

Acute interstitial nephritis offers an extremely variable picture in biopsy. In individual cases cortex and medulla can be diffusely flooded with infiltrating cells or multifocal infiltrates are present . At the other end of the spectrum, we find sparse infiltrates, particularly at the medullary-cortical border, without any other infiltrates in the cortex or medulla. Tubulitis is always present. Verification of tubulitis (infiltration, particularly T-lymphocytes in the tubules) is decisive for the diagnosis. Tubulitis may be frequent in one case but very rare in another. Tubulitis is usually more difficult to find in AIN than in transplant rejection. In AIN mostly the distal tubules are affected. However tubulitis may be overlooked due to the fact that very many cells invade the tubules so that the tubule vanishes within the infiltrate. Destruction of the tubular basement membrane is usually not found. It may be that the BM is not stainable with PAS or silver stains but complete destruction is not seen by EM. Therefore  AIN is best termed “non-destructive” AIN in contrast to pyelonephritis.

Interstitial edema and variable degrees of tubular epithelial damage e.g. tubular necrosis, apoptosis, desquamation, later regeneration and dedifferentiation of the epithelium are usually  present.

Just as variable as the extent of renal involvement is the composition of the interstitial infiltrate. Lymphocytes and histiocytes always form the majority of infiltrating cells. These may be mixed with many plasma cells (as in our case, plasma cell rich AIN) or with numerous eosinophilic leukocytes. The presence of clusters of eosinophils or plasma cells allow the differentiation of different types of AIN. Neutophilic leukocytes are also present in variable amounts; especially tubules containing cell debris may be surrounded by neutrophils. In very early stages of AIN some tubular basement membranes may be densely covered by neutrophils.

The variability of the morphological findings depends on the time point of biopsy and the severity of the clinical picture. The number of drugs where AIN has been described is huge.

Although in the standard literature AIN is rather uncritically  treated as an apparent single disease entity, it is possible to differentiate various forms according to the morphology.

1. Eosinophilic AIN is characterized by clusters of eosinophilic leukocytes (3 to 5 or more per HPF). In total, eosinophilic leukocytes form 10% of all infiltrating cells at most. Individual eosinophils  can practically always be found distributed as single cell infitrates. If the infiltrate is dominated by eosinophilic leukocytes, then  vasculitis, rather than eosinophilic interstitial nephritis should be considered. Etiologically, in the case of eosinophilic nephritis, primarily antibiotics should be considered.

In cases with acute disturbances of urinary flow with tubular rupture and acute backflow of urine into the iterstitial space, eosinophilic leukocytes are frequently seen (particularly in the medulla). The  best example is acute obstruction of the urinary tract or urine reflux during prostate resection.

2.  In the case of plasma cell rich AIN, the plasma cells (IgM, IgG, IgA) occur in clusters (3-5 or more per HPF). Here too, eosinophilic leukocytes may be found, but usually then scattered throughout the tissue. Etiologically, in particular NSAIDs should be considered.

3. Dominant lymphohistiocytic AIN (without clusters of eosinophils, or plasma cells) is rare. In these cases infections should be considered, e.g. M.Weil, other forms of leptospirosis, Hanta virus nephropathy etc.)

Differential diagnosis and comment

The distinction between AIN and infectious (destructive) interstitial nephritis (pyelonephritis) is important and as a rule simple. Pyelonephritis is characterized by a predominance  of neutrophilic leukocytes, that are not only found in the tubular lumen, but also in the surrounding interstitium and which destroy the tubular basement membrane. Destruction of tubular basement membrane is due to neutrophilic leukocytes.

The situation becomes complicated when glomerulonephritis or vasculitis is present in addition. Depending on the form of glomerulonephritis or vasculitis, interstitial nephritis is present with varying frequency and intensity. As a rule, interstitial nephritis is particularly evident in ANCA associated glomerulonephritis/vasculitis with or without systemic manifestations. In ANCA glomerulonephritis, frequently large numbers of plasma cells are found. In rarer vasculitides eosinophilic lekocytes may predominate. The accompanying interstitial nephritis can exhibit all the characteristics of interstitial nephritis described above. The degree of interstitial nephritis should always be mentioned in the diagnosis. In particularly striking cases of AIN (eosinophils/plasma cell rich/granulomatous) with marked tubulitis, a combined form of glomerulonephritis/vasculitis and drug induced AIN should be considered.

In cases with acute disturbances of urinary flow with tubular rupture and acute backflow of urine into the interstitial space, eosinophilic leukocytes are frequently seen (particularly in the medulla). The best example is acute obstruction of the urinary tract or urine reflux during prostate resection.

Patients with documented AIN can, following  repeated intake of the same substance, develop a granulomatous AIN, that in the worst case can lead to irreversible, terminal renal insufficiency.

Acetic acid derivatives and related substances, acetylsalicylic acid, acetylsalicylic acid, aciclovir, adefovir dipivoxil, ajmaline, allopurinol, amino(diphenylhydantoin) valeric acid, amlodipine, amoxicillin, ampicillin, atazanavir*, azapropazone, azathioprine, azithromycin, azlocillin, aztreonam, benzylpenicillin, Beta-lactamase resistant penicillins, Beta-lactamase sensitive penicillins, betanidine, Bismuth preparations, bismuth subcitrate, bortezomib, captopril*, carbamazepine, carbenicillin, carbimazole, cefaclor, cefalexin, cefaloridine, cefalotin, cefamandole, cefapirin, cefazolin, cefepime, cefixime, cefoperazone, cefotaxime, cefotetan, cefradine, ceftriaxone, celecoxib, celecoxib, chlorpropamide, cimetidine, ciprofloxacin, clofibrate, cloxacillin, clozapine, cocaine, colistin, copper sulfate, Coxibs, cyamemazine, diazepam, diclofenac, diflunisal, diltiazem, enalapril*, erythromycin, esomeprazole*, ethambutol, famotidine, fenbufen, fenofibrate, fenoprofen, First-generation cephalosporins, floctafenine, Fluoroquinolones, flurbiprofen, flurithromycin, foscarnet*, furosemide, glafenine, Glycopeptide antibacterials, Gold preparations*, griseofulvin, H2-receptor antagonists, hydrochlorothiazide, hydrochlorothiazide, combinations, ibuprofen, ibuprofen, ibuprofen, ibuprofen, ifosfamide*, Imidazole derivatives, indapamide, indinavir , indometacin, Interferons, Interleukins, isoniazid, ketorolac, lamotrigine, levofloxacin, lincomycin, Lincosamides, Macrolides, mefenamic acid*, mesalazine*, metamizole sodium, Methyldopa, meticillin*, mezlocillin, minocycline, minocycline, moxifloxacin, naproxen*, naproxen, nicergoline, niflumic acid, Nitrofuran derivatives, nitrofurantoin, norfloxacin, Nucleosides and nucleotides excl. reverse transcriptase inhibitors, omeprazole*, Other quinolones, oxacillin, Oxicams, pantoprazole*, paracetamol, Penicillins with extended spectrum, phenazone, phenindione, phenobarbital, Phenothiazines with aliphatic side-chain, phentermine, phenylbutazone, phenylpropanolamine, phenytoin, piperacillin, piromidic acid, piroxicam, polymyxin B, Polymyxins, Preparations increasing uric acid excretion, probenecid, Propionic acid derivatives, propranolol, propylthiouracil, Proton pump inhibitors*, Pyrazolones, Quinine and derivatives, Quinolone antibacterials, rabeprazole*, ranitidine, rifampicin, rofecoxib, Second-generation cephalosporins, sirolimus*, spiramycin, streptokinase, sulfamethoxazole and trimethoprim, sulfasalazine, sulfinpyrazone, sulindac, tacrolimus*, teicoplanin, telithromycin, tetracycline, Tetracycline and derivatives, Third-generation cephalosporins, ticlopidine, tienilic acid, tolmetin, triamterene, trimethoprim, valproic acid, vancomycin, warfarin, zomepirac