17 Nephritis Interstitial
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  • 1. Nephritis, Interstitial Chronic tubulointerstitial nephritis: o Drugs (eg, analgesics, lithium, cyclosporine, tacrolimus)1 o Heavy metals (eg, lead, cadmium, mercury) Introduction o Obstructive uropathy, nephrolithiasis, reflux disease o Immunologic diseases: Background  Lupus, Sjögren syndrome, primary Παθησεις ΕΝΔΟΝΕΦΡΙΚΕΣ ΠΟΥ ΔΕΝ ΑΦΟΡΟΥΝ ΤΟ ΣΠΕΙΡΑΜΑ = glomerulopathies, sarcoidosis - A study by ΔΙΑΜΕΣΟ ΣΩΛΗΝΑΡΙΑΚΕΣ Maripuri et al found that out of 24 patients with primary Sjögren syndrome who also had renal ΣΑΦΩΣ ΣΥΧΝΑ ΣΥΝΥΠΑΡΧΕΙ ΑΡΧΟΜΕΝΗ ΣΠΕΙΡΑΜΑΤΙΚΗ ΒΛΑΒΗ ΣΕ impairment, biopsies revealed that 17 individuals ΕΔΑΦΟΣ ΕΓΚΑΤΕΣΤΗΜΕΝΗΣ ΔΙΑΜΕΣΟΣΩΛΗΝΑΡΙΑΚΗΣ ΝΟΣΟΥ ΟΠΟΥ had tubulointerstitial nephritis as the primary ΚΥΡΙΑΡΧΟΥΝ ΟΙ ΕΚΔΗΛΩΣΕΙΣ ΤΗΣ ΣΠΕΙΡΑΜΑΤΙΚΗΣ ΝΟΣΟΥ lesion behind their kidney dysfunction.2 Eleven of the 17 patients had the chronic form of this nephritis. The results, according to the investigators, support the notion that in patients ΤΑ ΑΙΤΙΑ ΚΑΙ Η ΠΑΘΟΦΥΣΙΟΛΟΓΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ ΤΗΣ with primary Sjögren syndrome, chronic ΔΙΑΜΕΣΗΣ / ΣΩΛΗΝΑΡΙΑΚΗΣ ΝΟΣΟΥ ΠΟΙΚΙΛΛΟΥΝ, Ο ΔΕ ΑΣΘΕΝΗΣ tubulointerstitial nephritis is the most frequent cause of renal impairment found through kidney ΔΥΝΑΤΟ ΝΑ ΠΑΡΟΥΣΙΑΖΕΙ ΟΞΕΙΕΣ ΕΙΤΕ ΧΡΟΝΙΕΣ ΠΑΘΟΛΟΓΙΚΕΣ biopsy. ΚΑΤΑΣΤΑΣΕΙΣ  Vasculitis, antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides, Wegener ΕΚΘΕΣΗ ΣΕ ΦΑΡΜΑΚΑ – ΛΟΙΠΟΥΣ ΤΟΞΙΚΟΥΣ ΠΑΡΑΓΟΝΤΕΣ – ΒΑΡΕΑ granulomatosis ΜΕΤΑΛΛΑ – ΣΠΑΝΙΩΣ ΣΥΣΧΕΤΙΣΗ ΜΕ ΛΟΙΜΩΞΗ  Chronic transplant nephropathy Η ΠΛΕΟΝ ΤΥΠΙΚΗ ΕΙΚΟΝΑ ΕΞΟΡΜΑΤΑΙ ΑΠΟ ΑΝΟΣΟΛΙΓΙΚΗ o Neoplasia (eg, myeloma, leukemia, amyloidosis) ΦΛΕΓΜΟΝΗ o Atherosclerotic kidney disease (ischemic) - Cholesterol microembolism o Metabolic diseases (eg, hypercalcemia, cystinosis, potassium depletion, nephropathy, hyperoxaluria) o Genetics (eg, Alport syndrome, medullary cystic disease) o Miscellaneous (eg, Balkan endemic nephropathy, Chinese Tubulointerstitial diseases herb/aristolochic acid nephropathy)3,4 Acute tubulointerstitial nephritis: Pathophysiology o Hypersensitivity reactions (eg, drugs, penicillins, sulfa drugs, ΣΕ ΔΟΜΙΚΟ ΕΠΙΠΕΔΟ Η ΑΝΑΜΕΝΟΜΕΝΗ ΕΙΚΟΝΑ ΣΕ ΟΞΕΙΑ nonsteroidal anti-inflammatory drugs [NSAIDs] most common) ΑΛΛΑ ΚΑΙ ΣΕ ΧΡΟΝΙΟ ΔΙΑΜΕΣΗ ΝΕΦΡΟΠΑΘΕΙΑ ΕΙΝΑΙ ΤΟ o Immunologic diseases (eg, associated with lupus, Goodpasture ΑΠΟΤΕΛΕΣΜΑ ΤΗΣ ΑΛΛΗΛΕΠΙΔΡΑΣΗΣ ΤΩΝ ΝΕΦΡΙΚΩΝ ΚΥΤΤΑΡΩΝ ΜΕ syndrome) ΤΑ ΚΥΤΤΑΡΑ ΤΗΣ ΦΛΕΓΜΟΝΗΣ ΚΑΙ ΤΑ ΠΑΡΑΓΩΓΑ ΑΥΤΩΝ o Acute transplant rejection o Infections: Η ΚΥΤΤΑΡΙΚΗ ΚΑΤΑΣΤΡΟΦΗ ΣΥΝΕΠΑΓΕΤΑΙ ΤΗΝ ΠΑΡΟΥΣΙΑ ΑΝΤΙΓΟΝΩΝ ΣΕ ΤΟΠΙΚΟ ΕΠΙΠΕΔΟ, ΔΙΗΘΗΣ ΜΕ ΚΥΤΤΑΡΑ ΦΛΕΓΜΟΝΗΣ,  Bacterial (must be accompanied by obstruction or ΕΝΕΡΓΟΠΟΙΗΣΗ ΠΡΟΦΛΕΓΜΟΝΟΔΩΝ ΚΑΙ ΧΗΜΕΙΟΤΑΚΤΙΚΩΝ reflux) ΚΥΤΤΟΚΙΝΩΝ ΜΕ ΤΕΛΙΚΗ ΕΚΒΑΣΗ ΟΧΕΙΑ ΕΙΤΕ ΧΡΟΝΙΟ ΝΕΦΡΙΤΙΔΑ  Viral (eg, cytomegalovirus [CMV], hantavirus, HIV, hepatitis B) These cytokines are produced by  Fungal (eg, histoplasmosis) inflammatory cells (ie, macrophages, lymphocytes)  Parasitic (eg, Leishmania, Toxoplasma) and also by the renal cells (ie, proximal tubule, vascular endothelial cells, interstitial cells, fibroblasts). ΟΞΕΙΑ ΔΙΑΜΕΣΟΣ ΝΕΦΡΙΤΙΔΑ = ΣΩΛΗΝΑΡΙΑΚΗ ΚΑΤΑΣΤΡΟΦΗ / ΔΥΣΛΕΙΤΟΥΡΓΙΑ ΜΕ / ΑΝΕΥ ΝΕΦΡΙΚΗ ΑΝΕΠΑΡΚΕΙΑ ΑΝΕΞΑΡΤΗΤΑ ΑΠΟ ΤΗΝ ΕΚΤΑΣΗ ΤΗΣ ΣΩΛΗΝΑΡΙΚΑΗΣ ΚΑΤΑΣΤΡΟΦΗΣ, Η ΝΕΦΡΙΚΗ ΔΥΣΛΕΙΤΟΥΡΓΙΑ ΚΑΤΑ ΚΑΝΟΝΑ ΒΕΛΤΙΩΝΕΤΑΙ / ΑΝΑΣΤΡΕΦΕΤΑΙ, ΑΝΤΑΝΑΚΛΩΝΤΑΣ ΤΗΝ ΑΝΑΓΓΕΝΗΤΙΚΗ ΙΚΑΝΟΤΗΤΑ ΤΩΝ ΣΩΛΗΝΑΡΙΩΝ ΜΕ ΑΝΕΠΑΦΗ ΒΑΣΙΚΗ ΜΕΜΒΡΑΝΗ
  • 2. Frequency ΑΝΤΙΣΤΡΟΦΩΣ, Η ΧΡΟΝΙΟΣ ΔΙΑΜΕΣΗ ΝΕΦΡΙΤΙΔΑ ΧΑΡΑΚΤΗΡΙΖΕΤΑΙ United States ΑΠΟ : Primary tubulointerstitial diseases, ie, diseases of the renal o ΟΥΛΟΠΟΙΗΣΗ tubules and interstitium sparing the glomeruli, constitute 10-15% of o ΙΝΩΣΗ o ΣΩΛΗΝΑΡΙΑΚΗ ΑΤΡΟΦΙΑ all kidney diseases both in the United States and around the world. ΜΕ ΠΡΟΟΔΕΥΤΙΚΗ ΕΞΕΛΙΞΗ ΣΕ ΧΝΑ International In certain regions, such as the Balkans (ie, Yugoslavia, Bosnia, ΜΗΧΑΝΙΣΜΟΙ ΟΞΕΙΑΣ ΔΙΑΜΕΣΗΣ ΝΕΦΡΙΤΙΔΑΣ : Croatia, Romania, Bulgaria), where endemic nephropathy is common, interstitial diseases may be more prevalent.3,4 Mortality/Morbidity 1..ΑΝΤΙΔΡΑΣΗ ΥΠΕΡΕΥΑΙΣΘΗΣΙΑΣ ΣΕ ΦΑΡΜΑΚΑ o Tubulointerstitial disease may progress to end-stage renal ΠΕΝΙΚΙΛΛΙΝΗ – ΦΣΑΦ – sulfa drugs disease. o An increased incidence of uroepithelial cancers is found among patients with analgesic nephropathy, aristolochic acid nephropathy, and Balkan endemic nephropathy.3,4 Race 2..ΟΞΕΙΑ ΣΩΛΗΝΑΡΙΑΚΗ ΝΕΚΡΩΣΗ Neither acute nor chronic tubulointerstitial diseases ΑΠΟΦΡΑΞΗ ‘Η ΠΑΛΙΝΔΡΟΜΗΣΗ + ΛΟΙΜΩΞΗ of the kidney demonstrate racial predilections. Lead nephropathy may be more common in black people because of socioeconomic factors. The kidney is remarkably resistant to structural damage in bacterial infections, and, in the absence of obstruction, damage from bacterial Sex infection in the kidney parenchyma is extremely unlikely to occur. Analgesic nephropathy is 5-6 times more common in women. This is generally attributed to women taking more Studies have revealed transforming growth analgesics than men. However, a greater sensitivity to the toxic factor beta (TGF β) as a major participant in effects of analgesics or differences in analgesic metabolism in fibrogenesis. TGF β favors accumulation of collagen women cannot be ruled out. and noncollagen basement membrane components by direct stimulation of production and by Age inhibiting matrix degradation enzymes such as collagenases and metalloproteinases. All toxic nephropathies are related to the cumulative effects of toxic substances, particularly lead, and consequently Activation of nuclear transcription factors, are likely to be observed more frequently with advancing age. such as nuclear factor kappa B (NF-B) in injured kidney cells, with consequent transcription and However, this is highly variable. release of proinflammatory cytokines into the interstitium, appears to be a major mechanism of chronic tubulointerstitial inflammation For example, people with severe lead poisoning during accompanying proteinuric kidney diseases. childhood may present with chronic tubulointerstitial nephritis in early adult life. Atherosclerotic and/or ischemic kidney disease is increasingly more common in elderly individuals. Metabolic disorders, such as cystinosis, oxalosis, and hypercalcemia, can occur in younger individuals.
  • 3. Η ΑΜΕΣΗ ΔΙΑΚΟΠΗ ΤΟΥ ΤΟΞΙΟΥ ΠΑΡΑΓΟΝΤΑ, ΣΥΝΗΘΩΣ ΑΛΛΑ ΟΧΙ ΠΑΝΤΟΤΕ ΣΥΝΕΠΑΓΕΤΑΙ ΤΗΝ ΥΠΟΣΤΡΟΦΗ ΤΗΣ ΝΟΣΟΥ, ΚΑΠΟΤΕ Η ΝΟΣΟΣ ΕΠΙΜΕΝΕΙ ΕΒΔΟΜΑΔΕΣ ΠΡΙΝ ΤΗΝ ΕΝΑΡΞΗ Clinical ΒΕΛΤΙΩΣΗΣ History History depends on whether the tubulointerstitial nephritis is acute or Although any drug can potentially cause a chronic. hypersensitivity reaction involving the kidney, the following are the most frequently implicated: Acute tubulointerstitial nephritis (general features) o Antibiotics (eg, penicillins, cephalosporins, sulfa drugs, ΤΥΠΙΚΗ ΕΝΑΡΞΗ = ΤΑΧΕΙΑ ΕΓΚΑΤΑΣΤΑΣΗ ΟΝΑ quinolones) o NSAIDs ΚΑΤΑ ΚΑΝΟΝΑ ΕΝΤΟΣ ΗΜΕΡΩΝ ΑΠΟ ΤΗΝ ΕΝΑΡΞΗ ΕΚΘΕΣΗΣ ΣΤΟ o Diuretics (eg, thiazides, furosemide) ΤΟΞΙΚΟ ΠΑΡΑΓΟΝΤΑ o Allopurinol o Phenytoin o Rifampin o Interferon alfa o Proton pump inhibitors ΜΣΑΦ : ΜΕΤΑ ΑΠΟ ΕΚΘΕΣΗ ΜΗΝΩΝ o ΕΞΑΝΘΗΜΑ o ΠΥΡΕΤΟΣ o o ΕΩΣΙΝΟΦΙΛΙΑ ΕΩΣΙΝΟΦΙΛΟΥΡΙΑ Acute tubulointerstitial nephritis o ΑΥΞΗΣΗ ΤΩΝ IgE caused by NSAIDs ΕΞΑΙΡΕΣΗ = rifampin, ΜΣΑΦ This condition is more common in elderly people, perhaps because of the higher incidence of arthritic disorders in this population. Acute allergic interstitial nephritis should not be confused with the acute vasomotor renal insufficiency that can occur ΗΠΙΑ ΔΙΑΜΕΣΗ ΝΕΦΡΙΤΙΔΑ in patients with preexisting underperfusion of the kidney. ΕΝΙΟΤΕ = ΕΞΑΝΘΗΜΑ + ΑΙΜΑΤΟΥΡΙΑ A unique feature of allergic interstitial nephritis caused by NSAIDs is that patients may present with nephrotic ΥΠΟΥΛΗ ΕΓΚΑΤΑΣΤΑΣΗ ΣΩΛΗΝΑΡΙΑΚΗΣ ΔΙΑΤΑΡΑΧΗΣ syndrome. In such patients, massive proteinuria with hypoalbuminemia and edema are present in addition to the typical = [Fanconi syndrome : ΑΜΙΝΟΞΥΟΥΡΙΑ – ΓΛΥΚΟΖΟΥΡΙΑ – features of acute interstitial nephritis. ΝΕΦΡΟΣΩΛΗΝΑΡΙΑΚΗ ΟΞΕΩΣΗ ] Findings on kidney biopsy ΠΡΩΤΕΙΝΟΥΡΙΑ = ΑΠΟΥΣΙΑΖΕΙ Ή ΕΙΝΑΙ ΗΠΙΑ show features of minimal o ΟΥΡΙΝΑΛΥΣΗ = change nephrosis in addition to the characteristic findings o ΜΙΚΡΟΣΚΟΠΙΚΗ ΑΙΜΑΤΟΥΡΙΑΣΤΕΙΡΑ ΠΥΟΥΡΙΑ o ΜΕ / ΑΝΕΥ ΕΩΣΙΝΟΦΙΛΑ ΑΝ ΚΑΙ Η ΚΛΙΝΙΚΗ ΕΙΚΟΝΑ ΕΙΝΑΙ ΤΥΠΙΚΗ ΚΑΤΑ ΚΑΝΟΝΑ ΔΙΑΓΝΩΣΗ of interstitial nephritis ΤΙΘΕΤΑΙ ΜΟΝΟ ΜΕΤΑ ΑΠΟ ΒΙΟΨΙΑ ΜΣΑΦ ΤΟΞΙΚΟΤΗΤΑ = ΒΑΡΕΙΑ ΠΡΩΤΕΙΝΟΥΡΙΑ, ΣΥΧΝΑ ΔΙΚΗΝ ΝΕΦΡΩΣΙΚΟΥ ΣΥΝΔΡΟΜΟΥ
  • 4. Acute tubulointerstitial nephritis Antibiotic-induced acute tubulointerstitial caused by miscellaneous agents nephritis Infections with viral agents, bacteria, and fungi This form of nephritis is usually observed in the are occasionally associated with acute interstitial hospital setting during treatment of serious infections, within nephritis. Hantavirus, CMV, and HIV are common among the several days to weeks of initiation of antibiotic therapy. infectious agents associated with acute interstitial nephritis. Rash, eosinophilia, and eosinophiluria, as well as pyuria (sterile), In HIV disease, acute interstitial nephritis is usually hematuria, and modest proteinuria (usually <1 g/d), are common. observed in conjunction with glomerular disease (ie, focal segmental glomerulosclerosis). Unlike in NSAID-induced allergic interstitial nephritis, nephrotic range proteinuria is very rare. Parenchymal invasion by the virus is not always If a renal biopsy is performed, eosinophils can be a component of the present, and other characteristic features, such as eosinophilia interstitial nephritis and fever, are usually absent. Occasionally, ill-defined granulomas are present Bacterial infection with renal parenchymal invasion is sometimes responsible for acute interstitial nephritis, but this is exceedingly rare in the absence of obstruction. Other infections such as tuberculosis and histoplasmosis are also among the rare causes of acute tubulointerstitial nephritis and may be diagnostic challenges. Among antibiotics, rifampin is unique in that the interstitial nephritis generally occurs when the antibiotic is reintroduced after an interval. Chronic tubulointerstitial nephritis Furthermore, the interstitial nephritis associated with it does not manifest with eosinophilia. (general features) In some cases, rifampin-associated interstitial nephritis has The chronic form is an insidious disease and most probably been reported to show casts containing immunoglobulin light represents the common final response pattern of the kidney to a chains in tubular lumens without any evidence of myeloma in variety of insults and agents the patient. Important causes include analgesics; lead; drugs, including Flulike symptoms, flank pain, hypertension, and cyclosporine, cisplatin, and lithium; and metabolic disorders, notably hypercalcemia, potassium depletion, and hyperoxaluria. oliguric acute renal failure are common. In some patients, circulating antirifampin antibodies and immunoglobulin G (IgG) deposits along the tubular basement Because of its insidious nature, chronic tubulointerstitial membranes have been reported. nephritis is often diagnosed incidentally on routine laboratory screening or evaluation of hypertension. Patients are usually asymptomatic. Hypertension is common but not universal, and it is conspicuously absent in Balkan endemic nephropathy. Clinical investigations may show modest elevation in serum creatinine, evidence of tubular dysfunction (ie, renal tubular acidosis), or Fanconi syndrome (ie, aminoaciduria, glycosuria, hypophosphatemia, hypouricemia). Proteinuria is usually mild, often less than 1 g/d.
  • 5. In contrast to glomerular disease, a significant In some patients, a history can be elicited fraction of the protein is low molecular weight (eg, of episodes of : immunoglobulin light chains, beta2 microglobulin, lysozyme, peptide hormones). o papillary necrosis, ie, o gross hematuria with These proteins are normally taken o flank pain occasionally accompanied by up by the proximal tubules and o obstruction and o infection broken down there. Thus, in diseases predominantly involving Clinically, patients with analgesic nephropathy present with renal insufficiency, modest proteinuria, sterile tubular structures, decreased pyuria, and anemia. Diagnosis can be supported by history endocytosis of filtered proteins of heavy analgesic use, and computer-assisted tomograms may reveal microcalcifications at the leads to the characteristic tubular papillary tips. proteinuria. Treatment is supportive and includes Findings on kidney biopsy in chronic discontinuation of analgesic use. Long-term tubulointerstitial nephritis usually show varying degrees follow-up studies have shown progression to of interstitial fibrosis, tubular atrophy, arteriolar sclerosis, and, occasionally, mononuclear cell infiltration end-stage renal disease requiring dialysis, and (see image below). increased incidence of uroepithelial cancers is also observed in patients with analgesic Often, the findings are nonspecific and the nephropathy. etiology is not discernible from the biopsy; some diseases, such as sarcoidosis, show noncaseating granulomas, and, in viral diseases, immunostaining can yield clues to the cause. In patients with suspected lead exposure, an Lithium nephropathy ethylenediaminetetraacetic acid (EDTA) lead mobilization test or determination of tibial bone lead by Distal tubular dysfunction ie, radiographic fluorescence can confirm lead etiology. o polyuria, o concentrating defect, o down-regulation of aquaporin-2 Analgesic nephropathy1 occurs in up to 50% of patients receiving lithium. Analgesic nephropathy is the most common category of chronic interstitial nephritis worldwide. This disorder occurs Chronic interstitial nephritis occurs in a small subset of patients with long-term ingestion of combinations of receiving long-term lithium therapy who have had repeated phenacetin, aspirin, and caffeine or phenacetin- episodes of lithium toxicity with high serum levels. acetaminophen or NSAIDs and acetaminophen. In its most severe form, it is associated with papillary necrosis. The amount of phenacetin-acetaminophen combination required to cause chronic interstitial nephritis has been estimated to be at least 2-3 kg over many years. Although initially thought to be exclusively associated with phenacetin-containing combinations, all analgesics, including acetaminophen, aspirin, and NSAIDs, can cause analgesic-induced chronic tubulointerstitial nephritis. Analgesic nephropathy is most common in women in the sixth and seventh decades of life who have a history of low back pain, migraine headaches, or other chronic musculoskeletal pain.
  • 6. Cyclosporine- and tacrolimus-induced Lead nephropathy nephropathy Since antiquity, lead has been known to cause kidney These agents, although indispensable in the disease and gout. In the modern industrialized world, lead is a ubiquitous environmental and occupational toxin and is management of solid organ transplantation, can an important cause of chronic tubulointerstitial nephritis and cause acute and chronic nephrotoxicity. hypertension, mainly in urban poor communities and particularly among black people. The mechanism appears to be dependent largely on the potent vasoconstrictive effects of these drugs. Chronic Children with severe lead poisoning can present tubulointerstitial nephritis induced by cyclosporine or with encephalopathy and acute renal failure with tacrolimus is common among patients receiving kidney, heart, Fanconi syndrome. Because lead has a biologic half-life of liver, and pancreas transplants. several decades, if untreated by chelation, both intermittent acute poisoning and low-level environmental exposure result in chronic cumulative lead poisoning. The major However, it is rare in bone marrow transplant recipients consequence of chronic lead poisoning is chronic because they receive the drugs for a short time and generally at tubulointerstitial disease, usually in the third to fourth lower doses. decades of life. In renal transplant recipients, cyclosporine- or tacrolimus- A common source of lead poisoning is leaded paint induced chronic interstitial nephritis is similar to chronic chipping in old urban tenements. Young children rejection. attracted to the sweet taste of the leaded paint may ingest or inhale dust particles containing lead and are at particular Because the pathophysiology of both is poorly risk. In the industrial setting, welders, smelters, battery understood, these conditions tend to be included under workers, painters, and restorers of old buildings, especially in poorly ventilated work environments, can be exposed to the generic term of chronic transplant nephropathy. toxic amounts of lead. Most kidney transplant patients have a stable course with mild Hypertension is almost always present, and, in the impairment of renal function. However, up to 10% of heart absence of appropriate testing or careful exposure history, transplant recipients develop progressive renal insufficiency lead nephropathy is often misdiagnosed as so-called and eventually require dialysis. hypertensive kidney disease. Patients with lead nephropathy tend to have disproportionately worse hyperuricemia compared to patients with other kidney diseases because of the unique effects of lead on urate metabolism, and, Both cyclosporine and tacrolimus frequently cause consequently, gout is common. hypertension and hyperkalemia. In retrospect, after careful investigation including the EDTA lead mobilization test, many patients presumed to have Hypomagnesemia caused by renal magnesium wasting is either gouty nephropathy or hypertensive also common in cyclosporine-treated patients. nephrosclerosis are discovered to have lead nephropathy. Identification of the lead etiology in patients Concomitant use of calcium channel blockers presumed to have gout nephropathy has cast doubt on the reduces nephrotoxicity. existence of this entity. Long-term use of cyclosporine has been associated with patchy interstitial fibrosis, usually in a striped pattern and with tubular atrophy. Thrombotic microangiopathy might further contribute to both acute and chronic nephrotoxicity.
  • 7. Obstructive uropathy Atherosclerotic kidney disease Obstruction of urinary outflow as observed in : As life expectancy increases, atherosclerotic disease of the kidney is emerging as a major category of chronic o prostate disease, tubulointerstitial nephropathy. o stone disease, o neoplasm, and Unfortunately, no unanimity on nomenclature exists among o retroperitoneal fibrosis experts, and kidney disease in this category is variably termed is : among others, can cause chronic tubulointerstitial disease. o Ιchemic nephropathy, o renovascular disease, and Modest proteinuria and hyperkalemic renal tubular acidosis are o nephrosclerosis common. Vesicoureteral reflux disease, usually congenital, characteristically results in focal glomerulosclerosis In all likelihood, cases of so-called hypertensive with nephrotic syndrome and a prominent kidney disease or hypertensive nephrosclerosis tubulointerstitial component in adult life even if the belong in the category of atherosclerotic kidney reflux has been corrected early. disease. Superimposed infection and pyelonephritis often complicate Lack of appropriate diagnosis can explain the discrepancy in obstruction. the incidence of kidney disease in hypertensive populations in Europe and the United States. Recurrent urinary tract infection itself can cause ammonium magnesium phosphate stones, further aggravating In Europe, kidney disease is found in only about 1% of tubulointerstitial disease and perpetuating infection. hypertensive populations, while in the United States 30% of all end-stage disease requiring dialysis is attributed to hypertensive Similarly, papillary necrosis and infection may complicate the kidney disease. course and may lead to acute pyelonephritis with fever, flank pain, hematuria, and, especially in elderly patients, urosepsis. Atherosclerotic kidney disease is typically observed in elderly white males who smoke, but it is by no means confined to this population. Many individuals with dyslipidemia and other atherosclerotic phenomena, such as coronary artery disease, carotid artery disease, and peripheral arterial disease, are prone to involvement of renal arteries, regardless of age. Often, these patients have hypertension, not necessarily severe, with elevated serum creatinine and urea nitrogen and proteinuria, 1-2 g/d. The course of progression of the kidney disease is usually slower than in patients with glomerular diseases such as diabetic nephropathy. Diagnosis can usually be made clinically, and radiologic investigations, such as duplex scanning of the renal arteries, digital subtraction angiography, or magnetic resonance imaging, reveal atherosclerotic stenosis of the renal arteries. Kidney biopsy is seldom necessary and, if performed, shows nonspecific changes of chronic tubulointerstitial nephritis, ie, tubular atrophy, fibrosis, and arterial or arteriolar sclerosis with paucity of cellular infiltration. Because these patients tend to have atherosclerotic complications, they are likely to experience multiple contrast
  • 8. procedures and hence are at risk for acute recurrent contrast nephropathy, which can accelerate progression to end-stage Metabolic disorders and renal disease. nephropathy No specific therapy is available, but good control of o Hypercalcemia, hypertension, cessation of smoking, and vigorous control of o chronic potassium depletion, and dyslipidemia with diet and with hepatic 3-methylglutaryl o cystinosis coenzyme A (HMG-CoA) reductase inhibitors are expected to result in improved outcomes. can lead to chronic tubulointerstitial nephritis. Hypercalcemia is the most common cause. Cholesterol microembolic disease and nephropathy Chronic hypercalcemia can occur in : This is a unique syndrome that has been recognized in the setting of catheter procedures involving vasculature above the o primary hyperparathyroidism, renal arteries, such as coronary angiography, although it can o sarcoidosis, o multiple myeloma, and occur in patients on anticoagulation; it can even o other neoplasms (particularly with bone metastases) and spontaneously. in vitamin D intoxication. The pathophysiology is destabilization of atheroma plaques, Even transient hypercalcemia can lead to chronic renal either during catheter manipulation or spontaneously, resulting in showering of cholesterol crystals downstream and eventual insufficiency; renal involvement is mostly confined to the lodging of needle-shaped cholesterol crystals in small arterioles distal tubular structures. within the kidney vessels (see images below). Clinically, polyuria and concentrating defect are common. During acute hypercalcemia, urinary concentrating defect can Microemboli can also occur in the central nervous system and lead to dehydration and may aggravate acute renal failure. retinal arteries (called Hollenhorst plaques). In the extremities, distal vessel emboli may result in small superficial skin infarcts (scabs). Radiologic examinations may reveal nephrocalcinosis, and renal stone formation can be a complicating factor in hypercalcemia. More extensive cholesterol microembolization to the extremities can result in the characteristic livedo reticularis appearance in the lower extremities. Oddly, some patients have other systemic signs and symptoms, such as low-grade fever, leukocytosis, eosinophilia, elevated sedimentation rate, and hypocomplementemia. Cholesterol microembolism usually causes acute renal failure of varying degrees, with some spontaneous improvement in renal function but often with permanent residual renal damage. Kidney biopsy during the acute phase shows the characteristic needle-shaped clefts caused by the cholesterol crystals within the small- and medium-sized arterioles accompanied by patchy tubulointerstitial nephritis with mild mononuclear cellular infiltration. No effective treatment for this disorder is available.
  • 9. Balkan endemic nephropathy3,4 Physical This is an endemic kidney disease confined to well-defined A thorough physical examination may provide clues to the discrete settlements located along the Danube River and its diagnosis eg : tributaries. o fever, The caseload of patients is particularly heavy in the o rash in acute tubulointerstitial nephritis, Balkans (ie, Bosnia, Croatia, Yugoslavia, Romania, o livido reticularis and Bulgaria). The disease occurs in individuals, o Hollenhorst plaques in the optic fundi in atheroembolic autochthonous or immigrant, who have resided in disease the endemic regions for at least 15-20 years and does not occur among residents who move to nonendemic areas. but, in most patients, no characteristic findings exist. Thus, the evidence implicates environmental factor(s), but no Some patients present with hypertension, although others may definitive agent or factor has been identified yet. be normotensive or hypotensive (eg, Balkan endemic 5 nephropathy). Typically, patients are nonhypertensive and have disproportionately profound anemia. o Acute allergic tubulointerstitial nephritis: Physical examination in acute tubulointerstitial nephritis Patients are identified easily in the endemic regions by may show a rash accompanying renal findings. However, rash is highly variable. Although the presence checking for tubular proteinuria. Beta2 microglobulinuria of rash can be supportive evidence of an allergic etiology has proved particularly useful in identifying cases and has been of an acute renal insufficiency, its absence is not proposed and used as a marker of the disease. useful in ruling out acute allergic interstitial nephritis. Because a major criterion to identify the disease is residency in the endemic region, whether similar kidney diseases occur in o Cholesterol microembolic disease: In other parts of the world is not known. cholesterol microembolic disease, eyeground examination may reveal the characteristic cholesterol Most patients eventually develop end-stage renal crystals, also termed Hollenhorst plaques, in retinal disease and require dialysis. Up to 40% of patients develop vessels, which can support the diagnosis. Similarly, the upper urinary tract uroepithelial tumors. presence of small skin infarcts or scabs, especially on or between the toes or fingers, is a helpful clue to cholesterol microembolism. Sometimes, particularly after displacement of a large aortic plaque, marked ischemia of Chinese herb/aristolochic acid the lower extremities yields a bluish-purplish discoloration (ie, livedo reticularis) of the feet or lower portions of legs. nephropathy o Atherosclerotic (ischemic) kidney disease: Evidence for other atherosclerotic disease, such as Chronic progressive tubulointerstitial nephritis has been carotid or inguinal bruits, may be clues to so-called observed in many countries among patients using Chinese atherosclerotic kidney disease, particularly in elderly herbal medicines for weight reduction. white males who smoke. Most of these cases have been attributed to herbs containing aristolochic acid. The pathophysiology of nephrotoxicity is not well understood. Renal biopsies have shown severe interstitial fibrosis.
  • 10. nephropathy may not be an appropriate name Causes for the disease, however, because aristolochic acid can be present in herbal medicines from  Acute allergic interstitial nephritis: Any drug any country. The term aristolochic acid can cause an acute allergic reaction involving the nephropathy (AAN) more accurately kidneys. Drugs most commonly associated with acute characterizes this form of toxic nephropathy. allergic nephritides are listed in History. o Another interesting feature of AAN is its  Cholesterol microembolic disease: association with uroepithelial cancers Underlying atherosclerotic disease, dyslipidemia, and reminiscent of Balkan nephropathy. Aristolochic smoking are conditions commonly associated with acid not only can trigger severe renal fibrosis this disorder. Catheter manipulations above the level but also can cause oncogene mutations that can of the renal arteries or anticoagulation in a patient explain the high incidence of renal cancer with with atherosclerosis can trigger cholesterol this type of interstitial nephritis. Patients have microembolic disease. also been found to have abnormal function of  Balkan endemic nephropathy: Epidemiology p53, a known tumor suppressor gene. and natural history clearly implicate environmental factors in the pathophysiology of this disease. Lead contamination of food has been considered but ruled out as a cause. Some studies have implicated a fungal toxin, called "ochratoxin," which can grow in moist grains in storage and which has been shown to cause a similar kidney disease in pigs in several central European countries. However, most experts agree that the Differential Diagnoses evidence for its role in this endemic nephropathy is weak. Acute Renal Failure  Lead nephropathy: Environmental and Glomerulonephritis, Acute occupational exposure to lead can cause chronic Urinary Tract Obstruction tubulointerstitial nephritis. Occupations in welding, smelting, the battery industry, and mining have all been responsible for lead nephropathy cases. Environmental Other Problems to Be Considered exposure from leaded gasoline is decreasing because the use of leaded gasoline has ceased in the United Radiation nephritis States. Sporadic exposure is still observed, particularly Toxic nephropathies among children living in deteriorating housing in urban areas. Rarely, lead poisoning can be observed among individuals who consume moonshine whiskey and those who drink beverages from imported ceramics painted with leaded glaze.  Obstructive uropathy: A variety of causes contribute to obstructive uropathy. Prostate disease in elderly males and pelvic or colonic tumors involving both ureters in both sexes can cause obstructive uropathy. Nephrolithiasis, with or without urinary tract infection, may also cause obstructive uropathy. Radiation to the pelvic area and some drugs, such as methysergide, can cause retroperitoneal fibrosis and obstruction.  Chinese herb/aristolochic acid nephropathy o Aristolochic acid was recognized as a potent nephrotoxin that can cause rapidly progressive interstitial fibrosis and end-stage renal disease in young women using a Chinese herb as part of a slimming regimen in Belgium in early 1990s. o Since then, many other cases of so-called Chinese herb (CH) nephropathy have been reported from around the world. CH
  • 11. observed with lead nephropathy and NSAID-induced analgesic nephropathy, among other conditions. Urinalysis: Urinalysis may reveal : o proteinuria, o hematuria, and o the presence of white cells, o with or without bacteria A microscopic analysis of urine sediment may reveal : o casts, o white cells, o eosinophils, and o crystals. Workup If allergic interstitial nephritis is suspected, send a cytospin specimen to determine if eosinophils are in the urine. Laboratory Studies In NSAID-induced AIN, eosinophiluria is usually absent. Complete blood cell count with differential: Eosinophilia, when present, can be very helpful. However, this is neither specific nor sensitive enough to establish the diagnosis. Although the true incidence of eosinophilia in acute tubulointerstitial nephritis is unknown, it is estimated to be present in approximately half of patients. Unfortunately, the absence of eosinophiluria does not rule out the diagnosis, and it can be observed in other diseases, including : o cholesterol microembolism, o urinary tract infections, o parasitic disorders, and o glomerulonephritis Typically, eosinophilia is absent in AIN-induced by NSAIDs. Blood chemistry: A complete set of chemistries, including BUN and serum creatinine, provides information on whether renal insufficiency exists. A low bicarbonate level (total carbon dioxide <24-23 mEq/L) may indicate acidosis. Low serum potassium levels may indicate a proximal tubular disorder, and elevated serum potassium levels with a low bicarbonate level may indicate type 4 renal tubular acidosis, which can be
  • 12. Imaging Studies Diagnosis of lead nephropathy requires Ultrasonography: This noninvasive technique is extremely estimation of cumulative body stores of lead by either EDTA helpful in identifying hydronephrosis in obstructive disease, as lead mobilization test or by determination of bone lead well as calculi in stone disease. Both radiolucent and radiopaque content by radiographic fluorescence. stones can be visualized using ultrasonography. EDTA lead mobilization test is performed by measuring A combination of ultrasonography and flat plate kidney, 24-hour urine lead excretion after intravenous or ureter, and bladder (KUB) radiography is helpful in workup and intramuscular administration of 2 g EDTA (calcium identification of radiopaque versus radiolucent stones. disodium versenate). Normal kidney size by ultrasonographic examination generally favors Excretion of more than 0.6 g of lead per 24 hours is but does not prove a diagnosis of acute (thus potentially reversible) considered an abnormal finding. kidney disease. In contrast, small (shrunken) kidneys with increased echogenicity indicate chronic and irreversible kidney disease. Blood lead levels, although elevated during acute or recent exposure, are not very helpful Computer-assisted tomography (CT) scanning: in the evaluation of chronic lead poisoning. This technique provides information similar to ultrasonographic scanning in the workup of kidney disease, generally with greater During acute exposure, lead is concentrated in the red blood resolution. However, an ultrasonographic examination is sufficient cells and later extracted to tissues and bone as the red cells in most kidney diseases. A high-resolution scan showing senesce. microcalcifications in renal papillary tips can be very helpful in diagnosis of analgesic nephropathy. The kidneys may be very small in Balkan endemic nephropathy and Kidney biopsy is not diagnostic of lead etiology either and aristolochic acid nephropathy. shows nonspecific changes such as interstitial fibrosis, tubular atrophy, and vascular sclerosis, findings common to tubulointerstitial nephritides of other etiologies. Body burden of lead and bone lead concentration can be reduced by extended chelation treatment using EDTA (versenate). Intravenous pyelography: Once widely used, this technique seldom plays a role in the workup of kidney diseases Quantitative determination of urine protein in modern medicine. In many instances, similar information can be obtained by ultrasonography without exposing the patient may be helpful. to potentially nephrotoxic contrast dye. Low-molecular weight proteins, such as beta-2 microglobulin, retinol binding protein (RBP), alpha-1 Gallium scanning: microglobulin, and immunoglobulin light chains, are increased in chronic tubulointerstitial nephritides. Findings on gallium scanning have been reported to be confirmatory in the diagnosis of acute interstitial nephritis. Thus, a negative finding helps to rule out this diagnosis. However, Beta-2 microglobulinuria has been found helpful in the findings on this test have proved to be too nonspecific, except as a diagnosis of Balkan endemic nephropathy and cadmium confirmatory tool in suspected cases. nephropathy. Procedures Kidney biopsy: Kidney biopsy is the definitive test for Other Tests diagnosing acute allergic interstitial nephritis, particularly in cases where clinical diagnosis is difficult. The differential diagnosis of acute tubulointerstitial nephritis encompasses multiple etiologies, including acute tubular necrosis, acute, vasculitis, and atheroembolic disease. EDTA lead mobilization test Therefore, consider kidney biopsy when diagnosis is not obvious. Kidney biopsy shows mononuclear and often eosinophilic cellular infiltration of the renal parenchyma with sparing of the glomeruli (see Consider the possibility of lead nephropathy in second and third images below). Sometimes, interstitial changes such patients presenting with chronic renal insufficiency, as fibrosis and atrophy are also present. hypertension, and gout. In the absence of documented episodes of acute symptomatic lead poisoning, medical history is not reliable in ascertaining the lead etiology in patients presenting with chronic tubulointerstitial nephritis. Acute cellular infiltration, particularly with eosinophilia, can be diagnostic of acute allergic interstitial nephritis (see first five images below). In cholesterol microembolism in the kidney, the
  • 13. finding of a characteristic needle-shaped cleft in medium- or Chelation therapy with EDTA may slow progressive small-sized renal arterioles is diagnostic (see sixth and seventh images below). Chronic tubulointerstitial nephritis is renal insufficiency in patients with mild lead characterized by tubular atrophy, fibrosis, and patchy infiltrate intoxication. Several studies from Taiwan have shown that of mononuclear cells chelation therapy in patients with modest increases in body lead burden (ie, 80-600 µg of lead) significantly slowed and/or reversed the rate of decline in the glomerular filtration rate (GFR) compared to placebo. This was found in both diabetics and nondiabetics.6,7 Given that these studies took place in Taiwan, it is difficult to generalize Treatment – Medical Care these results. Further study is needed before this treatment can be recommended. Treatment of acute tubulointerstitial nephritis Because no effective therapy reverses the long-term consequences of lead poisoning, the best therapy is In most cases, cessation of the offending agent results in prevention and awareness of potential environmental and quick recovery and complete resolution of the renal occupational sources for lead exposure. disorder, although some patients progress to chronic renal insufficiency. In patients with established lead nephropathy, treatment consists of management of hypertension, gout, and chronic renal insufficiency. If no sign of improvement is observed within a few Many patients with lead nephropathy progress to end- days of discontinuation of the offending agent, consider stage kidney failure and require dialysis. therapy with steroids. Although controlled trials are lacking, many authors suggest using Treatment of cyclosporine/tacrolimus prednisone at relatively high doses, eg, 1 mg/kg for induced renal failure: 4-6 weeks, with rapid tapering of the dose. This intervention may improve the outcome, speeding renal recovery and reducing the requirement for dialysis. Treatment includes reducing cyclosporine/tacrolimus doses and target trough levels. Discontinuing these medications and/or switching to other Treatment of chronic tubulointerstitial immunosuppressives (eg, rapamycin), especially in those with more advanced renal failure, should also be disease: considered. Treatment depends on the etiology and generally consists of Diet supportive measures, such as : Hypertensive patients should be on a low-sodium diet. o adequate blood pressure control and For all patients with early renal disease, recommend general o management of anemia guidelines for a healthy diet, ie, low-fat (low-cholesterol) diet rich in fresh fruits and vegetables such as the dietary approaches to stop hypertension (DASH) diet. Treatment of lead nephropathy Chelation therapy is of proven value and must be implemented in acute lead poisoning. Although the oral chelating agent succimer (Chemet) has proved highly successful in treating children, it has not been widely used in adults. Nevertheless, it appears effective in reducing body lead stores.
  • 14. Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use Medication For acute allergic interstitial nephritis, if no spontaneous recovery in renal function is observed after cessation of the offending agent, implementing a short course of steroid therapy is generally recommended. No controlled studies exist on the effect of corticosteroids. Therefore, no well-defined dosage and Chelating agents duration exist. Most practitioners recommend a relatively high dose (eg, 1 mg/kg prednisone) with a rapidly tapering regimen within several weeks. These agents promote the excretion of lead. Glucocorticoids Immunosuppressants for treatment of autoimmune disorders. Succimer (Chemet) Metal chelator, analog of dimercaprol. Used in lead poisoning. Prednisone (Sterapred) Particularly useful in children with lead blood levels >45 mcg/dL. Has anti-inflammatory properties and causes profound and varied metabolic effects. Approved for chelation therapy in children for lead poisoning. Its value in chronic lead nephropathy is not established. Modifies the body's immune response to diverse stimuli. Adult o May decrease inflammation by reversing increased capillary permeability and 10 mg/kg PO q8h for 5 d, followed by 10 mg/kg PO q12h for 14 d; o suppressing PMN [= PML = polymorphonuclear leukocytes ] activity. repeat dosing may be necessary o Stabilizes lysosomal membranes and o suppresses lymphocytes and antibody production Precautions Adult Renal or hepatic impairment; to prevent toxicity, patients should be well hydrated 0.5-2 mg/kg/d PO, taper as condition improves; single am dose safer for long-term use, but divided doses have greater anti- inflammatory effect o Coadministration with estrogens may decrease prednisone clearance; o concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; o phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
  • 15. Edetate calcium disodium (Calcium Disodium Versenate) For lead chelation. Only the calcium disodium preparation should be used. In the context of this article, use of this medication is confined to testing, ie, to perform the EDTA lead mobilization test for Deterrence/Prevention diagnosing lead etiology of chronic tubulointerstitial nephritis. Extended therapy to reduce body lead stores may possibly be beneficial. o Allergic interstitial nephritis: Early recognition and prompt discontinuation of the offending drug are Adult helpful. o Lead nephropathy: Implement environmental EDTA lead mobilization test: 2 g IV/IM; measures, such as removal of lead from indoor paint and gasoline, and eliminate other sources of exposure. for IV, dilute with 500 mL of D5W or 0.9% NaCl and infuse over 8- Use caution with imported ceramics, particularly if 12 h; glazed if IM used, mix with 5 mL of 2% lidocaine to avoid pain at injection site Pediatric Complications Administer as in adults; not to exceed 1 g/d o Hypertension may complicate any renal disease, but not all cases of interstitial renal disease are associated with hypertension (ie, Balkan endemic nephropathy, acute allergic interstitial nephritides). o Electrolyte and acid-base disorders may be observed. Follow-up o Chronic tubulointerstitial disease may progress to end- stage renal disease, requiring dialysis or transplantation Further Inpatient Care  Patients with acute renal failure or with serious electrolyte or acid-base disorders may require inpatient care until stabilization or resolution. Further Outpatient Care Prognosis Provide patients with acute interstitial nephritis with o Allergic interstitial nephritis: Most patients follow-up care until resolution. recover renal function upon cessation of the offending agent. Patients who do not recover renal function and those with chronic o Cholesterol microembolic kidney disease: Often, some spontaneous improvement in renal function tubulointerstitial nephritis should receive long-term follow-up care to occurs after the embolic event. Complete resolution of renal ensure that : insufficiency is rare, however. o optimal control of blood pressure is achieved and o Chronic tubulointerstitial nephritides: o to protect kidneys from further potentially nephrotoxic Although the natural history of these diseases varies depending therapies and/or interventions on the etiology, most chronic tubulointerstitial renal disease eventually progresses to end-stage renal disease. However, the rate of progression is generally believed to be much slower in tubulointerstitial nephritis compared to glomerular diseases.
  • 16. Patient Education eMedicine's Diabetes Center and Cholesterol Center. articles Acute Kidney Failure, Multimedia Media file 1: Kidney biopsy. This is an example of acute High Cholesterol, and Cholesterol FAQs. interstitial nephritis. The renal cortex shows a diffuse interstitial, predominantly mononuclear, inflammatory infiltrate with no changes to the glomerulus. Tubules in the center of the field are separated by inflammation and Mayo Clinic - Kidney Transplant. edema, as compared with the more normal architecture in the right lower area (periodic acid-Schiff, 40 X). Miscellaneous Medicolegal Pitfalls  Allergic interstitial nephritis: Make sure to Media file 2: Kidney biopsy. Shown here is an example of acute interstitial nephritis. The diagnosis is based on the obtain a thorough history active inflammatory infiltrate on the right with unaffected of previously documented glomeruli. Interstitial edema and fibrosis are present on the left side of the field, where some tubules show thickened drug allergies before basement membrane (hematoxylin and eosin, 20 X). prescribing a new drug.
  • 17. Media file 3: Kidney biopsy. This image shows acute Media file 5: Kidney biopsy. This image shows acute interstitial nephritis. The interstitium is expanded by interstitial nephritis. The mononuclear inflammatory mononuclear inflammatory infiltrate and edema. Acute infiltrate contains abundant eosinophils, suggesting an tubular damage is present; some tubules are distended and allergic etiology. Severe tubular damage is observed contain granular casts (hematoxylin and eosin, 40 X). (hematoxylin and eosin, 40 X). Media file 4: Kidney biopsy in interstitial nephritis. Acute Media file 6: Kidney biopsy. This image shows acute crescentic glomerulonephritis. The glomerular tuft is interstitial nephritis. The inflammatory infiltrate forms an compressed by the proliferation of epithelial cells, forming ill-defined granuloma, suggesting allergic or infectious a crescent. The interstitium shows mononuclear etiologies. A partially destroyed tubule is present (periodic inflammatory infiltrate and edema (periodic acid-Schiff, 40 acid-Schiff, 40 X). X).
  • 18. Media file 7: Kidney biopsy. This image shows chronic tubulointerstitial nephritis. The interstitium is expanded by fibrosis, with distortion of tubules and periglomerular fibrosis. Glomeruli do not show pathologic changes (hematoxylin and eosin, 20 X). Media file 8: Kidney biopsy in interstitial nephritis. This image shows a cholesterol microembolism. The 2 arterioles in the center are occluded by elongated crystals (hematoxylin and eosin, 20 X). Media file 9: Kidney biopsy in interstitial nephritis. This image shows a cholesterol microembolism. The arteriole in the center of the field has a thickened wall. The lumen is occluded by elongated spaces, corresponding to dissolved crystals surrounded by cellular reaction. The 2 glomeruli flanking the arteriole are sclerotic and hardly recognizable (hematoxylin and eosin, 40 X).