TUBULOINTERSTICIAL NEPHRITIS AND AMYLOIDOSIS OF KIDNEYS

Tubulointersticial nephritis and amyloidosis of kidneys

Disease processes involving the part of the renal parenchyma that consists of the tubules and interstitium are primarily referred to as tubulointerstitial diseases. Tubulointerstitial diseases can be classified as acute or chronic and can present either as primary or secondary (to a systemic disease) processes. Histopathologically, the presentation can vary from a subtle accumulation of lymphocytes, monocytes, or macrophages in the interstitium or tubular atrophy or dilation to extensive interstitial fibrosis, which may be accompanied by glomerulosclerosis.

 

ACUTE INTERSTITIAL NEPHRITIS

 

Acute tubulointerstitial nephritis (AIN) defines a pattern of renal injury usually associated with an abrupt deterioration in renal function characterized histopathologically by inflammation and edema of the renal interstitium. The term was first used by Councilman in 1898 when he noted the histopathologic changes in autopsy specimens of patients with diphtheria and scarlet fever. Although the term acute interstitial nephritis is more commonly used, acute tubulointerstitial nephritis more accurately describes this disease entity because the renal tubules, as well as the interstitium, are involved. ATIN has become an important cause of acute renal failure caused by drug hypersensitivity reactions as a result of the increasing use of antibiotics and other medications that may induce an allergic response in the interstitium. ATIN has been reported to occur in approximately 1 percent of renal biopsies during the evaluation of hematuria or proteinuria

Patients with acute interstitial nephritis constitute 5-76% of people with acute kidney injury.

 

Etiology

The main causes of the ATIN development:

1.     Drug-induced ATIN:

a.     Antibiotics: Penicillins, Cephalosporins, Gentamicin, Tetracycline, Rifampicin, Lincomycin;

b.     Sulfonamides;

c.      Nonsteroidal anti-inflammatory drugs (NSAIDs);

d.     Anticonvulsants: Carbamazepine, Diazepam, Phenobarbital;

e.      Anticoagulants: Warfarin;

f.       Diuretics: Furosemide (Lasix), thiazides, triamterene (Dyrenium);

g.     Others: Allopurinol, Methyldopa, Azathioprine, Bismuth salts, Captopril, Cimetidine, Clofibrate, D-Penicillamine, Gold salts, Interferon, Omeprazole, Streptokinase

2.     Infection-associated ATIN:

a.     Direct injury: β-hemolitic streptococc, Leptospira, Brucella, Candida;

b.     Indirect injury: sepsis of any etiology;

3.     Toxic substances of chemical and plant origin:

a.     salts of heavy metals, insecticides, paints, organic solvents;

b.     poisonous herbs, berries and mushrooms;

c.      intoxications by: hepatotoxic substances, formaldehyde, chlorinated hydrocarbons;

4.     Systemic diseases:

a.     Immunologic diseases: systemic lupus erythematosus, acute transplant rejection, Sjögren syndrome, Wegener granulomatosis, Goodpasture syndrome;

b.     Metabolic disorders (increased concentration in blood urate, oxalate, calcium, potassium);

c.      Lymphoproliferative disease;

5.     Idiopatic acute tubulointerstitial nephritis.

 

Pathogenesis

The causes of ATIN are conveniently classified into three general categories: Drug-induced ATIN, infection-associated ATIN, and systemic disorders, with immune-mediated mechanisms.

The patient’s history is crucial in determining the exact cause of ATIN because the majority of cases have been causally related to medication use, with approximately one-third of such cases being secondary to antibiotic usage.

The list of medications causing ATIN continues to grow:

Drugs causing acute tubulointerstitial nephritis (ATIN).

Antimicrobial agents

Acyclovir	Cloxacillin	Nafcillin
Ampicillin	Colistin	Nitrofurantoin
Amoxicillin	Cotrimoxazole	Norfloxacin
Aztreonam	Erythromycin	Oxacillin
Carbenicillin	Ethambutol	Penicillin G
Cefaclor	Foscarnet	Piperacillin
Cefamandole	Gentamicin	Polymyxin acid
Cefazolin	Indinavir	Quinine
Cephalexin	Interferon	Rifampicin
Cephalothin	Isoniazid	Sulfonamides
Cefoxitin	Lincomycin	Teicoplanin
Cefotaxime	Methicillin2	Tetracycline
Cidofovir	Mezlocillin	Vancomycin
Ciprofloxacin	Minocycline

 

NSAIDs including salicylates

Alclofenac	Ibuprofen	Phenylbutazone
Azapropazone	Indomethacin	Piroxicam
Aspirin	Ketoprofen	Sulfasalazine
Diclofenac	Mefenamic acid	Sulindac
Diflunisal	Meloxicam	Tolmetin
Fenclofenac	Mesalazine (5-ASA)
Fenoprofen	Naproxen

 

Anticonvulsants

Carbamazepine

Diazepam

Phenobarbital

Phenytoin

Valproate sodium

 

Diuretics

Chlorthalidone

Ethacrynic acid

Furosemide

Hydrochlorothiazide

Indapamide

Triamterene

 

Others

Allopurinol	Clozapine	Phenylpropanolamine
Methyldopa	D-Penicillamine	Probenecid
Azathioprine	Fenofibrate	Propranolol
Bethanidineb	Gold salts	Propylthiouracil
Bismuth salts	Griseofulvin	Ranitidine
Captopril	Interferon	Streptokinase
Chlorpropamide	Interleukin-2	Sulfinpyrazone
Cyclosporine	Omeprazole	Warfarin
Cimetidine	Phenindione
Clofibrate	Phenothiazine

 

Antibiotic-Induced Acute Tubulointerstitial Nephritis

The prototype agent for antibiotic-induced ATIN is methicillin. Because of this it is rarely if ever used in clinical practice today.

All β-lactam antibiotics (penicillins and cephalosporins) have been associated with ATIN. It can occur from as much as 10–20 days after the first exposure to the culprit drug to as little as 2–3 days after reexposure to a drug to which an individual has previously been sensitized. Frequently, ATIN presents as an acute oliguric renal failure.

ATIN has also beeoted to occur secondary to drugs that are taken discontinuously, with the classic example being interrupted therapy with rifampin for tuberculosis.

Note, however, that the development of drug-induced ATIN is not dose dependent.

 

Nonsteroidal Anti-inflammatory Drug-Induced Acute Tubulointerstitial Nephritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce ATIN with several unique features. It usually occurs after several weeks to months of exposure to the culprit NSAID. In contrast to other causes of ATIN that typically present with mild proteinuria, NSAID-induced ATIN is characterized by the occurrence of nephrotic syndrome (hypoalbuminemia, edema, and nephrotic-range proteinuria). Typically, affected patients tend to be elderly, perhaps because of an increased incidence of painful arthritic conditions. In patients subjected to renal biopsy, features of minimal change disease have been reported, especially in those with concomitant nephrotic-range proteinuria.

It must be emphasized, however, that in the workup of acute renal failure, NSAIDs can cause not only ATIN, but also hemodynamic perturbations of renal perfusion related to its vasoconstrictive properties, especially in the setting of volume depletion. NSAID-induced ATIN is more likely to cause permanent renal injury as compared to other drugs causing ATIN.

Infection-Induced Acute Tubulointerstitial Nephritis

Infectious disease processes primarily involving the kidneys, such as acute pyelonephritis, have also been associated with ATIN.

Other Causes of Acute Tubulointerstitial Nephritis

Recently, proton pump inhibitors have been implicated in the causation of ATIN. The timing from initiation of proton pump inhibitors to presentation with renal involvement varies, with an average of 9–10 weeks. Reexposure after discontinuation of the drug results in a faster onset of kidney damage. Renal biopsy typically shows the presence of an interstitial infiltrate with or without tubulitis. The presence of eosinophils in the tubulointerstitium is seen in the majority of cases. Glomeruli are typically spared.

Figure. Acute tubulointerstitial nephritis in a 39-year-old male with a history of intake of omeprazole who presented with acute renal failure and a serum creatinine of 5.9 mg/dL. There is interstitial edema, an inflammatory infiltrate composed of lymphocytes, macrophages, and numerous eosinophils. Tubulitis is also evident (arrow). Hematoxylin and eosin (×400). (Courtesy of Dr. Shane Meehan, Department of Pathology, University of Chicago.)

 

Figure. Patient F., 12 years old. Diagnosis: Primary Sjögren syndrome. Tubulointerstitial nephritis with non-uniform infiltration of lymphocytes and plasma cells and acute tubular injury (Hematoxylin and eosin ×100) (Source: http://www.nephro.ru/magazine/article.php?id=26976)

 

Figure. Acute graft rejection: tubulointerstitial variant Banff 1. (PAS –reaction * 250) (Source: http://med.znate.ru/docs/index-54288.html)

Early recognition and prompt withdrawal of the offending proton pump inhibitor are crucial in portending a good prognosis. The majority of affected patients have partial or complete renal recovery.

 

Clinical Findings

SYMPTOMS AND SIGNS

The main histopathologic feature of ATIN is diffuse or patchy infiltration of inflammatory cells within the renal interstitial space, accompanied by edema, with particular sparing of the glomeruli and blood vessels; this is accompanied by pathologic changes in the renal tubules. The interstitial infiltrate can be T lymphocytes and monocytes, eosinophils, plasma cells, or neutrophils. The particularly type of inflammatory cell involved depends on the particular culprit causing the reaction. This cellular infiltrate is eventually replaced by interstitial fibrosis.

Figure. Acute and chronic tubulointerstitial nephritis in a 14-year-old female with a serum creatinine of 2.0 mg/dL and a history of exposure to amoxicillin. The interstitium has mononuclear inflammatory cell infiltrates and increased pink matrix material indicative of collagen deposition. The tubules are shrunken and focal tubulitis is evident (arrow). Hematoxylin and eosin (×200). (Courtesy of Dr. Shane Meehan, Department of Pathology, University of Chicago.)

 

In general, there is a poor correlation between clinical and laboratory findings and the underlying histopathology.

In NSAID-induced ATIN the typical glomerular lesion is that of minimal change disease with normal findings on light microscopy and a demonstration of foot process effacement on electron microscopy. Membranous nephropathy has also been associated with NSAID use in some published reports.

Histopathologic findings considered markers of poor prognosis include interstitial granulomas, interstitial fibrosis, and tubular atrophy.

Patients with ATIN usually present with generalized non-specific symptoms consistent with acute renal failure, such as oliguria, generalized malaise, nausea and vomiting, or decreased appetite. Typically, the diagnosis is initially suspected in a patient presenting with asymptomatic or symptomatic elevation of BUN and serum creatinine (azotemia) values in the setting of recent infection or usage of medications, in particular antibiotics.

Those with drug-induced ATIN can present with an allergic type reaction that consists of the triad of erythematous rash, fever, and peripheral eosinophilia. Recent studies, however, have demonstrated the occurrence of such a triad of symptoms in only a minority of cases.

Note: DRESS syndrome – drug rash with eosinophilia and systemic symptoms syndrome

 

LABORATORY FINDINGS

Aside from the usual elevation in blood urea nitrogen and serum creatinine, urinalysis shows a predominance of white blood cells, some red blood cells, and white blood cell casts. The presence of red blood cells casts point to underlying glomerular disease, which may be primary or may occur concomitantly.

Eosinophiluria is usually shown with a Hansel’s stain, which demonstrates the eosinophilic granules more clearly, in contrast to that of a simple Wright’s stain. Defined as the presence of ˃  1% eosinophils (out of white blood cells) in the urine, it is no longer considered specific for ATIN as it has been described in cases of acute cystitis or prostatitis, acute pyelonephritis, as well as postinfectious or rapidly progressive glomerulonephritis, and even renal atheroembolic disease.

It has also been seen during transplant rejection. In a recent review of four large series, the estimated sensitivity of eosinophiluria was 67% with a specificity of 83%. Current data suggest that the presence or absence of eosinophiluria neither confirms nor excludes the diagnosis of ATIN, respectively.

Mild proteinuria, usually ˂ 1 g/day, is a common occurrence in ATIN. Nephrotic-range proteinuria, ˃ 3 g/day, has been described in those using NSAIDs for a chronic period of time or those with biopsy-proven minimal change disease.

 

Laboratory Features Associated with ATIN

(Source: American Academy of Family Physicians; June 15, 2003 / Volume 67:2527-34,2539. Copyright© 2003; www.aafp.org/afp)

 

SPECIAL TESTS

Renal ultrasound shows nonspecific findings, such as normal to slightly enlarged kidney sizes, with a mild degree of increased echogenicity in ATIN. There are, however, no specific sonographic features that would reliably distinguish ATIN from other causes of acute renal failure.

Gallium scanning plays an important role in distinguishing ATIN from acute tubular necrosis (ATN). A positive result is usually indicated by showing diffuse, intense uptake bilaterally, consistent with the interstitial infl  ammatory infiltrate. In one small series, patients with ATIN were shown to have positive gallium scans; this is in contrast to those with ATN who have negative gallium scans. Such utility is limited, however, by its lack of specificity and increased occurrence of false-positive results, especially in those with iron overload or advanced liver disease. Gallium has some structural similarity to the ferric iron and can bind to transferrin and ferritin.

 

RENAL BIOPSY

Renal biopsy is the gold standard for diagnosis of AIN, with the typical histopathologic findings of plasma cell and lymphocytic infiltrates in the peritubular areas of the interstitium, usually with interstitial edema.

Renal biopsy is not needed in all patients. In patients for whom the diagnosis seems likely, for whom a probable precipitating drug can be easily withdrawn, or who improve readily after withdrawal of a potentially offending drug, supportive management can proceed safely without renal biopsy. Patients who do not improve following withdrawal of likely precipitating medications, who have no contraindications to renal biopsy and do not refuse the procedure, and who are being considered for steroid therapy, are good candidates for renal biopsy.

 

Indications and Contraindications for Renal Biopsy in Suspected AIN (Information from Tisher CC, Croker BP. Indications for and interpretation of the renal biopsy: evaluation by light, electron, and immunofluorescence microscopy. In: Scrier RW, Gottschalk CW, eds. Diseases of the kidney. 6th ed. Boston: Little, Brown, 1997:435-41. Source: American Academy of Family Physicians; June 15, 2003 / Volume 67:2527-34,2539. Copyright© 2003; www.aafp.org/afp)

 

Indications

1.     Acute renal failure from AIN suspected clinically

2.     Exposure to potential offending medications

3.     Typical symptoms of rash, fever, arthralgias

4.     Suggestive evidence on laboratory data

5.     No improvement after withdrawal of medication

6.     Patient agrees to procedure

Contraindications

1.     Bleeding diathesis* (may be controlled or may indicate open biopsy if required diagnostically)

2.     Solitary kidney

3.     Patient unable to cooperate with percutaneous procedure

4.     End-stage renal disease with small kidneys

5.     Severe uncontrolled hypertension

6.     Patient refusal

7.     Sepsis or renal parenchymal infection

 

CLINICAL VARIANTS OF COURSE

1.                Expanded form (the most frequent and the most typical) – there are back pain, low-grade fever, short oligouria or anuria, increasing of blood urea nitrogen and serum creatinine after 2-3 days after exposure to the etiological factor. These may require dialysis therapy. Gradually decreasing of blood urea nitrogen and serum creatinine, poliuria in these patients appears in 7-10 days. GFR is normalized within 4 weeks.

2.                “Banal” form of acute interstitial nephritis (long anuria with increased serum creatinine).

3.                Interstitial nephritis on the background of other kidney diseases.

4.                Abortive form (there is no anuria; polyuria appears early; there is not high, short-term azotemia; concentration function of kidney recovers during 1,5-2 monthes)

5.                Focal form with erased symptoms (there is no azotemia, polyuria appears quickly)

In some cases, the disease can progress rapidly with the development of massive necrosis of kidney tissue, especially of the renal cortex – nekronephrozis. Clinically it is manifested with acute uremia and death of the patient in the next 2-3 weeks.

Acute interstitial nephritis can terminate recovery or becomes chronic interstitial nephritis.

 

DIFFERENTIAL DIAGNOSIS

Although the history and clinical features are truly suggestive of ATIN, the definitive diagnosis can be arrived at only by performing a renal biopsy and demonstrating the histopathologic features discussed above.

In most cases, however, when ATIN is highly suspected, the offending agent is immediately removed or discontinued. If renal function subsequently shows an improving trend in the following days to a week, theo further evaluation or therapy is rendered. A renal biopsy is definitely indicated if there is no evidence of recovery or resolution after discontinuation of the offending agent, if the patient has rapidly progressed to overt renal failure, or if there is significant uncertainty concerning the actual diagnosis.

For those patients highly suspected of having ATIN who may have a contraindication for renal biopsy, a trial of steroids, eg, prednisone 1 mg/kg/day, may be considered. Those who respond to this form of treatment usually improve within 1–2 weeks of initiation of steroid therapy and return to baseline renal function.

Other Clinical Syndromes Manifesting as Interstitial Nephritis

Source: American Academy of Family Physicians; June 15, 2003 / Volume 67:2527-34,2539. Copyright© 2003; www.aafp.org/afp

 

TREATMENT

The mainstay of treatment in ATIN is primarily supportive therapy. Once a presumptive diagnosis of ATIN is made, the first step in management is immediate discontinuation of the offending agent or treatment of the underlying infection. The diagnosis should be made promptly as ATIN is usually easily reversible in the earlier stages. However, it may take several days to weeks to see an improvement in renal function (based on serum creatinine) and for it to return to baseline levels.

Pharmacologic therapy should be considered in those patients in whom drug discontinuation does not result in any evidence of improvement in renal function, such as declining serum creatinine.

In 40% of cases there is a persistent elevation in serum creatinine despite earlier removal of the culprit agent. In those patients who do not show any significant improvement in renal function within 10–15 days after the withdrawal of the suspected agent, the accepted treatment is pulse methylprednisolone followed by oral prednisone, tapered over 4–8 weeks, although this has not always been effective. At present, there is no definitive evidence that corticosteroid therapy offers any benefit to those with NSAID-induced ATIN. One study, however, suggested that a course of prednisone be tried in those with renal failure that is still persistent 1–2 weeks after the discontinuation of the culprit NSAID.

 

Supportive Care Measures

1.     Fluid and electrolyte management

2.     Maintain adequate hydration

3.     Avoid volume depletion or overload

4.     Identify and correct electrolyte abnormalities

5.     Symptomatic relief for fever and systemic symptoms

6.     Symptomatic relief for rash

7.     Avoid use of nephrotoxic drugs

8.     Avoid use of drugs that impair renal blood flow

9.     Adjust drug dosages for existing level of renal function

 

PROGNOSIS

The majority of patients with ATIN will have either partial or complete recovery of renal function depending on the underlying cause. If recovery of renal function is not achieved after 3 weeks, it is unlikely that there will be any recovery.

 

Algorithm for the diagnosis and treatment of acute tubulointerstitial nephritis. (Source: American Academy of Family Physicians; June 15, 2003 / Volume 67:2527-34,2539. Copyright© 2003; www.aafp.org/afp)

 

 

CHRONIC TUBULOINTERSTITIAL NEPHRITIS

 

As a rule, diseases of the kidney primarily affect the glomeruli, vasculature, or remainder of the renal parenchyma that consists of the tubules and interstitium. Although the interstitium and the tubules represent separate functional and structural compartments, they are intimately related. Injury initially involving either one of them inevitably results in damage to the other. Hence the term tubulointerstitial diseases is used. Because inflammatory cellular infiltrates of variable severity are a constant feature of this entity, the terms tubulointerstitial diseases and tubulointerstitial nephritis have come to be used interchangeably. The clinicopathologic syndrome that results from these lesions, commonly termed tubulointerstitial nephropathy, may pursue an acute or chronic course. The chronic course is discussed lower. The abbreviation CTIN is used to refer synonymously to chronic tubulointerstitial nephritis and chronic tubulointerstitial nephropathy.

Chronic tubulointerstitial nephritis may be classified as primary or secondary in origin. Primary chronic tubulointerstitial nephritis is defined as primary tubulointerstitial injury without significant involvement of the glomeruli or vasculature, at least in the early stages of the disease. Secondary chronic tubulointerstitial nephritis  is defined as secondary tubulointerstitial injury, which is consequent to lesions initially involving either the glomeruli or renal vasculature. The presence of secondary chronic tubulointerstitial nephritis  is especially important because the magnitude of impairment in renal function and the rate of its progression to renal failure correlate better with the extent of chronic tubulointerstitial nephritis  than with that of glomerular or vascular damage.

Renal insufficiency is a common feature of chronic tubulointerstitial nephritis, and its diagnosis must be considered in any patient who exhibits renal insufficiency. In most cases, however, chronic tubulointerstitial nephritis is insidious in onset, renal insufficiency is slow to develop, and earliest manifestations of the disease are those of tubular dysfunction. As such, it is important to maintain a high index of suspicion of this entity whenever any evidence of tubular dysfunction is detected clinically. At this early stage, removal of a toxic cause of injury or correction of the underlying systemic or renal disease can result in preservation of residual renal function. Of special relevance in patients who exhibit renal insufficiency caused by primary chronic tubulointerstitial nephritis is the absence or modest degree of the two principal hallmarks of glomerular and vascular disease of the kidney: salt retention, manifested by edema and hypertension; and proteinuria, which usually is modest and less than 1 to 2 g/d in chronic tubulointerstitial nephritis. These clinical considerations notwithstanding, a definite diagnosis of chronic tubulointerstitial nephritis can be established only by morphologic examination of kidney tissue.

 

Pathologic Features of chronic tubulointerstitial nephritis

Tubular atrophy and dilation comprise a principal feature of chronic tubulointerstitial nephritis. The changes are patchy in distribution, with areas of atrophic chronically damaged tubules adjacent to dilated tubules displaying compensatory hypertrophy. In atrophic tubules the epithelial cells show simplification, decreased cell height, loss of brush border, and varying degrees of thickened basement membrane. In dilated tubules the epithelial cells are hypertrophic and the lumen may contain hyalinized casts, giving them the appearance of thyroid follicles. Hence the term thyroidization is used.

The interstitium is expanded by fibrous tissue, in which are interspersed proliferating fibroblasts and inflammatory cells comprised mostly of activated T lymphocytes and macrophages. Rarely, B-lymphocytes, plasma cells, neutrophils, and even eosinophils may be present. The glomeruli, which may appear crowded in some areas owing to tubulointerstitial loss, usually are normal in the early stages of the disease. Ultimately, the glomeruli become sclerosed and develop periglomerular fibrosis. The large blood vessels are unremarkable in the early phases of the disease. Ultimately, these vessels develop intimal fibrosis, medial hypertrophy, and arteriolosclerosis. These vascular changes, which also are associated with hypertension, can be present even in the absence of elevated blood pressure in cases of chronic tubulointerstitial nephritis.

Chronic Interstitial Nephritis (McFarland). (a) Still functional glomerule with (b) mass of newly formed connective tissue surrounding Bowman’s capsule; (c) totally destroyed glomerule;( d) newly formed cellular connective tissue; (e) atrophic uriniferous tubules; (f) slightly altered uriniferous tubules. Source: http://chestofbooks.com/health/disease/Pathology/Chronic-Parenchymatous-Nephritis.html

 

Microscopically the picture is very definite, although all portions of the kidney may not be equally involved. As the glomeruli are the parts first brought into contact with the circulating toxic substances, it is there, as a rule, that the processes begin. The glomerulus becomes slowly transformed into a more or less homogeneous body that loses all lobulations.. At the same time the capsule becomes greatly thickened and the glomerulus is finally transformed into a minute fibrous nodule. The interlobular connective tissue increases until eventually the tubules may become completely atrophic, through compression. Although many of the tubules are atrophic, others will be found markedly dilated, so much so that small cysts may form. There is also a thickening of the walls of the blood-vessels, endarteritis. All these processes may go on to a point where there is very little renal secretory structure left. The parenchyma also shows some changes, but not so markedly as in the chronic parenchymatous variety. There is some atrophy and fatty degeneration.

 

Etiology

Analgesic nephropathy is an important cause of chronic kidney disease that results from the cumulative (in quantity and duration) effects of combination analgesic agents, usually phenacetin and aspirin. It is thought to be a more common cause of end-stage renal disease (ESRD) in Australia/New Zealand than elsewhere owing to the larger per capita ingestion of analgesic agents in that region of the world. Transitional cell carcinoma may develop. Analgesic nephropathy should be suspected in patints with a history of chronic headache or back pain with chronic kidney disease (CKD) that is otherwise unexplained.

Manifestations include papillary necrosis, calculi, sterile pyuria, and azotemia. A severe form of chronic tubulointerstitial fibrosis has been associated with the ingestion of Chinese herbal medicines, typically employed as part of a dieting regimen; Balkan endemic nephropathy (BEN), geographically restricted to patients from this region of southeastern Europe, shares many similarities with Chinese herbal nephropathy. These disorders are thought to be caused by exposure to aristolochic acid and/or other plant, endemic (in BEN), and medical toxins (the appetite suppressants fenfluramine and diethylpropion, in Chinese herbal nephropathy). Like analgesic nephropathies, these syndromes are both characterized by a high incidence of genitourinary malignancy.

Metabolic causes of chronic TIN include hypercalcemia (with nephrocalcinosis), oxalosis (primary or secondary, e.g., with intestinal disease and hyperabsorption of dietary oxalate), hypokalemia, and hyperuricemia or hyperuricosuria. The renal pathology associated with chronic hypokalemia includes a relatively specific proximal tubular vacuolization, interstitial nephritis, and renal cysts; both chronic and acute renal failure have been described. Chronic TIN can occur in association with several systemic diseases, including sarcoidosis, Sjögren’s syndrome, and following radiation or chemotherapy exposure (e.g., ifosfamide, cisplatin).

Analgesic nephropathy – a disease which is associated with excessive use of non-steroidal analgesics, and is characterized by the development of chronic tubulointerstitial nephritis and necrosis of renal papillae. Disease may develop in patients receiving more than 2 kg of non-steroidal analgesics per year. In the experiment necrosis of the renal papillae was developed while taking aspirin and phenacetin with a small amount of water. In this case, initially necrosis of renal papillaed developed an in further tubulointerstitial nephritis. Aspirin damages cells by inhibiting the action of vasodilator prostaglandins and ischemia. Phenacetin damages cells through oxidation reactions. At autopsy, analgesic nephropathy is characterized by the following changes: kidneys do not seem to have changed or somewhat reduced in size. In the cortical layer of the expansion areas interspersed with areas of retraction of the parenchyma. Sinking areas are areas of cortical atrophy, necrosis of the medullary pyramids. Necrosis of the renal papillae has different stages from calcification to rejection. These changes distinguish it from necrosis in diabetes mellitus, in which all the nipples are in the same stage of necrosis. Under the microscope the papilla are defined foci of necrosis; in the development of severe disease nipples are fully necrosis, and look structureless mass with foci of dystrophic calcification and contours tubules. Part of papilla can exfoliate and stand out in the urine. Tubule atrophy, interstitial fibrosis and inflammatory infiltration are determined in the cortical layer. This is a manifestation of obstructive atrophy necrosis of the tubules in the kidney papilla.

 (Source: http://pathanatom.ru/patologicheskaya-anatomiya/zabolevaniya-mochepolovoy-sistemyi/analgeticheskaya-nefropatiya-patologicheskaya-anatomiya)

 

CONDITIONS ASSOCIATED WITH PRIMARY CHRONIC TUBULOINTERSTITIAL NEPHRITIS:

1.     Drugs: analgesics, cyclosporine, nitrosourea, cisplatin, lithium, miscellaneous;

2.     Immunologic diseases: Systemic lupus erythematosus, Sjögren syndrome, transplanted kidney, cryoglobulinemia, Goodpasture’s syndrome, immunoglobulin A nephropathy, amyloidosis, pyelonephritis;

3.     Urinary tract obstructions: vesicoureteral reflux, mechanical;

4.     Hematologic diseases: sickle hemoglobinopathies, multiple myeloma, lymphoproliferative disorders, aplastic anemia;

5.     Miscellaneous: vascular diseases, nephrosclerosis, atheroembolic disease, radiatioephritis, diabetes mellitus, vasculitis;

6.     Hereditary diseases: medullary cystic disease, hereditary nephritis, medullary sponge kidney, polycystic kidney disease;

7.     Endemic diseases: Balkaephropathy, Nephropathia epidemica;

8.     Infections: systemic, renal, bacterial, viral, fungal, mycobacterial;

9.     Heavy metals: Lead, Cadmium;

10.           Metabolic disorders: hyperuricemia-hyperuricosuria, hypercalcemia-hypercalciuria, hyperoxaluria, potassium depletion, cystinosis;

11.           Granulomatous disease: sarcoidosis, tuberculosis, Wegener’s granulomatosis;

12.           Idiopathic  CHRONIC TUBULOINTERSTITIAL NEPHRITIS .

 

Pathogenesis of chronic tubulointerstitial nephritis

The mechanisms of chronic tubulointerstitial nephritis development have not been studied yet. Chronic tubular epithelial cell injury appears to be pivotal in the process. The injury may be direct through cytotoxicity or indirect by the induction of an inflammatory or immunologic reaction. Studies in experimental models and humans provide compelling evidence for a role of immune mechanisms. The infiltrating lymphocytes have been shown to be activated immunologically. It is the inappropriate release of cytokines by the infiltrating cells and loss of regulatory balance of normal cellular regeneration that results in increased fibrous tissue deposition and tubular atrophy. Another potential mechanism of injury is that of increased tubular ammoniagenesis by the residual functioning but hypertrophic tubules. Increased tubular ammoniagenesis contributes to the immunologic injury by activating the alternate complement pathway. Altered glomerular permeability with consequent proteinuria appears to be important in the development of chronic tubulointerstitial nephritis in primary glomerular diseases. By the same token, the proteinuria that develops late in the course of primary chronic tubulointerstitial nephritis may contribute to the tubular cell injury and aggravate the course of the disease.

In primary vascular diseases chronic tubulointerstitial nephritis has been attributed to ischemic injury. In fact, hypertension is probably the most common cause of chronic tubulointerstitial nephritis. The vascular lesions that develop late in the course of primary chronic tubulointerstitial nephritis, in turn, can contribute to the progression of chronic tubulointerstitial nephritis.

 

Clinical features of chronic tubulointerstitial nephritis

The principal manifestations of chronic tubulointerstitial nephritis are those of tubular dysfunction. Because of the focal nature of the lesions that occur and the segmental nature of normal tubular function, the pattern of tubular dysfunction that results varies, depending on the major site of injury.

The extent of damage determines the severity of tubular dysfunction. The hallmarks of glomerular disease (such as salt retention, edema, hypertension, proteinuria, and hematuria) are characteristically absent in the early phases of chronic tubulointerstitial nephritis. The type of insult determines the segmental location of injury. For example, agents secreted by the organic pathway in the pars recta (heavy metals) or reabsorbed in the proximal tubule (light chain proteins) cause predominantly proximal tubular lesions. Depositional disorders (amyloidosis and hyperglobulinemic states) cause predominantly distal tubular lesions. Insulting agents that are affected by the urine concentrating mechanism (analgesics and uric acid) or medullary tonicity (sickle hemoglobinopathy) cause medullary injury. The tubulointerstitial lesions are localized either to the cortex or medulla. Cortical lesions mainly affect either the proximal or distal tubule. Medullary lesions affect the loop of Henle and the colle chronic tubulointerstitial nephritis g duct. The change in the normal function of each of these affected segments then determines the manifestations of tubular dysfunction.

Essentially, the proximal nephron segment reabsorbs the bulk of bicarbonate, glucose, amino acids, phosphate, and uric acid. Changes in proximal tubular function, therefore, result in bicarbonaturia (proximal renal acidosis), β2-microglobinuria, glucosuria (renal glucosuria), aminoaciduria, phosphaturia, and uricosuria. The distal nephron segment secretes hydrogen and potassium and regulates the final amount of sodium chloride excreted. Lesions primarily affe chronic tubulointerstitial nephritis g this segment, therefore, result in the distal form of renal tubular acidosis, hyperkalemia, and salt wasting. Lesions that primarily involve the medulla and papilla disproportionately affect the loops of Henle, colle chronic tubulointerstitial nephritis g ducts, and the other medullary structures essential to attaining and maintaining medullary hypertonicity. Disruption of these structures, therefore, results in different degrees of nephrogenic diabetes insipidus and clinically manifests as polyuria and nocturia.

Although this general framework is useful in localizing the site of injury, considerable overlap may be encountered clinically, with different degrees of proximal, distal, and medullary dysfunction present in the same individual. Additionally, the ultimate development of renal failure complicates the issue further because of the added effect of urea-induced osmotic diuresis on tubular function in the remaining nephrons. In this later stage of  CHRONIC TUBULOINTERSTITIAL NEPHRITIS , the absence of glomerular proteinuria and the more common occurrence of hypertension in glomerular diseases can be helpful in the differential diagnosis.

 

SYMPTOMS AND SIGNS

Clinical manifestations of chronic interstitial nephritis determined progressive disorders of tubules, decreased concentration of kidney function. Course of the disease can sometimes be asymptomatic or accompanied with hypertension, anemia and / or minor changes in urine. Typically, no edema, sometimes patients complain of weakness, fatigue, dull pain, hypertension is usually benign.

Also characteristic polyuria with low specific gravity of urine, renal tubular acidosis and syndrome of “kidneys that lose salt” (kidney is unable to concentrate urine normal). Development of renal tubular acidosis, loss of calcium in the urine lead to muscle weakness, stone formation, osteodystrophy. Some patients exhibit glucosuria, aminoaciduria. Hypotension may occur due to loss of salt in the urine.

Primary chronic interstitial nephritis has a long course with slow progression, the gradual development of hypertension, slow formation of chronic renal failure; secondary – runs depending on the severity and speed of the underlying disease

Completion of the disease – the development of nephrosclerosis, which is the equivalent of clinical renal failure.

 

Laboratory diagnostics

Erythrocyturiais seen almost 100% of cases, most patients have proteinuria small – less than 1,0 g per day, mostly due to lack of protein reabsorption in the tubules. Changes in urinary sediment variable. There is a small aseptic leukocyturia, cylindruria, showing crystals of oxalate or calcium. Reducing the proportion of urine lasts for several months or years. Excretion renal function is disrupted early – the concentration of urea, creatinine increases, GFR decreased. Hyponatremia and hypokalemia are often.

In the initial stage of the disease diagnosis is based on history, clinical signs, changes in partial kidney function in persons in contact with pesticides or medicines. However, the history of disease, clinical and laboratory manifestations of the disease can only diagnose certain probability TIN. Nephrobiopsy is mandatory to confirm that the TIN.

 

Differential diagnosis

During the differential diagnosis it must be considered history, chronic fluctuating course, changes in the urinary sediment, the prevalence of glomerular tubular disorders, revealing a high concentration of uric acid, anemia, prevailing degree of renal failure. The differential diagnosis spend with glomerulonephritis, acute renal failure, chronic renal failure, tuberculosis, kidney, kidney tumor.

 

Treatment

Treatment of chronic interstitial nephritis is primarily to eliminate the causes that led to the disease. Equally important are diet and drinking regime in metabolic nephropathy, use of drugs that support kidney plasma flow, vitamins.

 

Prevention of interstitial nephritis is the early detection of causes of acute interstitial nephritis, it careful treatment, health and educational work among the population in order to prevent an overdose of analgesics, especially phenacetin.

 

 

RENAL AMILOIDOSIS

 

Definition

Amyloidosis refers to a number of protein deposition diseases in which normal or variant forms of proteins aggregate and forminsoluble fibrilsmeasuring 75–100A in cross-section and with indeterminant length. These fibrils characteristically have b-structure, are resistant to proteolysis, and accumulate in extracellular spaces. While tissue deposits of amyloid appear amorphous on routine histology, the ordered structure of the fibrils causes the deposits to have the crystalline property of birefringence and to bind specific histochemical dyes such as Congo red and thioflavin. The term “amyloid” – similar to starch – was proposed by the German pathologist Virhov in 1853. He called so a substance that accumulates in many organs in the “tallow disease” in patients with tuberculosis, syphilis, leprosy. Later it was found that a protein folded in a β-chain is the core of amyloid, in contrast to the normal physiological protein having α-structure, polysaccharides account for only 4%, but the term remained.

Renal amyloidosis. The glomerulus shows amyloid deposition, stained by Congo red, in the glomerular capillaries (magnification, 330×). (From Johnson RJ, Feehally J: Comprehensive Clinical Nephrology. London, Mosby, 2000, with permission.). Source: http://www.cixip.com/index.php/page/content/id/378

Histological sections of an endomyocardial biopsy from a patient with amyloid cardiomyopathy. (a) Amyloid deposits are eosinophilic and disrupt normal myocardial fibres (haemotoxylin and eosin). (b) Amyloid deposits have an affinity for Congo red. (c) Same section as in (b) in polarized light showing green birefringence characteristic of Congo red-stained amyloid fibril deposits.Sourse: http://www-sop.inria.fr/axis/cost282/kelsi04/Brito/Brito1.pdf

 

Сlassification

Amyloidosis is a collective term that includes all forms, including diseases caused by the accumulation of light chains, amyloid A and congenital forms of amyloidosis, a consequence of the accumulation transthyretin, apolipoprotein B, fibrinogen and lysozyme. This also applies to forms of localized amyloidosis, which is deposited in the brain (Alzheimer’s disease), urogenital tract, the tracheobronchial tree and skin. According to the modern classification of all types of amyloidosis are marked an acronym in which the first letter A means “amyloidosis”, and the next – short name of fibrillar amyloid proteins: A – amyloid protein A, L – light chains of immunoglobulins, TTR – transtyretyn, β2M – β2 microglobulin and others.

 

Types of amyloidosis

 

According to ICD 10 revision amyloidosis coded as E85. There are family hereditary amyloidosis with neuropathy (E85.0), neuropathic family hereditary amyloidosis (E85.1), hereditary amyloidosis Family unspecified (E85.2), secondary systemic amyloidosis (E85.3), local amyloidosis (E85.4), other forms of amyloidosis (E85.8), amyloidosis unspecified (E85.9).

 

An example of diagnosis amyloidosis wording.

Secondary systemic amyloidosis, chronic kidney failure (CKF) Stage III: renal amyloidosis, nephrotic syndrome, anemia of mild degree.

 

Despite the differences in the types of amyloid protein mechanisms of forming amyloidosis are identical. The main condition disease development is the presence of increasing the number of amyloidogenic precursor. The emergence or intensifying of amyloid formation may be due to molecular heterogeneity of protein precursors and the resulting instability of the protein molecules from aggregation of amyloid fibrils. At the last stage of amyloidogenesis there are interactions between amyloid protein and plasma proteins and tissues glycosaminoglycans.

 

Formation and deposition of AL and AA amyloid. (Source: http://www.medpath.info/MainContent/Immunopathology/Immuno_04.html)

 

MAIN CLINICAL FEATURES

The most common clinical manifestations of amyloidosis is nephrotic syndrome with or without renal impairment, heart failure, sensomotor and / or peripheral neuropathy and hepatomegaly.

KIDNEYS. In AA amyloidosis kidneys are affected virtually all patients, with AL amyloidosis nephropathy develops in 70-80%

Macroscopically the kidneys enlarged in size, whitish, with smooth surface, the boundary between cortical and medulla unclear. Amyloid shrunken kidney are approximately 20% of cases.

Here is a chronic renal disease that may actually increase the size of the kidney. This is amyloidosis. Pale deposits of amyloid are present in the cortex, most prominently at the upper center.

Source: http://library.med.utah.edu/WebPath/RENAHTML/RENAL025.html

 

Amyloid is deposited mainly in the glomeruli; but in 10% of patients amyloid deposition is out of glomeruli; also amyloid may be deposited in other renal structures: the basal membrane tubules, interstitium, vessel walls.

Clinically in most patients with AA-type amyloid nephropathy manifests with isolated proteinuria with next  change stages of the disease to proteinuria, nephrotic and stage of renal failure. In AL amyloidosis phasic course of amyloid nephropathy is less expressive. The special features of renal amyloidosis include rare hematuria and leukocyturia (empty urinary sediment), and hypertension, which even in chronic renal failure is observed only in 20% of patients with AA amyloidosis type, even less with AL amyloidosis.

Renal amyloidosis is often diagnosed in the stage of nephrotic syndrome in a third of cases – only in the development of chronic renal failure. In rare cases, amyloidosis manifests acute nephrotic syndrome and hematuria, which greatly complicates diagnosis.

HEART. Signs of heart disease dominate in 20% of patients. Characteristic is a violation of ECG as a decrease in the voltage standard leads and can be regarded as a myocardial infarction without evidence of ischemic damage during echocardiography. Echocardiographic features of cardiac amyloidosis is concentric thickening of the ventricular cavity of normal or reduced heart valve thickening and dilatation of the atria. Ejection fraction is usually maintained or even increased, preferably used in the diagnosis of Doppler studies to detect diastolic dysfunction, which often passes for routine examination. Characteristic is poor correlation between the ECG and echocardiographic examination. As a result of one of them, can be obtained from normal levels in the presence of significant cardiac amyloidosis. According to WHO, there are four stages of heart disease in amyloidosis:

І – There are no symptoms of the heart damage and missing data, according to myocardial biopsy or other invasive methods of examination

ІІ – Asymptomatic heart disease, the results of biopsy or non-invasive methods of examination, including the thickness of the posterior wall of the left ventricle ˃ 1,1 cm, without history of hypertension, low voltage ECG for no apparent reason

ІІІ – Compensated symptomatic heart disease

IV – Decompensated cardiomyopathy.

PERIPHERAL AND AUTONOMIC NEUROPATHY. AL neuropathy can manifest many symptoms. Symptoms of peripheral polyneuropathy like paresthesias and muscle weakness can be seen in more than 20% patients (Rajkumar et al., 1998). Sensory neuropathy is usually symmetrical, often affects the lower extremities and may be accompanied by pain; motor neuropathy is rare. Carpal tunnel syndrome is very common and can occur several years before the appearance of other symptoms. Often, a lot of time passes between the occurrence of neuropathy symptoms and diagnosis AL amyloidosis.

Autonomic neuropathy is more serious damage. It can show the development of orthostatic hypotension, severe gastrointestinal motility disorders and is often associated with some degree of peripheral neuropathy. The presence of orthostatic hypotension evidenced by a decrease in systolic blood pressure at least 20 mm Hg for 3-5 minutes after summing the vertical position from a seated position for 5 minutes.

GASTROINTESTINAL TRACT AND LIVER. Gastrointestinal lesions in AL amyloidosis can be local or diffuse, and its severity depends on the location of lesion sites and its degree. Macroglossia observed in 10% of patients and is a pathognomonic sign of amyloidosis, it may hamper the process of food and cause sleep apnea. Other manifestations include early satiety, diarrhea, chronic nausea, malabsorption and weight loss. Amyloidosis can cause gastrointestinal perforation of the intestine and rectal bleeding. Hepatomegaly occurs in approximately 25% of patients diagnosed with amyloidosis; it is difficult to distinguish cardiac amyloid infiltration of the liver from venous congestion as a result of heart failure.

HEMOSTATIC DISORDERS. Hemorrhages often accompany amyloidosis and can be a serious complication. They occur in one third of patients with amyloidosis; although bleeding disorders observed in almost half of the patients (Mumford et al., 2000). purple The most common manifestation is bleeding, which is caused by damage to blood vessels in endothelial putting off of amyloid deposits, but may develop life-threatening bleeding, are well described, and may be accompanied by a biopsy of the liver and kidneys. A purpurais the most common manifestation of bleeding. It caused by damage of blood vessels to endothelial putting off of amyloid deposits, but may develop life-threatening bleeding, are well described, and may be accompanied during a biopsy of the liver and kidneys. Periorbital purpura – “raccoon eyes” is the most prominent manifestation of hemorrhage.

Other organs that are affected in amyloidosis

 

SYSTEMIC AMYLOIDOSIS

There are four major types of systemic amyloidosis. They represent a greater number of disease states, however, since hereditary amyloidosis may be caused bymutations in several different proteins, and each represents a separate disease entity (Benson, 1995). Each major type of amyloidosis has a unique aetiology, with varying pathophysiology, treatment and clinical prognosis. Therefore, each needs to be considered separately.

 

Immunoglobulin light chain (AL) amyloidosis

This is the most common type of systemic amyloidosis. It is a sporadic disease with increasing incidence with age; true incidence is difficult to estimate because diagnosis is ofteot made prior to death and post-mortem studies are now performed infrequently. The incidence, based on case studies in the United States, probably approaches 1 in 100 000.

AL amyloidosis is the result of amyloid fibril formation from fragments of monoclonal immunoglobulin light chain proteins (kappa or lambda) (Glenner, 1980). Fibril deposition, which is extracellular, may occur in any vascular organ and pathology is related to the organ involved and the degree of deposition. The most prevalent and morbid clinical syndromes are nephrotic syndrome followed by progressive azotaemia, restrictive cardiomyopathy with low output heart failure, and hepatomegaly with subsequent hepatic decompensation. Polyneuropathy, carpal tunnel syndrome, gastrointestinal haemorrhage, pulmonary nodules or infiltrates, macroglossia, purpura, and cardiac arrhythmias are also commonly seen in varying combinations.

AL amyloidosis is the result of a monoclonal immunoglobulin dyscrasia. It may occur in patients with multiple myeloma, Waldenstrom macroglobulinaemia or B-cell lymphoma, but most AL amyloid patients have a benign monoclonal gammopathy (BMG) or monoclonal gammopathy of unknown significance (MGUS). The basic requirement for amyloid is overproduction of monoclonal immunoglobulin with a light chain protein that is capable of forming β-structured fibrils. The monoclonal immunoglobulin synthesis may be the result of malignant transformation of a B-cell clone or expansion of a plasma-cell clone without malignant features. It is assumed that the overproduction of monoclonal immunoglobulin leads to cellular inability to adequately catabolize the protein, so that it is available for fibril formation. It is also assumed that the primary structure of the immunoglobulin light chain (LC) protein is an important factor in amyloid formation, since lambda (l) LC proteins are more frequently associated with amyloid than are kappa (k) light chains.Within the l subgroups, lII and lVI proteins are more frequently found in amyloid cases than would be expected from the normal prevalence of these proteins in plasma. This classification of k and l LC proteins is based upon primary amino acid structure. Factors associated with AL amyloid deposition in specific organs have not been identified. Clinically, renal and cardiac amyloidosis are the most frequent, but organ involvement seems not to be related to structure of the LC protein. It is possible that individualized tissue factors may play a role in this phenomenon.

 

Computer graphic model of a kI amyloid light chain variable region protein (V_L) based on X-ray crystallographic diffraction data of V_L protein produced by recombinantDNA technology. This model has eight β-strands in two planes with extensive hydrogen bonding. Source: Encyclopedia of life sciences / & 2001 Nature Publishing Group / www.els.net.

 

Lifespan after diagnosis of AL amyloidosis varies with extent and degree of organ involvement, but median survival in most series is 1–2 years. Five-year survival is approximately 20%. Nonspecific treatment of organ failure can significantly prolong the life of patients with cardiac failure, cardiac arrhythmias and renal failure, but the disease is usually progressive. Specific therapy is aimed at decreasing the aberrant plasma cell clone that produces the amyloid precursor protein. The most frequently used chemotherapy has been with an alkylating agent (usually melphalan) plus corticosteroid (prednisone) given orally in 4- to 7-day courses every 6 weeks for 2 years as tolerated.

Definite response to this therapy may occur, but in only a minority of cases, and it cannot be predicted. Trials of high-dose intravenous melphalan with autologous stem cell rescue have shown promise of greater response. The extent of amyloid progression at the time of presentation dictates whether bone marrow transplantation is a therapeutic option. Many patients with severely impaired hepatic, cardiac, pulmonary or renal function cannot withstand the rigours of this procedure.

 

Reactive (secondary) amyloidosis

Reactive amyloidosis is the result of overproduction and incomplete catabolism of serum amyloid A protein (SAA). SAA is an apolipoprotein synthesized mainly by the liver. There are physiologically two types of SAA. SAA proteins of one type (SAA1 and SAA2) are part of the acute-phase response to tissue injury. Plasma concentrations may increase from less than 3 mg/ml to over 500 mg/ml during infections or inflammatory diseases. The second type of SAA (SAA4) is synthesized in a constitutive fashion without variation with inflammatory state. Only the acute-phase SAA1 and SAA2 provide substrate for amyloid fibril formation.Usually acute-phase SAA, which in the human has 104 amino acid residues in a single polypeptide chain, is degraded to give an amino-terminal fragment (residues 1–76) that serves as the basic constituent of amyloid fibrils. There is often considerable heterogeneity at the carboxyl end of the fibril peptidewith shorter and longer AA peptides present in the same fibril isolate.

The pathophysiology of reactive (AA) amyloidosis is similar to that of AL amyloid. Fibril deposition is extracellular and organ dysfunction is the result of displacement of normal tissues. Renal, hepatic and splenic amyloid deposition is more consistent in AA amyloidosis and significant cardiac amyloid is unusual. Amyloid peripheral neuropathy, which is often a part of AL or hereditary amyloidosis does not occur in AA amyloidosis.

Macroglossia is not part of the syndrome. Death is usually fromrenal failure but, if dialysis is used to prolong life, liver amyloid deposition progresses to give hepatic failure. Occasionally traumatic rupture of the liver or spleen related to the friable nature of the amyloid-infiltrated organs will cause fatal haemorrhage. Gastrointestinal haemorrhage is frequently seen in this disease.

Prognosis is variable. Sometimes AA amyloidosis runs a progressive course over 1–2 years, but often several years may pass before renal function deteriorates to the level of dialysis or death. The incidence of AA amyloidosis is not known. It probably varies with the type of inflammatory disease and the genetic background of the affected subject. It is now uncommon to see AA amyloidosis associated with chronic tuberculosis or osteomyelitis. A greater number of subjects with AA amyloidosis have rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or granulomatous colitis as the predisposing condition.Occasionally it is seen with cystic fibrosis, Gaucher disease and systemic lupus erythematosus or no evidence of any chronic inflammatory condition. Random gastrointestinal biopsies in Japanese patients with rheumatoid arthritis have shown approximately 8% incidence of AA amyloidosis, but only a fraction of this number has clinically significant consequences from the amyloid deposition. AA amyloidosis occurs in a majority of Sephardic Jews with familial Mediterranean fever (FMF) but only a minority of Armenians with FMF. This clinical observation suggests a role for other genetic factors in the pathogenesis of the disease.Mostmammalian species and some birds can have

AA amyloidosis and these have been used extensively to study reactive amyloidosis. In particular, them urine model in which amyloid is induced by repeated injections of casein or endotoxin has revealed many of the features of acute-phase SAA synthesis and pathogenesis of fibril formation.

Treatment of AA amyloidosis starts with control of the inflammatory predisposing condition. This is not always easy to accomplish, but anti-inflammatory and cytotoxic therapies have been shown to have some efficacy. Chlorambucil in patients with juvenile inflammatory arthritis has given positive results. Azathioprine is often used to slow the disease in adults with rheumatoid or other inflammatory arthritis. Colchicine, which prevents attacks of FMF, has been shown to prevent the occurrence of AA amyloidosis in that condition. However, its efficacy in AA amyloidosis secondary to other diseases is not proven.

 

β2-Microglobulin amyloidosis

β2-Microglobulin (β2M) amyloidosis occurs in subjects treated with dialysis for end-stage renal disease of any type. Most affected subjects have been treated with haemodialysis for 7 or more years. A few have been treated with peritoneal dialysis. The amyloid deposits, which have a predilection for bone and articular structures, may also be found in organs such as the intestine and muscle. Carpal tunnel syndrome due to amyloid deposition is commonly the presenting feature of the disease. The clinical syndrome most frequently seen includes shoulder and hip pain related to infiltrative, cystic, erosive lesions of the articular structures. Amyloid fibrils may be seen in synovial fluid. Occasionally, spinal vertebrae may be destroyed by amyloid deposition; this can lead to spinal cord impingement.

Pathogenesis of this type of amyloidosis is related to markedly elevated β2M plasma levels. This protein, which is the light chain portion of the major histocompatibility antigen (HLA) on all cell surfaces, is not adequately cleared from the plasma of patients with chronic renal insufficiency. It therefore serves as substrate for amyloid fibril formation as does monoclonal immunoglobulin light chain in AL amyloidosis. It should be recalled that β2M is derived from the ancestral immunoglobulin domain gene and has extensive β -sheet structure as do all immunoglobulin domains.

Treatment for β2M amyloidosis is directed toward lowering the plasma β2M concentration. Renal transplantation will do this if accomplished successfully. High-flux dialysis membranes are now commonly used, but their efficacy in preventing this disease will take years to determine.

 

Hereditary amyloidoses

Several diseases are included in the classification of hereditary amyloidosis (see the Table) (Benson, 1995). They are all inherited as autosomal dominant traits and each of the hereditary systemic amyloidoses is caused by a structural change in a specific plasma protein that is capable of forming β -sheet fibrils. In most cases the structural change is a single amino acid substitution, but a few have aminoacid deletions or aberrant peptides resulting from nucleotide gene deletions and shift of reading frame for the mRNA. The presently known proteins associated with hereditary systemic amyloidosis are listed in Table.

 

Mutant proteins associated with autosomal dominant systemic amyloidosis

Source: Encyclopedia of life sciences / & 2001 Nature Publishing Group / www.els.net.

 

Mutations in plasma transthyretin are themost frequent cause of hereditary amyloidosis. To date, 72 amyloid-associated mutations have been described. All are single amino acid substitutions except one (ΔVal122), which is the deletion of three nucleotides in the transthyretin gene and therefore a loss of one amino acid residue in the mature protein. Transthyretin is a plasma protein synthesized predominantly by the liver but also by the choroid plexus of the brain and retinal pigment epitheliumof the eye. Transthyretin is a single polypeptide chain of 127 amino acid residues (coded by a gene on chromosome 18) that folds to produce extensive β-structure. The plasma protein is a tetramer of four identical monomers and has the physiological functions of transporting thyroid hormone, which binds in a central channel of the tetramer, and retinal binding protein – vitamin A – which binds to the surface of the tetramer.

Computer graphic model of transthyretin tetramer. Thyroxine binds in the central channel and vitamin A–RBP binds on the surface of the tetramer. Each monomer has extensive β-sheet structure. Source: Encyclopedia of life sciences / & 2001 Nature Publishing Group / www.els.net.

 

The pathophysiology of transthyretin amyloidosis may be related to alterations in protein structure that affect molecular aggregation or metabolismof this major plasma protein (200–400 mg L-1), which has a plasma residence time of only 1–2 days. A limited number of studies have suggested equal expression of normal and variant transthyretin alleles in subjects heterozygous for amyloid-associated mutations, but it is not known whether equal amounts of the allelic protein products are secreted by hepatocytes.As with other types of amyloidosis, pathology is related to the location and extent of extracellular fibril deposits and the tissue dysfunction that these deposits cause. Clinically, transthyretin amyloidosis usually presents with progressive sensorimotor peripheral neuropathy affe chronic tubulointerstitial nephritis g the longest fibres first. Carpal tunnel syndrome, a compressioeuropathy at the wrist, may be an early indication of the disease.Restrictive cardiomyopathy is the most common cause of death, but some subjects die of renal amyloidosis or malnutrition due to bowel dysfunction. Liver and spleen are usually not significantly affected in this type of amyloidosis.

All of the transthyretin amyloid syndromes are adult-onset, most after age 50 years, but some present by age 30 and occasionally before age 20. Clinical disease course is usually 10–20 years with progressive organ dysfunction. Occasionally a rapid course of cardiac or renal failure may be seen, and some patients have fatal cardiac arrhythmia. Cardiac amyloidosis is most frequently seen and causes progressive restrictive cardiomyopathy, low-output failure and often supraventricular tachycardia late in the course. The terminal stage may be characterized by such low cardiac output that vital organs are not perfused sufficiently to sustain life.

The only specific treatment for transthyretin amyloidosis is liver transplantation. Since the sole source of plasma transthyretin is the liver, this procedure should be curative. There is, however, synthesis of transthyretin in the choroid plexus, which probably is the source of CSF transthyretin and therefore of leptomeningeal deposits, and in the retinal pigment epithelium,which probably leads to the frequently seen vitreal amyloid deposits. There is also concern that, after liver transplantation, normal transthyretin may be recruited to fibril formation on top of pre-existing deposits. There have been a fewreports of senile cardiac amyloidosis caused by transthyretin amyloid deposition in the absence of a demonstrable transthyretin mutation, so the possibility of normal transthyretin continuing the fibril process after an affected individual has had liver transplantation is real. Since many individuals express transthyretin amyloidosis in later life (60–80 years), liver transplantation is ofteot a therapeutic option. Therefore, nonspecific therapy for the organ dysfunction caused by amyloid deposition is important. Cardiac pacing, renal dialysis and nutritional supplementation all may be necessary to enhance quality and duration of life.Most antiarrhythmic drugs have negative inotropic effects on the myocardium and may cause worsening of heart failure. They should be used only when absolutely necessary and then with caution. Maintenance of normal sinus rhythm, however, is important for diastolic filling andmay require digitalis or electrical defibrillation. Predictive DNA testing and counselling are important for families with this disease and can help contain the extensive clinical diagnostic testing that is often the result of difficulty in recognizing amyloid signs and symptoms.

The incidence of transthyretin amyloidosis is unknown, but may approach 1:100 000 in most populations. One mutation (Val30Met) is common iorthern Portugal and northern Sweden population groups (perhaps 3%). Another mutation (Val122Ile) is present iearly 4% of American blacks and is also present in some population groups in Africa.

Other types of hereditary amyloidosis give more defined clinical syndromes than does transthyretin. Mutations in gelsolin, a plasma a chronic tubulointerstitial nephritis -binding protein, cause lattice corneal dystrophy, cranial neuropathy and some degree of systemic amyloid deposition.The corneal amyloid deposits may appear in early adult life, but the disease in heterozygous individuals seems not to significantly shorten lifespan. A few homozygous subjects have been shown to have more severe rapidly progressing systemic amyloidosis with renal and cardiac involvement.

One mutation in cystatin C, a serine protease inhibitor, has been shown to cause leptomeningeal vascular amyloidosis that leads to death from repeated intracranial haemorrhage. Mild systemic amyloid deposition has been described. This disease is found principally in Iceland and has beeamed hereditary cerebral haemorrhage with amyloidosis (HCHWA).

Severalmutations in apolipoproteinAI cause hereditary amyloidosis that usually affects the kidneys and liver. This is an autosomal dominant disease and all patients described so far have been heterozygous for a mutant form of apoAI. The amyloid deposits contain an amino-terminal peptide of apoAI (usually 83–93 residues) that evidently can assume β-structure to form fibrils. Native apoAI has mainly α-helix structure, so the pathogenesis of the disease must include major rearrangement of the fibril-forming peptide. The clinical course of apoAI amyloidosis may continue over a number of years. There is no specific therapy. ApoAI is synthesized by the liver and also the intestine, so the benefit of liver transplantation cannot be predicted. Renal dialysis has prolonged the life of some subjects.

Two mutations in lysozyme have been found to cause systemic amyloidosis. Hepatic and renal amyloid deposition and resultant organ failure are similar to the apoAI disease. Lysozyme is synthesized by polymorphonuclear leucocytes and macrophages. There is no specific therapy for this type of amyloidosis. Four mutations in the gene for fibrinogen Aa chain are associated with amyloidosis that is predominantly expressed as nephropathy. Two are missense mutations that give single amino acid substitutions and two are single nucleotide deletions that cause a shift in reading frame of the mRNA and aberrant peptides. All are in the carboxyl portion of the Aa-chain protein. This is the protease-sensitive region of the protein, and it is assumed that the proteolytic peptide products containing 49–83 amino acid residues are capable of forming β-structure and being incorporated into fibrils.

The clinical syndrome is characteristic for this type of amyloidosis. First, there is hypertension, which may start in early adult life. This is followed by proteinuria and then progressive azotaemia usually over 5–10 years. If dialysis is instituted to save life, splenic and hepatic amyloid will progress. A few renal transplants have been performed in these patients. Amyloid appears in the grafted organ in as short a time as 1–2 years. The graft may function for 5–10 years. Two patients have received liver transplants with good results. Fibrinogen is synthesized exclusively by the liver and liver transplantation may well be curative. No data on incidence are available for this disease, but this diagnosis should be considered for any unknown type of hereditary amyloidosis with nephropathy in the absence of neuropathy and cardiomyopathy.

 

DIAGNOSIS OF SYSTEMIC AMYLOIDOSIS

The most important factor in making the clinical diagnosis of amyloidosis is to be aware of the various amyloid diseases. Unfortunately, this is rarely the case. Amyloidosis can cause a wide variety of syndromes that mimic part or all of the clinical features of other diseases. The combination of signs for multiple organ system abnormalities should raise the possibility of amyloidosis. Particularly the concomitant presence of cardiomyopathy and proteinuria or azotaemia in the patient should be suggestive. Peripheral neuropathy with cardiomyopathy, nephropathy or hepatic enlargement is frequently seen with systemic amyloidosis.

Diagnosis is made by biopsy of an affected tissue (e.g. heart, kidney, liver, nerve), but random intestinal biopsy (rectum, stomach, duodenum) will give the answer in 70–80% of cases. The majority of AL patients will have monoclonal immunoglobulin proteins detected by serum and urine electrophoresis. Most hereditary amyloid patients will have a family history of similar disease, although penetrance of the autosomal dominant amyloidoses is not 100%.

Puncture of bone marrow is performed at suspicion of AL amyloidosis. Counting the number of plasma cells and color response to amyloid allow to differentiate primary and associated with multiple myeloma AL amyloidosis. There is a positive result in 60% of patients. Diagnosis of different types of amyloidosis is performed by biopsy rectal mucosa, kidney, liver (study of tissues with Congo red). Biopsy of the mucosa and submucosa of the rectum can detect amyloidosis in 70% of patients, aspiration biopsy of subcutaneous fat – 80%, renal biopsy – almost 100% of cases. However, despite the increased risk of complications compared with patients with different nosology and given availability, begin of subcutaneous fat and ash; in the event of a negative result of performing a biopsy of possible target organ (kidney, liver, or other organs). Next step is determine the type of amyloidosis. For this purpose use immunohistochemical studies of tissue obtained by biopsy with a set of antibodies to amyloid fibrils (almost 100%), perform electrophoresis and immunofixation plasma and urine (positive in 58% of patients), or performing SAP (serum amyloid protein) scan.

 

Noninvasive methods of examination for dete chronic tubulointerstitial nephritis g diseased organs and systems in amyloidosis

 

Treatment

The aim of therapy – reducing the number of precursor protein and prevent the progression of the disease. Negative outlook in case of amyloidosis justifies aggressive medication approaches followed by autologous stem cell transplantation in patients with AL amyloidosis.

Treatment of AA amyloidosis is aimed at the elimination of chronic inflammatory lesions surgically. Much attention is paid to the treatment of rheumatoid arthritis as one of the main causes of AA amyloidosis. Amyloidosis occurs less frequently on the basis therapy with cytostatics which appointed by for a long time (up to 12 months). In patients who have already had amyloidosis, treatment with cytostatics can, in most cases, reduce clinical signs and the rate of disease progression. As a result of this therapy, noted reduction of proteinuria, nephrotic syndrome symptoms, stabilization of renal function.

Treatment of AL amyloidosis. Objective – inhibition of proliferation or total eradication clone of plasma cells that produce light chains of immunoglobulins. Currently, the most effective use of melphalan and dexamethasone. There are three regimes of treatment – low-dose melphalan, medium and large doses.

Low dose – using melphalan 0.15-0.25 mg / kg is effective only in 20-30% of patients and, on average, only 12 months after treatment. The combination of melphalan and dexamethasone (20-40 mg/day) for 4 days every 28 days is more effective – 67% of patients can achieve a hematologic response and 33% – complete hematologic remission in 48% of patients have improvement target organs. The minimum duration of treatment – 12 months, the application of the scheme for more than 24 months often leads to hematological complications such as leukemia.

Average dose – monthly courses of vincristine, adriamycin, dexamethasone, or melphalan 25 mg/m² intravenously, alone or in combination with dexamethasone.

High doses – the use of melphalan at doses of 100-200 mg/m2 and transplantation of stem cells from bone marrow (TSCBM). Mortality in this scheme of treatment is 10-15%. This scheme is the most efficient, but it can be performed only in specialized centers. In the Mayo Clinic have compared survival of patients in the two modes of treatment – aggressive therapy TSCBM and reasonable treatment without transplant. In the group of patients aggressive treatment first year survival was 89%, four years – 71% in patients with moderate therapy 71 and 41%, respectively. However, under certain conditions, this scheme is not recommended. Thus, the average length of survival after TSCBM with involvement of more than 2 was 21,5 months, while patients with lesions of one body – over 6 years.

 

Conditions in which TSCBM is contraindicated

 

The effectiveness of treatment of amyloidosis evaluated 6-12 months after starting treatment. Dynamics of disease can be seen as positive, ie, improving the functioning of organs, stable, ie no dynamics and negative, ie deteriorating of organs condition.

 

Criteria of positive and negative responses to treatment

 

Treatment of a heart failure in patients with amyloidosis has certain features . Loop diuretics are traditionally used to treat heart failure, the addition of spironolactone could significantly increase the effectiveness of therapy. Application of β-blockers and calcium channel blockers in patients with amyloidosis is contraindicated, low cardiac output, and orthostatic hypotension may significantly limit the use of angiotensin-converting enzyme. Cardiac glycosides can be used, but remember that you can get signs of toxicity even at conventional doses.

Orthostatic hypotension is a manifestation of autonomic neuropathy, but its manifestations may be exacerbated cardiac amyloidosis and hypoproteinemia. The idea that hypotension is the result of adrenal amyloidosis is wrong, although amyloid deposits often found in this tissue. Midodryn is the most effective correction of hypotension. It application is starting with a dose of 2.5 mg 3 times a day, if necessary, gradually increase the dose to 15 mg 3 times a day.

Amyloidosis – relentlessly progressive disease. The fate of patients depends on the degree of damage of various organs and body systems. In AL amyloidosis the forecastis the most severe.

Forecast is variable, but generally poor in the absence of treatment. Patients with AL amyloidosis have an average survival time of 1-2 years.

Average term of patients’ life is 13 months. 7-8% of patients live 5 years; 1% – 10 years. If patient has multiple myeloma, a term of life is reduced to 5-6 months. The main causes of death are heart failure, uremia, sepsis. Forecast amyloidosis, compared with other lesions of the kidney is the worst, with the exception of rapidly progressive glomerulonephritis

Negative prognostic factors include:

–         Clinical or ultrasound signs of heart disease, with an average duration of survival – 6 months;

–         Significant accumulation of amyloid as a result of SAP-scintigraphy;

–         Autonomic neuropathy;

–         Liver lesion with hyperbilirubinemia;

–         Ineffectiveness of chemotherapy in inhibition of cell clone;

–         Associated multiple myeloma.

The best forecast occurs in the following cases:

–         Proteinuria or peripheral neuropathy (without autonomic neuropathy) as a clinical manifestation;

–         Inhibition of clone cells with chemotherapy;

–         Reduction of amyloid deposits as a result of SAP-scintigraphy;

–          Patchy tubular necrosis and foreign body giant cell reaction to oxalate crystals in the interstitium

 

Amyloid deposits are seen in the kidney of patient. The entire filtering apparatus pictured here is inundated with amyloid deposits (Source: http://stanfordhospital.org/cardiovascularhealth/amyloid/aboutamyloidosis/al_primary_amyloidosis.html)

 

 

 

 

Case report

(Source: Nayak S, Nandwani A, Rastogi A, Gupta V. Acute interstitial nephritis and drug rash with secondary to Linezolid. Indian J Nephrol [serial online] 2012 [cited 2013 Aug 11]; 22:367-9. Available from: http://www.indianjnephrol.org/text.asp?2012/22/5/367/103918)

 

 

 

Acute interstitial nephritis and drug rash with secondary to Linezolid

S Nayak¹, A Nandwani¹, A Rastogi², V Gupta¹

¹ Department of Nephrology, Institute of Liver and Biliary Sciences, New Delhi, India

² Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India

A 54-year-old male case of alcoholic cirrhosis (Child A) and diabetes mellitus without any evidence of nephropathy was admitted at our center with 2-day history of altered sensorium and fever. There was no prior history of headache, vomiting, seizures, or decreasing urine output. On physical examination, patient was febrile, disoriented, pulse rate was 100/min, blood pressure was 150/70 mm Hg, mild icterus, and pedal edema was present. There was no evidence of focal neurological deficit or signs of meningism. Fundus examination revealed no features of papilledema or retinitis. Bilateral pupils were equal and rea chronic tubulointerstitial nephritis g to light. Abdominal examination revealed free fluid with no organomegaly whereas other systems were unremarkable. Lab investigations revealed Hb 9.6 g/dL (normal range 14,0-17,5) , total leukocyte count (TLC) 16800/mm with normal eosinophil counts and platelet count 1,1l ac/mm³, with normal coagulation profile with INR (international normalized ratio) of 1,3 (normal range 0,8-1,2). Serum bilirubin was 3,0 mg/dL (normal range 0,3 to 1,9 mg/dL) with AST/ALT of 87/96 IU/L. Arterial ammonia was 239 μg/dL. Viral markers were positive for IgM anti-HEV; however, HBsAg, anti-HCV, IgM anti-HAV, and HIV were negative. Ascitic fluid analysis revealed high ascites with high serum-ascites albumin gradient normal cell counts. His ultrasonography abdomen was suggestive of chronic liver disease with coarse echotexture and normal bilateral kidneys. Renal functions were normal with 1+ proteinuria with full field leucocytes and 8-10 RBC/high-power field on urine analysis. Urine culture was positive for enterococcus faecalis, with sensitivity to linezolid only. Patient remained in altered sensorium, and was diagnosed as a case of hepatic encephalopathy and urosepsis on the basis of positive urine culture. He was managed with lactulose and supportive care for liver failure. Linezolid 600 mg twice a day was started in view of positive urine culture for enterococcus. On day 3 of linezolid therapy, he developed pruritus, erythematous macular rash involving all the extremities and trunk. Peripheral blood smear showed eosinophilia with an absolute eosinophil count of 2125 cells/mm³. His serum IgE levels were also elevated (430 IU/mL). Repeat urine examination revealed 2+ proteinuria with 15-20 leukocytes with WBC casts and RBC cast, with no evidence of eosinophils. Renal functions were deranged with serum creatinine rising upto 5,2 mg/dL with decreasing urine output requiring dialytic support. Dermatological opinion was taken and a diagnosis of DRESS syndrome was made. Keeping the clinical possibility of drug-induced AIN as a cause of renal dysfunction, his drugs were reviewed and linezolid was stopped. The rash and fever subsided in a few days. However, the renal functions remained deranged. Patient recovered from hepatic encephalopathy and liver functions showed improvement. Further investigations revealed ANA and ANCA to be negative, with normal complement levels.

Renal biopsy was performed in view of persistently deranged renal functions and microscopic hematuria. H-stained section showed normal glomeruli on light microscopy. Interstitium showed edema with moderate inflammatory infiltrate comprising predominantly of mononuclear cells with few eosinophil and proximal tubular dilatation with patchy necrosis. Birefringent oxalate crystals were also present in tubules and interstitium with foreign body giant cell reaction. There was no granuloma formation. The arterioles were unremarkable, with no evidence of vasculitis or thrombosis. Immunofluoroscence examination of biopsy showed no immune complex deposition. Thus, the renal biopsy established the diagnosis of acute tubulointerstitial nephritis with patchy tubular necrosis.

 

 

Oxalate crystals in tubules and mononuclear cell infiltrate in the interstitium

 

Patient was managed with short course of prednisolone for 2 weeks. Renal functions gradually improved with serum creatinine level decreasing to 1.4 mg/dL, which corresponds to an estimated creatinine clearance of 56 mL/min. Patient is being regularly followed-up and has not shown any deterioration in renal functions.

 

Discussion

AIN is a common cause of acute kidney injury. The incidence of AIN in patients biopsied for acute renal failure has been reported to be approximately 5-15%. The common underlying etiologies include drug-induced, infection-related, autoimmune, and idiopathic forms. The most common etiology of AIN is drug-induced disease, which is thought to underlie 60-70% of cases. Backer et al. reviewed about 128 patients of AIN and found drugs to be responsible for 71% cases with antibiotics responsible for around 1/3 of all.

Linezolid, potent antibiotic with excellent activity against multidrug-resistant gram-positive bacteria and good safety profile, has recently been found to be associated with DRESS syndrome and AIN presenting as acute kidney injury. Our patient developed nonoliguric renal failure, macular rash, pruritus, and eosinophilia 3 days after linezolid exposure. All other drugs known to cause AIN were excluded one by one; however, renal dysfunction improved only after withdrawal of linezolid and corticosteroid therapy. This is a strong supporting evidence of linezolid associated DRESS syndrome with accompanying AIN confirmed on renal biopsy. The DRESS syndrome is a hypersensitivity reaction, characterized by a widespread and long-lasting papulopustular or erythematous skin eruption often progressing to exfoliative dermatitis with fever, lymphadenopathy, and visceral involvement (hepatitis, pneumonitis, myocarditis, pericarditis, and nephritis) and accompanied by blood alterations like eosinophilia in about 90% and mononucleosis in about 40% of cases. Anticonvulsants, sulfonamides, dapsone, allopurinol, minocycline, and gold salts are among the most frequent culprit drugs. Linezolid-associated AIN with or without DRESS syndrome has been described in only three patients till now. Report by Savard et al. described an 88-year-old patient developing DRESS syndrome with AIN and mild hepatitis following linezolid, almost 7 days after initiation of therapy. As in our case, the renal biopsy of this patient also showed deposition of oxalate crystals, without any evidence of secondary hyperoxaluria. In another report, Hammer et al. reported linezolid-induced AIN in a patient with tibial osteomyelitis. Withdrawal of linezolid, short-term hemodialysis, and corticosteroid therapy led to resolution of symptoms and eventual recovery of the renal function. Residual renal insufficiency was not a feature of AIN in these patients with native kidneys in contrast to our case. Esposito et al. reported a renal transplant patient developing AIN without systemic symptoms on exposure to linezolid for management of an Enterococcus faecum of a huge liver cyst.

Renal biopsy is the only definitive method of establishing the diagnosis of AIN. Biopsy is usually done when either the diagnosis is not clear or patient does not show improvement in the renal function, despite discontinuation of suspected drug. Adverse prognostic factors in AIN recovery include diffuse versus patchy inflammation on biopsy, excess number of neutrophils (1% to 6%) and extent or severity of interstitial fibrosis, which correlates with the final glomerular filtration rate. Noninvasive tests such as ultrasonography, gallium scintigraphy, and eosinophiluria have limited diagnostic utility. The mainstay of therapy for drug-induced AIN is early discontinuation of the suspected drug. There are no randomized trials to support the use of corticosteroids in treatment of AIN; however, the decision to use steroids depends upon the clinical course following withdrawal of offending drug. In general, the prognosis for drug-induced AIN is good, and at least partial recovery of the kidney function is normally observed. Early recognition is crucial because patients can ultimately develop chronic kidney disease. In conclusion, AIN and DRESS syndrome are rare adverse effects of linezolid. Early detection of this rare adverse reaction and prompt discontinuation of the offending agent may potentially prevent acute kidney injury. This case indicates that linezolid can cause AIN, and we recommend close monitoring of renal function in patients who are prescribed this drug.

 

Case report

(Source: http://link.springer.com/content/pdf/10.1186%2F1746-1596-7-176.pdf

Zhang et al. Diagnostic Pathology 2012, 7:176 http://www.diagnosticpathology.org/content/7/1/176)

Ultrasound-guided percutaneous renal biopsyinduced accessory renal artery bleeding in an amyloidosis patient

Qing Zhang, Yongqiang Ji, Tianwei He and Jianping Wang

Case presentation

A 67-year old male was found having abnormalities in urine tests (blood -, protein ++) during treatment for his “mixed hemorrhoids” in the inpatient unit two months ago. But these abnormalities were not further investigated at that time. 20 days ago, the results of urine tests were: blood ++; protein +++; albumin 32.9 g/L. Eight days ago, the results were: blood +, protein +++; albumin 28.94 g/L, uric acid 568 umol/L. Patient did not have any of the following symptoms: fever, joint pain, hair loss, mouth ulcers, rash, gross hematuria, urinary discomfort or dysuria, skin purpura, abdominal pain, melena, headache, dizziness, chest tightness, suffocation, palpitation, lumbar pain, or other symptoms. The patient has had hypertension and token antihypertensive drugs for 10 years. But in the past six months, his blood pressure was normal and he stopped antihypertensive drugs.

He had repeated diarrhea with body weight loss of about 25 kg in the past six months. His father passed away 10 years ago due to “uremia”, and he denied any familial genetic history. The diagnosis was “nephrotic syndrome”.

Physical examination when hospitalized did not find anything abnormal in his lungs, heart, abdomen, and limbs. There was no bleeding or ecchymosis of the skin. Body temperature 36,4°C, pulse 82 beats/min, respiratory 20 beats/min, blood pressure 108/68 mmHg. Urine test: protein ++, blood -. Fecal occult blood test: negative. Blood test: WBC (white blood cell) 4,9 × 10⁹/L, HB 130 g/L, platelet 122 × 10⁹/L, albumin 29,57 g/L, BUN (blood urea nitrogen) 6,0 mmol/L, serum creatinine 98 μmol/L, uric acid 490,7 μmol/L, total cholesterol 5,2 mmol/L, triglycerides 2,89 mmol/L. Humoral immune function: complement C3: 0,876 g/L (slightly lower); urine total protein 5,30 g/24 h; The results from all the following tests were normal: erythrocyte sedimentation rate, coagulation, urine red blood cell morphology, hepatitis B, autoantibodies, antineutrophil cytoplasmic antibodies (ANCA), proteinase-3 (PR3), MPO (myeloperoxidase), urine and blood light chain. Echocardiography showed left ventricular dilatation and diastolic dysfunction. Other tests showed the hyperactivity of bone marrow cell proliferation, 3% of mature plasma cells. To provide further evidence for the diagnosis and treatment plans, we performed ultrasound-guided percutaneous renal biopsy at the lower pole of right kidney.

At half an hour after the biopsy, the patient had nausea, vomiting, abdominal pain, sweating, and discomfort on the right side of the waist. Blood pressure decreased to 90/50 mmHg. Hemoglobin was 110 g/L. Ultrasonography showed a 4,5 cm × 6,0 cm of hematoma in the lower pole of right kidney. After treatments with hemostasis, blood transfusion and the pressor agent, symptoms were improved and blood pressure rose up to 98/70 mmHg in four hours. 24 hours later, he walked around his bed and had abdominal pain again with sweating. Blood pressure decreased, hemoglobin dropped to 78 g/L. Abdominal computed tomography (CT) showed hematoma in perinephric and retroperitoneal area. Renal artery angiography found severe bleeding from the accessory renal artery at the lower pole of the right kidney.

Images from right renal arteriography. (A) The arrow points to the lower pole of right kidney without renal blood flow. (B) The arrow points to an accessory renal artery from the abdominal aorta with bleeding in the lower pole of right kidney. (C) The right accessory renal arterial bleeding stopped after the vascular embolization with gelatin sponge particles.

 

After the application of the accessory renal artery embolization with gelatin sponge particles, bleeding was stopped and blood pressure increased to normal in ten minutes. Hemoglobin returned to normal in 10 days after the surgery.

Microscopy with immunostaining showed positive staining of IgG + and IgM+ in the glomerular mesangial areas and capillary loops. Clumped distribution of light chain κ++ and λ + were seen in the mesangial area, capillary loops, interstitial vascular wall and parts of the tubular basement membrane. AA protein (amyloid protein A) was negative. Light microscopy showed three out of 16 glomeruli with global sclerosis, and mesangial cells and matrix mildly and diffusely proliferated in other glomeruli. Unstructured homogeneous nodules with mild pale staining have been seen in the mesangial area and the basement membrane. The capillary lumen was poorly open. Bowman’s capsule wall was segmentally thickening and its epithelial cells proliferated with adhesion to Bowman’s capsule. PASM-MASSON staining showed that the glomerular basement membrane was segmental thickening with tubular atrophy. The tubular wall without atrophy was mild thickening. Vacuolation and granular degeneration appeared in the tubular epithelial cells.

Some of the tubular epithelial cells became flat, with expanded lumen, protein cast in the lumen, and brush border’s defluvium. Other pathological findings: focal tubulointerstitial fibrosis (++), inner layer of the interstitial arterial wall thickening, and deposited amorphous materials with mild staining in middle and outer layers (Figure 2). Congo Red staining showed deposition of uniform brick red material in glomerular mesangial and tubulointerstitial regions, the basement membrane, and renal interstitium vascular wall (Figure 3A-B). Congo-Red staining in intestinal tissue was positive (Figure 3C). Electron microscopic examination revealed mild increase of segmental space without visible cells in the glomerular mesangial area, visible clutter of amyloid fibrils in the cavity, segmental fusion of the foot processes of podocytes, increased lysosome in renal tubular epithelium, renal interstitial few lymphocytes and mononuclear cells infiltration with collagen fiber hyperplasia.

Hematoxylin and eosin staining (X400). The arrows point to lightly stained homogeneous structure in glomerular mesangial areas.

 

Congo red staining (X400). The arrows point to Congo red positive material deposition in glomerular mesangial areas (A), walls of the renal arteries (B), and the intestine (C). (D) A polarization image of the Congo red stain shows positive material deposition in glomerular mesangial areas (red arrows) and walls of the renal arteries (yellow arrows).

 

Discussion

Primary systemic amyloidosis is a malignant plasma cell disease. Classification of the amyloidosis is based on the precursor protein that forms the amyloid fibrils and the distribution of amyloid deposition as either systemic or localized. To date, 25 structurally unrelated proteins are known to cause amyloidosis. The major types of systemic amyloidosis are Ig light chain (AL), Ig heavy chain (AH), amyloid A (AA), the familial or hereditary amyloidosis, senile systemic amyloidosis, and β2-microglobulin (β2m) amyloidosis. In AL amyloidosis, an immunoglobulin (Ig) light chain or light chain fragment produced by clonal plasma cells deposits in tissue as amyloid. In this case, the immunohistochemistry study showed renal IgG+, IgG light chain κ++ and λ+, suggesting it was AL amyloidosis in this case. The incidence of AL amyloidosis in the United States isestimated to be between 5,1 and 12,8 per million persons per year. The kidney is affected in 50 to 80% of AL amyloid individuals. The spectrum of renal symptoms and signs in amyloidosis is variable such as isolated proteinuria, nephrotic syndrome, hypertension, hypotension, renal insufficiency. Compared with other glomerular diseases, the kidney disease with primary systemic amyloidosis has poor prognosis, gets progressively worse over time and the kidney lesions are irreversible. The amyloidosis can also induce the damages in the heart, autonomic nervous system, gastrointestinal tract and other tissues, resulting in arrhythmia, heart failure, refractory orthostatic hypotension, severe diarrhea and other organ dysfunctions. Patient’s overall conditions are usually poor. It was reported that the median survival time was only 1,2 years. Early diagnosis and treatment is critical for the prognosis of this disease. Renal involvement is diagnosed through the evidence of renal amyloid deposits detected through biopsy, together with laboratory evidence of kidney dysfunction. Positive Congo red staining in the lesion area and the specific apple green birefringence under polarized fluorescence microscope provide evidence for the diagnosis of this disease.

Combined with blood and urine electrophoresis analysis for immunoglobulin free light chain or the quantitative analysis of serum free light chain which confirms the presence of monoclonal free light chain, the sensitivity of diagnosis of systemic light chain amyloidosis is up to 99%. The treatment principles and prognosis are different among different types of renal amyloidosis. Reducing the production of amyloidogenic precursor protein (AA and AL amyloidosis) and enhancing the clearance of amyloidogenic precursor protein (Aβ2M amyloidosis) as well as trying to break down the amyloid deposits are the aims of the therapy. Once end-stage renal disease develops, patients can be treated with either dialysis or renal transplantation. In patients with adequate criteria, stem celtransplantation has shown encouraging results in several recent studies, and the five-year survival rate has been estimated to be approximately 60%. The old male patient in this report had repeated diarrhea for six months and resisted to a variety of drug treatment. Colonoscopy showed nothing abnormal. He had the history of hypertension, but in the past six months his blood pressure was normal and he did not take any antihypertensive drugs. Lab tests found urine protein and decreased serum albumin, without evidence of myeloma. Renal biopsy and histological study showed the deposition of homogeneous material in the glomerular mesangial area and interstitial vessel wall, and positive Congo red staining. The immunofluorescence staining showed light chain κ++, λ+, pervaded in the mesangium, capillary loops, interstitial vessel wall and part of the tubular basement membrane. Amyloid protein A (−) confirmed for the AL-type renal amyloidosis. Electron microscopy showed mild segmental mesangial widened, amyloid fibers cluttered in the cavity, which further confirmed the diagnosis of renal AL-type amyloidosis. It also confirmed that amyloidosis not only affected glomeruluser, but also the interstitial blood vessels. Due to the tendency of the amyloid deposition in small blood vessels, the bleeding risk induced by kidney biopsy is increased. So the 18X16G fine puncture needle was used in the process of puncture. In this patient, there was more amyloid deposition in the vessel walls, which might be the main reason for the difficulty to stop bleeding. The reason for the repeated diarrhea in this patient was not clear. However, the intestinal amyloid deposition has been found by the Congo red staining in colonic tissue. As the systemic symptoms improved after the subsequent treatment, the diarrhea had stopped completely.

The anatomical variations of renal vasculation are common and it is easy to be found in Urologic Surgery. But because the renal arteriography is not routinely performed before the kidney biopsy in the department of nephrology, the situation of accessory renal artery is difficult to be assessed. The incidence of accessory renal artery in left kidney is higher than that in the right kidney. The diseases related to the renal accessory artery include: (1) stenosis: renal accessory artery is tenuous and tortuous, which results in ischemia in the related area. The local blood flow reduction in the kidney stimulates the macula densa cells and juxtaglomerular cells to increase the synthesis and release of renin, and the subsequent renal vascular hypertension. (2) bleeding: non-traumatic renal bleeding is very rare. As the accessory renal artery is tenuous, it is difficult for the diagnosis and the localization for the hemorrhage. New techniques, such as multidetector CT angiography (MDCTA) which can clearly show the accessory renal arteries, provide better approaches for the accessory renal artery disease. (3) Accessory renal artery going tothe lower pole of the kidney in front of ureter may compress the ureter and cause hydronephrosis. In this patient, we did renal biopsy from the lower pole of the right kidney and unfortunately hurt the accessory renal artery resulting in bleeding. There has been seldom damage to the renal artery during the puncture because a healthy artery is contractive with hemostatic function when a fine needle hits it. But in this patient of amyloidosis with the amyloidosis deposition mainly in blood vessel walls, the puncture caused serious bleeding. The conservative treatments were difficult to stop the bleeding. So the renal arteriography and the vascular embolization with gelatin sponge particles has been finally used. We have learned from this case that once large amount of bleeding occurred during renal biopsy for the patient with renal amyloidosis, renal arteriography and vascular embolization should be performed immediately to avoid adverse consequences.

 

 

 

 

 

 

References:

A – Main:

 

1. Davidson’s Principles and practice of medicine (21st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2. Harrison’s principles of internal medicine (18th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3. The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

 

Additional:

Tubulointerstitial nephritis:

1.                Appel GB, Bhat P: Nephrology VIII. Tubulointerstitial diseases. In: ACP Medicine. Dale DC (editor). WebMD, Inc., 2006.

2.                Baker RJ, Pusey CD: The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2004;19:8.

3.                Brewster UC, Perazella MA: Acute kidney injury following proton pump inhibitor therapy. Kidney Int 2007;71:589.

4.                Clarkson MR et al: Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant 2004;19:2778.

5.                González E et al: Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int 2008;73:940–946.

6.                Kodner CM, Kudrimoti A: Diagnosis and management of acute interstitial nephritis. Am Fam Phys 2003;67(12):2527–2534.

7.                Kshirsagar AV: The significance of urine eosinophils. In: UpToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

8.                Kshirsagar AV, Falk RJ: Treatment of acute interstitial nephritis. In: UpToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

9.                Miettinen MH et al: Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Kidney Int 2006;69(11):2043.

10.           Preddie DC et al: Mycophenolate mofetil for the treatment of interstitial nephritis. Clin J Am Soc Nephrol 2006;1:718.

11.           Rose B: NSAIDs: acute renal failure and nephritic syndrome. In: Up-ToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

12.           Rose BD, Appel GB: Clinical manifestations and diagnosis of acute interstitial nephritis. In:  UpToDate 15.3. Rose BD (editor). UpToDate 2008, Waltham, MA.

13.           Savard S, Desmeules S, Riopel J, Agharazii M. Linezolid-associated acute interstitial nephritis and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Am J Kidney Dis 2009;54:e17-20.

 

 

 

Amiloidosis of kidney

1.     Adeyi, OA.; Sethi, S. & Rennke, HG. (2001). Fibrillary glomerulonephritis: a report of 2 cases with extensive glomerular and tubular deposits. Hum Pathol, Vol.32, No.6, (June 2001), pp. 660-663, ISSN 0046-8177.

2.     Alpers, CE. & Kowalewska, J. (2008). Fibrillary glomerulonephritis and immunotactoid glomerulopathy.  J Am Soc Neprol, Vol.19, No.1, (January 2008), pp. 34-37, ISSN 1046-6673.

3.     Arbustini, E.; Verga, L.; Concardi, M.; Palladini, G.; Obici, L. & Merlini, G. (2002). Electron and immuno-electron microscopy of abdominal fat identifies and characterizes amyloid fibrils in suspected cardiac amyloidosis. Amyloid, Vol.9, No.2, (June 2002), pp. 108-14, ISSN 1350-6129.

4.     Bély, M.; Kapp, P.; Szabó, TS.; Lakatos, T. & Apáthy, A. (2005). Electron microscopic characteristics of beta2-microglobulin amyloid deposits in long-term haemodialysis.  Ultrastruct Pathol, Vol.29, No.6, (November-December 2005), pp. 483-491, ISSN 0191-3123.

5.     Caubet, C.; Bousset, L.; Clemmensen, O.; Sourigues, Y.; Bygum, A.; Chavanas, S.; Coudane, F.; Hsu, CY.; Betz, RC.; Melki, R.; Simon, M. & Serre, G. (2010). A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin.  FASEB J, Vol.24, No.9, (September 2010), pp. 3416-3426, ISSN 0892-6638.

6.     Dember, LM. (2006). Amyloidosis-associated kidney disease.  J Am Soc Nephrol, Vol.17, No.12, (December 2006), pp. 3458-3471, ISSN 1046-6673.\

7.     Fändrich M. (2007). On the structural definition of amyloid fibrils and other polypeptide aggregates. Cell Mol Life Sci, Vol.64, No.16, (August 2007), pp. 2066-78, ISSN 1420-682X.

8.     Fändrich M, Meinhardt J, Grigorieff N. (2009). Structural polymorphism of Alzheimer Abeta and other amyloid fibrils. Prion, Vol.3, No.2, (April 2009), pp. 89-93, ISSN 1933-6896.

9.     Friedrich RP, Tepper K, Rönicke R, Soom M, Westermann M, Reymann K, Kaether C, Fändrich M. (2010). Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A, Vol.107, No.5, (February 2010), pp. 1942-1947, ISSN 0027-8424.

10.                     Greenwald, J. & Riek, R. (2010). Biology of amyloid: structure, function, and regulation. Structure, Vol.18, No.10, (October 2010), pp. 1244-1260, ISSN 0969-2127.

11.                     Joh, K. Pathology of glomerular deposition disease. (2007).  Pathol Int, Vol.57, No.9, (September 2007), pp. 551-565, ISSN 1320-5463.

12.                     Benson MD (1995) Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 7th edn, vol. III, chap. 139, part 18, Connective Tissues, pp. 4159–4191. New York: McGraw Hill.

13.                     Glenner GG (1980) Amyloid deposits and amyloidosis: the b-fibrilloses. New England Journal of Medicine 302: 1283–1292, 1333–1343.

14.                     Levy E,CarmanMD,Fernandez-Madrid IJ et al. (1990)Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248: 1124–1126.