Tubulointerstitial Diseases PDF

TUBULAR AND INTERSTITIAL DISEASES BY EMEKA NWAFOR MBBS, PhD, FMCPath(Nig), DFHID(Lond) ASSOCIATE PROFESSOR OF PATHOLOGY  Tubular and Interstitial Diseases Most forms of tubular injury involve the interstitium as well; therefore, diseases affect...

TUBULAR AND INTERSTITIAL DISEASES BY EMEKA NWAFOR MBBS, PhD, FMCPath(Nig), DFHID(Lond) ASSOCIATE PROFESSOR OF PATHOLOGY  Tubular and Interstitial Diseases Most forms of tubular injury involve the interstitium as well; therefore, diseases affecting these two components are discussed together hence inflammatory reactions of the tubules and interstitium is called tubulointerstitial nephritis.  Two major processes or pathologies involving tubules and interstitium are: (1) ischemic or toxic tubular injury, (2) inflammatory reactions of the tubules and interstitium (tubulointerstitial nephritis).  TUBULOINTERS TITIAL NEPHRITIS TUBULOINTERSTITIAL NEPHRITIS This group of renal diseases is characterized by histologic and functional alterations that involve predominantly the tubules and interstitium. Can be primary or secondary. Secondary is seen in a variety of vascular, cystic (polycystic kidney disease), and metabolic (diabetes) renal disorders, in which it may also contribute to progressive damage.  PRIMARY CAUSES Infections  Acute bacterial pyelonephritis  Chronic pyelonephritis (including reflux nephropathy)  Other infections (e.g., viruses, parasites) Toxins  Drugs  Acute-hypersensitivity interstitial nephritis  Analgesics  Heavy metals  Lead, cadmium Metabolic Diseases  Urate nephropathy  Nephrocalcinosis (hypercalcemic nephropathy)  Acute phosphate nephropathy  Hypokalemic nephropathy  Oxalate nephropathy Physical Factors  Chronic urinary tract obstruction Neoplasms  Multiple myeloma (light-chain cast nephropathy) Immunologic Reactions  Transplant rejection  Sjögren syndrome  Sarcoidosis Vascular Diseases Miscellaneous  Balkan nephropathy  Nephronophthisis-medullary cystic disease complex  “Idiopathic” interstitial nephritis  Tubulointerstitial nephritis can be acute or chronic. Acute tubulointerstitial nephritis has a rapid clinical onset and is characterized histologically by interstitial edema, often accompanied by leukocytic infiltration of the interstitium and tubules, and focal tubular necrosis. In chronic interstitial nephritis there is infiltration with predominantly mononuclear leukocytes, prominent interstitial fibrosis, and widespread tubular atrophy.  Clinical features May be subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or nocturia; salt wasting; diminished ability to excrete acids (metabolic acidosis); and isolated defects in tubular reabsorption or secretion. It lacks the features of glomerular diseases by the absence, in early stages, of such hallmarks of glomerular injury such as nephritic or nephrotic syndrome.  The advanced forms, however, may be difficult to distinguish clinically from other causes of renal insufficiency. Pyelonephritis and Urinary Tract Infection Pyelonephritis is a renal disorder affecting the tubules, interstitium, and renal pelvis and is one of the most common diseases of the kidney. It occurs in two forms. (Acute and Chronic) Acute pyelonephritis is caused by bacterial infection and is the renal lesion associated with urinary tract infection.  Chronic pyelonephritis is a more complex disorder; bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) are involved in its pathogenesis. Bacterial infection of the lower urinary tract may be completely asymptomatic (asymptomatic bacteriuria). However, lower urinary tract infection always carries the potential of spread to the kidney. Etiology and Pathogenesis. The dominant etiologic agents, accounting for more than 85% of cases of urinary tract infection, are the gram-negative bacilli that are normal inhabitants of the intestinal tract (normal flora).  By far the most common is Escherichia coli, followed by Proteus, Klebsiella, Enterobacter. Streptococcus faecalis, also of enteric origin, staphylococci, and virtually every other bacterial and fungal agent can also cause lower urinary tract and renal infection.  In immunocompromised persons, particularly those with transplanted organs, viruses such as Polyomavirus, cytomegalovirus, and adenovirus can also be a cause of renal infection.  In most patients with urinary tract infection, the infecting organisms are derived from the patient's own fecal flora. This is thus a form of endogenous infection. There are two routes by which bacteria can reach the kidneys:  through the bloodstream (hematogenous infection)  from the lower urinary tract (ascending infection) ( Fig. 20-24).  HEMATOGENOUS ROUTE This route is the less common of the two and results from seeding of the kidneys by bacteria from distant foci in the course of septicemia or infective endocarditis. Hematogenous infection is more likely to occur in the presence of ureteral obstruction, in debilitated patients, in patients receiving immunosuppressive therapy, and with nonenteric organisms, such as staphylococci and certain fungi and viruses.  ASCENDING INFECTION This is the most common cause of clinical pyelonephritis. Normal human bladder and bladder urine are sterile; therefore, a number of steps must occur for renal infection to occur:  colonization of the distal urethra and introitus The first step in ascending infection seems to be the colonization of the distal urethra and introitus (in the female) by coliform bacteria. This colonization is influenced by the ability of bacteria to adhere to urethral mucosal epithelial cells by the help of adhesive molecules (adhesins) on the P-fimbriae (pili) of bacteria.  From the urethra to the bladder From the urethra to the bladder, organisms gain entrance during urethral catheterization or other instrumentation. Long-term catheterization, in particular, carries a risk of infection.  In the absence of instrumentation, urinary infections are much more common in females, and this has been ascribed to the shorter urethra in females, as well as the absence of antibacterial properties such as are found in prostatic fluid, hormonal changes affecting adherence of bacteria to the mucosa, and urethral trauma during sexual intercourse (honeymoon cystitis), or a combination of these factors. Urinary tract obstruction and stasis of urine. Ordinarily, organisms introduced into the bladder are cleared by the continual flushing of voiding and by antibacterial mechanisms. However, outflow obstruction or bladder dysfunction results in incomplete emptying and increased residual volume of urine.  In the presence of stasis, bacteria introduced into the bladder can multiply unhindered without being flushed out or destroyed. Accordingly, urinary tract infection is particularly frequent among patients with lower urinary tract obstruction, such as may occur with benign prostatic hypertrophy, tumors, or calculi, or with neurogenic bladder dysfunction caused by diabetes or spinal cord injury.  Vesicoureteral reflux Although obstruction is an important predisposing factor in ascending infection, it is incompetence of the vesicoureteral valve that allows bacteria to ascend the ureter into the renal pelvis. The normal ureteral insertion into the bladder is a competent one-way valve that prevents retrograde flow of urine, especially during micturition, when the intravesical pressure rises. An incompetent vesicoureteral orifice allows the reflux of bladder urine into the ureters (vesicoureteral reflux) ( Fig. 20-25 ).  Figure 20.25 Vesicoureteral reflux demonstrated by a voiding cystourethrogram. Dye injected into the bladder refluxes into both dilated ureters, filling the pelvis and calyces.  Reflux is most often due to a congenital absence or shortening of the intravesical portion of the ureter, such that the ureter is not compressed during micturition. Acquired vesicoureteral reflux in adults can result from persistent bladder atony caused by spinal cord injury.  The effect of vesicoureteral reflux is similar to that of an obstruction in that there is residual urine in the urinary tract after voiding, which favors bacterial growth.  Intrarenal reflux Vesicoureteral reflux also affords a ready mechanism by which the infected bladder urine can be propelled up to the renal pelvis and deep into the renal parenchyma through open ducts at the tips of the papillae (intrarenal reflux). Intrarenal reflux is most common in the upper and lower poles of the kidney. Fig 20.26  Figure 20-26 Vesicoureteral reflux demonstrated by a voiding cystourethrogram. Dye injected into the bladder refluxes into both dilated ureters, filling the pelvis and calyces.  In the absence of vesicoureteral reflux, infection usually remains localized in the bladder. Thus, the majority of individuals with repeated or persistent bacterial colonization of the urinary tract suffer from cystitis and urethritis (lower urinary tract infection) rather than pyelonephritis.  Acute Pyelonephritis Acute pyelonephritis is an acute suppurative inflammation of the kidney caused by bacterial and sometimes viral (e.g., polyomavirus) infection, and could be either by hematogenous or ascending spread of infection.  Morphology Macroscopically, the suppuration may occur as discrete haphazard focal abscesses involving one or both kidneys, which can extend to large wedge-shaped areas of suppuration ( Fig. 20-27,28 )  Acute pyelonephritis. Cortical surface shows grayish white areas of inflammation and abscess formation  Morphology. Microscopically, the hallmarks of acute pyelonephritis are patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis. Characteristically, glomeruli seem to be relatively resistant to the infection. Large areas of severe necrosis, however, eventually destroy the glomeruli, and fungal pyelonephritis (e.g., Candida) often affects glomeruli. Acute pyelonephritis marked by an acute neutrophilic exudate within tubules and interstitial inflammation.  Complications of acute pyelonephritis Papillary necrosis which is seen mainly in diabetics and in those with urinary tract obstruction. Pyonephrosis: The suppurative exudate is unable to drain and thus fills the renal pelvis, calyces, and ureter with pus. Perinephric abscess is an extension of suppurative inflammation through the renal capsule into the perinephric tissue. Without treatment, the disease progresses to chronic pyeloniphritis.  Risk factors for Acute pyelonephritis Urinary tract obstruction, either congenital or acquired Instrumentation of the urinary tract, most commonly catheterization Pregnancy. Between 4% and 6% of pregnant women develop bacteriuria sometime during pregnancy, and 20% to 40% of these eventually develop symptomatic urinary infection if not treated. Gender and age. After the first year of life (when congenital anomalies in males commonly become evident) and up to around age 40 years, infections are much more frequent in females. With increasing age the incidence in males rises as a result of prostatic hypertrophy and instrumentation.  Preexisting renal lesions, causing intrarenal scarring and obstruction Diabetes mellitus, in which there is increased susceptibility to infection due to neurogenic bladder dysfunction, and more frequent instrumentation are predisposing factors Vesicoureteral reflux Immunosuppression and immunodeficiency  Clinical features The onset is usually sudden, with pain at the costovertebral angle and systemic evidence of infection, such as fever and malaise. Dysuria, frequency, and urgency (indications of bladder and urethral irritation). Investigation The urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate. CHRONIC PYELONEPHRITIS AND REFLUX NEPHROPATHY Chronic pyelonephritis is a disorder in which chronic tubulointerstitial inflammation and renal scarring are associated with pathologic involvement of the calyces and pelvis (Fig. 20-31 ). Chronic pyelonephritis is an important cause of end-stage kidney disease and remains an important cause of kidney destruction in children with severe lower urinary tract abnormalities. Reflux and obstruction are well known predisposing conditions.  Chronic pyelonephritis can be divided into two forms: chronic reflux- associated and chronic obstructive.  Reflux Nephropathy This is by far the more common form of chronic pyelonephritic scarring. Renal involvement in reflux nephropathy occurs early in childhood as a result of superimposition of a urinary infection on congenital vesicoureteral reflux and intrarenal reflux. Reflux may be unilateral or bilateral.  Chronic Obstructive Pyelonephritis Obstruction predisposes the kidney to infection. Recurrent infections superimposed on diffuse or localized obstructive lesions lead to recurrent bouts of renal inflammation and scarring, resulting in a picture of chronic pyelonephritis. The disease can be bilateral, as with posterior urethral valves, resulting in renal insufficiency unless the anomaly is corrected, or unilateral, such as occurs with calculi and unilateral obstructive anomalies of the ureter. Morphology.( Figs. 20-32 and 20-33 ). The kidneys usually are irregularly scarred; if bilateral, the involvement is asymmetric. This contrasts with chronic glomerulonephritis, in which both kidneys are diffusely and symmetrically scarred.  The hallmarks of chronic pyelonephritis are coarse, discrete, corticomedullary scars overlying dilated, blunted, or deformed calyces, and flattening of the papillae. The scars can vary from one to several in number and may affect one or both kidneys. Most are in the upper and lower poles, consistent with the frequency of reflux in these sites  Chronic pyelonephritis. The surface (left) is irregularly scarred. The cut section (right) reveals blunting and loss of several papillae  Microscopy The tubules show atrophy in some areas and hypertrophy or dilation in others. Dilated tubules with flattened epithelium may be filled with colloid casts (thyroidization). There are varying degrees of chronic interstitial inflammation and fibrosis in the cortex and medulla.  corticomedullary renal scar with an underlying dilated deformed calyx. Note the thyroidization of tubules in the cortex  Clinical Features Chronic obstructive pyelonephritis may be insidious in onset or present with clinical manifestations of acute recurrent pyelonephritis, such as back pain, fever, frequent pyuria, and bacteriuria. Chronic pyelonephritis associated with reflux may have a silent onset.  Although proteinuria is usually mild, some individuals with pyelonephritic scars develop secondary focal segmental glomerulosclerosis with significant proteinuria, even in the nephrotic range. The appearance of proteinuria and focal segmental glomerulosclerosis is a poor prognostic sign, and patients with these findings may proceed to chronic or end- stage renal failure.  The glomerulosclerosis, may be attributable to the adaptive glomerular alterations secondary to loss of renal mass caused by pyelonephritic scarring (renal ablation nephropathy).  Tubulointerstitial Nephritis Induced by Drugs and Toxins  Toxins and drugs can produce renal injury in at least three ways: (1) They may trigger an interstitial immunological reaction, exemplified by the acute hypersensitivity nephritis induced by such drugs as methicillin; (2) they may cause acute renal failure, (3) they may cause subtle but cumulative injury to tubules that takes years to become manifest, resulting in chronic renal insufficiency. Acute Drug-Induced Interstitial Nephritis This is a well-recognized adverse reaction to a constantly increasing number of drugs. Acute tubulointerstitial nephritis most frequently occurs with synthetic penicillins (methicillin, ampicillin), other synthetic antibiotics (rifampin), diuretics (thiazides), NSAIDs, and miscellaneous drugs (allopurinol, cimetidine) and sulfonamides.  The disease begins about 15 days (range: 2–40) after exposure to the drug and is characterized by fever, eosinophilia (which may be transient), a rash in about 25% of patients, and renal abnormalities.  The latter take the form of hematuria, mild proteinuria, and leukocyturia (often including eosinophils). A rising serum creatinine level or acute renal failure with oliguria develops in about 50% of cases, particularly in older patients. Drug-induced tubulointerstitial nephritis is the second most common cause of acute kidney injury.  Pathogenesis. Many features of the disease suggest an immune mechanism. The immune response is idiosyncratic and not dose-related. Clinical evidence of hypersensitivity includes the latent period, the eosinophilia and rash, the fact that the onset of nephropathy is not dose-related, and the recurrence of hypersensitivity after re- exposure to the same or a cross-reactive drug.  Type I and IV hypersensitivity reactions play a role. The most likely sequence of events is that the drugs act as haptens, which covalently bind to some cytoplasmic membrane or extracellular component of tubular cells and become immunogenic. The resultant injury is then due to IgE and/or cell-mediated immune reactions to tubular cells or their basement membranes.  Morphology. (Fig 20.33) On histologic examination the abnormalities are in the interstitium, which shows variable but frequently pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages. Eosinophils and neutrophils may be present , often in clusters and large numbers, and plasma cells and basophils are sometimes found in small numbers.  “Tubulitis,” the infiltration of tubules by lymphocytes, is common with variable degrees of tubular necrosis. The glomeruli are normal except in some cases caused by NSAIDs. In analgesic nephropathy, papillae can show various stages of necrosis, calcification, fragmentation, and sloughing Drug-induced interstitial nephritis, with prominent eosinophilic and mononuclear cell infiltrate  Clinical Features It is important to recognize drug-induced renal failure because withdrawal of the offending drug is followed by recovery, although it may take several months, and irreversible damage occurs occasionally in older subjects. It is also important to remember that while drugs are the leading identifiable cause of acute interstitial nephritis, in many affected patients (approximately 30% to 40%) an offending drug or mechanism cannot be identified.  Occasionally, necrotic papillae are excreted, and may cause gross hematuria or renal colic due to ureteric obstruction. Causes of papillary necrosis are analgesic nephropathy, diabetes mellitus, in urinary tract obstruction, sickle cell disease or trait and focally in renal tuberculosis. Nephropathy Associated with NSAIDs NSAIDs, are one of the most commonly used classes of drugs. The produce several forms of renal injury. Although these complications are uncommon, they should be kept in mind since NSAIDs are frequently administered to patients with other potential causes of renal disease.  Pathogenesis Many NSAIDs are nonselective cyclooxygenase inhibitors, and their adverse renal effects are related to their ability to inhibit cyclooxygenase- dependent prostaglandin synthesis. The selective COX-2 inhibitors do affect the kidneys because COX-2 is expressed in human kidneys. NSAID-associated renal syndromes include:  Acute kidney injury, due to the decreased synthesis of vasodilatory prostaglandins and resultant ischemia. Acute hypersensitivity interstitial nephritis, resulting in renal failure.  Acute interstitial nephritis and minimal- change disease. This curious association of two diverse renal conditions, one leading to renal failure and the other to nephrotic syndrome, suggests a hypersensitivity reaction affecting the interstitium and possibly the glomeruli Membranous nephropathy, with the nephrotic syndrome, though of unclear pathogenesis.  In summary, NSAIDs can cause tubulointerstitial nephritis and/or glomerular injury, such as minimal change disease or membranous nephropathy.