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Tubulointerstitial Disorders

• Acute tubular injury
• Tubulointerstitial nephritis

Acute Tubular Injury

• Formerly called acute tubular necrosis
• It is a severe, but potentially reversible, renal failure due to impairment of the tubular epithelium caused by ischemia or toxic injury

Causes of Acute Tubular Injury

• Ischemia causes include systemic issues like massive hemorrhage and congestive heart failure
• Ischemia also commonly results from septic shock, severe burns, dehydration, prolonged diarrhea and volume redistribution
• Nephrotoxins include antibiotics like aminoglycosides and amphrotericin B
• Radiographic contrast agents can cause acute tubular injury
• Heavy metals such as mercury, lead, and cisplatin can cause acute tubular injury
• Organic solvents such as ethylene glycol and carbon tetrachloride can cause acute tubular injury
• Poisons such as paraquat and Heme proteins can cause acute tubular injury
• Myoglobin from rhabdomyolysis or a crush injury can result in acute tubular injury
• Hemoglobin from hemolysis or a transfusion reaction can cause acute tubular injury

Ischemic ATI

• Occurs in a variety of conditions that result in decreased renal perfusion
• It is the most common type of ATI and one of the most common causes of acute renal failure
• Onset is most commonly signaled by oliguria, which is less than 400 ml of urine per day
• Pathogenesis is mediated by both disturbance in blood flow and tubule cell injury

Toxic ATI

• Considered an uncommon type of ATI
• The majority of cases are associated with drugs, such as antibiotics
• The most likely pathogenetic mechanism is direct toxicity against the tubular epithelium

Pathology of Acute Tubular Injury

• Ischemic ATI causes patchy focal tubular epithelial necrosis with preferential involvement of straight segments of proximal tubules and thick ascending limb of Henle
• Toxic ATI causes extensive tubular epithelial necrosis along the proximal tubule segments

Clinical Course of Acute Tubular Injury

• No specific treatment is known for ATI once it is established
• Renal function often recovers within 1 to 2 weeks after the cause of ATI is immediately removed
• Dialysis may be required for those who develop uremia
• Increased urine output and a fall in serum creatinine herald the recovery phase

Tubulointerstitial Nephritis

• Disorders which affect the tubules and interstitium
• Causes functional alterations clinically manifested by defects in tubular function such as impaired ability to concentrate urine, salt wasting, and diminished ability to excrete acids
• Can be broadly divided into two categories: infectious or non-infectious

Causes of Tubulointerstitial Nephritis

• Infectious causes include acute bacterial pyelonephritis and chronic pyelonephritis
• Other infections such as viruses and parasites can cause tubulointerstitial nephritis
• Toxin causes include drugs and acute hypersensitivity interstitial nephritis
• Analgesic nephropathy and heavy metals like lead and cadmium can cause tubulointerstitial nephritis
• Metabolic diseases include urate nephropathy and nephrocalcinosis
• Hypokalemic nephropathy and oxalate nephropathy can cause tubulointerstitial nephritis
• Physical Factors include chronic urinary tract obstruction and radiation nephropathy
• Neoplasms include multiple myeloma, that causes cast nephropathy
• Immunologic Reactions can cause tubulointerstitial nephritis like transplant rejection, Sjögren syndrome and Sarcoidosis
• Vascular Diseases can cause tubulointerstitial nephritis
• Miscellaneous causes include Balkan nephropathy and Nephronophthisis-medullary cystic disease complex
• An "Idiopathic" interstitial nephritis can occur

Pyelonephritis

• Infection of the renal parenchyma with involvement of the pelvis and Calyces
• Clinically divided in acute and chronic variants

Acute Pyelonephritis

• It is a renal lesion associated with urinary tract infection
• Bacteria gain access to the kidney via the ureters (ascending infection) in 95% of cases
• In the remaining cases, bacteria gain access to the kidney through the blood (hematogenous infection)
• Common bacteria associated with urinary tract infection is Escherichia coli, Proteus, Klebsiella and Enterobacter
• Hematogenous infections are usually due to bacteremia with virulent organisms, such as Staph_aureus

Clinical Features of Acute Pyelonephritis

• Fever, back pain, and dysuria are classic symptoms
• The white blood cell count is usually elevated
• Urinalysis shows bacteriuria, pyuria, and frequently hematuria
• Urine culture demonstrates more than 10^5 colony-forming units per milliliter in more than 80% of patients
• Antibiotic therapy results in complete recovery in the majority of cases
• Complications are occasionally seen, most frequently associated to urinary tract obstruction, diabetes, immunosuppression or severe systemic infection
• Feared complications are papillary necrosis, pyonephrosis associated to total obstruction and perinephric abscess

Chronic Pyelonephritis

• Chronic infection of the renal parenchyma or the sequela of past episodes of repeated infections
• It is an important cause of end-stage kidney disease
• Consists of reflux nephropathy, and chronic obstructive pyelonophritis

Reflux Nephropathy

• More common form of chronic pyelonephritis
• Associated with permanent renal scarring that results in a urinary tract infection on congenital vesicoureteral reflux and intrarenal reflux

Clinical Features of Reflux Nephropathy

• Many patients show impaired renal function
• Many patients will not show a prior history of renal disease or urinary tract infection
• External surface shows single or multiple large, broad-based, U-shaped depressions
• Deformed papillae, calyces flattening, and pelvis dilation are commonly seen beneath the surface scars

Chronic Obstructive Pyelonephritis

• Morphology: Generalized atrophy of the parenchyma and dilation of all portions of the pelvis
• Calculi commonly is present

Microscopy of Chronic Pyelonephritis

• Atrophic dilated tubules appear in thyroidization
• Chronic interstitial inflammation and interstitial fibrosis is apparent

Xanthogranulomatous Pyelonephritis

• Rare form of chronic pyelonephritis that is often associated with calculi and Proteus infection
• Results in a yellow nodular appearance owing to presence of lipid-laden foamy macrophages

Clinical Course of Chronic Pyelonephritis

• Chronic obstructive form may be insidious in onset or may present with acute recurrent pyelonephritis
• Reflux type may have a silent onset, with patients coming to medical attention late in the course of the disease
• Patients with reflux nephropathy who develop proteinuria are prone to have focal segmental glomerulosclerosis
• Patients show an increased likelihood of progression to chronic renal failure

Non-Infectious Tubulointerstitial Nephritis

• Primarily induced by drugs and toxins
• Includes induction of interstitial immunologic reaction, immediate direct injury to tubules and subtle but cumulative injury to tubules

Acute Drug-Induced Interstitial Nephritis

• Commonly associated with the use of antibiotics, NSAID's and diuretics
• The most common cause of interstitial nephritis
• Believed to result from allergic or immune reaction to the medications
• A combination of the medication bound to the tubular basement membrane elicits an immune reaction with production of antibodies against the antibiotic-TBM complex.

Clinical Features of Acute Drug-Induced Interstitial Nephritis

• Non-specific symptoms includes nausea, vomiting, malaise and fever
• The most common clinical finding is renal insufficiency, with functional defects of tubules, and low-grade proteinuria
• Usually develops after being on the medication between 1 and 30 days, with a mean of approximately one week

Laboratory Values of Drug-Induced Interstitial Nephritis

• Blood eosinophilia, greater than 400 cells per microliter, is seen in 50% of cases
• Eosinophils may be present in the urine, and may show proteinuria and hematuria
• Interstitial edema with prominent eosinophils may occur
• Fibrosis may be present

Clinical Course of Drug-Induced Interstitial Nephritis

• Favorable prognosis providing the cause is promptly recognized and removed
• The presence of interstitial fibrosis indicated probable long-term decrease in renal function

Analgesic Nephropathy

• Tubulointerstitial disorder caused by excessive intake of analgesic mixtures associated with chronic tubulointerstitial inflammation and papillary necrosis
• Cases have been associated with intake of products containing phenacetin or acetaminophen, acetylsalicylic acid, and caffeine, codeine, or barbiturates

Pathogenesis of Analgesic Nephropathy

• Toxic effect of analgesics and their metabolites on renal tubules and blood vessels
• Ischemic damage is induced by aspirin intake, which decreases the vasodilatory effects of prostaglandin

Clinical Features of Analgesic Nephropathy

• Insidious onset of renal failure with complications including hypertension, pyelonephritis, hydronephrosis, pyonephrosis and urolithiasis
• Urothelial carcinoma of the renal pelvis is the most serious potential complication

Morphology of Analgesic Nephropathy

• Bilateral small kidneys with yellow and friable papillae and cortical scarring
• Microscopically shows papillary necrosis, tubular atrophy, chronic interstitial inflammation and interstitial fibrosis

Clinical Course of Analgesic Nephropathy

• The disease frequently runs a progressive course
• Prognosis is better if discontinued before the development of severe renal insufficiency

Causes & Features of Papillary Necrosis

• Diabetes cases show more infections and have worse outcomes
• Analgesic cases have a significant likelihood of developing carcinoma

Renal Transplantation

• Cadaveric and living related donors can be used
• Living related organs show slight success

Rejection of Renal Transplantation

• Major barrier to transplantation
• The recipient immune system recognizes the graft as being foreign and attacks it

Graft Failure

• Apart from rejection, graft failure also occurs from ATI, acute infectious pyelonephritis, obstruction, recurrent or de novo glomerulonephritis, or toxicity due to therapeutics to modulate immune response

T-cell Mediated Rejection

• Also called cellular rejection
• Destruction of graft cells by CD8+ CTLs, Cytokines-secreting activated CD4+ helper cells

B-cell Mediated Rejection

• Also called, humoral or antibody-mediated rejection
• Preformed, or produced antibodies attack alloantigens in graft activating complement via the classical pathway

Banff Diagnostic Categories for Renal Allograft Biopsies

• Normal or antibody-mediated rejection
• Consists of acute or chronic active rejection
• Borderline/Suspicious for acute T-cell rejection
• T-cell mediated rejection with acute or chronic active rejection
• Non-specific interstitial fibrosis and tubular atrophy can be a complication

Hyperacute Antibody-Mediated Rejection

• Occurs from minutes to hours after transplantation
• Presence preformed circulating antibodies against donor endothelial antigens trigger rejection
• Clinically, results in sudden cessation of urine output pain
• Immediate graft removal is necessary

Acute Antibody-Mediated Rejection

• Seen within the first few weeks or months after transplantation
• Characterized by abrupt onset of azotemia and oliguria due to the development of anti-donor antibodies
• Patients show vascular damage with positive immunofluorescence for C4d
• Patients will shows poor immunosuppressive therapy response

Acute T-cell Mediated Rejection

• It occurs days or weeks after transplantation
• Shows interstitial infiltrates of lymphocytes and macrophages, edema, lymphocytic tubulitis and tubular necrosis
• Most benign and treatable form of rejection with immunosuppressive therapy

Chronic Rejection

• Appears from months to years after transplantation
• Progressively shows azotemia, oliguria, hypertension and weight gain
• Shows arterial/arteriolosclerosis, tubular atrophy and interstitial fibrosis, which require immunosuppressive therapy

Other Pathologic Processes in Transplanted Kidneys

• Kidney diseases that can recur: recurrent disease, acute tubular necrosis, Cyclosporine or FK506 toxicity, BK virus or cytomegalovirus infection and post-transplant lymphoproliferative disorder