Chronic Tubulointerstitial Nephritis Flashcards
Background on CTIN
CTIN is characterized by tubulointerstitial scarring and fibrosis, tubular atrophy, with or without significant macrophage and lymphocytic infiltration.
CTIN
Clinical Manifestations of CTIN
Patients are typically asymptomatic with incidental abnormal laboratory findings:
Mild proteinuria < 1.5 to 2.0 g/d
CTIN
Clinical Manifestations of CTIN
Proteinuria is predominantly LMW proteins.
“Bland” urinalysis: no (or rare granular) casts, minimal white and/or red blood cells
CTIN
Clinical Manifestations of CTIN
Anemia severity out of proportion to degree of kidney injury due to damage of peritubular erythropoietin producing cells
CTIN
Clinical Manifestations of CTIN
Other signs of tubular injury may be present: sodium wasting, metabolic acidosis, Fanconi syndrome, nephrogenic insipidus.
CTIN
Histopathology of CTIN
Fibrotic hypocellular interstitium
Tubular Atrophy
CTIN
Causes of CTIN
Common causes (drugs, crystals [e.g., calcium phosphate, uric acid, oxalate], infections, autoimmune, obstruction, chronic ischemia, heavy metals)
CTIN
Causes of CTIN
Drug-induced CTIN:
Analgesic nephropathy:
Traditionally referred to the chronic use of the drug mixture containing (phenacetin, paracetamol, or acetaminophen) plus (salicylate) plus a potentially addicting agent (caffeine or codeine). Any of the drugs belonging to the first group can be metabolized to acetaminophen and subsequent toxic metabolites which require glutathione for detoxification. Accumulation of these toxic metabolites may form covalent bonds with kidney tissue and induce tissue injury and vascular endothelial damage. Salicylate is a glutathione depletor which can limit the neutralization process of toxic metabolites of acetaminophen.
CTIN
Causes of CTIN
Drug-induced CTIN:
Analgesic nephropathy:
Analgesic nephropathy affects predominantly the medulla and papillary tip. Characteristic presentations include CKD, CT revealing papillary necrosis and calcifications, or kidney ultrasound revealing small echogenic kidneys
CTIN
Causes of CTIN
Drug-induced CTIN:
Analgesic nephropathy:
Single analgesic use may also lead to analgesic nephropathy.
Acetaminophen:
There are data to suggest that chronic, daily, high dose use of acetaminophen may lead to long-term nephrotoxicity in women.
CTIN
Causes of CTIN
Drug-induced CTIN:
Analgesic nephropathy:
Salicylates: Most studies suggest that the long-term use of daily therapeutic dose of aspirin (ASA) alone (i.e., without concurrent use of acetaminophen) do not lead to kidney injury.
CTIN
Causes of CTIN
Drug-induced CTIN:
Analgesic nephropathy:
NSAIDS:
High dose of NSAIDS may induce CKD in those with underlying or high risk for kidney injury, but not in healthy individuals.
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury:
Chronic interstitial nephritis: characterized by cortical and medullary distal and collecting tubular dilatations/cysts, tubular atrophy, and interstitial fibrosis
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury:
Toxic intracellular lithium levels are thought to alter primary cilia function and lead to tubular cyst formation.
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury:
Commonly associated glomerular lesions: global sclerosis, FSGS, minimal change disease.
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury:
Lithium may also be associated with nephrogenic diabetes insipidus, distal RTA, hypercalcemia, and hypothyroidism.
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury
Histopathology:
Severe lithium-associated tubulointerstitial nephropathy with diffuse interstitial fibrosis, tubular cysts, dilations, and tubular atrophy (flattened tubular epithelial cells) and relative sparing of glomeruli. Tubular cysts may be evident on CT imaging.
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury
Management:
Discontinue lithium if safe and possible (there are reports of patients committing suicide with lithium discontinuation).
Routine CKD management to slow down progression of disease
CTIN
Causes of CTIN
Drug-induced CTIN:
Lithium-induced kidney injury
Management:
Amiloride may be considered to reduce lithium reabsorption at collecting tubules.
Thiazides may be considered in the treatment of nephrogenic diabetes insipidus.
CTIN
Causes of CTIN
Drug-induced CTIN:
Famotidine:
case report of famotidine-induced autoantibody formation against carbonic anhydrase II in the kidneys
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Rare granulomatous disease of infectious etiology (bacterial, fungal, tuberculosis, etc.)
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Presents as friable yellow plaques that may involve urinary tract, GI tract, other visceral organs, skin (erythematous nodular lesions, ulcerations, to draining fistulas/abscesses).
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Seen in immunocompromised hosts (e.g., diabetes mellitus, malignancy, malnutrition, alcoholism, immunosuppressive therapy)
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Pathogenesis:
Pathogenesis: thought to be due to poor T-cell function, inadequate killing of bacteria by macrophages, or defective phagolysosomal activity by monocytes. Inadequate levels of intracellular cyclic guanosine monophosphate (cGMP) have been attributed to reduced microtubular function and lysosomal activity, hence ineffective bacterial killing. Accumulation of partially digested bacteria in monocytes or macrophages leads to calcium and iron deposition on residual bacterial glycolipids. The presence of the resulting basophilic inclusion structure, the Michaelis–Gutmann (MG) body, is considered pathognomonic for malakoplakia.
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Diagnosis:
Diagnosis: urine culture and biopsy
Imaging studies may reveal mass-like lesions, mimicking renal cell carcinoma (RCC).
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Histopathology:
Haematoxylin and eosin staining reveals sheets of histiocytes with basophilic inclusions with concentric laminations (MG bodies). These MG bodies may be stained for calcium and iron. EM: MG bodies consist of lysosomes filled with partially digested bacteria. Identification of responsible organism may be possible with bacterial gram staining or immune staining with antibody against Mycobacterium bovis.
CTIN
Causes of CTIN
Infection-related CTIN:
Malakoplakia:
Management:
Surgical, antibiotics (e.g., quinolones, trimethoprim-sulfomethoxazole), bethanecol (choline agonist), ascorbic acid. The latter two agents are thought to increase levels of cGMP.
CTIN
Causes of CTIN
Infection-related CTIN:
Xanthogranulomatous pyelonephritis
Condition associated with chronic obstruction (e.g., staghorn calculi) and urinary tract infections with resulting granulomatous inflammation and diffuse cellular infiltrate of lipid-laden foam cells replacing normal renal parenchyma. CT may reveal low-density masses with associated calcifications resembling malignancy.
CTIN
Causes of CTIN
Infection-related CTIN:
Xanthogranulomatous pyelonephritis
Clinical manifestations: commonly affect middle-aged women who may present with fevers/chills, chronic flank pain, possibly palpable mass. Urine cultures may reveal common gram-negative organisms such as Escherichia coli, Klebsiella, Proteus and less commonly staphylococcal species.
CTIN
Causes of CTIN
Infection-related CTIN:
Xanthogranulomatous pyelonephritis
Management:
organism specific antibiotics, surgical resection as needed
CTIN
Causes of CTIN
Infection-related CTIN:
Emphysematous pyelonephritis
Life-threatening necrotizing acute pyelonephritis ± obstruction, predominantly seen in diabetic patients that is caused by gas-forming organisms such as E. coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and Proteus mirabilis.
CTIN
Causes of CTIN
Infection-related CTIN:
Emphysematous pyelonephritis
Gas pockets may be detected on plain abdominal radiograph, ultrasound, or CT.
Management: organism-specific antibiotics, relief of obstruction and surgical resection as needed
CTIN
Causes of CTIN
Infection-related CTIN:
HIV immune restoration inflammatory syndrome (IRIS):
Seen in patients with prolonged severe immunodeficiency, recently treated for an opportunistic infection, now receiving never-before-seen or intensified antiretroviral therapy with resultant marked viral load reduction, increase in CD4, and multiorgan inflammatory response
CTIN
Causes of CTIN
Infection-related CTIN:
HIV immune restoration inflammatory syndrome (IRIS):
Kidney involvement may manifest as interstitial nephritis with granulomas.
Treatment: prednisone 1 mg/kg/d × 1 month followed by taper.
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Lead (Pb):
Pathogenesis: thought to be due to chronic lead deposition and its associated toxicity in proximal tubules, hyperuricemia, and HTN
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Lead (Pb):
Clinical manifestations:
Chronic: anemia with basophilic stippling, gout, CKD, peripheral motor neuropathies, perivascular cerebellar calcifications, small shrunken kidneys
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Lead (Pb):
Acute lead intoxication: encephalopathy, abdominal pain, hemolytic anemia, Fanconi syndrome, and peripheral neuropathy
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Lead (Pb):
Management:
Routine CKD management
Consider Pb chelation therapy.
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Mercury:
Found in alloy and mirror plants, batteries
Mercury dichloride (HgCl2) may also induce acute tubular necrosis in addition to CTIN.
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Cadmium:
Found in glass/metal alloy plants, electrical equipments
Outbreak of cadium toxicity in Japan due to industrial contamination lead to itai-itai, a.k.a. “ouch ouch” disease because of significant bone pain associated with condition. Kidney involvement includes hypercalciuria, kidney stones, proximal tubular dysfunction, anemia, CTIN.
CTIN
Causes of CTIN
Heavy metal–associated CTIN:
Arsenic:
Found in poison gas, insecticides, weed killers, paints
Proximal RTA and CTIN
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
A condition characterized by dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, with or without associated elevated serum IgG4 concentrations
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Mass lesions in various organs including pancreas, enlarged salivary glands, kidneys (TIN), lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, skin, and even bone (destructive lesions resembling granulomatous polyangiitis).
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Patient characteristics:
Male predominance (estimated 62% to 83% are males)
Older age (i.e., >50 years)
Up to 40% with history of allergic diseases (e.g., bronchial asthma or chronic sinusitis)
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Clinical diagnosis:
Elevated serum IgG4 (although 30% have normal values)
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Affected tissue biopsy is characterized by:
Dense lymphoplasmacytic infiltrates consisting of lymphocytes, plasma cells, eosinophils, and fibroblasts
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Ratio of IgG4-bearing plasma cells to IgG-bearing plasma cells > 50% is highly suggestive of IgG4-related disease.
Obliterative phlebitis
Storiform fibrosis (likened to cartwheel pattern)
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Pathogenesis is thought to involve:
Autoimmune process or presence of an infectious agent that trigger an immune response driven predominantly by type 2 helper T (Th2) cells and activation of regulatory T (Treg) cells. The influx of inflammatory cells leads to multiorgan enlargement, cytokine release, eosinophilia, elevated IgG4 and IgE levels, and eventual progression to fibrosis of affected organs.
CTIN
Causes of CTIN
Other conditions associated with CTIN:
IgG4-related disease:
Treatment of IgG4-related disease:
Glucocorticoids: suggested regimen: prednisolone 0.6 g/kg body weight/d for 2 to 4 weeks, tapered over 3 to 6 months to 5 mg/d and maintain for up to 3 years.
Others: Azathioprine (AZA), mycophenolate mofetil (MMF), and methotrexate have been suggested as glucocorticoid-sparing agents.
For recurrent or refractory disease, consider rituximab.
Relapse may occur.
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Balkan nephropathy-like CTIN:
Arises from chronic exposure to aristolochic acid (environmental or contaminant from herbal preparation)
Associated with uroepithelial malignancies
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Mesoamerican nephropathy:
Described in Central America
Affects predominantly males, often sugar cane field workers
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Mesoamerican nephropathy:
Underlying etiology thought to be due to repeated exposures to severe dehydration and rehydration, hyperosmolality-stimulated aldose reductase activity leading to conversion of glucose to sorbitol and fructose with subsequent metabolism by fructokinase to oxidant mediators. Exacerbating or contributing factors may include concurrent high intake of fructose and/or NSAIDS, contaminated drinking water (e.g., arsenic, pesticides), leptospirosis, and/or genetic susceptibility.
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Mesoamerican nephropathy:
Typical manifestations: mild proteinuria, hyperuricemia, hypokalemia
Kidney biopsy is characterized by extensive glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Of note, glomerulosclerosis is a prominent feature of this condition which is thought to reflect glomerular ischemic injury.
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Inflammatory bowel disease is associated with an increased risk of CTIN, independent of exposure to 5-aminosalicylates. Although 5-aminosalicylates may be associated with ATIN.
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Granulomatous (noncaseating) CTIN:
common causes
Drugs: sulfas, synthetic penicillins, NSAIDS, thiazides, quinolones
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Granulomatous (noncaseating) CTIN:
Infections: tuberculosis, leprosy, xanthogranulomatous pyelonephritis, histoplasmosis, glandular fever
Systemic diseases: granulomatous polyangiitis, sarcoidosis.
Others: urate, oxalosis
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Karyomegalic interstitial nephritis:
Rare systemic disease noted for bizarre enlarged nuclei found in brain, lung, biliary/intestinal cells, and renal tubular epithelial cells.
CTIN
Causes of CTIN
Other conditions associated with CTIN:
Karyomegalic interstitial nephritis:
Patients may present with slowly progressive CTIN and ESRD in late adulthood, transaminitis. Etiology and treatment remain to be defined.
Diagnosis of CTIN:
Kidney biopsy is gold standard.
