Tubular, Interstitial, and Cystic Disorders
Phuong-Chi T. Pham
Monica Deshmuk
Cynthia C. Nast
Phuong-Truc T. Pham
Phuong-Thu T. Pham
RENAL TUBULAR DISORDERS AND FANCONI SYNDROME
Fanconi Syndrome
Proximal tubular dysfunction causing renal wasting of low-molecular weight (LMW) proteins, glucose, bicarbonate, phosphate, uric acid, carnitine, and others
Clinical Manifestations of Fanconi Syndrome
Polyuria, polydipsia, tendency for volume depletion
Glucosuria in the absence of hyperglycemia
Low-level proteinuria due to inability of proximal tubules to reabsorb LMW proteins that are normally filtered
LMW proteinuria is known as “tubular proteinuria,” which typically totals <1.0 to 2 g/d and comprises of less than 25% albumin.
Examples of LMW proteins: amino acids, β2-microglobulin, cystatin C, retinol-binding protein, α1-macroglobulin
Metabolic acidosis due to reduced bicarbonate reabsorption
Hypophosphatemia (Phosphaturia is typically only seen in early disease. Once new steady state has been achieved, the degree of phosphaturia matches intake.)
Hypokalemia (likely due to high distal sodium delivery to ENaC and subsequent potassium loss; high potassium filtered load associated with acidemia)
Hypouricemia due to hyperuricosuria
Carnitine deficiency (Carnitine is required for the transport of fatty acids from cytosol into mitochondria during the breakdown of lipids for the generation of metabolic energy. Carnitine deficiency has been implicated in poor fatty acid metabolism, reduced antioxidant activities, poor glucose control, and osteoporosis.)
Rickets, osteomalacia, and growth failure due to reduced proximal tubular 1,25(OH)2D3 production due to reduced 1-α hydroxylase activity, chronic metabolic acidosis, and electrolyte disturbances related to calcium, phosphate, and magnesium
Conditions Associated With Fanconi Syndrome
Inherited conditions
Cystinosis: Most common inherited condition associated with Fanconi syndrome; associated with defective tubular reabsorption of Cysteine, Ornithine, Lysine, and Asparagine, known as COLA. Two cysteine molecules can dimerize via a disulfide bond to form cystine, a poorly soluble molecule that can easily crystalize in tubular lumen to form stones.
Others: galactosemia, hereditary fructose intolerance, tyrosinemia type 1, glycogenosis, Wilson disease (inherited disorder involving copper metabolism), oculocerebrorenal syndrome (i.e., Lowe syndrome, X-linked mutation involving the enzyme phosphatidylinositol-4,5-bisphosphate 5 phosphatase in the trans-Golgi network, associated with severe bilateral cataracts and hypotonia at birth), mitochondrial cytopathies
Acquired conditions
Heavy metals: lead, cadmium, mercury, platinum
Drugs: cisplatin, ifosfamide, imatinib, gentamicin, rifampin, expired tetracycline, tenofovir, adefovir, azathioprine, valproic acid, suramin, streptozocin, ranitidine, nucleoside reverse transcriptase inhibitors including abacavir, didanosine, and lamivudine and both formulations of tenofovir (tenofovir disoproxil fumarate, tenofovir alafenamide)
Other exogenous agents: glue sniffing, diachrome, some herbal medicines
Dysproteinemias: multiple myeloma/light-chain nephropathy (most common condition associated with Fanconi syndrome in adults), amyloidosis, Sjögren
Others: acute tubular necrosis (ATN), nephrotic syndrome, kidney transplantation
Crystalluria
Crystal nephropathy
Drug precipitation/crystallization within renal tubules leads to microtubular obstruction and associated tubulointerstitial nephritis.
Risk factors for drug crystallization: supersaturation of drug level in urine, volume depletion (low urine flow), urine pH, reduced levels of inhibitors for crystallization
Common inciting agents (Table 6.1)
Drugs: sulfadiazine, ciprofloxacin, acyclovir, indinavir, atazanavir, darunavir, methotrexate, triamterene, orlistat, oral sodium phosphate, ampicillin, foscarnet, pseudoephedrine
Natural sources: star fruit, rhubarb leaves, cranberry juice (oxalate); ma huang (ephedrine); djenkol beans (needle like)
Figure 6.1 shows tubular injury due to intraluminal crystals.
Most drug-induced crystal nephropathy resolves with drug withdrawal and supportive fluid support.
Table 6.1 Drug-induced crystalluria | ||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||
 FIGURE 6.1 Tubular injury due to intraluminal crystals: A. Indinavir crystals are within the lumina of tubules (arrows) admixed with sloughed epithelium (periodic acid-Schiff ×400). B. There are clear to yellow crystalline aggregates of oxalate within tubular lumina (arrows) with tubular cell flattening, simplification and attenuation, and relative dilatation of tubular lumina (hematoxylin and eosin ×250). |
TUBULOINTERSTITIAL NEPHRITIS
Acute Interstitial Nephritis
Epidemiology of acute interstitial nephritis
Acute interstitial nephritis (AIN) may be due to infections, drugs, or autoimmune diseases. Drug-induced AIN predominates all forms of AIN since the advent of antibiotics.
Biopsy-proven AIN in all kidney biopsies reported globally ranges from 1% to 10%.
Biopsy-proven AIN performed for acute kidney injury (AKI) ranges from 6.5% to 35%.
Pathogenesis of AIN
Suggested role of the inciting agent:
Hapten: The inciting agent (i.e., drug [or infection]) binds to an otherwise non-immunogenic native kidney protein (e.g., albumin or host amino acid) and renders it immunogenic.
Prohapten: The inciting agent is a prohapten that becomes a hapten after it has been digested or metabolized by the host.
Pharmacologic interaction: The inciting agent binds to the host HLA molecules and is presented to T cells.
Circulating immune complexes formed against the inciting agent deposit into the kidney interstitium and induce an inflammatory immunologic response that is:
Predominantly cell mediated: Kidney biopsy typically reveals predominant T-cell infiltrates in interstitium.
Less commonly antibody mediated:
Most biopsies do not reveal immune complex deposits.
In some cases, however, immune complex deposits may be seen in tubular basement membranes (TBMs).
Of note, drug-induced AIN is idiosyncratic, unrelated to drug dose, host dependent, and recurs with re-exposure.
Clinical manifestations of AIN
Classic triad of skin rash, leukocyturia, and fevers:
Not common, seen in <10% of cases
Classic triad is uncommonly seen in nonsteroidal anti-inflammatory drugs (NSAIDs)-induced AIN but may be commonly seen with antibiotic-induced AIN.
AKI and subacute kidney injury:
Onset of kidney injury typically occurs within 10 to 20 days of exposure to the inciting agent but may occur within 2 to 3 days with re-exposure.
Kidney injury may be subacute and occurring over months.
De novo kidney injury from a medication previously tolerated may be observed.
Abnormal urine sediment: leukocytes (50% to 60%), microscopic or gross hematuria (˜50%), eosinophils (<50%), white blood cell casts (<5%), granular casts (<50% to 70%), low-grade tubular proteinuria <1 to 2 g/d (˜90%)
Eosinophiluria:
Eosinophiluria is not a sensitive marker for AIN:
Eosinophils may not shed into urine and/or lyse prior to visualization.
Not all causes of AIN have eosinophils in renal interstitium.
Eosinophiluria is not specific to AIN. It may also be seen with urinary tract infections, prostatitis, bladder malignancy, and glomerulonephritis.
The use of urine eosinophils to diagnose suspected AIN is not recommended, given its poor sensitivity and specificity.
Proteinuria:
Non-nephrotic range
LMW proteinuria predominance
May be nephrotic if associated with NSAIDs use/concurrent glomerular disease
Blood tests: elevated serum creatinine (SCr), leukocytosis with increased eosinophilia, anemia, elevated erythrocyte sedimentation rate, transaminitis. Antineutrophil cytoplasmic antibody (ANCA) may be positive without associated glomerular disease.
Histopathology of AIN (Fig. 6.2)
Light microscopy
Inflammatory infiltrates within the interstitium: Infiltrative lesions can be diffuse, but are often patchy, predominating in the deep cortex and outer medulla. Inflammatory cells are primarily T cells and monocytes, macrophages, plasma cells, some eosinophils, and a few neutrophilic granulocytes.
Tubulitis may be seen in AIN. Tubulitis refers to leukocytes and lymphocytes infiltration into tubular epithelium.
Granulomas may be seen in AIN or chronic interstitial nephritis (CIN) associated with sarcoidosis, Sjögren syndrome, granulomatous polyangiitis, infections (e.g., tuberculosis, leprosy, histoplasmosis, xanthogranulomatous pyelonephritis), crystals/foreign bodies (e.g., urate, oxalosis, recreational drug impurities), medications (e.g., sulfas, synthetic penicillins, NSAIDs, thiazides, levofloxacin, checkpoint inhibitors; see Causes of AIN: Drug-Induced below).
 FIGURE 6.2 Acute tubulointerstitial nephritis. A. Lymphocytes are in the edematous interstitium and walls of tubules (arrows) with acute tubular cell injury (periodic acid-Schiff ×250). B. Interstitial edema and inflammation with prominent plasma cells (arrow) admixed with lymphocytes and plasma cells (hematoxylin and eosin ×350). C. Granulomatous interstitial nephritis. There is a non-necrotizing granuloma (arrow) in the interstitium composed of epithelioid histiocytes and multinucleated giant cells (periodic acid methenamine silver ×200). D. Neutrophils are in the interstitium (arrows) and tubular walls and lumen in infection (pyelonephritis) (periodic acid methenamine silver ×425). |
Immunofluorescent (IF) microscopy and electron microscopy (EM)
Diagnosis of AIN
Gold standard: kidney biopsy
Urinalysis with abnormalities above
Gallium scan:
Gallium binds to lactoferrin on white blood cells, originally thought to be specific to AIN, but later found to be positive in other conditions as well (e.g., glomerular diseases, pyelonephritis, atheroembolic disease).
Poor sensitivity and specificity and not recommended for the diagnosis of AIN
Future direction: measurement of urinary T-cell-derived cytokines (e.g., urine interleukin 19 [IL-9], tumor necrosis factor a [TNF-a]).
Elevated IL-9 levels may be seen in allergic conditions, including dermatitis, allergic asthma, food allergy.
IL-9 is produced from Th9 cells and leads to mast cell accumulation. Of interest, mast cells are seen in kidney biopsies of patients with AIN.
Causes of AIN
Etiologies of AIN
70% to 75% is due to drugs.
10% is related to infections (more common in children and developing countries).
10% to 20% is due to autoimmune diseases, for example, sarcoid, Sjögren, systemic lupus erythematosus.
5% is associated with anti-TBM disease, tubulointerstitial nephritis and uveitis, and immunoglobulin G4 (IgG4)-related disease.
<5% involves other causes including hereditary/toxic/metabolic conditions such as hyperoxaluria, heavy metal toxicity, hyperuricemia, hypercalcemia.
Drug induced
Well-described drugs associated with AIN: antibiotics (β-lactams, sulfas , quinolones), NSAIDs including cyclooxygenase-2 (COX-2) inhibitors, proton-pump inhibitor (PPI), check point inhibitors, diuretics (with sulphonamide moiety, such as furosemide and thiazides).
NSAIDs and COX-2 inhibitors may induce kidney injury via various mechanisms:
ATN due to acute afferent arteriolar vasoconstriction and resultant reduction in intraglomerular filtration pressure
Interstitial nephritis that may present as acute, chronic, or granulomatous disease
Papillary necrosis in patients with underlying ischemic renal disease (e.g., diabetes mellitus and associated arteriosclerosis, sickle cell disease)
Three-fourths of NSAIDs-induced AIN is associated with nephrotic syndrome and glomerular lesions, including minimal change disease, membranous nephropathy, and, less commonly, focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephropathy. Risks include older age, chronic use, and use of fenoprofen.
Rifampin:
Likely the leading cause of AIN/AKI among patients receiving therapy for antituberculosis, although pyrazinamide and isoniazid may also induce AIN
Patients may present with AIN and/or ATN.
Consider switching to levofloxacin (consult infectious disease specialist)
Allopurinol:
Thought to be due to immunologic reactions between the metabolite oxypurinol with purines, ribonucleoproteins, and nucleic acids. Accumulation of
oxypurinol increases with reduced kidney function. Dose reduction in chronic kidney disease (CKD) is recommended.
Clinical manifestations:
In addition to AIN and/or granulomas, patients may also develop toxic epidermal necrolysis, exfoliative dermatitis, or diffuse maculopapular rash, hepatic necrosis, and cholangitis.
Antihistamines:
Suggested pathogenesis: Histamine stimulates a subset of suppressor T cells via H2 receptors. Blockage of H2 receptors may lead to increased cell-mediated responses.
Antihistamines associated with AIN include cimetidine, ranitidine, famotidine.
Of interest:
5-Aminosalicylates (sulfasalazine, mesalamine, olsalazine): AIN typically occurs within the first year of use.
Aristolochic acid nephropathy (i.e., Chinese herb nephropathy):
First reported in Belgium where the use of slimming regimens containing aristolochic acid was used
Balkan nephropathy is also thought to be associated with aristolochic acid.
Affected patients may develop rapidly progressive interstitial nephritis, which can progress to end-stage kidney disease (ESKD).
Associated with uroepithelial malignancy
Oxalate nephropathy: ascorbic acid (vitamin C), star fruit, orlistat (induces malabsorptive state that promotes gastrointestinal [GI] oxalate absorption), rhubarb leaves
Checkpoint inhibitors:
Checkpoint proteins are T-cell surface proteins that serve to dampen immune responses from T cells upon interaction with antigen-presenting cells. Checkpoint inhibitors allow T cells to remain “unchecked” in their active state to attack foreign antigens or tumor cells. Two checkpoint proteins that have been targeted in oncology include the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein 1 (PD-1). Inhibitors against these checkpoint proteins allow T cells to remain in their active state to fight tumor cells. The unchecked active T cells, however, can mount a more aggressive and/or sustained response to any presenting antigen including AIN-prone drugs or self-antigens associated with autoimmune diseases. That is, a subclinical AIN from a drug such as PPI may be unmasked as overt AIN during checkpoint inhibitor therapy for underlying malignancy.
AIN and/or granulomatous features have been reported with the use of CTLA-4 and PD-1 inhibitors:
CTLA-4 antagonist ipilimumab: AIN presents within 6 to 12 weeks after initiation of therapy and/or associated podocytopathy.
PD-1 inhibitors: nivolumab and pembrolizumab: AIN presents within 3 to 12 months following initiation of therapy.
Inflammatory responses involving other organs (e.g., thyroiditis, hepatitis, colitis, dermatitis, pancreatitis) may also occur with the use of checkpoint inhibitors.
Other reported drug-induced AIN: liraglutide, varenicline, rosuvastatin, kudzu root (Japanese arrowroot) juice ingestion, B-rapidly accelerated fibrosarcoma oncogene inhibitors vemurafenib and dabrafenib (used for BRAF V600E mutation-positive melanoma, lung, colorectal carcinoma), linezolid, clindamycin
Drug reaction with eosinophilia and systemic symptoms (DRESS):
Clinical manifestations: fevers, facial edema, skin lesions (diffuse macular/papular erythematous lesions with lymphocytic infiltrates, exfoliative dermatitis), lymphadenopathy, multiorgan inflammatory response (e.g., pneumonitis, hepatitis, AIN)
Laboratory findings: eosinophilia, lymphocytosis, elevated aminotransferase (ALT)
Reported responsible agents: phenytoin, phenobarbital, allopurinol, sulfonamides, dapsone, vancomycin, minocycline, raltegravir, vemurafenib, lenalidomide, β-lactams
Treatment: drug withdrawal, supportive care, steroids
Infection related:
May involve various bacteria, viruses, parasites, atypical microorganisms, fungi
Granulomatous AIN may be seen, particularly with fungal, mycobacteria, and parasites.
AKI during treatment of infections may result from infection-related AIN, independent of antibiotic/treatment.
Glomerular disease-associated tubulointerstitial nephritis
Nonselective proteinuria involving proinflammatory proteins and growth factors may induce peritubular inflammatory response, complement activation, and progressive interstitial fibrosis.
Immunologic or autoimmune-mediated AIN:
Associated with systemic diseases: sarcoid, Sjögren, tubulointerstitial nephritis and uveitis, (TINU), IgG4-related disease (see Chronic Interstitial Nephritis section), systemic lupus erythematosus, ANCA-associated disease, IgM plasma cell interstitial nephritis, primary biliary cirrhosis, others
Tubulointerstitial nephritis and uveitis (TINU):
Inflammatory disease involving dysregulated T cells that affect both the eyes and the kidneys
Mechanism of disease is not known.
Commonly seen in young women
Clinical manifestations: painful red eyes (uveitis), AIN, possibly transaminitis
Treatment: prednisone 1 mg/kg/d × 3 to 6 months with slow taper. Addition of cytotoxic agent may be necessary (e.g., mycophenolate, calcineurin inhibitor).
Primary renal AIN with tubulointerstitial immune complex deposits:
Anti-brush border antibody (ABBA) disease (also known as LRP2 nephropathy):
Rare ABBA condition with autoantibody directed against low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin)
Abundant IgG4-positive plasma cells may be seen.
Idiopathic hypocomplementemic tubulointerstitial nephritis
Giant cell tubulitis with TBM immune deposits
Primary renal AIN without immune complex deposits: anti-TBM nephritis
Kidney transplant setting
AIN may occur due to acute rejection in allograft, immunosuppressive therapy, and infections, particularly polyomavirus BK nephropathy and adenovirus nephritis.
Other causes of AIN
Heavy metals, herbal products, idiopathic
Prognosis of AIN
Recovery depends on duration of drug exposure, duration of AKI, and severity of interstitial fibrosis and tubular atrophy.
Recovery may take several weeks. 50% recover fully, whereas the other 50% will have elevated SCr.
Management of AIN
Supportive, dialysis as needed
Prompt removal of offending agent
Role of glucocorticoids:
Optimal benefits:
Early initiation <7 days is most important.
Lower degree of fibrosis is associated with better response.
Expert opinion: Avoid steroids if >75% tubulointerstitial fibrosis on biopsy.
Optimal dose:
No consensus
Consider pulse intravenous (IV) methylprednisolone, 250 to 1,000 mg every day (qd) × 3 days, followed by prednisone 1 mg/kg/d (maximum 80 mg qd) × 3 months (ASN Annual Scientific Meeting, 2019, AIN session)—taper per response/discretion of treating physician due to side effects of high-dose steroids
May lead to prompt recovery if given early, but not necessarily overall outcome
Consider systemic glucocorticoids if severe systemic involvement (e.g., DRESS)
Chronic Interstitial Nephritis
Background
CIN is characterized by tubulointerstitial scarring and fibrosis, tubular atrophy, with or without significant macrophage and lymphocytic infiltration.
Clinical manifestations of CIN
Patients are typically asymptomatic with incidental abnormal laboratory findings:
Mild proteinuria <1.5 to 2.0 g/d
Proteinuria predominantly consists of LMW proteins.
“Bland” urinalysis: no (or rare granular) casts, minimal white and/or red blood cells
Anemia severity is out of proportion to the degree of kidney injury due to damage of peritubular erythropoietin-producing cells in chronic tubulointerstitial nephritis (CTIN).
Other signs of tubular injury may be present: sodium wasting, metabolic acidosis, Fanconi syndrome, nephrogenic insipidus
Causes of CTIN
Common causes (drugs, crystals [e.g., calcium phosphate, uric acid, oxalate], infections, autoimmune, obstruction, chronic ischemia, heavy metals)
Drug-induced CTIN
Analgesic nephropathy:
Traditionally, analgesic nephropathy 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 its 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 that limits the neutralization process of toxic acetaminophen metabolites.
FIGURE 6.3 Chronic tubulointerstitial nephritis. The interstitium contains a lymphocytic infiltrate that is restricted to the area of interstitial fibrosis and tubular atrophy. Note the adjacent preserved tubulointerstitium in the upper left corner, in which there is no inflammation (periodic acid-Schiff ×250).
Analgesic nephropathy affects predominantly the medulla and papillary tip. Characteristic presentations include CKD, computed tomography (CT) revealing papillary necrosis and calcifications, or kidney ultrasound revealing small echogenic kidneys (Fig. 6.4).
Single analgesic use may also lead to analgesic nephropathy.
Acetaminophen:
Physicians’ Health Study (11,000 healthy men): no increased relative risk of CKD with exposure ≥2,500 pills over a period of 11 years
Nurses’ Health Study (˜1,700 healthy women), follow-up over 11 years: >3,000 g of acetaminophen gave an odds ratio of 2.04 for a decrease in glomerular filtration rate (GFR) of >30 mL/min/1.73 m2 compared to <1,000 g use.
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.
High dose of NSAIDs may induce CKD in those with underlying or high risk for kidney injury, but not in healthy individuals.
Physicians’ Health Study (healthy men): no increased risk of CKD with ingestion of ≥2,500 pills
Nurses’ Health Study (healthy women): no association with decline in GFR over lifetime use
Lithium-induced kidney injury:
CIN: characterized by cortical and medullary distal and collecting tubular dilatations/cysts, tubular atrophy, and interstitial fibrosis
Toxic intracellular lithium levels are thought to alter primary cilia function and lead to tubular cyst formation.
FIGURE 6.4 Papillary necrosis. Coronal postcontrast excretory phase maximum intensity projection images showing classic appearance of papillary necrosis.
Commonly associated glomerular lesions: global sclerosis, FSGS, minimal change disease
Lithium may also be associated with nephrogenic diabetes insipidus, distal renal tubular acidosis (RTA), hypercalcemia, and hypothyroidism.
Histopathology (Fig. 6.5): 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.
Management:
Discontinue lithium if safe and possible. There are reports of patients committing suicide with lithium discontinuation.
Amiloride may be considered during lithium use to reduce reabsorption of the drug at the collecting tubules.
Thiazides may be considered in the treatment of nephrogenic diabetes insipidus.
Proton-pump inhibitors (PPIs):
More commonly reported in older patients
Tend to present as subacute rather than AIN (i.e., slow rise in SCr over months)
Kidney biopsy reveals interstitial nephritis and/or granulomatous changes.
Infection-related CTIN (Table 6.2)
Emphysematous pyelonephritis (Fig. 6.6):
Life-threatening necrotizing acute pyelonephritis and/or obstruction, predominantly seen in diabetic patients
Commonly caused by gas-forming organisms such as Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and Proteus mirabilis
FIGURE 6.5 Lithium-induced chronic tubulointerstitial nephritis. There are focal tubular atrophy and interstitial fibrosis with associated lymphocytic inflammation. Microcystic dilatation of distal tubule (arrow left lower corner) and a globally sclerotic glomerulus are also seen (periodic acid-Schiff ×200).
Table 6.2 Infection-related chronic tubulointerstitial nephritis
Characteristics
Radiologic and Histologic Findings
Management
Emphysematous pyelonephritis
Life-threatening necrotizing acute pyelonephritis and/or obstruction; predominantly seen in patients with diabetes mellitus
Commonly caused by gas-forming organisms including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Proteus mirabilis
Plain abdominal radiograph, ultrasound, or CT: presence of gas pockets
Histology: interstitial nephritis may be present
Antibiotic specific to microorganism involved
Relief of obstruction
Surgical resection as needed
Xanthogranulomatous pyelonephritis
Condition associated with chronic obstruction (e.g., staghorn calculi) and urinary tract infections
CT: low-density masses with calcifications resembling renal malignancy
Histology: granulomatous inflammation with diffuse cellular infiltrate of lipid-laden foam cells replacing normal renal parenchyma
Antibiotic specific to microorganism involved
Relief of obstruction
Surgical resection as needed
HIV immune restoration inflammatory syndrome
IRIS refers to a disease- or pathogen-specific inflammatory response that may be triggered after antiretroviral therapy (ART) initiation, reinitiation, or intensification/modification.
IRIS may present as worsening of a diagnosed disease (e.g., ongoing opportunistic infection) or unmasking of an undiagnosed disease.
Ultrasound: Kidneys may be slightly enlarged due to acute inflammatory response
Histology: chronic interstitial nephritis and/or granulomas
Treat opportunistic infections, provide supportive and symptomatic care
Severe IRIS:
Consider holding ART
If IRIS is not caused by cryptococcal meningitis or Kaposi sarcoma, treat with 1-2 mg/kg prednisone for 1-2 wk followed by taper; monitor for other opportunistic infections
Malakoplakia
Rare granulomatous disease of infectious origin
Pathogenesis: defective macrophage function
Characterized by presence of Michaelis-Gutmann (MG) bodies that are lysosomes filled with partially digested bacteria and/or calcium and iron deposits
Ultrasound/CT: mass-like lesions mimicking renal carcinoma
Histology: notable for sheets of histiocytes with basophilic inclusions of concentric laminations (MG bodies) and calcium and iron deposits
Surgical resection
Antibiotics (quinolones, trimethoprim-sulfamethoxazole, rifampicin)
Abbreviations: CT, computed tomography; IRIS, immune restoration inflammatory syndrome.
Gas pockets may be detected on plain abdominal radiograph, ultrasound, or CT.
Management: organism-specific antibiotics, relief of obstruction, and surgical resection as needed
Xanthogranulomatous pyelonephritis (Fig. 6.7):
Condition associated with chronic obstruction (e.g., staghorn calculi) and urinary tract infections with resulting granulomatous inflammation
CT: low-density masses with calcifications mimicking renal malignancy
Histology: granulomatous inflammation with diffuse cellular infiltrate of lipid-laden foam cells replacing normal renal parenchyma
Clinical manifestations: commonly affect middle-aged women who may present with fevers/chills, chronic flank pain, and, possibly, palpable mass. Urine cultures may reveal gram-negative organisms such as E. coli, Klebsiella, or Proteus and, less commonly, Staphylococcal species.
Management: organism-specific antibiotics, relief of obstruction, surgical resection as needed
HIV immune restoration inflammatory syndrome (IRIS):
IRIS refers to a disease- or pathogen-specific inflammatory response that may be triggered after antiretroviral therapy (ART) initiation, reinitiation, or intensification/modification. IRIS may present as worsening of an ongoing disease (e.g., ongoing opportunistic infection) or unmasking of an undiagnosed disease.
Kidney involvement may manifest as interstitial nephritis and/or granulomas.
Management
Treat opportunistic infections and provide supportive and symptomatic care.
ART should not be interrupted unless ongoing IRIS is life-threatening.
FIGURE 6.6 Emphysematous pyelonephritis. Axial and coronal noncontrast computed tomography images showing crescentic collection of gas within Gerota fascia (indicative of infection within the perinephric spaces) consistent with emphysematous pyelonephritis.
FIGURE 6.7 Xanthogranulomatous pyelonephritis. A. Axial and coronal noncontrast computed tomography (CT) images showing enlarged kidneys containing staghorn calculi with resulting contraction of the renal pelvises and associated ballooning of the renal calyces and inflammation of the perinephric fat. The appearance of xanthogranulomatous pyelonephritis on CT has been compared to a “bear claw” with the ballooned renal calyces representing the paws. B. The renal pelvis and medulla are diffusely infiltrated with foamy (xanthomatous) cells, which are lipid-laden macrophages, and lymphocytes obliterating the normal renal parenchyma (hematoxylin and eosin ×200).
Severe IRIS:
Consult infectious disease specialist regarding possibility of holding ART.
If IRIS is not caused by cryptococcal meningitis or Kaposi sarcoma, treat with 1 to 2 mg/kg prednisone or equivalent for 1 to 2 weeks followed by taper; monitor for development of other opportunistic infections, including cytomegalovirus retinitis and tuberculous disease, while receiving prednisone.
Malakoplakia:
Background:
Rare granulomatous disease of infectious etiology (bacterial, fungal, tuberculosis, etc.)
Presents as friable yellow plagues that may involve genitourinary tract, GI tract, other visceral organs, skin (erythematous nodular lesions, ulcerations, fistulas/abscesses)
Reported in immunocompromised hosts and patients with asthma
Pathogenesis: thought to be due to defective macrophage function
Diagnosis: urine culture and biopsy
Imaging studies may reveal mass-like lesions, mimicking renal tumor.
Histopathology (Fig. 6.8):
Hematoxylin and eosin staining reveals sheets of histiocytes with basophilic inclusions of concentric laminations called Michaelis-Gutmann (MG) bodies. MG bodies are lysosomes filled with partially digested bacteria with calcium and iron deposits on residual bacterial glycolipids. The presence of MG body is considered pathognomonic for malakoplakia.
EM: MG bodies consist of lysosomes filled with partially digested bacteria. Identification of the responsible organism may be possible with bacterial gram staining or immune staining with antibody against Mycobacterium bovis if such is the pathogenic organism.
FIGURE 6.8 Malakoplakia. A. Interstitial macrophages with abundant granular cytoplasm containing rounded calcifications (Michaelis-Gutmann bodies, arrows) (hematoxylin and eosin ×600). B. Electron micrograph of a macrophage showing forming calcospherule (Michaelis-Gutmann body, arrow) (×12,000).
Management: surgical, antibiotics (e.g., quinolones, trimethoprim-sulfamethoxazole, rifampicin)
Heavy metal-associated CTIN
Lead (Pb):
Pathogenesis: chronic lead deposition and associated toxicity in proximal tubules, hyperuricemia, and hypertension (HTN)
Clinical manifestations:
Chronic: anemia with basophilic stippling, gout, CKD, peripheral motor neuropathies, perivascular cerebellar calcifications, small shrunken kidneys
Acute lead intoxication: encephalopathy, abdominal pain, hemolytic anemia, Fanconi syndrome, and peripheral neuropathyRelated posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
