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What is the primary immunoglobulin present in most cases of membranous nephropathy?
What is the primary immunoglobulin present in most cases of membranous nephropathy?
Which type of microscopy reveals the thickening of the glomerular capillary wall in membranous nephropathy?
Which type of microscopy reveals the thickening of the glomerular capillary wall in membranous nephropathy?
Which of the following is NOT a clinical feature of membranous nephropathy?
Which of the following is NOT a clinical feature of membranous nephropathy?
What is the most frequent cause of nephrotic syndrome in children?
What is the most frequent cause of nephrotic syndrome in children?
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What is the leading hypothesis for the cause of minimal change disease?
What is the leading hypothesis for the cause of minimal change disease?
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Which of these diseases is characterized by diffuse effacement of foot processes of visceral epithelial cells?
Which of these diseases is characterized by diffuse effacement of foot processes of visceral epithelial cells?
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What is the typical appearance of the basement membrane in membranous nephropathy under silver staining?
What is the typical appearance of the basement membrane in membranous nephropathy under silver staining?
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What is the role of PLA2R and THSD7A in membranous nephropathy?
What is the role of PLA2R and THSD7A in membranous nephropathy?
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What is the most common cause of primary membranous nephropathy?
What is the most common cause of primary membranous nephropathy?
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Which of the following is NOT a potential secondary cause of membranous nephropathy?
Which of the following is NOT a potential secondary cause of membranous nephropathy?
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What is the characteristic feature of membranous nephropathy at the glomerular level?
What is the characteristic feature of membranous nephropathy at the glomerular level?
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What is the typical mechanism by which immune complexes contribute to the development of membranous nephropathy?
What is the typical mechanism by which immune complexes contribute to the development of membranous nephropathy?
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Which of the following is a common manifestation of nephrotic syndrome?
Which of the following is a common manifestation of nephrotic syndrome?
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What is the most common antigen implicated in the development of primary membranous nephropathy?
What is the most common antigen implicated in the development of primary membranous nephropathy?
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What is the likely outcome of the complement activation triggered by immune complexes in membranous nephropathy?
What is the likely outcome of the complement activation triggered by immune complexes in membranous nephropathy?
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How does membranous nephropathy cause the glomerular capillary wall to become leaky?
How does membranous nephropathy cause the glomerular capillary wall to become leaky?
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What percentage of nephrotic syndrome cases in adults are caused by primary or idiopathic FSGS?
What percentage of nephrotic syndrome cases in adults are caused by primary or idiopathic FSGS?
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Which of the following is NOT a clinical sign that distinguishes FSGS from Minimal Change Disease?
Which of the following is NOT a clinical sign that distinguishes FSGS from Minimal Change Disease?
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What is the ultrastructural hallmark of FSGS?
What is the ultrastructural hallmark of FSGS?
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In what percentage of FSGS cases does progression to chronic kidney disease occur within 10 years?
In what percentage of FSGS cases does progression to chronic kidney disease occur within 10 years?
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What is the characteristic proteinuria in FSGS?
What is the characteristic proteinuria in FSGS?
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Which gene, associated with inherited forms of FSGS, encodes nephrin?
Which gene, associated with inherited forms of FSGS, encodes nephrin?
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How does the incidence of FSGS compare to other causes of nephrotic syndrome in adults?
How does the incidence of FSGS compare to other causes of nephrotic syndrome in adults?
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Which of the following statements regarding the response to corticosteroid therapy in FSGS is true?
Which of the following statements regarding the response to corticosteroid therapy in FSGS is true?
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What is the name of the genetic mutation that encodes uromodulin, a protein expressed in the thick ascending limb of the loop of Henle, and is associated with Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)?
What is the name of the genetic mutation that encodes uromodulin, a protein expressed in the thick ascending limb of the loop of Henle, and is associated with Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)?
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Which of the following is a characteristic feature of light-chain cast nephropathy (Myeloma Kidney)?
Which of the following is a characteristic feature of light-chain cast nephropathy (Myeloma Kidney)?
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Which of the following is NOT a potential complication of light-chain cast nephropathy (Myeloma Kidney)?
Which of the following is NOT a potential complication of light-chain cast nephropathy (Myeloma Kidney)?
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What is the primary cause of renal dysfunction in light-chain cast nephropathy?
What is the primary cause of renal dysfunction in light-chain cast nephropathy?
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What percentage of individuals with gout are estimated to have uric acid stones?
What percentage of individuals with gout are estimated to have uric acid stones?
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What is the likely outcome of Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) in adults?
What is the likely outcome of Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) in adults?
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What is the name given to the type of amyloidosis associated with light-chain cast nephropathy?
What is the name given to the type of amyloidosis associated with light-chain cast nephropathy?
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What is the primary factor contributing to renal damage in half of those with multiple myeloma?
What is the primary factor contributing to renal damage in half of those with multiple myeloma?
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What is a characteristic feature of collapsing glomerulopathy?
What is a characteristic feature of collapsing glomerulopathy?
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Which factor is associated with the rapid progression of Focal Segmental Glomerulosclerosis?
Which factor is associated with the rapid progression of Focal Segmental Glomerulosclerosis?
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What is the prognosis for adults with idiopathic Focal Segmental Glomerulosclerosis compared to children?
What is the prognosis for adults with idiopathic Focal Segmental Glomerulosclerosis compared to children?
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Which of the following conditions is commonly associated with HIV-associated nephropathy?
Which of the following conditions is commonly associated with HIV-associated nephropathy?
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In terms of recurrences after allografts, what percentage of patients typically experience them?
In terms of recurrences after allografts, what percentage of patients typically experience them?
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What are tubuloreticular inclusions, and where are they found in HIV-associated nephropathy?
What are tubuloreticular inclusions, and where are they found in HIV-associated nephropathy?
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What is the most significant characteristic seen on electron microscopy in both sclerotic and nonsclerotic areas?
What is the most significant characteristic seen on electron microscopy in both sclerotic and nonsclerotic areas?
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What commonly influences the presence of IgM and C3 in the context of immunofluorescence microscopy?
What commonly influences the presence of IgM and C3 in the context of immunofluorescence microscopy?
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What is primarily found in the glomerular deposits of IgA nephropathy?
What is primarily found in the glomerular deposits of IgA nephropathy?
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What is the common consequence of the activation of the complement system in IgA nephropathy?
What is the common consequence of the activation of the complement system in IgA nephropathy?
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Which demographic is most commonly affected by IgA nephropathy?
Which demographic is most commonly affected by IgA nephropathy?
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What percentage of IgA nephropathy cases experience slow progression to chronic renal failure over 20 years?
What percentage of IgA nephropathy cases experience slow progression to chronic renal failure over 20 years?
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What type of microscopy confirms the presence of electron-dense deposits in IgA nephropathy?
What type of microscopy confirms the presence of electron-dense deposits in IgA nephropathy?
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What are potential triggers for increased synthesis of abnormal IgA in IgA nephropathy?
What are potential triggers for increased synthesis of abnormal IgA in IgA nephropathy?
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What is the primary feature of the immunofluorescent picture in IgA nephropathy?
What is the primary feature of the immunofluorescent picture in IgA nephropathy?
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Which of the following disorders is characterized by mutations in collagen genes leading to glomerular injury?
Which of the following disorders is characterized by mutations in collagen genes leading to glomerular injury?
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Study Notes
Diseases of the Kidneys
- The study of kidney diseases is facilitated by dividing them into those that affect the four basic morphologic components:
- Glomeruli
- Tubules
- Interstitium
- Blood vessels.
- Most glomerular diseases are immunologically mediated, while tubular and interstitial disorders are frequently caused by toxic or infectious agents.
- Some disorders affect more than one structure, and the anatomic and functional interdependence of the components of the kidney means that damage to one usually secondarily affects the others. Primary disorders of the blood vessels, for example, inevitably affect all structures supplied by these vessels.
- Whatever the origin, all forms of chronic kidney disease ultimately damage all four components of the kidney, culminating in what are called end-stage kidneys.
Clinical Manifestations of Renal Diseases
- Azotemia is a biochemical abnormality that refers to an elevation of blood urea nitrogen (BUN) and creatinine levels, and is related largely to a decreased glomerular filtration rate (GFR).
- Azotemia is a consequence of many renal disorders, but it also arises from extrarenal disorders. It is a typical feature of both acute and chronic kidney injury.
- Prerenal azotemia is encountered when there is hypoperfusion of the kidneys that impairs renal function in the absence of parenchymal damage. It may be caused by hypotension, excessive fluid losses from any cause, or if the effective intravascular volume is decreased due to shock, volume depletion, congestive heart failure, or cirrhosis of the liver.
- Postrenal azotemia is seen whenever urine flow is obstructed distal to the kidney. Relief of the obstruction is followed by correction of the azotemia.
- When azotemia leads to clinical signs and symptoms associated with biochemical abnormalities, it is termed uremia.
- Uremia is characterized not only by failure of renal excretory function but also by a host of metabolic and endocrine alterations resulting from renal damage. Uremic patients frequently manifest secondary involvement of the gastrointestinal system (e.g., uremic gastroenteritis), peripheral nerves (e.g., peripheral neuropathy), and heart (e.g., uremic fibrinous pericarditis).
Nephritic Syndrome
- Nephritic syndrome is a clinical entity caused by inflammatory glomerular disease and is dominated by the acute onset of either grossly visible hematuria (red blood cells in urine) or microscopic hematuria with dysmorphic red cells and red cell casts on urinalysis, diminished GFR, mild to moderate proteinuria, and hypertension. It is the classic presentation of acute poststreptococcal glomerulonephritis. Rapidly progressive glomerulonephritis (RPGN) is a form of nephritic syndrome in which there is rapid decline in GFR (within hours to days).
- Nephrotic syndrome, also due to glomerular disease, is characterized by heavy proteinuria (more than 3.5 g/day), hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipid in the urine). Clinical features of nephritis and nephrotic syndrome are discussed elsewhere.
Asymptomatic Hematuria or Proteinuria
- Asymptomatic hematuria or proteinuria, or a combination of these two, is usually a manifestation of subtle or mild glomerular abnormalities.
Acute Kidney Injury
- Acute kidney injury (previously called acute renal failure) is characterized by rapid decline in GFR (within hours to days) with concurrent dysregulation of fluid and electrolyte balance, and retention of metabolic waste products normally excreted by the kidney, including urea and creatinine. In its most severe forms, it is manifested by oliguria or anuria (reduced or no urine flow). It can result from glomerular, interstitial, vascular, or acute tubular injury (ATI).
Chronic Kidney Disease
- Chronic kidney disease (previously called chronic renal failure) is defined as the presence of a diminished GFR that is persistently less than 60 mL/min/1.73 m2 for at least 3 months, from any cause, and/or persistent albuminuria. It may present with a clinically silent decline in renal excretory function in milder forms or with prolonged symptoms and signs of uremia in more severe cases. It is the end result of all chronic renal parenchymal diseases.
- In end-stage renal disease, the GFR is less than 5% of normal; this is the terminal stage of uremia.
Renal Tubular Defects
- Renal tubular defects are dominated by polyuria (excessive urine formation), nocturia, and electrolyte disorders (e.g., metabolic acidosis). They are the result of diseases that either directly affect tubular structures (e.g., the nephronophthisis) or cause defects in specific tubular functions. The latter can be inherited (e.g., familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g., lead nephropathy).
Urinary Tract Obstructions and Renal Tumors
- Urinary tract obstruction and renal tumors have varied clinical manifestations based on the specific anatomic location and nature of the lesion. Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney (pyelonephritis) or the bladder (cystitis).
Nephrolithiasis (Renal Stones)
- Nephrolithiasis (renal stones) is manifested by spasms of severe pain (renal colic) and hematuria, often with recurrent stone formation.
Glomerular Diseases
- Glomeruli may be injured by secondary glomerular diseases, (more common), or primary glomerulonephritis (less common).
- Secondary glomerular diseases include systemic immunologic diseases (e.g., SLE), vascular disorders (e.g., hypertension), metabolic diseases (e.g., diabetes mellitus), and some hereditary conditions (e.g., Fabry disease).
- Primary glomerulonephritis includes disorders in which the kidney is the only or predominant organ involved, and some that do not have a cellular inflammatory component.
Pathologic Responses to Glomerular Injury
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Hypercellularity: Mesangial proliferation, endocapillary proliferation or crescent formation; crescent formation following immune/inflammatory injury.
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Basement membrane thickening: Deposition of amorphous electron-dense material (immune complexes), increased synthesis of basement membrane proteins, formation of additional basement membrane layers.
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Hyalinosis: Accumulation of homogeneous, eosinophilic material (plasma proteins) in glomerular structures; often a consequence of endothelial or capillary wall injury.
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Sclerosis: Deposition of extracellular collagenous matrix; may be confined to mesangial areas or involve capillary loops.
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Many primary glomerulopathies are classified by their histology. The histologic changes can be further subdivided by their distribution into diffuse, global, focal, segmental, capillary loop or mesangial categories
Pathogenesis of Glomerular Injury
- Antibody-mediated injury: In situ immune complex deposition (fixed intrinsic tissue antigens, planted antigens), circulating immune complex deposition (endogenous/exogenous antigens), Cell-mediated immune injury (activation of alternate complement pathway)
- Two established forms of antibody-associated injury: In situ injury (antibodies reacting to intrinsic/extrinsic molecules within the glomerulus) and injury resulting from deposition of circulating antigen-antibody complexes.
Diseases Caused by In Situ Immune Complex Formation
- Immune complexes formed locally by antibodies that react with intrinsic tissue antigens or with extrinsic antigens planted in the glomerulus from the circulation. (Membranous nephropathy, resulting from local formation of immune complexes by antibodies reactive with endogenous antigens and a granular pattern of immune deposition).
- Electron microscopy shows discrete subepithelial dense deposits composed of immune reactants. This results in thickened basement membrane appearance via light microscopy, hence the term membranous nephropathy.
Disease Caused by Antibodies Directed Against Normal Components of the Glomerular Basement Membrane
- In anti-GBM antibody-induced glomerulonephritis, antibodies bind to intrinsic antigens homogeneously distributed along the entire length of the GBM, resulting in a diffuse linear pattern of staining for the antibodies via immunofluorescence techniques.
- Although anti-GBM antibody-induced glomerulonephritis accounts for less than 5% of cases of human glomerulonephritis, it causes severe necrotizing and crescentic glomerular damage and the clinical syndrome of RPGN.
Glomerulonephritis Resulting From Deposition of Circulating Immune Complexes
- Caused by trapping of circulating antigen-antibody complexes within glomeruli. The antibodies have no immunologic specificity for glomerular constituents, and the complexes localize because of physicochemical properties and hemodynamic factors peculiar to the glomerulus.
- The antigens that trigger the formation of circulating immune complexes may be endogenous (SLE, IgA nephropathy) or exogenous(bacterial products, hepatitis B virus, hepatitis C virus, etc.).
Cell-Mediated Immunity in Glomerulonephritis
- Although antibody-mediated mechanisms may initiate most forms of glomerulonephritis, there is evidence that sensitized T cells cause glomerular injury and are involved in the progression of some glomerulonephritides.
Mediators of Glomerular Injury
- Cells: Neutrophils, monocytes, macrophages, and T lymphocytes.
- Soluble mediators: Complement activation, eicosanoids, nitric oxide, angiotensin, endothelin, cytokines (IL-1, TNF), chemokines (e.g., MCP-1), growth factors (e.g., PDGF), and coagulation system components.
Epithelial Cell Injury
- Podocyte injury is common to many forms of both primary and secondary glomerular diseases.
- Injury is reflected by morphologic changes:
- Effacement of foot processes
- Vacuolization, retraction, and detachment from the GBM
- Functionally by proteinuria
Mechanisms of Progression in Glomerular Diseases
- Glomerulosclerosis: Develops after many types of renal injury; leads to proteinuria and progressive functional impairment.
- Tubular injury and interstitial fibrosis: Manifested by tubular damage and interstitial inflammation, ischemia of tubular segments, acute and chronic inflammation in the adjacent interstitium, and damage/loss of peritubular capillary blood supply.
Nephritic Syndrome
- Glomerular diseases presenting with a nephritic syndrome and inflammation in the glomeruli.
- Clinical features include hematuria, proteinuria, edema, azotemia and hypertension.
Examples of Diseases That Exhibit Nephritic Syndrome
- Acute Proliferative (Postinfectious and infection-associated glomerulonephritis)
- Crescentic (Rapidly Progressive) Glomerulonephritis.
- Others: Membranoproliferative Glomerulonephritis, IgA nephropathy, Hereditary nephritis, Alport syndrome, Thin Basement membrane nephropathy.
Chronic Pyelonephritis
- A disorder in which chronic tubulointerstitial inflammation and scarring involve the calyces and renal pelvis.
Nephropathy Associated With NSAIDs
- NSAIDs are nonselective cyclo-oxygenase inhibitors, and their adverse renal effects are related to their ability to inhibit cyclooxygenase-dependent prostaglandin synthesis.
- NSAID-associated renal syndromes include acute kidney injury, acute hypersensitivity interstitial nephritis, acute interstitial nephritis, and membranous nephropathy.
Urate Nephropathy
- Three types of nephropathy: Acute uric acid nephropathy, Chronic urate nephropathy, and Nephrolithiasis (uric acid stones).
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)
- Previously known as medullary cystic kidney disease.
- Mutations in genes encoding MUC1, UMOD, REN, and HNF1β, resulting in progressive renal failure in adult life.
Light Chain Cast Nephropathy
- Characterized by light-chain proteinuria and cast nephropathy, amyloidosis of AL type, and light-chain deposition disease; caused by complications of the tumor and/or therapy.
Bile Cast Nephropathy
- Occurs in patients with severe acute or advanced chronic liver disease. Serum bilirubin levels are markedly elevated. The casts extend to proximal tubules, leading to direct toxic effects on tubular epithelial cells and obstruction of the involved nephron. Reversibility of the renal injury depends on the severity and duration of the liver dysfunction.
Vascular Diseases of Kidneys, Nephrosclerosis
- Nephrosclerosis is the term used for the renal pathology in which renal arterioles and small arteries are affected by vascular sclerosis, and is associated with hypertension, which can both be a cause and consequence of nephrosclerosis.
- Pathogenesis includes medial and intimal thickening (in response to hemodynamic changes, aging, and genetic defects), hyalinizaton of arteriolar walls (extraravation of plasma proteins and increased basement membrane deposition), ischemia, and glomerulosclerosis and chronic tubulointerstitial injury producing reduction in functional renal mass.
Vascular Diseases of Kidneys, Renal Artery Stenosis
- Unilateral renal artery stenosis is potentially curable by surgery, and is caused by the increased production of renin due to ischemia and resulting production of the vasoconstrictor angiotensin II.
- Common causes include narrowing at the origin of the renal artery (atheromatous plaque, more common in men and patients with diabetes) or fibromuscular dysplasia (more common in women).
Vascular Diseases of Kidneys, Thrombotic Microangiopathies
- Encompasses thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS).
- Caused by diverse insults that produce thrombi in capillaries and/or arterioles, producing microangiopathic hemolytic anemia and microvascular occlusions that cause tissue ischemia and organ dysfunction, leading to thrombocytopenia.
Vascular Diseases of Kidneys, Sickle Cell Nephropathy
- Most common abnormalities include hematuria and diminished concentrating ability (hyposthenuria).
- Due to accelerated sickling in the hypertonic, hypoxic renal medulla, dehydration of red cells increases intracellular sickle hemoglobin (HbS) concentrations.
- Patchy papillary necrosis may occur, associated with cortical scarring. Proteinuria is also common.
Vascular Diseases of Kidneys, Renal Infarcts
- Renal infarcts are often due to emboli, particularly mural thrombosis in the left atrium and ventricle.
- Morphology: Renal infarcts are often wedge-shaped, white, and ringed by a zone of intense hyperemia.
- In time, infarcts undergo progressive fibrous scarring, showing a V-shape on section.
Congenital and Anomalies of Kidneys
- Agenesis: Bilateral agenesis is incompatible with life; unilateral agenesis is uncommon and has a good prognosis. Some may eventually develop chronic kidney disease due to adaptive changes in hypertrophied nephrons.
- Hypoplasia: Failure of kidney to reach normal size, may be unilateral, usually resulting in renal failure early childhood.
- Ectopic Kidneys: Located outside normal position in the pelvis or just above the pelvic brim.
- Horseshoe Kidneys: Fused kidneys at upper or lower poles, continuous across the midline anterior to the great vessels.
Other Glomerular Diseases
- Hereditary Nephritis: Group of heterogeneous familial renal diseases, mainly associated with mutations in collagen genes.
- Alport syndrome: X-linked trait; characterized by hematuria, nerve deafness, and various eye disorders (e.g., lens dislocation, posterior cataracts, and corneal dystrophy).
- Thin basement membrane nephropathy: Benign familial hematuria; characterized by diffuse thinning of the glomerular basement membrane.
Minimal Change Disease
- A benign disorder characterized by diffuse effacement of podocyte foot processes, detectable only by electron microscopy.
- The most frequent cause of nephrotic syndrome in children, but less common in adults. Peak incidence between 2 and 6 years of age.
Focal Segmental Glomerulosclerosis (FSGS)
- The most common cause of nephrotic syndrome among adults.
- Characterized by focal sclerosis of some glomeruli, with only a portion of the capillary tuft involved.
- Clinically manifest by acute or subacute onset of nephrotic syndrome or nonnephrotic proteinuria, hypertension, microscopic hematuria, and some degree of azotemia, when first observed clinically.
HIV-Associated Nephropathy
- Characterized by rapidly progressive, collapsing form of FSGS. Often associated with acute renal failure.
- Morphologically characterized by the presence of collapsing glomerulopathy, cystic dilation of tubular segments, and other pathology, in 5%-10% HIV-infected individuals.
Membranoproliferative Glomerulonephritis (MPGN)
- Pattern of immune-mediated injury rather than a discrete disease.
- MPGN accounts for up to 10% of cases of nephrotic syndrome in children and young adults.
- Type I: Characterized by subendothelial electron-dense deposits containing IgG and complement; frequent clinical association with conditions characterized by excessive complement activation.
- Type II (Dense-Deposit Disease): Characterized by dense deposits in the glomerular basement membrane (GBM). The activation of complement appears to be the most important factor. Some patients have a combined nephrotic-nephritic picture, while others present with only hematuria or minimal proteinuria.
Fibrillary Glomerulonephritis
- Rare disease characterized by fibrillary deposits in the mesangium and glomerular capillary walls.
- DNAJB9, a chaperone for heat shock protein 70s, has been identified as a highly sensitive and specific marker for fibrillary GN.
IgA Nephropathy (Berger Disease)
- Most common type of glomerulonephritis worldwide; characterized by prominent IgA deposits in the mesangial regions.
- Recurrent hematuria and often associated with infections of the respiratory or gastrointestinal tract; typically seen among older children and young adults.
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Test your knowledge on membranous nephropathy, including its primary immunoglobulin, clinical features, and the microscopy techniques used in diagnosis. This quiz covers key concepts such as nephrotic syndrome in children and the underlying causes of this condition.
