Kidney Renal Pathology 2025 Part 1 PDF

Diseases of the Kidneys NEAL CAFÉ RANA, MD, DPCOM, DPSP Pathologist and Occupational Medicine Specialist  The study of kidney diseases is facilitated by dividing them into those that affect the four basic morphologic components: 1. Glomeruli 2. Tubules 3. Interstitium 4. Blood v...

Diseases of the Kidneys NEAL CAFÉ RANA, MD, DPCOM, DPSP Pathologist and Occupational Medicine Specialist  The study of kidney diseases is facilitated by dividing them into those that affect the four basic morphologic components: 1. Glomeruli 2. Tubules 3. Interstitium 4. Blood vessels. “Most glomerular diseases are immunologically mediated, whereas 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. 1. 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 hear failure, or cirrhosis of the liver. 2. Postrenal azotemia is seen whenever urine flow is obstructed distal to the kidney. Relief of the obstruction is followed by correction of the CLINICAL MANIFESTATIONS OF RENAL DISEASES 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). CLINICAL MANIFESTATIONS OF RENAL DISEASES 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). CLINICAL MANIFESTATIONS OF RENAL DISEASES 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). The clinical features of nephritis and the nephrotic syndrome are discussed in more detail later. CLINICAL MANIFESTATIONS OF RENAL DISEASES Asymptomatic hematuria or proteinuria, or a combination of these two, is usually a manifestation of subtle or mild glomerular abnormalities. CLINICAL MANIFESTATIONS OF RENAL DISEASES 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). CLINICAL MANIFESTATIONS OF RENAL DISEASES 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. CLINICAL MANIFESTATIONS OF RENAL DISEASES In end-stage renal disease, the GFR is less than 5% of normal; this is the terminal stage of uremia CLINICAL MANIFESTATIONS OF RENAL DISEASES 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). CLINICAL MANIFESTATIONS OF RENAL DISEASES 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). CLINICAL MANIFESTATIONS OF RENAL DISEASES 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 1. Secondary glomerular diseases. (More common) Systemic immunologic diseases such as systemic lupus erythematosus (SLE), vascular disorders such as hypertension, metabolic diseases such as diabetes mellitus, and some hereditary conditions such as Fabry disease often affect the glomerulus. 2. Primary glomerulonephritis. (Less common) Disorders in which the kidney is the only or predominant organ involved constitute the various types of primary glomerulonephritis or, because some do not have a cellular inflammatory component, primary glomerulopathy. Note: both the clinical manifestations and glomerular histologic changes in primary and secondary forms can be similar. Pathologic Responses of the Glomerulus to Injury 1. Hypercellularity Increased number of cells in the glomerular tufts which can be caused by either one of the following or in combination: 1. Proliferation of mesangial or endothelial cells. 2. Infiltration of leukocytes. including neutrophils, monocytes, and, in some diseases, lymphocytes. The combination of infiltration of leukocytes and swelling and proliferation of mesangial and/or endothelial cells is often referred to as endocapillary proliferation. 3. Formation of crescents. These are accumulations of cells composed of proliferating glomerular epithelial cells and infiltrating leukocytes. The epithelial cell proliferation that characterizes crescent formation occurs following an immune/inflammatory injury involving the capillary walls. 2. Basement Membrane Thickening 1. Is the thickening the capillary walls, best seen in sections stained with periodic acid–Schiff (PAS). 2. By electron microscopy, such thickening takes one of three forms: 1. Deposition of amorphous electron-dense material, most often immune complexes, on the endothelial or epithelial side of the basement membrane or within the GBM itself. 2. Increased synthesis of the protein components of the basement membrane, as occurs in diabetic glomerulosclerosis. 3. Formation of additional layers of basement membrane matrices, which most often occupy subendothelial locations and may range from poorly organized matrix to fully duplicated lamina densa, as occurs in membranoproliferative glomerulonephritis (MPGN). 3. Hyalinosis as applied to the glomerulus, denotes the accumulation of material that is homogeneous and eosinophilic by light microscopy. Hyalin is an extracellular, amorphous material composed of plasma proteins that have insudated from the circulation into glomerular structures. When extensive, these deposits may obliterate the capillary lumens of the glomerular tuft. Hyalinosis is usually a consequence of endothelial or capillary wall injury and typically the end result of various forms of glomerular damage. 4. Sclerosis is characterized by deposition of extracellular collagenous matrix. It may be confined to mesangial areas, as is often the case in diabetic glomerulosclerosis, involved the capillary loops, or both. The sclerosing process may also result in obliteration of some or all of the capillary lumens in affected glomeruli. Pathologic Responses of the Glomerulus to Injury Many primary glomerulopathies are classified by their histology. The histologic changes can be further subdivided by their distribution into the following categories: 1. Diffuse, involving all of the glomeruli in the kidney; 2. Global, involving the entirety of individual glomeruli; 3. Focal, involving only a fraction of the glomeruli in the kidney; 4. Segmental, affecting a part of each glomerulus; 5. Capillary loop or mesangial, affecting predominantly capillary or mesangial regions. Pathogenesis of Glomerular Injury Although much remains unknown about etiologic agents and triggering events, it is clear that immune mechanisms underlie most forms of primary glomerulopathy and many secondary glomerular disorders. Pathogenesis of Glomerular Injury Two forms of antibody-associated injury have been established: 1. Injury by antibodies reacting in situ within the glomerulus, either binding to insoluble fixed (intrinsic) glomerular antigens or extrinsic molecules planted within the glomerulus. 2. Injury resulting from deposition of circulating antigen- antibody complexes in the glomerulus. It is clear that the major cause of glomerulonephritis resulting from formation of antigen-antibody complexes is the consequence of in situ immune complex formation, and not deposition of circulating complexes as was once thought. Diseases Caused by In Situ Formation of Immune Complexes Immune complexes are formed locally by antibodies that react with intrinsic tissue antigens or with extrinsic antigens “planted” in the glomerulus from the circulation. Membranous nephropathy is the classic example of glomerular injury resulting from local formation of immune complexes by antibodies reactive with endogenous antigens. The pattern of immune deposition by immunofluorescence microscopy is granular pattern, reflecting the very localized antigen-antibody interaction. On electron microscopy, the glomerulopathy is characterized by the presence of numerous discrete subepithelial electron-dense deposits (made up of immune reactants). These subepithelial complexes, with resultant host responses, can result in a thickened basement membrane appearance by 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 by 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 (Rapidly progressive GN). Glomerulonephritis Resulting From Deposition of Circulating Immune Complexes is caused by the trapping of circulating antigen-antibody complexes within glomeruli. The antibodies have no immunologic specificity for glomerular constituents, and the complexes localize within the glomeruli because of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus. The antigens that trigger the formation of circulating immune complexes may be of endogenous origin, as in the glomerulonephritis associated with SLE or in IgA nephropathy, or they may be exogenous, as may occur in the glomerulonephritis that follows certain infections. Microbial antigens that are implicated include bacterial products (streptococcal proteins), the surface antigen of hepatitis B virus, hepatitis C virus antigens, and antigens of Treponema pallidum, Plasmodium falciparum, and several viruses. Some tumor antigens are also thought to cause immune complex–mediated nephritis. In many cases, the inciting antigen is unknown. 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 Once immune reactants or sensitized T cells have localized in the glomerulus, how does the glomerular damage ensue? The mediators—both cells and molecules—are the usual suspects involved in acute and chronic inflammation. A. Cells 1. Neutrophils and monocytes as a result of activation of complement, resulting in generation of chemotactic agents (mainly C5a). Neutrophils release proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to the reductions in GFR. 2. Macrophages and T lymphocytes, which infiltrate glomeruli in antibody- and cell-mediated reactions, when activated, release a vast number of biologically active molecules. 3. Resident glomerular cells, particularly mesangial cells, can be stimulated to produce inflammatory mediators, including reactive oxygen species (ROS), cytokines, chemokines B. Soluble Mediators A. Complement activation leads to the generation of chemotactic products that induce leukocyte influx (complement neutrophil– dependent injury) and the formation of C5b–C9, the membrane attack complex. B. Eicosanoids, nitric oxide, angiotensin, and endothelin are involved in the hemodynamic changes. C. Cytokines, particularly IL-1 and TNF, which may be produced by infiltrating leukocytes and resident glomerular cells, induce leukocyte adhesion and a variety of other effects. D. Chemokines such as monocyte chemoattractant protein 1 promote monocyte and lymphocyte influx. Growth factors such as platelet-derived growth factor (PDGF) are involved in mesangial cell proliferation. E. Coagulation system is also a mediator of glomerular damage. Fibrin is frequently present in the glomeruli and Bowman space in glomerulonephritis Epithelial Cell Injury Podocyte injury is common to many forms of both primary and secondary glomerular diseases. injury is reflected by morphologic changes 1. Effacement of foot processes, 2. Vacuolization retraction and detachment of cells from the GBM 3. Functionally by proteinuria Mechanisms of Progression in Glomerular Diseases 2 major histologic characteristics of such progressive renal damage 1. Glomerulosclerosis develops after many types of renal injury and can lead to proteinuria and increasing functional impairment. Seen in Post Streptococcal Glomerulonephritis 2. Tubular Injury and Interstitial Fibrosis manifested by tubular damage and interstitial inflammation Example in Diabetic nephropathy, progression of renal dysfunction Causes: ischemia of tubular segments downstream from sclerotic glomeruli, acute and chronic inflammation in the adjacent interstitium, and damage or loss of the peritubular capillary blood supply. Activated tubular cells in turn express adhesion molecules and elaborate proinflammatory cytokines, chemokines, and growth factors that contribute to interstitial fibrosis. Nephritic Syndrome Glomerular diseases presenting with a nephritic syndrome are characterized by inflammation in the glomeruli. Main clinical features of nephritic syndrome include the following: 1. Hematuria (red blood cells and red cell casts in urine) 2. Proteinuria (usually subnephrotic range) with or without 3. Edema 4. Azotemia 5. Hypertension is the typical clinical presentation of most proliferative types of GN such as postinfectious GN, crescentic GN, and proliferative lupus GN. Cause of lesions: Proliferation of the cells within the glomeruli, often accompanied by an inflammatory leukocytic infiltrate. This inflammatory reaction severely injures the capillary walls, permitting blood to pass into the urine and inducing hemodynamic changes that lead to a reduction in GFR. The reduced GFR is manifested clinically by oliguria, fluid retention, and azotemia. Hypertension probably is a result of both the fluid retention and renin release from the ischemic kidneys. Examples of Diseases that exhibit Nephritic Syndrome: Acute Proliferative (Postinfectious- and Infection- Associated) Glomerulonephritis Characterized histologically by diffuse proliferation of glomerular cells associated with influx (exudation) of leukocytes, typically caused by immune complexes. The inciting antigen may be exogenous or endogenous. 1. Prototype of Exogenous antigen-induced disease pattern is Postinfectious glomerulonephritis. 2. Prototype of an endogenous antigen-induced disease is the nephritis of SLE. Most common are Exogenous- caused by underlying infections, commonly streptococcal in origin. Pathogenesis: Poststreptococcal GN is caused by immune complexes containing streptococcal antigens and specific antibodies. Only certain strains of group A β-hemolytic streptococci are nephritogenic, more than 90% of cases being traced to types 12, 4, and 1, which can be identified by typing of the M protein of the bacterial cell walls. streptococcal pyogenic exotoxin B (SpeB) as the principal antigenic determinant in most but not all cases of poststreptococcal glomerulonephritis. This toxin can directly activate the complement system. Serum complement levels are low, compatible with activation of the complement system and consumption of complement components. There are granular immune deposits in the glomeruli, indicative of an immune complex–mediated mechanism. “humplike” deposits characteristic of this disease Examples of Diseases that exhibit Nephritic Syndrome: Acute Proliferative (Postinfectious- and Infection- Associated) Glomerulonephritis Clinical Features 1. Children: young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cola-colored urine) 1 to 2 weeks after recovery from a sore throat. dysmorphic red cells or red cell casts in the urine, mild proteinuria (usually less than 1 g/day), periorbital edema, and mild to moderate hypertension. 2. Adult: onset is more likely to be atypical, such as the sudden appearance of hypertension or edema, frequently with elevation of BUN. Prognosis 1. Children: 1. More benign. 95% of affected children eventually recover. Less than 1% do not improve, become severely oliguric, and develop a rapidly progressive form of glomerulonephritis (RPGN). 2. Adult: 1. Less benign. 60% of sporadic cases recover promptly. In the remainder, the glomerular lesions fail to resolve quickly, as manifested by persistent proteinuria, hematuria, and hypertension. Others develop chronic glomerulonephritis or even RPGN. Examples of Diseases that exhibit Nephritic Syndrome: Crescentic (Rapidly Progressive) Glomerulonephritis RPGN is a clinical syndrome associated with severe glomerular injury but it does NOT denote a specific etiology. is characterized by relatively rapid and progressive loss of renal function associated with severe oliguria and signs of nephritic syndrome; if untreated, death from renal failure may occur within weeks to months. The most common histologic picture is the presence of crescents in most of the glomeruli, hence the name crescentic glomerulonephritis. Pathogenesis: most cases the glomerular injury is immunologically mediated. Crescentic GN into three groups: 1. Type 1: Anti-GBM antibody–mediated disease characterized by linear deposits of IgG and, in many cases, C3 in the GBM. 1. Anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure (Goodpasture syndrome). Plasmapheresis to remove the pathogenic circulating antibodies is part of the treatment. The antigen common to the alveoli and GBM is a peptide within the noncollagenous portion of the α3 chain of collagen type IV. Exposure to viruses or hydrocarbon solvents (found in paints and dyes) has been implicated in some patients, as have various drugs and cancers. 2. Type 2: Diseases caused by immune complex deposition, with granular deposits of antibodies and complement by immunofluorescence. 1. Crescentic GN can be a complication of any of the immune complex nephritides, including postinfectious glomerulonephritis, lupus nephritis, IgA nephropathy, and Henoch-Schönlein purpura. These patients usually cannot be helped by plasmapheresis, and they require treatment for the underlying disease. 3. Type 3: Pauci-immune crescentic GN, defined by the lack of detectable anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy. 1. Most patients with this type of RPGN have circulating antineutrophil cytoplasmic antibodies (ANCAs) that produce a cytoplasmic (c-ANCA) or perinuclear (p-ANCA) staining pattern. This type of RPGN may be a component of a systemic vasculitis such as granulomatosis with polyangiitis (formerly called Wegener granulomatosis) or microscopic polyangiitis. 2. Updates: c-ANCAs (now called PR3-ANCA because the antibodies are specific for the neutrophil granule protein proteinase-3) or p-ANCAs (now called MPO-ANCA indicating reactivity with neutrophil myeloperoxidase) in the serum Examples of Diseases that exhibit Nephritic Syndrome: Crescentic (Rapidly Progressive) Glomerulonephritis Morphology: Gross: Kidneys: Pale with hemorrhages, segmental necrosis Light Microscopy: 1. Presence of Crescents adjacent to glomerular segments uninvolved by inflammatory or proliferative changes is the feature most typical of pauci-immune RPGN. Escape of procoagulant factors, fibrin, and cytokines into Bowman space may contribute to crescent formation. 2. Fibrin strands are frequently prominent between the cellular layers in the crescents. Electron Microscopy show ruptures in the GBM, a severe injury that allows leukocytes, plasma proteins such as coagulation factors and complement, and inflammatory mediators to reach the urinary space,where they trigger crescent formation. Examples of Diseases that exhibit Nephritic Syndrome: Crescentic (Rapidly Progressive) Glomerulonephritis Clinical Features hematuria with red blood cell casts in the urine, moderate proteinuria occasionally reaching the nephrotic range, and variable hypertension and edema. Prognosis 1. Recovery of renal function may follow early intensive plasmapheresis (plasma exchange) combined with steroids and cytotoxic agents in Goodpasture syndrome. This therapy can reverse both pulmonary hemorrhage and renal failure. 2. Despite therapy, many patients eventually require chronic dialysis or transplantation, particularly if the disease is discovered at a late stage Nephrotic Syndrome is caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. Manifestations include: 1. Massive proteinuria, with the daily loss of 3.5 g or more of protein (less in children. 2. Hypoalbuminemia, with plasma albumin levels less than 3 g/dL 3. Generalized edema 4. Hyperlipidemia and lipiduria Pathophysiology: PROTEINURIA; glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the plasma filtrate passes. Increased permeability resulting from either structural or physicochemical alterations in this barrier allows proteins to escape from the plasma into the urinaryspace, resulting in proteinuria. ALBUMINURIA: Heavy proteinuria depletes serum albumin levels at a rate beyond the compensatory synthetic capacity of the liver, resulting in hypoalbuminemia. EDEMA: The generalized edema is a direct consequence of decreased intravascular colloid osmotic pressure. There is also sodium and water retention, which aggravates the edema. HYPERLIPIDEMIA AND LIPIDURIA: The genesis of the hyperlipidemia is due to increased blood levels of cholesterol and lipids as a result from increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased lipid catabolism. Lipiduria follows. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cells and then shed along with injured tubular cells that have detached from the basement membrane. Nephrotic Syndrome Pathogenesis 1. Children: is almost always caused by a lesion primary to the kidney The most important of the primary glomerular lesions are minimal change disease, membranous nephropathy, and FSGS (Focal Segmental Glomerulo Sclerosis). 2. Adults: is often associated with a systemic disease The most frequent systemic causes of the nephrotic syndrome are diabetes, amyloidosis, and SLE. Vulnerability to infection, especially staphylococcal and pneumococcal infections, due to loss of immunoglobulins in the urine. Thrombotic and thromboembolic complications due in part to loss of endogenous anticoagulants (e.g., antithrombin III) in the urine. Renal vein thrombosis, once thought to be a cause of nephrotic syndrome, is most often a consequence of this hypercoagulable state. Examples of Diseases that exhibit Nephrotic Syndrome: Membranous Nephropathy is characterized by diffuse thickening of the glomerular capillary wall due to the accumulation of deposits containing Ig along the subepithelial side of the basement membrane. 75% are primary. Primary (formerly idiopathic) membranous nephropathy is an autoimmune disease caused in most cases by antibodies to a renal autoantigen. M-type phospholipase A2 receptor (PLA2R) is the antigen that underlies 60% to 70% of human membranous nephropathy Secondary membranous nephropathy include: 1. Drugs (penicillamine, captopril, gold, nonsteroidal antiinflammatory drugs [NSAIDs]). 2. Underlying malignant tumors (5-10%), particularly carcinomas of the lung and colon, and melanoma. 3. SLE. About 10% to 15% of glomerulonephritis in SLE is of the membranous type. 4. Infections (chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria) 5. Thyroiditis Examples of Diseases that exhibit Nephrotic Syndrome: Membranous Nephropathy Pathogenesis is a form of chronic immune complex–mediated disease. Antigens may be endogenous or exogenous. Endogenous antigens may be renal or nonrenal. Membranous nephropathy in SLE is associated with deposition of complexes of self nuclear proteins and autoantibodies. Exogenous antigens include those from hepatitis B virus and Treponema pallidum in infected patients. Autoantibody binding to PLA2R, a membrane protein at the basal surface of the glomerular epithelial cell, is followed by complement activation and then shedding of the immune aggregates from the cell surface to form characteristic deposits of immune complexes along the subepithelial aspect of the basement membrane Immunostains reveal PLA2R or THSD7A glomerular positivity How does the glomerular capillary wall become leaky in membranous nephropathy? C5b–C9 Membrane Attack Complex activates glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage. IgG 4 is the principal immunoglobulin deposited in most cases of membranous nephropathy. Examples of Diseases that exhibit Nephrotic Syndrome: Membranous Nephropathy Morphology Light Microscopy: early stages of the disease or exhibit uniform, diffuse thickening of the glomerular capillary wall Electron Microscopy: thickening is caused by irregular electron-dense deposits containing immune complexes between the basement membrane and the overlying epithelial cells, with effacement of podocyte foot processes. Basement membrane material appear as irregular spikes best seen by silver stains, appearing as black Examples of Diseases that exhibit Nephrotic Syndrome: Membranous Nephropathy Clinical Features: insidious onset of the nephrotic syndrome or, in 15% of patients, with nonnephrotic proteinuria. In contrast to minimal change disease the proteinuria is nonselective and usually does not respond well to corticosteroid therapy. Complete or partial remissions may occur in up to 40% of patients, even in some patients without therapy. Progression is associated with increasing sclerosis of glomeruli, rising serum creatinine reflecting renal insufficiency, and development of hypertension. Only about 10% die or progress to renal failure within 10 years PLA2R and THSD7A may be useful biomarkers of disease activity and thereby aid in the diagnosis and management of membranous nephropathy. Examples of Diseases that exhibit Nephrotic Syndrome: Minimal Change Disease Is a benign disorder is characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes), detectable only by electron microscopy, in glomeruli that appear normal by light microscopy. It is the most frequent cause of nephrotic syndrome in children, but it is less common in adults. The peak incidence is between 2 and 6 years of age. The disease sometimes follows a respiratory infection or routine prophylactic immunization. Examples of Diseases that exhibit Nephrotic Syndrome: Minimal Change Disease current leading hypothesis is that minimal change disease involves some immune dysfunction that results in the elaboration of factors that damage visceral epithelial cells and cause proteinuria. There is absence of immune deposits in the glomerulus and excludes immune complex–mediated injury but several points suggest immunologic basis: 1. clinical association with respiratory infections and prophylactic immunization 2. response to corticosteroids other immunosuppressive therapy 3. Association with other atopic disorders (e.g., eczema, rhinitis) 4. increased prevalence of certain HLA haplotypes in case associated with atopy (suggesting a genetic predisposition) 5. increased incidence of minimal change disease in patients with Hodgkin lymphoma, in whom defects in T cell–mediated immunity are well recognized ultrastructural changes point to: 1. Primary visceral epithelial cell injury (podocytopathy) 2. Loss of glomerular polyanions. Examples of Diseases that exhibit Nephrotic Syndrome: Minimal Change Disease Morphology LIGHT MICROSCOPY: glomeruli are normal by light microscopy ELECTRON MICROSCOPY: GBM appears normal, and no electrondense material is deposited. The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes, these being reduced to a rim of cytoplasm with loss of recognizable intervening slit diaphragms (Fig. 20.12B). This change, often incorrectly termed “fusion” of foot processes, actually represents simplification of the epithelial cell architecture with flattening, retraction, and swelling of foot processes. NOTE: Foot process effacement is also present in other proteinuric states ( states (e.g., membranous glomerulopathy, diabetic nephropathy); it is only when effacement is associated with normal glomeruli by light microscopy that the diagnosis of minimal change disease can be made. The cells of the proximal tubules are often laden with lipid and protein, reflecting tubular reabsorption of lipoproteins passing through diseased glomeruli (thus, the historical name lipoid nephrosis for this disease). Immunofluorescence studies show no Ig or complement deposits. Examples of Diseases that exhibit Nephrotic Syndrome: Minimal Change Disease Clinical Features Despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria. The proteinuria usually is highly selective, most of the protein being albumin. A characteristic feature is its usually dramatic response to corticosteroid therapy. Most children (>90%) with minimal change disease respond rapidly to this treatment. However, proteinuria may recur in a significant proportion of patients, and some patients may become steroid-dependent or resistant. Long-term prognosis for patients is excellent, and even steroid-dependent disease usually resolves when children reach puberty. Although adults are slower to respond, their long-term prognosis is also excellent. Minimal change disease in adults can be associated with Hodgkin lymphoma and, less frequently, other lymphomas and leukemias. In addition, secondary minimal change disease may follow NSAID therapy, usually in association with acute interstitial nephritis. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis is the most common cause of nephrotic syndrome in adults in the United States. It is considered to be a primary disorder of podocytes, like minimal change disease. As the name implies, this lesion is characterized by sclerosis of some, but not all, glomeruli (thus, it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus, it is segmental). FSGS is frequently manifest clinically by the acute or subacute onset of nephrotic syndrome or non-nephrotic proteinuria. Hypertension, microscopic hematuria, and some degree of azotemia are commonly present when the disease is first clinically recognized. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis Classification and Types 1. As a primary disease (idiopathic FSGS) 2. In association with other known conditions, such as HIV infection (HIV- associated nephropathy), heroin addiction (heroin nephropathy), sickle cell disease, and morbid obesity 3. As a secondary event, reflecting scarring of previously active necrotizing lesions, in cases of focal glomerulonephritis (e.g., IgA nephropathy) 4. As a component of the adaptive response to loss of renal tissue (renal ablation), whether from congenital anomalies (e.g., unilateral renal agenesis or renal dysplasia) or acquired causes (e.g., reflux nephropathy), in advanced stages of other renal disorders, such as hypertensive nephropathy. 5. In uncommon inherited forms of nephrotic syndrome where the disease may be caused by mutations in gene that encode proteins localized to the slit diaphragm. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis Classification and Types 1. Primary or Idiopathic FSGS 1. accounts for 10% and 35% of cases of nephrotic syndrome in children and adults, respectively. 2. FSGS (both primary and secondary forms) has increased in incidence and is now the most common cause of nephrotic syndrome in adults. 3. clinical signs differ from those of minimal change disease in the following: 1. There is a higher incidence of hematuria reduced GFR, and hypertension 2. Proteinuria is more often nonselective; 3. Poor response to corticosteroid therapy; 4. There is progression to chronic kidney disease, with at least 50% developing ESRD within 10 years 4. ultrastructural hallmark of FSGS is epithelial damage (characteristic degeneration and focal disruption of visceral epithelial cells with effacement of foot processes resemble the diffuse epithelial cell change typical of minimal change disease and other podocytopathies). Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis Classification and Types 1. Primary or Idiopathic FSGS 1. Accounts for 10% and 35% of cases of nephrotic syndrome in children and adults, respectively. 2. FSGS (both primary and secondary forms) has increased in incidence and is now the most common cause of nephrotic syndrome in adults. 3. clinical signs differ from those of minimal change disease in the following: 1. There is a higher incidence of hematuria reduced GFR, and hypertension 2. Proteinuria is more often nonselective; 3. Poor response to corticosteroid therapy; 4. There is progression to chronic kidney disease, with at least 50% developing ESRD within 10 years 4. ultrastructural hallmark of FSGS is epithelial damage (characteristic degeneration and focal disruption of visceral epithelial cells with effacement of foot processes resemble the diffuse epithelial cell change typical of minimal change disease and other podocytopathies). Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis Classification and Types 1. Primary or Idiopathic FSGS 1. Inherited forms of FSGS may be associated with the following: 1. The first relevant gene to be identified, NPHS1, maps to chromosome 19q13 and encodes the protein nephrin. 1. Nephrin is a key component of the slit diaphragm, the structure that controls glomerular permeability. Several mutations of the NPHS gene have been identified that give rise to congenital nephrotic syndrome of the Finnish type, producing a minimal change disease–like glomerulopathy with extensive foot process effacement. 2. A distinctive pattern of autosomal recessive FSGS results from mutations in the NPHS2 gene, which maps to chromosome 1q25–q31 and encodes the protein product podocin. Podocin has also been localized to the slit diaphragm. Mutations in NPHS2 result in a syndrome of steroid-resistant nephrotic syndrome of childhood onset. 3. Mutations in the gene encoding the podocyte actin-binding protein α-actinin 4 underlie some cases of autosomal dominant FSGS, which can be insidious in onset but has a high rate of progression to renal insufficiency. 4. Mutations in the gene encoding TRPC6. Pathogenic mutations may perturb podocyte function by increasing calcium flux in these cells. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis Classification and Types 2. Renal Ablation FSGS secondary form of FSGS, occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue. occurs are reflux nephropathy and unilateral agenesis. These may lead to progressive glomerulosclerosis and renal failure. The glomerulosclerosis seems to be initiated by the adaptive change that occurs in the relatively unaffected glomeruli of diseased kidneys. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis MORPHOLOGY: LIGHT MICROSCOPY: focal and segmental lesions may involve only a minority of the glomeruli In the sclerotic segments, there is collapse of capillary loops, increase in matrix, and segmental deposition of plasma proteins along the capillary wall (hyalinosis), which may become so pronounced as to occlude capillary lumens. Lipid droplets and foam cells are often present. Glomeruli that do not show segmental lesions usually appear normal on light microscopy but may show increased mesangial matrix. On electron microscopy, both sclerotic and nonsclerotic areas show diffuse effacement of foot processes, and there may also be focal detachment of the epithelial cells and denudation of the underlying GBM. On immunofluorescence microscopy, IgM and C3 may be present inN the sclerotic areas and/or in the mesangium. Collapsing glomerulopathy, is characterized by retraction and/or collapse of the entire glomerular tuft, with or without additional FSGS lesions. A characteristic feature is proliferation and hypertrophy of glomerular visceral epithelial cells. it is the most characteristic lesion of HIV-associated nephropathy. is typically associated with prominent tubular injury with formation of microcysts and prominent interstitial inflammation. It has a particularly poor prognosis. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis PROGNOSIS little tendency for spontaneous remission in idiopathic FSGS, and responses to corticosteroid therapy are variable. In general, children have a better prognosis than adults do. About 20% of patients follow an unusually rapid course, with intractable massive proteinuria ending in renal failure within 2 years. Factors associated with rapid progression include the degree of proteinuria, the degree of renal insufficiency at diagnosis, and histologic subtype (the collapsing variant has an unfavorable course; the tip variant has a relatively good prognosis). Recurrences are seen in 25% to 50% of patients receiving allografts. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis 3. HIV-Associated Nephropathy 1. Directly or indirectly cause several renal complications, including acute renal failure or acute interstitial nephritis induced by drugs or infection, thrombotic microangiopathies, postinfectious glomerulonephritis, and, most commonly, a severe form of the collapsing variant of FSGS, termed HIV-associated nephropathy. 1. reported in 5% to 10% of HIV-infected individuals 2. Morphologic features of HIV-associated nephropathy are: 1. A high frequency of the collapsing variant of FSGS. 2. A striking focal cystic dilation of tubule segments, which are filled with proteinaceous material, and inflammation and fibrosis. 3. The presence of large numbers of tubuloreticular inclusions within endothelial cells, detected by electron microscopy. Such inclusions, also present in SLE, have been shown to be modifications of endoplasmic reticulum induced by circulating interferon-α. 3. Pathogenesis of HIV-associated FSGS is unclear, but may be primarily due to the presence of the G1/G2 risk alleles for APOL1. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis 4. Membranoproliferative Glomerulonephritis (MPGN) MPGN is best considered a pattern of immune-mediated injury rather than a specific disease. MPGN accounts for up to 10% of cases of nephrotic syndrome in children and young adults. 2 Groups: 1. Type I- characterized by deposition of immune complexes containing IgG and complement. 1. Has Subendothelial electron Dense Deposits 2. Type II, (now called Dense Deposit Disease) in which activation of complement appears to be the most important factor. The latter belong to a group of disorders called C3 glomerulopathies. Some patients present only with hematuria or proteinuria in the nonnephrotic range, but many others have a combined nephroticnephritic picture. Pathogenesis: Antigens are unknown… believed to be proteins derived from infectious agents such as hepatitis C and B viruses, which presumably behave either as “planted” after first binding or being trapped. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis 4. Membranoproliferative Glomerulonephritis (MPGN) Clinical Features Most patients with primary MPGN present in adolescence or as young adults with nephrotic syndrome and a nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not proven to be of any benefit About 50% develop chronic renal failure within 10 years. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis 4. Membranoproliferative Glomerulonephritis (MPGN) MORPHOLOGY: 1. Glomeruli are large and hypercellular. 1. The hypercellularity is produced both by proliferation of cells in the mesangium and so-called endocapillary proliferation involving capillary endothelium and infiltrating leukocytes. 2. The glomeruli have an accentuated “lobular” appearance due to the proliferating mesangial cells and increased mesangial matrix. 2. Basement Membrane GBM is thickened, and often shows a “double- contour” or “tramtrack” appearance, especially evident in silver or PAS stains. 1. This is caused by “duplication” of the basement membrane (also commonly referred to as splitting), usually as the result of new basement membrane synthesis in response to subendothelial deposits of immune complexes. 2. Between the duplicated basement membranes, there is inclusion or interposition of cellular elements, which can be of mesangial, endothelial, or leukocytic origin. Such interposition also gives rise to the appearance of “split” basement membranes Crescents are present in many cases. Examples of Diseases that exhibit Nephrotic Syndrome: Focal Segmental Glomerulosclerosis 1. Secondary Membranoproliferative Glomerulonephritis (invariably type I) 1. is more common in adults and arises in the following settings: 1. Chronic immune complex disorders, such as SLE; 2. hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; 3. endocarditis; infected ventriculoatrial shunts; 4. chronic visceral abscesses; 5. HIV infection; and schistosomiasis 6. α1-Antitrypsin deficiency 7. Malignant diseases, particularly lymphoid tumors such as chronic lymphocytic leukemia, which are commonly complicated by development of autoantibodies. 2. Dense Deposit Disease 1. Most patients with dense-deposit disease (formerly called type II MPGN) have abnormalities resulting in excessive activation of the alternative complement pathway. 2. Consistently decreased serum C3 but normal C1 and C4, the early components of complement. 3. They also have diminished serum levels of Factor B and properdin, components of the alternative complement pathway. The glomeruli contain deposits of C3 and properdin but not IgG. 4. The precise nature of the dense deposits is unknown. Mutations in components of the alternate pathway such as Factor H have also been associated with dense deposit disease 5. Morphology: defining feature is revealed by election microscopy, which demonstrates permeation of the lamina densa of the GBM by a ribbonlike, homogeneous, extremely electron dense material of unknown composition 6. By immunofluorescence, C3 is present in irregular granular or linear foci in the basement membranes on either side but not within the dense deposits. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent. 7. Prognosis is poor, with over one-half of patients progressing to ESRD. There is a high incidence of recurrence in transplant recipients; dense deposits recur in 90% of such patients Examples of Diseases that exhibit Nephrotic Syndrome: Fibrillary Glomerulonephritis rare disease characterized by fibrillary deposits in the mesangium and glomerular capillary walls that resemble amyloid fibrils superficially but differ ultrastructurally and do not stain with Congo red. The pathogenesis is unknown, but DNAJB9, a co-chaperone for heat shock protein 70s, recently has been identified as a highly sensitive and specific marker for fibrillary GN. glomerular lesions usually show mesangioproliferative or membranoproliferative patterns by light microscopy. By immunofluorescence microscopy, there is selective deposition of polyclonal IgG, often of the IgG4 subclass, complement C3, and Igκ and Igλ light chains. Clinically, patients develop nephrotic syndrome, hematuria, and progressive renal insufficiency. Prognosis: Recurs in kidney transplants. Other Glomerular Diseases: IgA Nephropathy (Berger Disease) characterized by the presence of prominent IgA deposits in the mesangial regions and recurrent hematuria. is the most common type of glomerulonephritis worldwide. can be suspected by light microscopic examination, but the diagnosis is made only by the detection of glomerular IgA deposition. Mild proteinuria is usually present, and the nephrotic syndrome may occasionally develop. Rarely, patients may present with crescentic GN. IgA nephropathy is typically an isolated renal disease, similar IgA deposits are present in Henoch-Schönlein purpura, which has many overlapping features with IgAnephropathy. In addition, secondary IgA nephropathy occursin patients with liver and intestinal diseases. Pathogenesis: “multi-hit” etiology for this disorder involving several steps. levels of plasma polymeric IgA are increased, but increased production is not sufficient to cause this disease. A clue comes from the observation that in IgA nephropathy, the glomerular deposits consist predominantly of polymeric IgA molecules with aberrant glycosylation.. This aberrantly glycosylated IgA is either deposited by itself in glomeruli, or it elicits anautoimmune response and forms immune complexes in the circulation with IgG autoantibodies directed against the abnormal IgA molecules. The deposited IgA and IgA-containing immune complexes activate the complement system via the alternate pathway, and hence the presence of C3 and the absence of C1q and C4 in glomeruli are typical of this disorder. increased synthesis of abnormal IgA may occur in response to respiratory or gastrointestinal exposure to environmental agents (e.g., viruses, bacteria, food proteins). The specific initiating antigens are unknown. Other Glomerular Diseases: IgA Nephropathy (Berger Disease) MORPHOLOGY characteristic immunofluorescent picture is of mesangial deposition of IgA often with C3 and properdin and lesser amounts of IgG or IgM. Electron microscopy confirms the presence of electron-dense deposits predominantly in the mesangium. Glomeruli may be normal or may show mesangial widening and endocapillary proliferation (mesangioproliferative glomerulonephritis) Clinical Features most commonly older children and young adults present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract; 30% to 40% haveonly microscopic hematuria, with or without proteinuria, 10% with RPGN. Prognosis Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years. Recurrence of IgA deposits in transplanted kidneys is frequent Other Glomerular Diseases: Hereditary Nephritis Hereditary nephritis refers to a group of heterogeneous familial renal diseases associated with mutations in collagen genes that manifest primarily with glomerular injury. Two deserve discussion: 1. Alport syndrome, because the lesions and genetic defects have been well studied 2. Thin basement membrane nephropathy, the most common cause of benign familial hematuria. Other Glomerular Diseases: Hereditary Nephritis, Alport Syndrome Alport syndrome is caused by mutations affecting type IV collagen that result in hematuria with progression to chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy. X-linked trait in approximately 85% of cases. males express the full syndrome, while female heterozygotes typically present with hematuria. Approximately 90% of affected males progress to ESRD before 40 years of age. recessive and autosomal dominant pedigrees also exist, in which males and females are equally susceptible to the full syndrome Pathogenesis: mutations in the collagen IV moleculewhich interfere with assembly of type IV collagen, which is crucial for function of the GBM, the lens of the eye, and the cochlea. large deletions in the collagen IV α5 chain (COL4A5) are associated with ESRD at an earlier age. Other Glomerular Diseases: Hereditary Nephritis, Alport Syndrome MORPHOLOGY irregular foci of thickening alternating with attenuation (thinning), and pronounced splitting and lamination of the lamina densa, often producing a distinctive basket-weave appearance. antibodies to α3, α4, and α5 collagen fail to stain both glomerular and tubular basement membranes in the classic X-linked form. There is also absence of α5 staining in skin biopsy specimens from these patients. Clinical Features most common presenting sign is gross or microscopic hematuria, frequently accompanied by red cell casts. Symptoms appear at 5 to 20 years of age, and the onset of overt renal failure is between 20 and 50 years of age in men. The auditory defects may be subtle, requiring sensitive testing. Other Glomerular Diseases: Hereditary Nephritis, Thin Basement Membrane Nephropathy (Benign Familial Hematuria) fairly common hereditary entity manifested clinically by familial asymptomatic hematuria—usually uncovered on routine urinalysis—and morphologically by diffuse thinning of the GBM to widths between 150 and 225 nm (compared with 300 to 400 nm in healthy adults). Although mild or moderate proteinuria may also be present, renal function is normal and prognosis is excellent. The abnormality is estimated to affect 1% of the general population. In contrast to Alport syndrome, hearing loss, ocular abnormalities, and a family history of renal failure are absent. PATHOGENESIS: mutations in genes encoding α3 orα4 chains of type IV collagen Glomerular Lesions Associated With Systemic Diseases Lupus Nephritis Clinical manifestations can include recurrent microscopic or gross hematuria, nephritic syndrome, RPGN, nephrotic syndrome, acute and chronic renal failure, and hypertension. Glomerular Lesions Associated With Systemic Diseases Henoch-Schönlein Purpura This childhood syndrome consists of purpuric skin lesions, abdominal pain and intestinal bleeding, and arthralgias along with renal abnormalities. Not all components of the syndrome need to be present for the diagnosis Characteristically involve the extensor surfaces of arms and legs as well as buttocks; Disease is most common in children 3 to 8 years of age, In adults, renal manifestations are usually more severe. Strong background of atopy in about one-third of patients, and onset often follows an upper respiratory infection. IgA nephropathy and Henoch- Schönlein purpura are manifestations of the same disease. Morphology: pathognomonic feature by fluorescence microscopy is the deposition of IgA, sometimes with IgG and C3, in the mesangial region Skin lesions consist of subepidermal hemorrhages and a necrotizing vasculitis involving the small vessels of the dermis. Deposits of IgA, along with IgG and C3, are also present in such vessels. Prognosis: is variable, but recurrences of hematuria may persist. Most children have an excellent prognosis. Patients with the more diffuse lesions, crescents, or the nephrotic syndrome have a somewhat poorer prognosis. Glomerular Lesions Associated With Systemic Diseases Essential mixed cryoglobulinemia is another systemic condition in which deposits of cryoglobulins composed principally of IgG-IgM complexes induce cutaneous vasculitis, synovitis, and a proliferative glomerulonephritis, typically MPGN. Most cases of essential mixed cryoglobulinemia have been associated with infection with hepatitis C virus, and this condition in particular is associated with glomerulonephritis, usually MPGN type I. TUBULAR AND INTERSTITIAL DISEASES Most forms of tubular injury involve the interstitium as well; therefore, diseases affecting these two components are discussed together. Under this heading, we consider two major processes: 1. Ischemic or toxic tubular injury, 2. Inflammation of the tubules and interstitium (tubulointerstitial nephritis) TUBULAR AND INTERSTITIAL DISEASES, Acute Tubular Injury/Necrosis ATI is characterized by acute renal failure and often, but not invariably, morphologic evidence of tubular injury, in the form of necrosis of tubular epithelial cells. Because necrosis is often not present, the term ATI is preferred by pathologists over the older name acute tubular necrosis (ATN). It is the most common cause of acute kidney injury. ATI can be caused by a variety of conditions, including the following: 1. Ischemia, due to decreased or interrupted blood flow (ischemic ATI). Examples include diffuse involvement of the intrarenal blood vessels such [HUS] or thrombotic thrombocytopenic purpura [TTP]), or decreased effective circulating blood volume, as occurs in hypovolemic shock like in trauma or hypotension. 2. Direct toxic injury to the tubules (nephrotoxic ATI). This may be caused by endogenous agents, e.g., myoglobin, hemoglobindrugs, radiocontrast dyes, heavy metals, organic solvents. drugs, radiocontrast dyes, heavy metals, organic solvents. ATI is a reversible process. TUBULAR AND INTERSTITIAL DISEASES, Acute Tubular Injury/Necrosis Pathogenesis: The critical events in both ischemic and nephrotoxic ATI are (1) tubular injury and (2) persistent and severe disturbances in blood flow. 1. Tubular cell injury: Tubular epithelial cells, especially those of proximal tubules, are particularly sensitive to ischemia and are also vulnerable to toxins. One early reversible result of ischemia is loss of cell polarity due to redistribution of membrane proteins. resulting in abnormal ion transport across the cells and increased sodium delivery to distal tubules, which incites vasoconstriction via tubuloglomerular feedback. Injury expresses cytokines and adhesion molecules, thus recruiting leukocytes that appear to participate in the subsequent injury. Leukocytes that appear to participate in the subsequent injury. In time, injured cells detach from the basement membranes and cause luminal obstruction, increased intratubular pressure, and further decrease in GFR glomerular filtrate in the lumen of the damaged tubules can leak back into the interstitium, resulting in interstitial edema. TUBULAR AND INTERSTITIAL DISEASES, Acute Tubular Injury/Necrosis Pathogenesis: 2. Disturbances in blood flow: hemodynamic alterations that cause reduced GFR. major one is intrarenal vasoconstriction, which results in both reduced glomerular blood flow and reduced oxygen delivery to the functionally important tubules in the outer medulla. Decreased blood pressure leads to increased release of the vasoconstrictor endothelin and decreased production of the vasodilators nitric oxide and prostacyclin (prostaglandin I2). TUBULAR AND INTERSTITIAL DISEASES, Acute Tubular Injury/Necrosis Morphology ATI is characterized by tubular epithelial injury at multiple points along the nephron, with large skip areas in between, often accompanied by rupture of basement membranes (tubulorrhexis) and occlusion of tubular lumens by casts Other findings in ischemic ATI are interstitial edema and accumulations of leukocytes within dilated vasa recta. There is also evidence of epithelial regeneration in the form of flattened epithelial cells with hyperchromatic nuclei and mitotic figures. In time, this regeneration repopulates the tubules so that no residual evidence of damage is seen. Toxic ATI is manifested by ATI, most obvious in the proximal convoluted tubules. TUBULAR AND INTERSTITIAL DISEASES, Acute Tubular Injury/Necrosis Clinical Features 1. Initiation phase, lasting about 36 hours, is dominated b the inciting medical, surgical, or obstetric event. The only indication of renal involvement is a slight decline in urin output with a rise in BUN. At this point, oliguria could be explained by a transient decrease in blood flow and declining GFR. 2. Maintenance phase is characterized by sustained decreases in urine output to between 40 and 400 mL/day (oliguria), salt and water overload, rising BUN concentrations, hyperkalemia, metabolic acidosis, and other manifestations of uremia. With appropriate management, the patient can overcome this oliguric crisis. 3. Recovery phase is ushered in by a steady increase in urine volume that may reach up to 3 L/day. The tubules are still damaged, so large amounts of water, sodium, and potassium are lost in the flood of urine. Hypokalemia, rather than hyperkalemia, becomes a clinical problem. There is a peculiar increased vulnerability to infection at this stage. Eventually, renal tubular function is restored and concentrating ability improves. At the same time, BUN and creatinine levels begin to return to normal. Subtle tubular functional impairment may persist for months, but most patients who reach this phase eventually recover completely. TUBULAR AND INTERSTITIAL DISEASES, Acute Tubular Injury/Necrosis Prognosis The prognosis of ATI depends on the magnitude and duration of injury. 1. NEPHROTOXIC ATI: Recovery is expected with nephrotoxic ATI when the toxin has not caused serious damage to other organs, such as the liver or heart. With supportive care 95% of those who do not succumb to the precipitating cause recover. 2. SEPSIS/MULTIORGAN FAILURE: Conversely, in shock related to sepsis, extensive burns, or other causes of multiorgan failure, the mortality rate can exceed 50%.  TUBULAR AND INTERSTITIAL DISEASES, Tubulointerstitial Nephritis involves inflammatory injuries of the tubules and interstitium that are often insidious onset and are principally manifest by azotemia. 2 Categories 1. Acute tubulointerstitial nephritis rapid clinical onset, interstitial edema, leukocytic infiltration of the interstitium and tubules, and tubular injury. 2. Chronic tubulointerstitial nephritis Infiltration with predominantly mononuclear leukocytes, prominent interstitial fibrosis, and widespread tubular atrophy. Tubulointerstitial disorders are distinguished clinically from the glomerular diseases by the following hallmarks: 1. Absence of nephritic or nephrotic syndrome 2. Presence of defects in tubular function 1. maybe subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or nocturia; 2. salt wasting; diminished ability to excrete acids (metabolic acidosis) 3. and isolated defects in tubular reabsorption or secretion. Advanced forms, however, may be difficult to distinguish clinically from other causes of renal insufficiency. Pyelonephritis and Urinary Tract Infection Pyelonephritis is one of the most common diseases of the kidney and is defined as inflammation affecting the tubules, interstitium, and renal pelvis. 2 forms: 1. Acute pyelonephritis is generally caused by bacterial infection and is associated with urinary tract infection. 2. Chronic pyelonephritis is a more complex disorder; bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) predispose to repeat episodes of acute pyelonephritis. Pyelonephritis is a serious complication of urinary tract infections that affect the bladder (cystitis), the kidneys and their collecting systems (pyelonephritis), or both. Pyelonephritis Pathogenesis More than 85% of urinary tract infections are caused by the gram-negative bacilli that are normal inhabitants of the intestinal tract. most common is Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter Immunocompromised persons, fungal, and particularly those with transplanted organs, viruses such as polyomavirus commonly in allografts, cytomegalovirus, and adenovirus. two routes by which bacteria can reach the kidneys: 1. through the bloodstream (hematogenous infection)- less common 2. from the lower urinary tract (ascending infection)- most common Pyelonephritis Pathogenesis of Ascending Pyelonephritis 1. The first step is colonization of the distal urethra and introitus (in the female) by coliform bacteria. 1. (adhesins) on the P-fimbriae (pili) of bacteria that interact with receptors on the surface of urothelial cells 2. From the urethra to the bladder 1. organisms gain entrance during urethral catheterization or other instrumentation. 2. In the absence of instrumentation, urinary infections are much more common in females due to: 1. shorter urethra in females 2. absence of antibacterial properties in prostatic fluid 3. hormonal changes affecting bacterial adherence to the mucosa 4. urethral trauma during sexual intercourse 3. From the bladder to the kidneys: 1. Urinary tract obstruction and stasis of urine. 1. outflow obstruction or bladder dysfunction results in incomplete emptying and residual urine. In the presence of stasis, bacteria introduced into the bladder can multiply unhindered. (Seen in Prostate Problems, tumours, neurogenic bladder caused by diabetes or spinal injury) 2. Vesicoureteral reflux. 1. Incompetence of the vesicoureteral valve allows bacteria to ascend theureter into the renal pelvis. 3. Intrarenal reflux. 1. propel infected bladder urine up to the renal pelvis and deep into the renal parenchyma through open ducts at the tips of the papillae (intrarenal reflux). 2. most common in the upper and lower poles of the kidney, where papillae tend to have flattened or concave tips rather than the convex Acute Pyelonephritis is a suppurative inflammation of the kidney caused by bacterial and sometimes viral (e.g., polyomavirus) infection. Morphology: patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, neutrophilic tubulitis, and tubular injury. Characteristically, glomeruli are relatively resistant to the infection. Extensive disease, however, eventually also destroys the glomeruli, and fungal pyelonephritis (e.g., Candida) often results in granulomatous interstitial inflammation. 3 complications of Pyelonephritis 1. Papillary necrosis is seen mainly in diabetics, sickle cell disease, and in those with urinary tract obstruction. Papillary necrosis is usually. 2. Pyonephrosis is seen when there is total or almost complete obstruction. The suppurative exudate is unable to drain and fills the renal pelvis, calyces, and ureter with pus. 3. Perinephric abscess is an extension of suppurative inflammation through the renal capsule into the perinephric tissue. Acute Pyelonephritis Clinical Features 1. Sudden onset of pain at the costovertebral angle 2. systemic evidence of infection, such as fever and malaise. 3. indications of bladder and urethral irritation, such as dysuria, frequency, and urgency. 4. The urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate, but pyuria does not differentiate upper from lower urinary tract infection. 5. The finding of leukocyte casts, typically rich in neutrophils (pus casts), indicates renal involvement, because casts are formed only in tubules. 6. The diagnosis of infection is established by quantitative urine culture Uncomplicated acute pyelonephritis follows a benign course, and symptoms disappear within a few days after the institution of appropriate antibiotic therapy Chronic pyelonephritis disorder in which chronic tubulointerstitial inflammation and scarring involve the calyces and pelvis. Note: only (1) chronic pyelonephritis and (2) analgesic nephropathy affect the calyces, making pelvocalyceal damage an important diagnostic clue. Morphology: Irregularly SCARRED Kidneys In pyelonephritis kidneys usually are irregularly scarred; if bilateral, the involvement is asymmetric. In contrast, both kidneys in chronic glomerulonephritis 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 vary from one to several, and most are in the upper and lower poles, consistent with the frequency of reflux in these sites. Chronic pyelonephritis Nephropathy Associated With NSAIDs Many NSAIDs are nonselective cyclo-oxygenase inhibitors, and their adverse renal effects are related to their ability to inhibit cyclooxygenase– dependent prostaglandin synthesis. The selective COX-2 inhibitors, while sparing the gastrointestinal tract, do affect the kidneys because COX-2 is expressed in human kidneys. NSAID-associated renal syndromes include the following: 1. Acute kidney injury, due to the decreased synthesis of vasodilatory prostaglandins and resultant ischemia. 2. Acute hypersensitivity interstitial nephritis, resulting in renal failure. 3. Acute interstitial nephritis and minimal change disease suggests a hypersensitivity reaction affecting the interstitium and possibly the glomeruli, but also is consistent with injury to podocytes mediated by cytokines 4. Membranous nephropathy, with the nephrotic syndrome, is a recently appreciated association, also of unclear pathogenesis. Urate Nephropathy Three types of nephropathy: 1. Acute uric acid nephropathy is caused by the precipitation of uric acid crystals in the renal tubules, principally in collecting ducts, leading to obstruction of nephrons and the development of acute renal failure. 1. individuals with leukemias or lymphomas who are undergoing chemotherapy (tumor lysis syndrome); the drugs kill tumor cells, and uric acid is produced as released nucleic acids are broken down. Precipitation of uric acid is favored by the acidic pH in collecting tubules. 2. Chronic urate nephropathy, or gouty nephropathy occurs rarely in protracted forms of hyperuricemia. The monosodium urate crystals deposit in the acidic distal tubules and collecting ducts, and form distinct birefringent needlelike crystals. 3. Nephrolithiasis: uric acid stones are present in 22% of individuals with gout and 42% of those with secondary hyperuricemia. Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) Previously known as medullary cystic kidney disease. now recognized as ADTKD due to following genetic mutations: 1. MUC1 encodes mucin-1 (expressed in distal nephrons) 2. UMOD encodes uromodulin (expressed in thick ascending limb of loop of Henle) 3. REN encodes preprorenin (expressed by juxtaglomerular apparatus) 4. HNF1β encodes hepatocyte nuclear factor 1β, a transcription factor that regulates multiple genes, including UMOD nonspecific clinical and pathologic findings and causes progressive renal failure in adult life pathogenic mechanisms are unknown Light-Chain Cast Nephropathy (“Myeloma Kidney”) Overt renal insufficiency occurs in half of those with multiple myeloma The most common involvements are tubulointerstitial, caused by complications of the tumor (hypercalcemia, ureteral obstruction) or therapy (irradiation, hyperuricemia, chemotherapy, hematopoietic cell transplantation, infections in immunosuppressed patients. Several factors contribute to renal damage: 1. Bence-Jones proteinuria and cast nephropathy. The main cause of renal dysfunction is related to Bence-Jones (light- chain) proteinuria and correlates with the degree of proteinuria. 2. Amyloidosis of AL type, formed from free light chains (usually of λ type), occurs in 6% to 24% of individuals with myeloma. 3. Light-chain deposition disease. In some patients, light chains (usually of κ type) deposit in GBMs and mesangium in nonfibrillar forms, causing a glomerulopathy (described earlier), and in tubular basement membranes, which may cause tubulointerstitial nephritis. 4. Hypercalcemia and hyperuricemia are often present in these patients. Morphology tubulointerstitial changes in light-chain cast nephropathy are characteristic. Bence-Jones tubular casts appear as pink to blue amorphous masses, sometimes concentrically laminated and often fractured, which fill and distend the tubular lumens Clinical Features/Prognosis most common form, chronic kidney disease develops insidiously and progresses slowly. Bence-Jones proteinuria occurs in 70% of individuals with multiple myeloma Bile Cast Nephropathy Impairment of renal function often occurs in patients with severe acute or advanced chronic liver disease. serum bilirubin levels can be markedly elevated, particularly in jaundiced patients, with bile cast formation (also known as cholemic nephrosis) in distal nephron segments. Casts can extend to proximal tubules, resulting in both 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 associated with sclerosis of renal arterioles and small arteries; it is strongly associated with hypertension, which can be both a cause and a consequence of nephrosclerosis. Pathogenesis: 1. Medial and intimal thickening, a response to hemodynamic changes, aging, genetic defects, or some combination. 2. Hyalinization of arteriolar walls, caused by extravasation of plasma proteins through injured endothelium and by increased deposition of basement membrane matrix. Because of thickened walls, the affected vessels have narrowed lumens, which results in focal parenchymal ischemia. Ischemia leads to glomerulosclerosis and chronic tubulointerstitial injury, and it produces a reduction in functional renal mass Morphology: Kidneys are normal or moderately reduced in size due to cortical scarring and shrinking. Microscopy: narrowing of the lumens of arterioles and small arteries, caused by thickening and hyalinization of the walls (hyaline arteriolosclerosis) Other findings: Fibroelastic hyperplasia consisting of medial hypertrophy, replication of the internal elastic lamina, and increased myofibroblastic tissue in the intima, all of which narrow the lumen. glomerulosclerosis (both global and segmental), which can subsequently cause interstitial fibrosis and tubular atrophy. Vascular Diseases of Kidneys, Renal Artery Stenosis Unilateral renal artery stenosis is responsible for 2% to 5% of hypertension cases, and it is important to recognize because it is potentially curable by surgery. Pathogenesis: Hypertension secondary to renal artery stenosis is caused by increased production of renin from the ischemic kidney by the juxtaglomerular apparatus and the subsequent production of the vasoconstrictor angiotensin II. Other factors: sodium retention Morphology: 1. Most common cause of renal artery stenosis (70% of cases) is narrowing at the origin of the renal artery by an atheromatous plaque (more common in men at older age and those with diabetes). 2. Second most frequent cause of stenosis is fibromuscular dysplasia (more common in women at younger age)of the renal artery. This heterogeneous entity is characterized by fibrous or fibromuscular thickening that may involve the intima, the media, or the adventitia of the artery. 3. Ischemic kidney is reduced in size and shows signs of diffuse ischemic atrophy, with crowded glomeruli, atrophic tubules. Prognosis: cure rate after surgery is 70% to80% in well-selected cases. Vascular Diseases of Kidneys, Renal Artery Stenosis Vascular Diseases of Kidneys, Thrombotic Microangiopathies Thrombotic microangiopathy encompasses a spectrum of clinical syndromes that include thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome(HUS). HUS and TTP are caused by diverse insults that lead to thrombi in capillaries and/ or arterioles in various tissue beds, including those of the kidney. thrombi create flow abnormalities that shear red cells, producing a microangiopathic hemolytic anemia. Of greater importance, the thrombi produce microvascular occlusions that cause tissue ischemia and organ dysfunction. Widespread “consumption” of platelets leads to thrombocytopenia. Vascular Diseases of Kidneys, Thrombotic Microangiopathies 1. Typical HUS (synonyms: epidemic, classic, diarrhea- positive) most frequently associated with consumption of food contaminated by bacteria producing Shiga-like toxins. 2. Atypical HUS (synonyms: non-epidemic, diarrhea- negative) is associated with the following Inherited mutations of or autoantibodies targeting complement- regulatory proteins, Diverse acquired causes of endothelial injury, including: antiphospholipid antibodies; complications of pregnancy and oral contraceptives; vascular renal diseases such as scleroderma and malignant hypertension; chemotherapeutic and immunosuppressive drugs; and radiation. 3. TTP is characterized by inherited or acquired deficiencies of ADAMTS13, a plasma metalloprotease that regulates the function of von Willebrand factor (vWF). Vascular Diseases of Kidneys, Thrombotic Microangiopathies Pathogenesis: 1. Endothelial injury appears to be the primary cause of HUS For typical HUS, the trigger for endothelial injury and activation is usually a Shiga-like toxin (epidemic- ground beef hamburgers, water, milk) E coli strain O157:H7 For inherited atypical HUS, the trigger is excessive, inappropriate activation of complement 2. Excessive platelet activation is the inciting event in TTP platelet aggregation induced by very large multimers of vWF, which accumulate due to a deficiency of ADAMTS13, a plasma protease that cleaves vWF multimers into smaller sizes. Deficiency is caused by autoantibodies that inhibit ADAMTS13 function. Vascular Diseases of Kidneys, Sickle Cell Nephropathy most common abnormalities are hematuria and a diminished concentrating ability (hyposthenuria). due to accelerated sickling in the hypertonic hypoxic milieu of the renal medulla; the hyperosmolarity dehydrates red cells and increases intracellular sickle hemoglobin (HbS) concentrations, which likely explains why even those with sickle cell trait are affected. Patchy papillary necrosis may occur in both homozygotes and heterozygotes; this is sometimes associated with cortical scarring. Proteinuria is also common in sickle cell disease. Vascular Diseases of Kidneys, Renal Infarcts common sites for the development of infarcts due to the extensive blood flow to the kidneys (one-fourth of the cardiac output) but probably more important is the limited collateral circulation from extrarenal sites. most infarcts are due to embolism. major source of such emboli is mural thrombosis in the left atrium and ventricle as a result of myocardial infarction. Morphology: most renal infarcts are of the “white” anemic ringed by a zone of intense hyperemia. Vascular Diseases of Kidneys, Renal Infarcts common sites for the development of infarcts due to the extensive blood flow to the kidneys (one-fourth of the cardiac output) but probably more important is the limited collateral circulation from extrarenal sites. most infarcts are due to embolism. major source of such emboli is mural thrombosis in the left atrium and ventricle as a result of myocardial infarction. Morphology: most renal infarcts are of the “white” anemic ringed by a zone of intense hyperemia. infarcts are wedge-shaped. In time, undergo progressive fibrous scarring, giving rise to depressed, pale, gray-white scars that assume a V-shape on section. CONGENITAL AND DEVELOPMENTAL ANOMALIES OF KIDNEYS 10% of people are born with significant malformations of the urinary system. Renal dysplasias and hypoplasias account for 20% of chronic kiDney disease. 1. Agenesis of the Kidney Bilateral agenesis is incompatible with life seen in stillborn infants. Unilateral agenesis is uncommon and compatible with normal life. The solitary kidney enlarges as a result of compensatory hypertrophy. Some eventually develop progressive glomerular sclerosis due to adaptive changes in hypertrophied nephrons. CKD ensues. 2. Hypoplasia of Kidney refers to failure of the kidneys to develop to a normal size. This anomaly may occur bilaterally, resulting in renal failure in early childhood, but it is more commonly encountered as a unilateral defect. truly hypoplastic kidney shows no scars and has a reduced number of renal lobes and pyramids, usually six or fewer. 3. Ectopic Kidneys kidneys lie either just above the pelvic brim or sometimes within the pelvis. normal or slightly small in size but otherwise are not remarkable. Because of their abnormal position, kinking or tortuosity of the ureters may cause obstruction to urinary flow, which predisposes to bacterial infections. 4. Horseshoe Kidneys Fusion of the upper (10%) or lower poles (90%) of the kidneys produces a horseshoe-shaped structure that is continuous across the midline anterior to the great vessels. This anomaly is found in 1 in 500 to 1000 autopsies. CYSTIC DISEASES OF THE KIDNEY, Autosomal Dominant (Adult) Polycystic Kidney Disease (ADPKD) Autosomal dominant (adult) polycystic kidney disease is a hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure. disease is bilateral; reported unilateral cases probably represent multicystic dysplasia. The cysts initially involve a minority of the nephrons, so renal function is retained until about the fourth or fifth decade of life. Genetics and Pathogenesis 1. PKD1 gene-PKD1 account for about 85% of cases. Has polycystin 1 with domains that are usually involved in cell-cell and cell-matrix interactions In individuals with these mutations, the likelihood of developing renal failure is less than 5% by 40 years of age to 95% at 70s. (more severe) 2. PKD2 gene accounts for most of the remaining cases of polycystic disease. Has Polycystin-2 functions as a Ca2+-permeable cation channel. Less severe than PKD1, 45% renal failure at 70s. 40% have cysts in the liver (polycystic liver disease) that are usually asymptomatic Mitral valve prolapse and other cardiac valvular anomalies occur in 20% to 25% of patients, but most are asymptomatic. 40% of adult patients die of coronary or hypertensive heart disease, 25% of infection, 15% of a ruptured berry aneurysm. Cystic Diseases of the Renal Medulla, Medullary Sponge Kidney restricted to multiple cystic dilations of the collecting ducts in the medulla. occurs in adults and is usually discovered radiographically. Renal function is usually normal. Cortical scarring is absent. The pathogenesis is unknown. Cystic Diseases of the Renal Medulla, Nephronophthisis is now the most common genetic cause of ESRD in children and young adults. Most common form is familial. Group of progressive renal disorders is characterized by variable number of cysts in the medulla, usually concentrated at the corticomedullary junction. Initial injury involves the distal tubules with tubular basement membrane disruption eventually cortical tubulointerstitial damage is the cause of the eventual renal insufficiency. Morphology: kidneys are small, have contracted granular surfaces, and show cysts in the medulla, most prominently at the corticomedullary junction. Genetics and Pathogenesis: NPHP1 to NPHP11 (that encode proteins called nephrocystins)are mutated in the juvenile forms Multicystic Renal Dysplasia sporadic disorder that can be unilateral or bilateral and is often cystic. The kidney is usually enlarged, extremely irregular, and multicystic. characteristic histologic feature is the presence of islands of undifferentiated mesenchyme, often with cartilage, and immature collecting ducts. Most cases are associated with ureteropelvic obstruction, ureteral agenesis or atresia, and other anomalies of the lower urinary tract If unilateral, opposite kidney functions normally, and have an excellent prognosis after surgical removal. If bilateral, renal failure may ultimately result Acquired Cystic Disease Patients with ESRD who have undergone prolonged dialysis sometimes show numerous cortical and medullary renal cysts. Form as a result of obstruction of tubules by interstitial fibrosis or by oxalate crystals. Asymptomatic, but can bleed, causing hematuria. 100-fold increased risk of renal cell carcinoma, which develops in 7% of patients observed for 10 years. Simple Cysts single or multiple and usually involve the cortex. commonly 1 to 5 cm but may reach 10 cm or more in size. Translucent, lined by a gray, glistening, smooth membrane, and filled with clear fluid. membranes are composed of single layer of cuboidal or flattened cuboidal epithelium, which in many instances may be completely atrophic. Hemorrhage may cause pain, distention, calcification and bizarre radiologic finding. Main importance: have smooth contours, are almost always avascular, and give fluid rather than solid signals on ultrasonography.