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Pathology (Cystic Diseases of the Kidney (Medullary Diseases with Cysts…

- - - - PKD2 : in 10-15%, resides on chromosome 4 and encodes polycystin 2, a smaller protein. thought to function as a calcium-permeable membrane channel, and also expressed in cilia
      - PKD1:85-90% of families, on the short arm of chromosome 16 (a large and complex cell membrane– associated pr: polycystin-1)
- - - - Primary Glomerular Disease (Lesions) (first 2 most important)
        
        Minimal-Change Disease
        
        Clinical Course: responsiveness to therapy
        
        morphology
        
        electron microscope: GBM appears normal; only obvious glomerular abnormality: uniform and diffuse effacement of the foot processes of podocytes; [There are also epithelial cell] vacuolization,..
        
        light microscope: glomeruli appear normal (thus the name); [cells of proximal] tubules often heavily laden w/ protein droplets and lipids [but this is secondary to tubular reabsorption of lipoprs passing through diseased glomeruli]
        
        [relatively benign]; most frequent cause of nephrotic syndrome in children; [may develop at any age] most common between ages of 1 and 7
        
        pathogenesis: circulating, possibly T cell–derived, factor that causes podocyte damage and effacement of foot processes
        
        Membranoproliferative Glomerulonephritis and
        Dense Deposit Disease
        
        pathogenesis
        
        [Some cases of type I may be caused by circulating immune complexes / due to a planted Ag w/ subsequent in situ immune complex formation] In either case, inciting Ag not known. Type I MPGN also occurs in a. w/ hepatitis B and C antigenemia, SLE, infected AV shunts, and extrarenal infections w/persistent or episodic antigenemia
        
        dense deposit disease: excessive complement activation. Some have an autoAb against C3 convertase, called C3 nephritic factor, which is believed to stabilize the enzyme and lead to uncontrolled cleavage of C3 and activation of the alternative complement pathway. Mutations the gene encoding the complement regulatory protein factor H or autoAbs to factor H described in some
        
        morphology
        
        light microscopy: both similar; glomeruli large, w/ an accentuated lobular appearance, and show proliferation of mesangial and endothelial cells as well as infiltrating leukocytes; GBM thickened, and glomerular capillary wall often shows a double contour, or “tram track,” appearance (due to extension of processes of mesangial and infl cells into peripheral capillary loops and deposition of mesangial matrix)
        
        electron microscopy
        
        Type 1: discrete subendothelial electron-dense deposits
        
        Type 2: lamina densa + subendothelial space of GBM transformed into an irregular, ribbon-like, extremely electron-dense structure, resulting from deposition of material of unknown composition
        
        IF
        
        Type 1: C3 deposited in an irregular granular pattern, and IgG and early complement components (C1q and C4) often also present, indicative of an immune complex pathogenesis.
        
        Type 2: C3 present in irregular chunky and segmental linear foci in basement membranes + in mesangium. IgG + C1q + C4 u. absent
        
        accounts for 5-10% of cases of idiopathic nephrotic syndrome; some present non-nephrotic range; others exhibit a combined nephrotic–nephritic picture. Two major types of MPGN (I and II) traditionally recognized but now recognized to be separate entities, termed MPGN type I and dense deposit disease (formerly MPGN type II). Of the two types of disease, MPGN type I is far more common (about 80% of cases).
        
        Clinical Course: prognosis of MPGN generally poor.
        
        Membranous Nephropathy
        
        pathogenesis: a form of chronic immune complex glomerulonephritis induced by Abs reacting in situ to endogenous or planted glomerular Ags. An endogenous podocyte antigen, the phospholipase A2 R, is the antigen most often recognized by causative autoAbs; complement activation--> assembly of C5b-C9 membrane attack complex--> damages mesangial + podocytes directly--> loss of slit filter integrity and proteinuria
        
        morphology
        
        IF: typical granular deposits
        
        Electron microscopy: thickening caused by subepithelial deposits-->nestle against GBM + separated from each other by small, spike like protrusions of GBM matrix that form in reaction to the deposits (spike and dome pattern); As disease progresses-->spikes close over deposits, incorporating them into the GBM. [In addition, as in other causes of nephrotic syndrome, podocytes show effacement of foot processes];
        
        main feature: diffuse thickening of capillary wall
        
        a slowly progressive disease, most common betw ages 30 and 60; origin:
        
        primary: ~85% of cases: caused by autoAbs that cross-react w/ Ags
        
        secondary
        
        • Infections (chronic hepatitis B, syphilis, schistosomiasis, malaria)
        
        • Malignant tumors, particularly carcinoma of the lung and colon and melanoma
        
        • SLE and other AI conditions
        
        • Exposure to inorganic salts (gold, mercury)
        
        • Drugs (penicillamine, captopril, NSAIDs)
        
        Clinical Course
        
        Focal Segmental Glomerulosclerosis
        
        pathogenesis: injury to podocytes: initiating event of primary FSGS. [As with MCD, permeability-increasing factors produced by] lymphocytes [have been proposed]
        
        morphology
        
        affects only some glomeruli (hence focal) [and, in case of primary FSGS, initially only juxtamedullary glomeruli]
        affects some tufts within a glomerulus and spares others (hence segmental).
        
        affected glomeruli: incr mesangial matrix, obliterated capillary lumina, and deposition of hyaline masses (hyalinosis) and lipid droplets.
        
        IF: nonspecific trapping of Igs in affected glomeruli, u. IgM, and complement in areas of hyalinosis.
        
        electron microscopy: the podocytes exhibit effacement of foot processes, as in minimalchange disease.
        
        A morphologic variant (collapsing glomerulopathy): charac by collapse of glomerular tuft and podocyte hyperplasia. This is a more severe manifestation of FSGS that may be idiopathic or a. w/ HIV infection, drug-induced toxicities, [and some microvascular injuries. It carries a particularly poor prognosis]
        
        origin
        
        Primary/Idiopathic: FSGS accounts for 20-30% of all cases of nephrotic syndrome; an increasingly common cause of nephrotic syndrome in adults [remains a frequent cause in children]
        
        secondary to
        
        • a. w/ other conditions, ex HIV infection or heroin abuse
        
        • secondary event in other forms of GN (IgA nephropathy)
        
        • a maladaptation to nephron loss
        
        • In inherited or congenital forms. auto dominant forms a. w/ mutations in cytoskeletal prs and podocin both required for integrity of podocytes. In addition, a sequence variant in the apolipoprotein L1 gene (APOL1) on chromosome 22 strongly a. w/ an incr risk of FSGS and renal failure in individuals of African descent.
        
        Clinical Course: incidence of hematuria + HTN higher in FSGS than MCD; FSGS proteinuria is nonselective; and in general response to corticosteroid therapy is poor. Most patients w/ FSGS develop ESRD
      - Systemic Diseases w/ Renal Manifestations: Diabetes mellitus, Amyloidosis, SLE, Ingestion of drugs (gold, penicillamine, “street heroin”), Infections (malaria, syphilis, hepatitis B, HIV infection), Malignancy (carcinoma, melanoma), Miscellaneous (bee sting allergy, hereditary nephritis)
    - - Hypoalbuminemia (plasma [Alb]< 3 g/dL): long-standing or extremely heavy proteinuria--> serum Alb decr--> hypoalbuminemia + a drop in plasma colloid osmotic P.
      - Generalized edema (most obvious clinical manifestation): (plasma colloid osmotic P), decr in intravascular volume and renal BF--> incr release of renin from renal juxtaglomerular cells--> angiotensin-aldosterone axis--> retention of salt and water; exacerbated by reductions in cardiac secretion of natriuretic factors; continuing proteinuria if unchecked--> generalized edema (anasarca). [At the onset, there is little or no azotemia, hematuria, or HTN]
      - Massive proteinuria (daily pr loss in urine of 3.5 g or more in adults): In all there is a derangement in capillary walls of glomeruli--> incr permeability to plasma prs
      - Hyperlipidemia : hypoalbuminemia triggers incr synth of lipoprs in liver or massive proteinuria causes loss of an inhibitor of their synthesis; also abnormal transport of circulating lipid particles and impairment of peripheral breakdown of lipoprs
        lipiduria: incr permeability of GBM to lipoprs.
  - - - pathogenesis: an immune complex disease in which tissue injury primarily caused by complement activation by classical pathway. Typical features of immune complex disease (hypocomplementemia + granular deposits of IgG and complement on the GBM) seen. relevant Ags probably strep prs. Specific ags: strep exotoxin B (Spe B) and strep GAPDH. Both activate alternative complement pathway and have affinity for glomerular pr and plasmin
      - morphology
        
        light: incr cellularity of glomerular tufts that affects nearly all glomeruli (diffuse) (caused both by prolif + swelling of endothelial and mesangial cells and by infiltrating neutrophils and monocytes); Sometimes necrosis of capillary walls.
        
        Electron: deposited immune complexes arrayed as subendothelial, intramembranous, or, most often, subepithelial “humps” nestled against GBM
        
        IF: scattered granular deposits of IgG and complement within capillary walls and some mesangial areas ; deposits u. cleared over a period of about 2 months.
      - clinical course: gross hematuria, urine appearing smoky brown rather than bright red. Recovery occurs in most **children. In adults, [15% to 50% of affected persons] develop ESRD**
      - prototype: infections streptococci ; others: certain pneumococcal and staphylococcal infections as well as several common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C;
        classic case develops in a child 1 to 4 weeks after recovery from a group A strepinfection. Only certain “nephritogenic” strains of β-hemolytic strepevoke glomerular disease. most cases: initial infection localized to pharynx or skin.
    - - pathogenesis
        
        primary
        
        genetic influence: occurrence in families and in HLA–identical siblings, incr frequency of certain HLA and complement genotypes in some populations;
        
        abnormality in glycosylation of IgA1--> reduces plasma clearance and favors deposition in mesangium + elicit glycan-specific IgG Abs
        
        prominent mesangial deposition of IgA may stem from entrapment of IgA immune complexes.
        
        secondary: IgA nephropathy occurs w/ incr frequency in individuals w/ celiac disease (intestinal mucosal defects), and in liver disease (defective hepatobiliary clearance of IgA complexes)
      - morphology
        
        IF: mesangial deposition of IgA, often w/ C3 and properdin [and smaller amounts of IgG or IgM; Early components of the classical complement pathway u. absent
        
        glomeruli may be
        
        normal
        
        showing mesangial widening + segmental infl confined to some glomeruli (focal proliferative GN);
        
        diffuse mesangial prolif (mesangioproliferative GN);
        
        (rarely) overt crescentic GN.
      - u. affects children and young adults and begins as an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper respiratory tract infection; hematuria lasts several days and then subsides, only to recur every few months. may be associated w/ local pain.
        most common glomerular disease revealed by renal biopsy worldwide; is a localized variant of Henoch-Schönlein purpura, also characterized by IgA deposition in mesangium (IgA nephropathy: purely renal, Henoch-Schönlein purpura: systemic syndrome involving skin (purpuric rash), GI tract (abdominal pain), joints (arthritis), and kidney)
      - clinical course
    - - pathogenesis
      - morphology
      - clinical course
  - - - ex classic antiGBM antibody–mediated crescentic GN; Abs directed against fixed Ags in GBM; Deposition of these Abs--> linear pattern of staining in IF in contrast w/ granular pattern for other forms of immune complex–mediated nephritis
      - conformational change in α3 chain of type IV collof GBM --> inciting autoimmunity. Sometimes the anti-GBM Abs cross-react w/ basement membranes of lung alveoli--> simultaneous lung and kidney lesions (Goodpasture syndrome)
    - - Podocyte Injury
      - Nephron Loss
  - - - • fenestrated endothelial cells (each fenestra 70-100 nm diameter)
      - • A glomerular basement membrane w/ thick, electron-dense central layer, the lamina densa, and thinner, electron-lucent peripheral layers, the lamina rara interna and lamina rara externa; consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin, and several other glycoproteins
      - • Podocytes (structurally complex cells possess interdigitating processes embedded in and adherent to lamina rara externa): Adjacent foot processes separated by 20- to 30-nm-wide filtration slits, which are bridged by a thin slit diaphragm composed in large part of nephrin; Nephrin + associated proteins( ex podocin): a crucial role in maintaining selective permeability
      - • glomerular tuft supported by mesangial cells lying betw capillaries. Basement membrane–like mesangial matrix forms a meshwork through which the mesangial cells are scattered; mesenchymal origin (and only found in kidney tissue), contractile (so it can affect blood flow), capable of proliferation, of laying down collagen and other matrix components, forming BM, of secreting a number of biologically active mediators and phagocyte
- - - - gross: kidney may be essentially normal in size or slightly shrunken, depending on duration and severity of hypertensive disease. Small, pinpoint petechial hemorrhages may appear on cortical surface from rupture of arterioles or glomerular capillaries, giving the kidney a peculiar, flea-bitten appearance.
      - microscopic
        
        fibrinoid necrosis of the arterioles
        
        interlobular arteries + larger arterioles: prolif of intimal cells after acute injury-- > onion-skin appearance
    - - full-blown syndrome: papilledema, encephalopathy, cardiovascular abnormalities, and renal failure.
      - early symptoms related to incr ICP: headache, nausea, vomiting, and visual impairment (development of scotomas, or “spots" before the eyes)
      - At onset of rapidly mounting BP: marked proteinuria + microscopic (spmetimes macroscopic) hematuria but no significant alteration in renal function. Soon, however, acute kidney injury develops (also maybe thrombotic microangiopathy). The syndrome represents a true medical emergency
  - - - Gross: kidneys symmetrically atrophic; renal surface shows diffuse, fine granularity , resembles grain leather
      - microscopic
        
        basic anatomic change:hyaline thickening of walls of small arteries and arterioles (hyaline arteriolosclerosis)
        
        larger vessels (interlobar and arcuate arteries): reduplication of internal elastic lamina along w/ fibrous thickening of media (fibroelastic hyperplasia) + subintima.
    - - alone rarely causes severe damage to kidney except in persons w/ genetic susceptibility (African Americans)--> uremia and death.; tars ma dar in bimaran malignant HTN hast
      - all pxs u. show some functional impairment, ex loss of concentrating ability or a variably diminished GFR, mild degree of proteinuria frequent
- - - - Papillary Renal Cell Carcinomas
        
        افراد دیالیزی کیست پیدا می کنند. مهمترین کیست در آن ها PRCC است. 15 درصد تومور های کلیه را تشکیل می دهند. معمولا دو طرفه و متعدد و multi focal است. ممکن است به صورت اسپورادیک یا familial باشد. ژن met protoancogene )کروموزوم 7( است. ضایعات پاپیلاری انگشتی شکل دارد. سلول هایی می بینیم که سیتوپلاسمش حالت صورتی کم رنگ است. محتوای لیپیدش کمتر است. بیشتر صورتی دیده می شود.
      - Chromophobe Renal Carcinomas
        
        انتظار داریم سلول ها روشن باشند ولی خیلی هم روشن نیست. شیوعش کم است ) 5%( . Chromosome loss های متعدد دارد کروموزوم ها در تومور)نه در فرد!( حذف می شوند.هایپودیپلوئیدی شدیدی پیدا می کنند.)مثلا به جای 46 کروموزوم 43 کروموزوم دارد( منشا: توبول)سلول های intercalated مجاری جمع کننده(. سلول ها هسته بزرگ دارند و غشایی با ضخامت بالا دارند)مثل سلول های گیاهی(
      - Clear Cell Carcinomas
        
        شایع ترین - 25 درصد موارد -موتاسیون در ژن VHL در کروموزوم 3 همراه translocation ها) VHL ( -به صورت منفرد در قطب فوقانی کلیه -به خاطر محتوای گلیکوژن و لیپید داخل سلول بر اساس مقدارش که گلیکوژن بیشتر رنگ تیره تر و لیپید بیشتر رنگ روشن تر -نمای شبیه توبول -استرومای اندک
      - Clinical Course
        
        مریض با علائم کنسر کلیه تریاد دارد. در 10 درصد موارد فقط این سه تا را دارد: درد، توده، هماچوری که بین این سه تا علامت هماچوری قابل اعتمادتر است. وقتی به مرحله ی درد و توده برسد به قدری ضایعه پیشرفته است که survival مریض به دو سه ماه هم نمی رسد. علائم پارانئوپلاستیک به دلیل ترشح یک سری مدیاتور از تومور مثل هایپرکلسمی، هایپرتانسیون، کوشینگ و علائم زنانه یا مردانه شدن.
      - derived from renal tubular epithelium--> located predominantly in cortex.
        2% to 3% of all cancers in adults.
        [most common from sixth-seventh decades] and men are affected about twice as commonly as women
        RFs: smokers, HTN or obese patients, and those who have had occupational exposure to cadmium. The risk of developing renal cell cancer is increased 30-fold in persons who acquire polycystic disease as a complication of chronic dialysis. The role of genetic factors in the causation of these cancers is discussed later on.
- - - - Chronic Obstructive Pyelonephritis
      - Chronic Reflux–Associated Pyelonephritis
        (Reflux Nephropathy)
- - - - most pxs who develop calcium stones: idopathic calciuria (the rest: Hypercalcemia and hypercalciuria, Hyperoxaluria, Hyperuricosuria)
      - struvite: always in persons w/ persistently alkaline urine resulting from UTIs. In particular, infections w/ urea-splitting bacteria, such as Proteus vulgaris and staphylococci
      - uric acid: high uric acid levels in urine + persistently acid urine (pH <5.5)
      - Cystine: genetically determined defect
    - - • 80% calcium oxalate or calcium oxalate mixed w/ calcium phosphate.
      - • 10%: magnesium ammonium phosphate (struvite)
      - • 6-9%: either uric acid or cystine stones.
    - - w/o producing either symptoms or significant renal damage. (particularly large stones lodged in renal pelvis)
      - Smaller stones may pass into ureter + lodge--> typical intense pain (renal or ureteral colic: paroxysms of flank pain radiating toward groin); Often at this time: gross hematuria.
      - clinical significance of stones: capacity to obstruct urine flow or to produce sufficient trauma to cause ulceration + bleeding--> predispose to bacterial infection.
  - - - • Congenital: atresia of urethra, valve formations in either ureter or urethra, aberrant renal artery compressing ureter, renal ptosis w/ torsion, or kinking of ureter
      - • Acquired
        
         Foreign bodies: calculi, sloughed necrotic papillae
        
         Proliferative lesions: BPH, carcinoma of prostate, bladder tumors (papilloma and carcinoma), contiguous malignant disease (retroperitoneal lymphoma, carcinoma of cervix or uterus)
        
         Inflammation: prostatitis, ureteritis, urethritis, retroperitoneal fibrosis
        
         Neurogenic: spinal cord damage with paralysis of bladder
        
         Normal pregnancy: mild and reversible
        
         Uterine prolapse and cystocele