Glomerulus in health & diseases

Anannya ghosh Ritasman Baisya Shinjan Patra Chirantan Mandal

Medical College &Hospital Bengal 88 college street, Kolkata West Bengal India Anannya ghosh Ritasman Baisya Shinjan Patra Chirantan Mandal

Glomerular anatomy Glomerular physiology Glomerular pathology

About 70-80% of renal diseases are of glomerular origin.

Stuctural & functional unit of kidney. Parts—1.renal corpuscle 2.renal tubule

Bowman’s capsule Glomerulus The average diameter of the glomerulus is approximately 200 mm in the human kidney The average glomerular volume has been reported to be 3 to 7 million mm 3 in humans

composed of a capillary network lined by a thin layer of endothelial cells a central region of mesangial cells with surrounding mesangial matrix material; the visceral epithelial cells and the associated basement membrane; and the parietal layer of Bowman's capsule with its basement membrane.

Between the two epithelial layers is a narrow cavity called Bowman's space, or the urinary space.

The glomerulus is responsible for the production of an ultrafiltrate of plasma. protein free filtrate.

a fenestrated endothelium, the peripheral glomerular basement membrane (GBM), the slit pores between the foot processes of the visceral epithelial cells.

The mean area of filtration surface per glomerulus has been reported to be 0.203 mm 2 in the human kidney .

Structure of the Glomerular Microcirculation

The glomerular capillaries are lined by a thin fenestrated endothelium , pores or fenestrae, in the human kidney range from 70 nm to 100 nm in diameter . The endothelial cell nucleus usually lies adjacent to the mesangium, away from the urinary space. Nonfenestrated, ridge-like structures termed cytofolds are found near the cell borders.

Afferent arterioles lose their internal elastic layer and smooth muscle cell layer prior to entering the glomerular tuft. Efferent arterioles may acquire a smooth muscle cell layer . Smooth muscle cells are replaced by granular cells that are in close contact with the extraglomerular mesangium The efferent arteriole is also in close contact with the glomerular mesangium as it forms inside the tuft and with the extraglomerular mesangium as it exits the tuft.

Negetively charged the presence of a surface coat or glycocalyx rich in polyanionic glycosaminoglycans and glycoproteins synthesized by the endothelial cells

Synthesis of NO endothelium-derived relaxing factor, Presence of eNOS endothelin-1, a vasoconstrictor

Synthesis --- glomerular visceral epithelial cells an important regulator of microvascular permeability. endothelial cell survival repair in glomerular dis-eases due to endothelial cell damage

The visceral epithelial cells, also called podocytes, are the largest cells in the glomerulus . long cytoplasmic processes or trabeculae, that extend from the main cell body and divide into individual foot processes, or pedicels.

SLIT DIAPHARGM In the normal glomerulus, the distance between adjacent foot processes near the GBM varies from 25 nm to 60 nm . (SLIT PORE )

Slit diaphragm Zo-1& podocin protein stitches the slit diaphragm to the foot processes. Actin & actinin stabilises the diaphargm in the pore.

Slit diaphargm main protein ---nephrin other proteins (CD2AP) P cadherin NEPH-1

The mesangial cells and their surrounding matrix material constitute the mesangium, separated from the capillary lumen by the endothelium . Mesangial cells possess an extensive array of microfilaments ( actin, α-actinin, and myosin)

A glomerular basement membrane (GBM) with a thick electron-dense central layer, the lamina densa , and thinner electron-lucent peripheral layers, the lamina rara interna and lamina rara externa .

functions as a sieve or filter that allows the passage of small molecules but almost completely restricts the passage of molecules the size of albumin or larger Ultrastructural tracer studies have provided evidence that the GBM constitutes both a size-selective and a charge-selective barrier

The parietal epithelium , which forms the outer wall of Bowman's capsule, is continuous with the visceral epithe-lium at the vascular pole

Glomerular Physiology RITASMAN BAISYA

The First Step in Urine Formation

Filtration of large amount of fluid through the glomerular capillaries into Bowman’s Capsule which is essentially protein free and devoid of cellular elements including red blood cells.

In normal adults the GFR ranges from 90 to 140 mL/min in males and 80 to 125 mL/min in females. Thus in 24 hours as much as 180 L of plasma is filtered by the glomeruli.

The glomerular filtration barriers determines the composition of plasma ultrafiltrate . Despite of having three layers, this filtration barrier filtes several hundred times as much water an d solutes as the usual capillary membrane.

Fenestration (70 to 90 nm) Slit pore 25 nm

Effect of Size and Electric charge on GFR

Filterability of Solute is inversely related to their size. Substance MW Filterability Water 18 1 Sodium 23 1 Glucose 180 1 Albumin 69000 0.005

the filtration barrier is freely permeable to water and crystalloids, MW £ 30,000 however, is virtually impermeable to colloids small quantities, mainly of albumin escape at the rate 50 mg/L

The negatively charged large molecules are filtered less easily than positively charged molecules of equal molecular size. In minimum change nephropathy the negative charges on basement membrane are lost even before noticeable changes in kidney, histology resulting in albuminuria .

Effect of Net Filtration Pressure - The Starling Forces

Ultrafiltration occurs because the Starling Forces drive fluid across the filtration barriers. Algebraic sum of hydrostatic and colloidal osmotic forces across glomerular membrane gives the Net Filtration Pressure. This is the principle of Starling’s Forces .

GFR = K f [(P GC – P B ) – ( π GC – π B )] Under Normal condition the π B is considered to be zero.

GFR is also dependent on hydraulic H 2 O permeability and surface area (SA) GFR = hydraulic permeability x SA x NFP the first two combined to give the filtration coefficient ( K f ) GFR = K f x NFP

K f = GFR/NFP = 125/10 or 12.5 ml/min/mm Hg In chronic uncontrolled hypertension and diabetes mellitus K f is decreased by - Decreased no. of glomerular cappillaries leading to decreased surface area. Increased thickness of glomerular capillary membrane leading to decreased permeability.

K f can be altered by the Messengial Cells . With contraction of these cells producing decreasing K f , i.e., largely due to reduction of surface area of filtration.

Agents influcing Messengial cells: Contraction : Endothelins, Angiotensin-II, Vasopressin, Norepinephrine. PAF, PDGF, etc. Relaxation : ANP, Dopamine, PGE 2, cAMP, etc.

FILTRATION FRACTION The fraction of renal plasma flow that is filtered. FF = GFR/ Renal Plasma Flow. The value of FF averages about 0.2.

Increase P B , decrease GFR. Precipitation of Calcium or Uric acid (stones) in urinary tract leads to increased P B .

Increase π GC , decrease GFR. Two factors determine π GC : Arterial plasma colloidal OP The Filtration Fraction, higher the FF higher the π GC, less the GFR.

Increase P GC , increase GFR . Factors determining P GC Arterial Pressure Increase afferent arterial resistance, decrease GFR, vice versa. Efferent Arterial resistance.

Constriction of efferent arteriole. PGC increase If within normal limit. FF increase If severe. RPF decrease GFR decrease. π GC increase GFR slightly increase.

Angiotensin II constricts Efferent arteriole leading to increase P GC which maintains GFR. Due to Efferent arteriole constriction by Angiotensin II, renal blood flow is decreased, so flow through peritubular capillaries is decreased leading to sodium and water reabsorption. NO causes renal vasodilatation, GFR is increased. Postaglandins, Bradykinin cause increase GFR.

Strong activationof the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow. The renal sympathetic nerves seem to be most important in reducing GFR during severe, acute disturbances lasting for a few minutes to a few hours,such as those elicited by the defense reaction, brain ischemia, or severe hemorrhage.

Membrane size , pores, charge Particle size, shape, electrostatic charge Filtering forces Amount of blood flow Autoregulation Mesangial cells Sympathetic nerves.

Glomerulonephritis shinjan patra

Primary Glomerulonephropathies Acute diffuse proliferative glomerulonephritis Poststreptococcal Non-poststreptococcal Rapidly progressive (crescentic) glomerulonephritis Chronic glomerulonephritis

Membranous glomerulopathy Minimal change disease Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis IgA nephropathy

Systemic lupus erythematosus Diabetes mellitus Amyloidosis Goodpasture syndrome Microscopic polyarteritis/polyangiitis Wegener granulomatosis Henoch-Schönlein purpura Bacterial endocarditis

Hereditary Disorders Alport syndrome Thin basement membrane disease Fabry disease

In situ immune complex deposition Antibodies against fixed intrinsic tissue antigens. Antibody against planted antigens Circulating Immune Complex Deposition

Hypercellularity Basement Membrane Thickening. Hyalinization and Sclerosis.

Nephritic syndrome ( HEMATURIA) Morphology. ---1 . enlarged, hypercellular glomeruli 2. interstitial edema and inflammation 3.hump appearance

It is called rapid because of early clinical signs. glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation crescents Fibrin strands are prominent between the cellular layers in the crescents

The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes 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 term lipoid nephrosis

Massive proteinuria>3.5 g daily Hypoalbuminemia Edema

END STAGE OF ALL GLOMERULAR DISEASES. thinned cortex Obliteration of glomeruli Atrophy of tubules

Glomerular changes Capillary Basement Membrane Thickening Diffuse Mesangial Sclerosis Nodular Glomerulosclerosis

Focal Segmental Glomerulosclerosis

HIV also affects glomerular and tubular cells Resembles that of the collapsing variant of FSGS

diffuse thickening of the glomerular capillary wall due to the accumulation of Ig deposits along the subepithelial side of the GBM thickened GBM producing “duplication”, as if formation of a new basement Membrame above the existing 1 Membranous Nephropathy

proliferation of mesangium, capillary loops & glomerular cells (mesangiocapillary glomerulonephritis) two major types: Type 1 Type 2 (dense deposits)

Renal Amyloidosis Lupus Nephritis Diabetic Nephropathy

Renal amyloidosis Deposits thickenings of the mesangial matrix and along the basement membranes cause capillary narrowing and distortion of the glomerular vascular tuft. obliterate the glomerulus and capillary lumens completely

immune complex deposition in the glomeruli, peritubular capillary basement membranes due to antibodies Lupus Nephritis

Class Features Class I Normal looking glomeruli Class II Mesangial expansion Class III Focal proliferative <50% Class IV Diffuse Prolif. >50% Class V Membranous Class VI Adv. sclerosing lesions

IgA Nephropathy (Berger Disease) Alport Syndrome GoodPasture Syndrome

presence of prominent IgA1 immune complexes deposited in the mesangium activate the complement pathway and initiate glomerular injury the most common type & most frequent cause of recurrent gross glomerulonephritis worldwide

Alport Syndrome X-linked hereditary disorder of basement membrane collagen Abnormal mutation of type IV collagen

1)subepithelial humps, as in acute glomerulonephritis 2) epimembranous deposits, as in MGN 3) subendothelial deposits, as in SLE nephritis & MPGN 4) mesangial deposits, as in IgA nephropathy 5) basement membrane. EN = endothelium EP = epithelium LD = lamina densa LRE = lamina rara externa LRI = lamina rara interna MC = mesangial cell MM = mesangial matrix

Glomerulus in health & diseases

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