Introduction to Glomerular Diseases

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Chapter 502 Introduction to Glomerular Diseases

502.1 Anatomy of the Glomerulus

The kidneys lie in the retroperitoneal space slightly above the level of the umbilicus. They range in length and weight, respectively, from approximately 6 cm and 24 g in a full-term newborn to ≥12 cm and 150 g in an adult. The kidney (see imageFig. 502-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com) has an outer layer, the cortex, which contains the glomeruli, proximal and distal convoluted tubules, and collecting ducts; and an inner layer, the medulla, that contains the straight portions of the tubules, the loops of Henle, the vasa recta, and the terminal collecting ducts (see Fig. 502-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com).

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Figure 502-1 Gross morphology of the renal circulation.

(From Pitts RF: Physiology of the kidney and body fluids, ed 3, Chicago, 1974, Year Book Medical Publishers.)

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Figure 502-2 Comparison of the blood supplies of cortical and juxtamedullary nephrons.

(From Pitts RF: Physiology of the kidney and body fluids, ed 3, Chicago, 1974, Year Book Medical Publishers.)

The blood supply to each kidney usually consists of a main renal artery that arises from the aorta; multiple renal arteries can occur. The main artery divides into segmental branches within the medulla, becoming the interlobar arteries that pass through the medulla to the corticomedullary junction. At this point, the interlobar arteries branch to form the arcuate arteries, which run parallel to the surface of the kidney. Interlobular arteries originate from the arcuate arteries and give rise to the afferent arterioles of the glomeruli. Specialized muscle cells in the wall of the afferent arteriole and specialized distal tubular cells adjacent to the glomerulus (macula densa) form the juxtaglomerular apparatus that controls the secretion of renin. The afferent arteriole divides into the glomerular capillary network, which then recombines into the efferent arteriole (Fig. 502-2). The juxtamedullary efferent arterioles are larger than those in the outer cortex and provide the blood supply, as the vasa recta, to the tubules and medulla.

Each kidney contains approximately 1 million nephrons (glomeruli and associated tubules). There is a large distribution of “normal nephron number” in humans, with the mean ±2 standard deviations (SD) ranging from 200,000 to 2 million nephrons/kidney. This variation can have major pathophysiologic significance as a risk factor for the later development of hypertension and progressive renal dysfunction. In humans, formation of nephrons is complete at 36-40 wk of gestation, but functional maturation with tubular growth and elongation continues during the 1st decade of life. Because new nephrons cannot be formed after birth, any disease that results in progressive loss of nephrons can lead to renal insufficiency. A decreased number of nephrons secondary to low birth weight, prematurity, and/or unknown genetic or environmental factors is hypothesized to be a risk factor for the development of primary hypertension and progressive renal dysfunction in adulthood. Low nephron number presumably results in hyperfiltration and eventual sclerosis of “overworked” nephron units.

The glomerular network of specialized capillaries serves as the filtering mechanism of the kidney. The glomerular capillaries are lined by endothelial cells (Fig. 502-3) and have very thin cytoplasm that contains many holes (fenestrations). The glomerular basement membrane (GBM) forms a continuous layer between the endothelial and mesangial cells on one side and the epithelial cells on the other. The membrane has 3 layers: (1) a central electron-dense lamina densa; (2) the lamina rara interna, which lies between the lamina densa and the endothelial cells; and (3) the lamina rara externa, which lies between the lamina densa and the epithelial cells. The visceral epithelial cells cover the capillary and project cytoplasmic foot processes, which attach to the lamina rara externa. Between the foot processes are spaces or filtration slits. The mesangium (mesangial cells and matrix) lies between the glomerular capillaries on the endothelial cell side of the GBM and forms the medial part of the capillary wall. The mesangium may serve as a supporting structure for the glomerular capillaries and probably has a role in the regulation of glomerular blood flow, filtration, and the removal of macromolecules (such as immune complexes) from the glomerulus. Bowman’s capsule, which surrounds the glomerulus, is composed of a basement membrane, which is continuous with the basement membranes of the glomerular capillaries and the proximal tubules, and the parietal epithelial cells, which are contiguous with the visceral epithelium (Fig. 502-4).

502.2 Glomerular Filtration

As the blood passes through the glomerular capillaries, the plasma is filtered through the glomerular capillary walls. The ultrafiltrate, which is cell free, contains all of the substances in plasma (electrolytes, glucose, phosphate, urea, creatinine, peptides, low molecular weight proteins) except proteins having a molecular weight of ≥68 kd (such as albumin and globulins). The filtrate is collected in Bowman’s space and enters the tubules, where its composition is modified by tightly regulated secretion and absorption of solute and fluid, until it leaves the kidney as urine.

Glomerular filtration is the net result of opposing forces applied across the capillary wall. The force for ultrafiltration (glomerular capillary hydrostatic pressure) is a result of systemic arterial pressure, modified by the tone of the afferent and efferent arterioles. The major force opposing ultrafiltration is glomerular capillary oncotic pressure, created by the gradient between the high concentration of plasma proteins within the capillary and the almost protein-free ultrafiltrate in Bowman’s space. Filtration may be modified by the rate of glomerular plasma flow, the hydrostatic pressure within Bowman’s space, and/or the permeability of the glomerular capillary wall.

Although glomerular filtration begins at approximately the 6th wk of fetal life, kidney function is not necessary for normal intrauterine homeostasis because the placenta serves as the major fetal excretory organ. After birth, the glomerular filtration rate (GFR) increases until renal growth ceases (by age ~18-20 years in most people). To compare GFRs of children and adults, the GFR is standardized to the body surface area (1.73 m2) of an “ideal” 70-kg adult. Even after correction for surface area, the GFR of a child does not approximate adult values until the 3rd yr of life (Fig. 502-5).

The GFR may be estimated by measurement of the serum creatinine level (Fig. 502-6). Creatinine is derived from muscle metabolism. Its production is relatively constant, and its excretion is primarily through glomerular filtration, although tubular secretion can become important in renal insufficiency. In contrast to the concentration of blood urea nitrogen, which is affected by state of hydration and nitrogen balance, the serum creatinine level is primarily influenced by the level of glomerular function. The serum creatinine is of value only in estimating the GFR in the steady state. A patient can have a normal creatinine level without effective renal function very shortly after the onset of acute renal failure with anuria. In this clinical setting, serum creatinine may be an insensitive measure of decreased renal function because its level does not rise above normal until the GFR falls by 30-40%.

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Figure 502-6 The serum creatinine in relation to age.

(From McCrory W: Developmental nephrology, Cambridge, MA, 1972, Harvard University Press.)

The precise measurement of the GFR is accomplished by quantitating the clearance of a substance that is freely filtered across the capillary wall and is neither reabsorbed nor secreted by the tubules. The clearance (Cs) of such a substance is the volume of plasma that, when completely cleared of the contained substance, would yield a quantity of that substance equal to that excreted in the urine over a specified time. The clearance is represented by the following formula:

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where Cs equals the clearance of substance s, Us reflects the urinary concentration of s, V represents the urinary flow rate, and Ps equals the plasma concentration of s. To correct the clearance for body surface area, the formula is

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The GFR is optimally measured by the clearance of inulin, a fructose polymer having a molecular weight of approximately 5 kd. Because the inulin clearance technique is cumbersome, the GFR is commonly estimated by the clearance of endogenous creatinine. Formulas that estimate creatinine clearance accurately in clinical settings have been useful tools in patient care. The Schwartz formula is the most widely used pediatric formula and is based on the serum creatinine, patient height, and an empirical constant. Another endogenous marker, cystatin C, a 13.6-kd protease inhibitor produced by nucleated cells, might prove to be a more reliable marker than serum creatinine in estimating the GFR because its serum levels are unaffected by sex, height, muscle mass, bilirubin, or red blood cell hemolysis.

The absence of plasma proteins larger than the size of albumin from the glomerular filtrate confirms the effectiveness of the glomerular capillary wall as a filtration barrier. Major factors restricting the filtration of these and other macromolecules include their size and their ionic charge. Morphologic studies suggest that the size-selective filtration barrier resides within the GBM. The endothelial cell, basement membrane, and epithelial cell of the glomerular capillary wall possess strong negative ionic charges (heparan sulfate and glycoproteins containing sialic acid). Proteins in the blood have a relatively low isoelectric point and carry a net negative charge, and they are repelled by the negatively charged sites in the glomerular capillary wall, thus restricting filtration.

502.3 Glomerular Diseases

Pathogenesis

Glomerular injury may be a result of genetic, immunologic, perfusion, or coagulation disorders. Genetic disorders of the glomerulus result from mutations in the exons of DNA encoding proteins located within the glomerulus, interstitium, or tubular epithelium; mutations in the regulatory genes controlling DNA transcription; abnormal post-transcriptional modification of RNA transcripts; or abnormal post-translational modification of proteins. Immunologic injury to the glomerulus results in glomerulonephritis, which is a generic term for several diseases and a histopathologic term signifying inflammation of the glomerular capillaries. Evidence that glomerulonephritis is caused by immunologic injury includes morphologic and immunopathologic similarities to experimental immune-mediated glomerulonephritis; the demonstration of immune reactants (immunoglobulin, complement) in glomeruli; abnormalities in serum complement; and the finding of autoantibodies (anti-GBM) in some of these diseases (see imageFig. 502-7 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). There appear to be 2 major mechanisms of immunologic injury: glomerular deposition of circulating antigen-antibody immune complexes and interaction of antibody with local antigen in situ. In the latter circumstance, the antigen may be a normal component of the glomerulus (the noncollagenous domain [NC-1] of type IV collagen, a putative antigen in human anti-GBM nephritis) or an antigen that has been deposited in the glomerulus.

In immune complex–mediated diseases, antibody is produced against and combines with a circulating antigen that is usually unrelated to the kidney (see Fig. 502-7). The immune complexes accumulate in GBMs and activate the complement system, leading to immune injury. Acute serum sickness in rabbits is produced by a single intravenous injection of bovine albumin. Within 1 wk after injection, a rabbit produces antibody against bovine albumin, and the antigen remains in the blood in high concentration. As antibody enters the circulation, it forms immune complexes with antigen. Although the amount of antigen in the circulation exceeds that of antibody (antigen excess), the complexes formed are small, remain soluble in the circulation, and are deposited in glomeruli. The processes involved in glomerular localization are not well understood but include characteristics of the complex (concentration, charge, size), and/or the glomerulus (mesangial trapping, negatively charged capillary wall); hydrodynamic forces, and the influence of various chemical mediators (angiotensin II, prostaglandins).

With deposition of immune complexes in glomeruli, rabbits develop an acute proliferative glomerulonephritis. Immunofluorescence microscopy demonstrates granular (lumpy-bumpy) deposits containing immunoglobulin and complement in the glomerular capillary wall. Electron microscopic studies show these deposits to be on the epithelial side of the GBM and in the mesangium. For the next few days, as additional antibody enters the circulation, the antigen is ultimately removed from the circulation and the glomerulonephritis subsides.

An example of in situ antigen-antibody interaction is anti-GBM antibody disease, in which antibody reacts with antigen(s) of the GBM. Immunopathologic studies reveal linear deposition of immunoglobulin and complement along the GBM as in Goodpasture syndrome and certain types of rapidly progressive glomerulonephritis.

The inflammatory reaction that follows immunologic injury results from activation of 1 or more mediator pathways. The most important of these is the complement system, which has 2 initiating sequences: the classic pathway, which is activated by antigen-antibody immune complexes, and the alternative or properdin pathway, which is activated by polysaccharides and endotoxin. These pathways converge at C3; from that point on, the same sequence leads to lysis of cell membranes (Chapter 127). The major noxious products of complement activation are produced after activation of C3 and include anaphylatoxin (which stimulates contractile proteins within vascular walls and increases vascular permeability) and chemotactic factors (C5a) that recruit neutrophils and perhaps macrophages to the site of complement activation, leading to consequent damage to vascular cells and basement membranes.

The coagulation system may be activated directly, after endothelial cell injury that exposes the thrombogenic subendothelial layer (thereby initiating the coagulation cascade), or it may be activated indirectly, after complement activation. Consequently, fibrin is deposited within glomerular capillaries or within Bowman’s space as crescents. Activation of the coagulation cascade can also activate the kinin system, which produces additional chemotactic and anaphylatoxin-like factors.

Pathology

The glomerulus may be injured by several mechanisms, but it has only a limited number of histopathologic responses; different disease states can produce similar microscopic changes.

Proliferation of glomerular cells occurs in most forms of glomerulonephritis and may be generalized, involving all glomeruli, or focal, involving only some glomeruli and sparing others. Within a single glomerulus, proliferation may be diffuse, involving all parts of the glomerulus, or segmental, involving only 1 or more tufts, but not others. Proliferation commonly involves the endothelial and mesangial cells and is often associated with an increase in the mesangial matrix (see Fig. 502-7). Mesangial proliferation can result from deposition of immune complex within the mesangium. The resultant increase in cell size and number, and production of mesangial matrix, can increase glomerular size and narrow the lumens of glomerular capillaries, leading to renal insufficiency.

Crescent formation in Bowman’s space (capsule) is a result of proliferation of parietal epithelial cells. Crescents develop in several forms of glomerulonephritis (termed rapidly progressive or crescenteric) and are a characteristic response to deposition of fibrin in Bowman’s space. Newly formed crescents contain fibrin, the proliferating epithelial cells of Bowman’s space, basement membrane–like material produced by these cells, and macrophages that might have a role in the genesis of glomerular injury. Over the subsequent days to weeks, the crescent is invaded by connective tissue and becomes a fibroepithelial crescent. This process generally results in glomerular obsolescence. Crescent formation is often associated with glomerular cell death. The necrotic glomerulus has a characteristic eosinophilic appearance and usually contains nuclear remnants. Crescent formation is usually associated with generalized proliferation of the mesangial cells and with either immune complex or anti-GBM antibody deposition in the glomerular capillary wall.

Certain forms of acute glomerulonephritis show glomerular exudation of blood cells, including neutrophils, eosinophils, basophils, and mononuclear cells. The thickened appearance of GBM can result from a true increase in the width of the membrane (as seen in membranous glomerulopathy), from massive deposition of immune complexes that have staining characteristics similar to the membrane (as seen in systemic lupus erythematosus), or from the interposition of mesangial cells and matrix into the subendothelial space between the endothelial cells and the GBM. The last can give the basement membrane a split appearance, as seen in type I membranoproliferative glomerulonephritis and other diseases.

Sclerosis refers to the presence of scar tissue within the glomerulus. Occasionally, pathologists use this term to refer to an increase in mesangial matrix.

Tubulointerstitial fibrosis is present in all patients who have glomerular disease and who develop progressive renal injury. This fibrosis is initiated by injury to the renal tubules, resulting in mononuclear cell infiltrates that release soluble factors that have fibrosis-promoting effects. Matrix proteins of the renal interstitium begin to accumulate, leading to eventual destruction of renal tubules and peritubular capillaries. The actual transformation of tubular epithelium to mesenchymal tissue can contribute to progressive tubulointerstitial fibrosis.