Two human kidneys harbor nearly 1.8 million glomerular capillary tufts. Each glomerular tuft resides within Bowman's space. The capsule circumscribing this space is lined by parietal epithelial cells that transition into tubular epithelia forming the proximal nephron or migrate into the tuft to replenish podocytes. The glomerular capillary tuft derives from an afferent arteriole that forms a branching capillary bed embedded in mesangial matrix (Fig. 283-1). This capillary network funnels into an efferent arteriole, which passes filtered blood into cortical peritubular capillaries or medullary vasa recta that supply and exchange with a folded tubular architecture. Hence the glomerular capillary tuft, fed and drained by arterioles, represents an arteriolar portal system. Fenestrated endothelial cells resting on a glomerular basement membrane (GBM) line glomerular capillaries. Delicate foot processes extending from epithelial podocytes shroud the outer surface of these capillaries, and podocytes interconnect to each other by slit-pore membranes forming a selective filtration barrier.
Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles, leading to an afferent arteriole, glomerular capillary bed (tuft), and a draining efferent arteriole. (From VH Gattone II et al: Hypertension 5:8, 1983.) B. Scanning electron micrograph of podocytes that line the outer surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron micrograph of the fenestrated endothelia lining the glomerular capillary. D. The various normal regions of the glomerulus on light microscopy (A–C, courtesy of Dr. Vincent Gattone, Indiana University; with permission).
The glomerular capillaries filter 120–180 L/d of plasma water containing various solutes for reclamation or discharge by downstream tubules. Most large proteins and all cells are excluded from filtration by a physicochemical barrier governed by pore size and negative electrostatic charge. The mechanics of filtration and reclamation are quite complicated for many solutes (Chap. 271). For example, in the case of serum albumin, the glomerulus is an imperfect barrier. Although albumin has a negative charge, which would tend to repel the negatively charged GBM, it only has a physical radius of 3.6 nm, while pores in the GBM and slit-pore membranes have a radius of 4 nm. Consequently, variable amounts of albumin inevitably cross the filtration barrier to be reclaimed by megalin and cubilin receptors along the proximal tubule. Remarkably, humans with normal nephrons do not excrete more than 8–10 mg of albumin in daily voided urine, approximately 20–60% of total excreted protein. This amount of albumin, and other proteins, can rise to gram quantities following glomerular injury.
The breadth of diseases affecting the glomerulus is expansive because the glomerular capillaries can be injured in a variety of ways, producing many different lesions and several unique changes to urinalysis. Some order to this vast subject is brought by grouping all of these diseases into a smaller number of clinical syndromes.
There are many forms of glomerular disease with pathogenesis variably linked to the presence of genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or diabetes mellitus. Even after careful study, however, the cause often remains unknown, and the lesion is called idiopathic. Specific or unique features of pathogenesis are mentioned with the description of each of the glomerular diseases later in this chapter.
Some glomerular diseases result from genetic mutations producing familial disease or a founder effect: congenital nephrotic syndrome from mutations in NPHS1 (nephrin) and NPHS2 (podocin) affect the slit-pore membrane at birth, and TRPC6 cation channel mutations produce focal segmental glomerulosclerosis(FSGS) in adulthood; polymorphisms in the gene encoding apolipoprotein L1, APOL1 are a major risk for nearly 70% of African Americans with nondiabetic end-stage renal disease (ESRD), particularly FSGS; mutations in complement factor H associate with membranoproliferative glomerulonephritis(MPGN) or atypical hemolytic uremic syndrome (aHUS), type II partial lipodystrophy from mutations in genes encoding lamin A/C, or PPARγ cause a metabolic syndrome associated with MPGN, which is sometimes accompanied by dense deposits and C3 nephritic factor; Alport's syndrome, from mutations in the genes encoding for the α3, α4, or α5 chains of type IV collagen, produces split-basement membranes with glomerulosclerosis; and lysosomal storage diseases, such as α-galactosidase A deficiency causing Fabry's disease and N-acetylneuraminic acid hydrolase deficiency causing nephrosialidosis, produce FSGS.
Systemic hypertension and atherosclerosis can produce pressure stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis. Malignant hypertension can quickly complicate glomerulosclerosis with fibrinoid necrosis of arterioles and glomeruli, thrombotic microangiopathy, and acute renal failure. Diabetic nephropathy is an acquired sclerotic injury associated with thickening of the GBM secondary to the long-standing effects of hyperglycemia, advanced glycosylation end products, and reactive oxygen species.
Inflammation of the glomerular capillaries is called glomerulonephritis. Most glomerular or mesangial antigens involved in immune-mediated glomerulonephritis are unknown (Fig. 283-2). Glomerular epithelial or mesangial cells may shed or express epitopes that mimic other immunogenic proteins made elsewhere in the body. Bacteria, fungi, and viruses can directly infect the kidney producing their own antigens. Autoimmune diseases like idiopathic membranous glomerulonephritis (MGN) or MPGN are confined to the kidney, while systemic inflammatory diseases like lupus nephritis or granulomatosis with polyangiitis (Wegener's) spread to the kidney, causing secondary glomerular injury. Antiglomerular basement membrane disease producing Goodpasture's syndrome primarily injures both the lung and kidney because of the narrow distribution of the α3 NC1 domain of type IV collagen that is the target antigen.
Log In to View More
If you don't have a subscription, please view our individual subscription options
below to find out how you can gain access to this content.
Want access to your institution's subscription?
Sign in to your MyAccess Account while you are actively authenticated on this website
via your institution (you will be able to tell by looking in the top right corner
of any page – if you see your institution’s name, you are authenticated). You will
then be able to access your institute’s content/subscription for 90 days from any
location, after which you must repeat this process for continued access.
If your institution subscribes to this resource, and you don't have a MyAccess account,
please contact your library's reference desk for information on how to gain access
to this resource from off-campus.
AccessMedicine Full Site: One-Year Subscription
Connect to the full suite of AccessMedicine content and resources including more than 250 examination and procedural videos, patient safety modules, an extensive drug database, Q&A, Case Files, and more.
Pay Per View: Timed Access to all of AccessMedicine
48 Hour Subscription
Pop-up div Successfully Displayed
This div only appears when the trigger link is hovered over.
Otherwise it is hidden from view.