Nephritic Syndrome & Glomerulonephritis

Here we'll learn about the nephritic syndrome, associated histopathological patterns, and key etiologies. For a review of healthy renal filtration and urine formation, please see the links in our notes. Nephritic syndrome is characterized by inflammation and damage to the filtration barrier that leads to hematuria. Glomerulonephritis refers to a group of renal inflammatory diseases that can produce nephritic syndrome. Glomerulonephritis pathophysiology Review glomerular histology Immune complexes deposit within the mesangium, between the podocytes and glomerular basement membrane, or on the capillaries (the location depends on size and charge of the immune complexes). The immune complexes can travel in the circulation already formed, or they can arise from circulating antibodies that bind antigens within the glomerulus. The deposited immune complexes activate complement and trigger inflammation with leukocyte infiltration, which leads to cellular injury and glomerular basement membrane degradation. Inflammation can have immune- or pauci-immune-mediated etiologies: It can be primary or secondary to another disorder, such as lupus. It can be acute or chronic; in chronic conditions, repeated cycles of inflammation and healing lead to fibrosis and crescent formation, as we'll soon see. Sporadic acute inflammation progresses to chronic in approximately 30% of adults. Inflammation and basement membrane degradation lead to hematuria, the leakage of red blood cells into the urine; we often see mild proteinuria, too (usually sub-nephrotic levels, but occasionally the conditions co-occur). Dysmorphic red blood cells and red blood cell casts in the urine (along with some proteins) and reduced glomerular filtration rate (GFR). The reduced GFR leads to water and salt retention, which produces oliguria, azotemia, and volume overload; Volume overload, in turn, leads to edema and hypertension. Be aware that these patterns are not diagnostic, but they can help us exclude some etiologies and determine disease severity. Furthermore, some patterns are found in both nephritic and nephrotic conditions (which is why we rely on other variables, like the presence or absence of immune complexes in diagnosis). Lesions can be focal or diffuse: if more than 50% of glomeruli are affected, the lesion is diffuse. Lesions can be segmental or global: segmental affects only part of (segments of) the glomerulus, whereas global affects the entire glomerulus. Lesions are often characterized as membranoproliferative or proliferative: in both types, we see hypercellularity with overgrowth of mesangium and/or endothelial cells, but in membranoproliferative, the glomerular basement membrane is also involved. Rapidly progressive glomerulonephritis, aka, crescentic glomerulonephritis, is a complication of other glomerular diseases characterized by rapidly deteriorating renal function (within days to weeks) and poor prognosis. Though rare overall, this finding should prompt immediate treatment to avoid renal failure. In light microscopy we see ruptured basement membranes with crescent-moon shapes occupying the glomerular space; the crescents comprise fibrin and plasma proteins, with parietal cells, monocytes, macrophages. See histopathology sample Membranoproliferative patterns are characterized by mesangial hypercellularity and capillary wall thickening due to subendothelial extension of the mesangium. The glomerular basement membrane "splits," forming a double contour or "tram-track" appearance; this is the result of the proliferative response, which traps immune complexes between the old and new basement membrane. See histopathology sample Membranoproliferative patterns are commonly seen in chronic glomerulonephritis and autoimmune conditions. Be aware that there are subtypes of this histopathological pattern, but details are beyond the scope of this tutorial. Diffuse proliferative pattern is characterized by mesangial and/or capillary proliferation, but the basement membrane is not involved. Instead, look for "wire looping" capillaries. Recall that "diffuse" means that more than 50% of the glomeruli show this pattern. See histopathology sample Diffuse proliferative histopathology is associated with IgA nephropathy and systemic lupus erythematosus, among other conditions. Other histopathological patterns associated with glomerulonephritis include exudative, necrotic, sclerosing, and mixed. Immune-complex, pauci-immune, and hereditary. Diagnosis of a specific disorder often relies on immunofluorescence microscopy, which can tell us if immune complexes are present. IgA nephropathy, aka, Berger disease, is the most common primary glomerular disease. It is characterized by excessive circulating IgA, which deposits in the mesangium. The specific causes of this disorder are uncertain, but it's thought to have multi-hit origins with both genetic and environmental components. Notably, hematuria tends to occur after or during a respiratory illness. Prognosis is poor, and IgA nephropathy often leads to end-stage renal disease. There is no cure for the disorder, but ACE inhibitors, ARBs, and corticosteroids are often used in supportive care. IgA vasculitis, aka Henoch-Schölein purpua, is characterized by IgA collection in the small blood vessels, which leads to inflammation and leakage. This disorder has multi-organ manifestations, and often produces a rash of purple spots where vessels under the skin leak blood (purpura). Most patients recover on their own, but some can develop chronic nephritis. Triggers for IgA vasculitis include infections, medicines, and foods. To learn more about small vessel vasculitis, please review here. Some authors suggest that IgA nephropathy and IgA vasculitis are the same disease entity with varied clinical manifestations, given that both involve IgA deposits in the kidneys; why some patients also have systemic manifestations is unclear. Infection-related glomerulonephritis (aka, post-infectious glomerulonephritis) is a Type II hypersensitivity reaction to certain infections. In children, the reaction most often appears 2-4 weeks after Group A streptococcal infection (hence, it's often referred to as post-streptococcal glomerulonephritis). In adults, it most often occurs concurrently with Group A streptococcal or staphylococcus infections. Helpful diagnostic indicator: Approximately 90% of patients with infection-related glomerulonephritis have elevated anti-streptolysin O titer, which is indicative of a pervious streptococcal infection. A common histopathological finding is "humps" on the epithelial side of the glomerular basement membrane on electron microscope; however, these humps are found in other renal disorders and are not conclusive. Lupus nephritis, which often co-exists with nephrotic syndrome, is also caused by immune-complex deposition in the glomeruli. There are 6 subtypes of lupus nephritis; details are this is beyond the scope of this tutorial. Another autoimmune disorder characterized by small vessel vasculitis; in this version, we see linear IgG deposition along the basement membrane. When basement membranes in the lungs are also involved, we call this Goodpasture's syndrome. In addition to nephritic syndrome, these patients also have hemorrhaging from the alveolar capillaries. Timely diagnosis and treatment with plasma exchange and corticosteroids improve prognosis; otherwise, this disorder proceeds to rapidly progressing GN (crescentic GN). Includes PR3-ANCA, MPO-ANCA, and ANCA-negative glomerulonephritis. As the name suggests, these disorders are associated with few or no immune complexes; instead, we see antibodies to proteinase 3 (PR3- ANCA) or myeloperoxidase (MPO-ANCA). Includes proliferative glomerulonephritis and monoclonal deposition disease (often with IgG deposition, but other antibodies have also been found). Characterized by excessive activation of the alternative complement pathway.

• C3 glomerulonephritis
• Dense deposit disease

Basement membrane is affected. Thin basement membrane disease is one example. Alport syndrome is another: Caused by a mutation in type IV collagen that leads to irregular thinning, thickening, and glomerular basement membrane splitting. Genes involved in this disorder include COL4A3, COL4A4, and COL4A5.

• Alport syndrome is usually X-linked and therefore more severe in males.

The classic triad consists of eye pathologies (retinopathy), glomerulonephritis, and sensorineural deafness –easily recalled with the rhyme: "can't see, can't pee, can't hear a bee" (although full vision loss is rare).

• For references, please see full tutorial.