Case 1: Nephritic Syndrome Flashcards
POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
● Poststreptococcal glomerulonephritis is prototypical for acute endocapillary proliferative glomerulonephritis. The incidence of this disease has dramatically decreased in developed countries and in these locations is typically sporadic; epidemics are less common.
● Acute poststreptococcal glomerulonephritis in underdeveloped countries usually affects children between the ages of 2 and 14 years, but in developed countries is more typical in the elderly, especially in association with debilitating conditions.
● It is more common in males, and the familial or cohabitant incidence is as high as 40%. Skin and throat infections with particular M types of streptococci (nephritogenic strains) antedate glomerular disease; M types 47, 49, 55, 2, 60 and 57 are seen following impetigo and M types I, 2, 4, 3, 25, 49, and 12 with pharyngitis.
Poststreptococcal glomerulonephritis due to impetigo develops 2-6 weeks after skin infection and I-3 weeks after streptococcal pharyngitis.(Harrisson’s Internal Medicine 18th ed.)
● By light microscopy, the most characteristic change in postinfectious GN is a fairly uniformly increased cellularity of the glomerular tufts that affects nearly all glomeruli, hence the term “diffuse”. The increased cellularity is caused both by proliferation and swelling of endothelial and mesangial cells and by a neutrophilic and monocytic infiltrate. Sometimes there is necrosis of the capillary walls.
● In a few cases there may also be “crescents” (described next) within the urinary space in response to the severe inflammatory injury. In general, these findings are ominous. Electron microscopy shows deposited immune complexes arrayed as subendothelial, intramembranous, or, most often, subepithelial “humps” nestled against the GBM. Mesangial deposits are also occasionally present.
● Immunofluorescence studies reveal scattered granular deposits of lgG and complement within the capillary walls and some mesangial areas, corresponding to the deposits visualized by electron microscopy. These deposits are usually cleared over a period of about 2 months. (Robbins Basic Pathology 8th ed.)
● The classic presentation is an acute nephritic picture with hematuria, pyuria, red blood cell casts, edema, hypertension, and oliguric renal failure, which may be severe enough to appear as RPGN. Systemic symptoms of headache, malaise, anorexia, and flank pain (due to swelling of the renal capsule) are reported in as many as 50% of the cases. Five percent of children and 20% of adults have proteinuria in the nephrotic range. In the first week of symptoms, 90% of patients will have a depressed CH50 and decreased levels of C3 with normal levels of C4.
● Positive rheumatoid factor (30-40%), cryoglobulins and circulating immune complexes (60-70%), and ANCA against myeloperoxidase (10%) are also reported. Positive cultures for streptococcal infection are inconsistently present (10-70%), but increased titers of ASO (30%), anti-DNAse, (70%), or antihyaluronidase antibodies (40%) can help confirm the diagnosis.
● Consequently, the diagnosis of poststreptococcal glomerulonephritis rarely requires a renal biopsy. A subclinical disease is reported in some series to be four to five times as common as clinical nephritis, and these latter cases are characterized by asymptomatic microscopic hematuria with low serum C3 complement levels.
● Treatment is supportive, with control of hypertension, edema, and dialysis as needed. Antibiotic treatment for streptococcal infection should be given to all patients and their cohabitants. There is no role for immunosuppressive therapy, even in the setting of crescents. Recurrent poststreptococcal glomerulonephritis is rare despite repeated streptococcal infections.
● Early death is rare in children but does occur in the elderly. Overall, the prognosis is good, with permanent renal failure being very uncommon, less than 1% in children.
● Complete resolution of the hematuria and proteinuria in the majority of children occurs within 3-6 weeks of the onset of nephritis but 3-10% of children may have persistent microscopic hematuria, non-nephrotic proteinuria, or hypertension.
● The prognosis in elderly patients is worse with a high incidence of azotemia (60%), nephrotic-range proteinuria and end-stage renal disease. (Harrisson’s Internal Medicine 18th ed.)
SUBACUTE BACTERIAL ENDOCARDITIS
● Endocarditis-associated glomerulonephritis is typically a complication of subacute bacterial endocarditis, particularly in patients who remain untreated for a long time, have negative blood cultures, or have right-sided endocarditis.
● Glomerulonephritis is unusual in acute bacterial endocarditis because it takes 10-14 days to develop immune complex-mediated injury, by which time the patient has been treated, often with emergent surgery. Grossly, the kidneys in subacute bacterial endocarditis have subcapsular hemorrhages with a “flea-bitten” appearance, and microscopy on renal biopsy reveals focal proliferation around foci of necrosis associated with abundant mesangial, subendothelial, and subepithelial immune deposits of lgG, IgM, and C3. Patients who present with a clinical picture of RPGN have crescents
● Embolic infarcts or septic abscesses may also be present. The pathogenesis hinges on the renal deposition of circulating immune complexes in the kidney with complement activation. Patients present with gross or microscopic hematuria, pyuria, and mild proteinuria, or less commonly, RPGN with rapid loss of renal function.
● A normocytic anemia, elevated erythrocyte sedimentation rate, hypocomplementemia, high titers of rheumatoid factor, type Ill cryoglobulins, and circulating immune complexes are often present. Levels of serum creatinine may be elevated at diagnosis, but with modem therapy there is little progression to chronic renal failure.
● Primary treatment is eradication of the infection with 4-6 weeks of antibiotics, and if accomplished expeditiously, the prognosis for renal recovery is good ANCA-associated vasculitis sometimes accompanies or is confused with subacute bacterial endocarditis (SBE) and should be ruled out, as the treatment is different.
● As variants of persistent bacterial infection in blood, glomerulonephritis can occur in patients with ventriculoatrial and ventriculoperitoneal shunts, pulmonary, intraabdominal, pelvic, or cutaneous infections; infected vascular prostheses.
● The clinical presentation of these conditions is variable and includes proteinuria, microscopic hematuria, and acute renal failure. Blood cultures are usually positive and serum complement levels low, and there may be elevated levels of C-reactive proteins, rheumatoid factor, antinuclear antibodies, and cryoglobulin.
● Renal lesions include membranoproliferative glomerulonephritis (MPGN), diffuse proliferative glomerulonephritis (DPGN), or mesangioproliferative glomerulonephritis, sometimes leading to RPGN.
● Treatment focuses on eradicating the infection, with most patients treated as if they have endocarditis.
LUPUS NEPHRITIS
● Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE) and most severe in African-American female adolescents. Thirty to fifty percent (30-50%) of patients will have clinical manifestations of renal disease at the time of diagnosis, and 60% of adults and 80% of children develop renal abnormalities at some point in the course of their disease.
● Lupus nephritis results from the deposition of circulating immune complexes, which activate the complement cascade leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of various cytokines.
● In situ immune complex formation following glomerular binding of nuclear antigens, particularly necrotic nucleosomes, also plays a role in renal injury. The presence of antiphospholipid antibodies may also trigger a thrombotic microangiopathy in a minority of patients.
● The clinical manifestations, course of disease, and treatment of lupus nephritis are closely linked to renal pathology. The most common clinical sign of renal disease is proteinuria, but hematuria, hypertension, varying degrees of renal failure, and active urine sediment with red blood cell casts can all be present.
● Although significant renal pathology can be found on biopsy even in the absence of major abnormalities in the urinalysis, most nephrologists do not biopsy patients until the urinalysis is convincingly abnormal.
● The extrarenal manifestations of lupus are important in establishing a firm diagnosis of systemic lupus because, while serologic abnormalities are common in lupus nephritis, they are not diagnostic, Anti-dsDNA antibodies that fix complement correlate best with the presence of renal disease.
● Hypocomplementemia is common in patients with acute lupus nephritis (70-90%) and declining complement levels may herald a flare. Although urinary biomarkers of lupus nephritis are being identified to assist in predicting renal flares, renal biopsy is the only reliable method of identifying the morphologic variants of lupus nephritis.
● Class I nephritis describes normal glomerular histology by any technique or normal light microscopy with minimal mesangial deposits on immunofluorescent or electron microscopy. Class Il designates mesangial immune complexes with mesangial proliferation.
● Both class I and Il lesions are typically associated with minimal renal manifestation and normal renal function nephrotic syndrome is rare. Patients with lesions limited to the renal mesangium have an excellent prognosis and generally do not need therapy for their lupus nephritis.
● The subject of lupus nephritis is presented under acute nephritic syndromes because of the aggressive and important proliferative lesions seen in class Ill-V renal disease. Class Ill describes focal lesions with proliferation or scarring, often involving only a segment of the glomerulus.
● Class Ill lesions have the most varied course. Hypertension, and active urinary sediment, and proteinuria are common with nephrotic-range proteinuria in 25-33% of patients.
● Elevated serum creatinine is present in 25% of patients. Patients with mild proliferation involving a small percentage of glomeruli respond well to therapy with steroids alone, and fewer than 5% progress to renal failure over 5 years.
● Patients with more severe proliferation involving a greater percentage of glomeruli have a far worse prognosis and lower remission rates. Treatment of those patients is the same as that for class IV lesions. Most nephrologists believe that class Ill lesions are simply an early presentation of a class IV disease.
● Others believe severe class Ill disease is a discrete lesion also requiring aggressive therapy. Class IV describes global diffuse proliferative lesions involving the vast majority of glomeruli. Patients with class IV lesions commonly have high anti-DNA antibody titers, low serum complement, hematuria, red blood cell casts, proteinuria, hypertension and decreased renal function; 50% of patients have nephrotic-range proteinuria. Patients with crescents on biopsy often have a rapidly progressive decline in renal function.
● Without treatment, this aggressive lesion has the worst renal prognosis. However, if a remission-defined as a return to near-normal renal function and proteinuria <330 mg/dL per day — is achieved with treatment, renal outcomes are excellent.
● Current evidence suggests that inducing a remission with administration of high-dose steroids and either cyclophosphamide or mycophenolate mofetil for 2-6 months, followed by maintenance therapy with lower doses of steroids and mycophenolate mofetil, best balances the likelihood of successful remission with the side effects of therapy.
● There is no consensus on use of high-dose intravenous methylprednisolone versus oral prednisone, monthly intravenous cyclophosphamide or other immunosuppressants such as cyclosporine, tacrolimus, rituximab, or azathioprine.
● The class V lesion describes subepithelial immune deposits producing a membranous pattern; a subcategory of class V lesions is associated with proliferative lesions and is sometimes called mixed membranous and proliferative disease; this category of injury is treated like class IV glomerulonephritis.
● Sixty percent of patients present with nephrotic syndrome or lesser amounts of proteinuria. Patients with lupus nephritis class V, like patients with idiopathic membranous nephropathy, are predisposed to renal-vein thrombosis and other thrombotic complications.
● A minority of patients with class V will present With hypertension and renal dysfunction. Patients with severe nephrotic syndrome, elevated serum creatinine, and a progressive course will probably benefit from therapy with steroids in combination with other immunosuppressive agents.
● Therapy with inhibitors of the renin-angiotensin system also may attenuate proteinuria. Antiphospholipid antibodies present in lupus may result in glomerular microthrombosis and complicate the course in up to 20% of lupus nephritis patients. The renal prognosis is worse even with anticoagulant therapy.
ANTIGLOMERULAR BASEMENT MEMBRANE DISEASE
● Patients who develop autoantibodies directed against glomerular basement antigens frequently develop a glomerulonephritis termed anti glomerular basement membrane disease (anti-GBM) disease. When they present with lung hemorrhage and glomerulonephritis, they have a pulmonary renal syndrome called Goodpasture’s syndrome.
● The target epitopes for this autoimmune disease lie in the quatemary structure of a3 NCI domain of collagen IV. MHC-restricted T cells initiate the autoantibody response because humans are not tolerant to the epitopes created by this quaternary structure.
● The epitopes are normally sequestered in the collagen IV hexamer and can be exposed by infection, smoking, oxidants, and solvents.
● Goodpasture’s syndrome appears in two age groups: in young men in their late 20s and in men and women in their 60-70s. Disease in the younger age group is usually explosive, with hemoptysis, a sudden fall in hemoglobin, fever, dyspnea, and hematuria.
● Hemoptysis is largely confined to smokers, and those who present with lung hemorrhage as a group do better than older populations who have prolonged, asymptomatic renal injury; presentation with oliguria is often associated with a particularly bad outcome. The performance of an urgent kidney biopsy is important in suspected cases of Goodpasture’s syndrome to confirm the diagnosis and assess prognosis. (Harrison’s Internal Medicine 18th ed. )
● The kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. Glomeruli show segmental necrosis and GBM breaks, with resulting proliferation of the parietal epithelial cells in response to the exudation of plasma proteins including fibrin into Bowman’s space. These distinctive lesions of proliferation are called crescents due to their shape as they fill Bowman’s space.
● Crescents are formed both by proliferation of parietal cells and by migration of monocytes/macrophages into Bowman’s space (Fig. 14-12). Smaller numbers of other types of leukocytes may also be present. The uninvolved portion of the glomerulus shows no proliferation. Immunofluorescence is characteristic with strong linear staining of deposited IgG and C3 along the GBM.
● However, deposits are not visualized by electron microscopy, because the endogenous collagen IV antigen to which the antibody is reacting is diffusely distributed, and so the large lattices of antigens and antibodies that occur in deposited immune complexes are not formed.
● Electron microscopy may show distinct ruptures in the GBM. The crescents eventually obliterate Bowman’s space and compress the glomeruli. Fibrin strands are prominent between the cellular layers in the crescents. In time, crescents may undergo scarring. (Robbin’s Clinical Pathology 8’ ed.)
● The presence of anti-GBM antibodies and complement is recognized on biopsy by linear immunofluorescent staining for IgG. In testing serum for anti-GBM antibodies, it is particularly important that the a3 NCI domain of collagen IV alone be used as the target. Between 10 and 15% of sera from patients with Goodpasture’s syndrome also contain ANCA antibodies against myeloperoxidase.
● This subset of patients has a vasculitis-associated variant which surprisingly has a good prognosis with treatment. Prognosis at presentation is worse if there are >50% crescents on renal biopsy with advanced fibrosis, if serum creatinine is >5-6 mg/dL, if oliguria is present, or if there is a need for acute dialysis.
● Although frequently attempted, most of these latter patients will not respond to plasmapheresis and steroids. Patients with advanced renal failure who present with hemoptysis should still be treated for their lung hemorrhage, as it responds to plasmapheresis and can be lifesaving.
● Treated patients with less severe disease typically respond to 8-10 treatments of plasmapheresis accompanied by oral prednisone and cyclophosphamide in the first 2 weeks.
● Kidney transplantation is possible but because there is a risk of recurrence, experience suggests that patients should wait for 6 months and until serum antibodies are undetectable. (Harrison’s Internal Medicine 18th ed.)
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
● MPGN is sometimes called mesangiocapillary glomerulonephritis or lobar glomerulonephritis.
● It is an immune-mediated glomerulonephritis characterized by thickening of the GBM with mesangioproliferative changes; 70% of patients have hypocomplementemia. MPGN is rare in African Americans, and idiopathic disease is usually present in childhood or young adulthood. MPGN is subdivided pathologically into Type l, Type Il, and Type Ill disease.
● Type I MPGN is commonly associated with persistent Hepatitis C infections, autoimmune diseases like Lupus or cryoglobulinemia, or neoplastic diseases. Types Il and Ill MPGN are usually idiopathic, except in the presence of C3 nephritic factor and/or in partial lipodystrophy producing Type Il disease or complement receptor deficiency in Type Ill disease.
● Type I MPGN, the most proliferative of the three types, shows mesangial proliferation with lobular segmentation on renal biopsy and mesangial interposition between the capillary basement membrane and endothelial cells, producing a double contour sometimes called tram-tracking.
● Subendothelial deposits with low serum levels of C3 are typical, although 50% of patients have normal levels of C3 and occasional intra-mesangial deposits.
● Low serum C3 and a dense thickening of the GBM containing ribbons of dense deposits and C3 characterize Type Il MPGN, sometimes called dense deposit disease.
● Classically, the glomerular tuft has a lobular appearance; intra mesangial deposits are rarely present and subendothelial deposits are generally absent. Proliferation in Type Ill MPGN is less common than the other two types and is often focal; mesangial interposition is rare, and subepithelial deposits can occur along widened segments of the GBM that appear laminated and disrupted.
● Type I MPGN is secondary to glomerular deposition of circulating immune complexes or their in situ formation. Types Il and Ill MPGN may be related to “nephritic factors,” which are autoantibodies that stabilize C3 convertase and allow it to activate serum C3.
● Patients with MPGN present with proteinuria, hematuria, and pyuria (30%), systemic symptoms of fatigue and malaise that are most common in children with Type I disease, or an acute nephritic picture with RPGN and a speedy deterioration in renal function in up to 25% of patients.
● Low serum C3 levels are common. Fifty percent of patients with MPGN develop end-stage disease 10 years after diagnosis and 90% have renal insufficiency after 20 years. Nephrotic syndrome, hypertension, and renal insufficiency all predict poor outcomes.
● In the presence of proteinuria, treatment with inhibitors of the renin-angiotensin system is prudent. (Harrisson’s Internal Medicine 18th ed )
● By light microscopy, both types of MPGN are similar. The glomeruli are large, with an accentuated lobular appearance, and show proliferation of mesangial and endothelial cells as well as infiltrating leukocytes.
● The GBM is thickened, and the glomerular capillary wall often shows a double contour, or “tram track,” appearance, especially evident in silver or periodic acid-Schiff (PAS) stains. This is caused by “splitting” of the GBM due to the inclusion within it of processes of mesangial and inflammatory cells extending into the peripheral capillary loops.
● Types I and Il have different ultrastructural and immunofluorescence microscopic features. Type I MPGN is characterized by discrete subendothelial electron-dense deposits.
● By immunofluorescence microscopy, C3 is deposited in an irregular granular pattern, and lgG and early complement components (C1q and C4) are often also present, indicative of an immune complex pathogenesis.
● In type Il lesions the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbon-like, extremely electron-dense structure, resulting from the deposition of material of unknown composition, giving rise to the term dense-deposit disease.
● C3 is present in irregular chunky and segmental linear foci in the basement membranes and in the mesangium in characteristic circular aggregates (mesangial rings).
● lgG is usually absent, as are the early components of the classical complement pathway (Clq and C4). (Robbins Clinical Pathology 8”’ ed.)
● Evidence for treatment with dipyridamole, Coumadin, or cyclophosphamide is not strongly established nor recommended There is some evidence supporting the efficacy of treatment of primary MPGN With steroids, particularly in children.
● In secondary MPGN, treating the associated infection, autoimmune disease, or neoplasms is of demonstrated benefit. Although all primary renal diseases can recur over time in transplanted renal allografts, patients with MPGN are well known to be at risk for this adverse event (Harrisson’s Internal Medicine 18th ed.)
MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS
● Mesangioproliferative glomerulonephritis is characterized by expansion of the mesangium, sometimes associated with mesangial hypercellularity; thin, single contoured capillary walls; and mesangial immune deposits.
● Clinically, it can present with varying degrees of proteinuria and, commonly, hematuria. Mesangioproliferative disease may be seen in IgA nephropathy, P. falciparum malaria, resolving postinfectious glomerulonephritis, and Class Il nephritis from lupus, all of which can have a similar histologic appearance.
● With these secondary entities excluded, the diagnosis of primary mesangioproliferative glomerulonephritis is made in less than 15% of renal biopsies.
● As an immune-mediated renal lesion with deposits of IgM, Clq, and C3, the clinical course is variable. Patients with isolated hematuria may have a very benign course, and those with heavy proteinuria occasionally progress to renal failure.
● There is little agreement on treatment. but some clinical reports suggest benefit from use of inhibitors of the renin-angiotensin system, steroid therapy, and even cytotoxic agents.
