Figure 62.1. Hematuria workup.

ISOLATED NONNEPHROTIC PROTEINURIA

Isolated nonnephrotic proteinuria is defined as proteinuria >150 mg/dL (60% of which is usually albuminuria). Figure 62.2 depicts causes of functional and persistent proteinuria. A renal biopsy is rarely indicated in those with low-grade proteinuria (<500–1000 mg/day) if there is an absence of hematuria, absence of clinical or serological evidence of systemic disease that can cause a glomerulonephritis, and normal renal function (Figure 62.2).

NEPHROTIC SYNDROME

The nephrotic syndrome is defined as heavy proteinuria (≥3.5 g/day/1.73 m² surface area), edema, hypoalbuminemia, and hyperlipidemia.

    Causes of nephrotic syndrome are shown in box 62.1. The most common causes of the nephrotic syndrome in adults are primary focal and segmental glomerulosclerosis and membranous glomerulonephritis. In children, the most common cause of nephrotic syndrome is minimal change disease. Selected causes of nephrotic syndrome are discussed below.

Box 62.1 CAUSES OF NEPHROTIC SYNDROME

ACUTE NEPHRITIC SYNDROME

This is characterized by hematuria, red cell casts, azotemia, variable proteinuria, oliguria, edema, and hypertension. It is often caused by a systemic disease that requires a renal biopsy to establish its diagnosis and guide treatment. The classic example of this is acute postinfectious glomerulonephritis. Examples include systemic lupus erythematosus (SLE), microscopic polyangiitis, Wegener’s granulomatosis (granulomatosis with polyangitis), and antiglomerular basement membrane (GBM) disease.

UNEXPLAINED ACUTE KIDNEY INJURY

Most often the diagnosis is not based on a renal biopsy. Biopsy is indicated in those settings in which the diagnosis is uncertain, as may sometimes be the case with acute interstitial nephritis secondary to drugs.

IMPORTANT CAUSES OF NEPHROTIC SYNDROME

Minimal Change Disease

Minimal change disease (MCD), is a major cause of nephrotic syndrome in children and accounts for 15–20% of adult cases. The exact underlying cause of MCD is unclear. Accumulating evidence suggests that systemic T-cell dysfunction results in the production of a circulating permeability factor or cytokine abnormality. IL-13, an antiinflammatory Th2 cytokine, is implicated. These circulating factors directly affect the podocytes, resulting in foot process effacement and marked proteinuria. While idiopathic (primary) MCD is the most common form, secondary forms of MCD occur in various settings that include Hodgkin disease and other lymphoproliferative disorders, allergic response (bee sting, immunization, drugs such as NSAIDs) and infections (HIV).

    The abrupt onset of a nephrotic syndrome (glomerular proteinuria >3.5 g/day in an adult or >40 mg/hour/m² in a child, hypoalbuminemia, and edema) is the typical presentation of MCD. Hematuria and/or hypertension may be present in about 20% of cases. Renal function (as evaluated by either serum creatinine or estimated glomerular filtration rate [eGFR]) is usually normal, but 15–30% of adults (usually over the age of 40 years) may present with or develop acute kidney injury.

    The renal pathology is characterized by minimal or absent glomerular abnormalities by light or immunofluorescent microscopy (Figure 62.3). The most consistent observation is seen on electron microscopy: simplification of the visceral epithelial cells with widespread and diffuse effacement of the podocyte foot processes.

    Treatment is with a trial of prednisone at 1 mg/kg/day. The response to steroids is usually dramatic. Treatment in children consists of prednisone 60 mg/m²/day (maximum doses of 80 mg/m²/day) until a remission has been induced (or for 4 weeks, whichever is shorter) and then 35–40 mg/m² every other day for about 12 weeks followed by slow tapering. Adults with established MCD are treated with prednisone 1 mg/kg/day until remission (or for 6 weeks, whichever is shorter) followed by slow tapering. Treatment is generally continued for about 8 weeks in children and 16 weeks in adults, with slow tapering thereafter. About 95% of children and about 90% of adults will respond with a complete remission of proteinuria with this initial regimen, earlier in children and later in adults. However, many patients (40–60%) will relapse either during the tapering phase of treatment (steroid-dependent relapses) or weeks, months, or even years later. Intercurrent infections or allergies may trigger a relapse. Some patients have frequent relapses (>2 year) and require repeated courses of therapy.

Focal and Segmental Glomerulosclerosis

This is a pattern of injury that results from glomerular podocyte injury. The broad category includes primary and secondary forms of focal and segmental glomerulosclerosis (FSGS). Primary FSGS is a clinicopathological diagnosis characterized by the absence of clinical or histological evidence of an antecedent glomerulonephritis, immune complex deposition, or systemic disease with glomerular involvement. The primary form of FSGS is due to podocyte injury of unknown cause. Secondary forms of FSGS may be due to familial/genetic abnormalities (α-actinini-4 mutations), drug-induced (heroin, pamidronate), adaptive structural and functional responses of the glomerulus (in the setting of reduced nephron mass such as renal agenesis, dysplasia, cortical necrosis, oligomeganephronia) or normal nephron mass (e.g., obesity, hypertension) or viruses (HIV).

    The typical clinical presentation is with the insidious onset of nonnephrotic proteinuria or the nephrotic syndrome. Hypertension and renal insufficiency are common at the time of presentation. Urinary protein excretion may be very high, sometimes in excess of 20 g/day, and the proteinuria is nonselective with a high fractional excretion of IgG (often >0.2). Serum complement components are normal.

    It is important to differentiate primary from secondary forms of FSGS. A history of sub-nephrotic–range proteinuria, slower onset of symptoms, and predisposing factors accompanied by typical biopsy findings are useful in making the diagnosis of secondary FSGS.

    Renal biopsy findings of FSGS are variable. There are several histological variants:collapsing, tip, cellular, perihilar and FSGS (NOS). In FSGS (NOS) there is at least one glomerulus with segmental matrix expansion with obliteration of capillary lumina (Figure 62.4). The collapsing variant, observed in HIV-associated nephropathy, is less common and shows collapse of the segment or entire glomerular tuft with hyperplasia and hypertrophy of the overlying podocytes. In the tip variant, electron microscopy is useful to differentiate primary and secondary forms of FSGS. In primary forms of FSGS, in addition to the abnormalities on light microscopy, there are distinct abnormalities on electron microscopy—diffuse effacement of epithelial cell foot processes even in areas where there are no light microscopic abnormalities and an electron microscopy in the absence of microvillous degeneration, and focal detachment of foot processes from the GBMs. Secondary FSGS is characterized by relative preservation of the podocyte foot processes in nonsclerosed glomeruli.

    Unlike MCD, FSGS is generally resistant to steroid therapy. If steroids are used alone, oral prednisone in a dose of 1 mg/kg/day or 2 mg/kg every other day is given for 2–3 months with slow tapering over another 2–3 months. However, only about one-half of the patients respond to steroid therapy, and patients frequently need adjunctive therapy, such as cyclosporine (4–5 mg/kg/day for 3–6 months). Treatment resistance (lack of a complete or partial remission) is strongly associated with a high risk of progression to end-stage renal disease (ESRD), which may be very rapid if proteinuria is in excess of 15–20 g/day. Patients with FSGS may relapse after a complete or partial remission. A higher incidence of recurrence after transplantation is also present.

Membranous Glomerulopathy

Membranous nephropathy (MN) is among the most common causes of the nephrotic syndrome in nondiabetic adults over age 40 years. MN can be primary/ idiopathic (75–85% of adults). Only about 25% of children with MN have the idiopathic form.

    Autoantibodies to PLA₂R on podocyte is detected in up to 70% of primary MN. MN may be secondary to other diseases such as hepatitis B antigenemia, autoimmune diseases, thyroiditis, malignancies, the use of certain drugs such as gold, penicillamine, captopril, and nonsteroidal antiinflammatory drugs, and more recently it has been associated with IgG4 related diseases.

    MN may affect all age groups but has a peak incidence in the 40s and 50s. It has no racial predilection. At presentation, 60–70% of patients have the nephrotic syndrome with the remainder having subnephrotic proteinuria (<3.5 g/ 24 hours). Microscopic hematuria is common (30–40%), but macroscopic hematuria and red cell casts are rare. At presentation, most patients are not hypertensive (<20%), and most do not have renal insufficiency (<20%). In patients with severe nephrotic syndrome, clinical manifestations of hypercoagulability may arise (deep venous thrombosis, pulmonary embolism, or renal vein thrombosis).

    On renal biopsy the characteristic lesion on light microscopy is a diffuse uniform and global thickening of the GBM in the absence of significant mesangial or endocapillary hypercellularity (Figure 62.5). Spikes and craters are identified on silver stains. The thickness is due to subepithelial deposits with basement membrane response. The basement membrane encases the subepithelial deposits, resulting in “spike formation.” There are four stages of evolution: Stage 1 is irregular subepithelial electron-dense deposits without basement membrane response. When GBM material accumulates between deposits forming spikes, it is stage 2. The basement membrane completely encircles and incorporates the deposits (stage 3) and then resolution of the deposits occurs with partial resorption and areas of lucencies (stage 4).

Treatment with glucocorticoids alone is insufficient therapy for membranous glomerulopathy. Recommended treatment is with a combination of steroids and alkylating agents cyclophosphamide or chlorambucil. The efficacy of mycophenolate mofetil for treatment of MN is unknown. Rituximab, an anti-CD20 monoclonal antibody, has been found efficacious in case series and case reports, and a randomized controlled trial is currently underway. Angiotensin blockade at high doses with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker should be used to treat hypertension and control proteinuria The disease may recur in the renal transplant, but this is relatively uncommon (10–15%).

    The prognosis of MN is very much a function of the quantity of proteinuria. Patients with nephrotic-range proteinuria, over 6 g for over 6 months, tend to pursue a progressive course. Young women with moderate proteinuria tend to do very well; older males fare less well. Spontaneous complete or partial remissions of proteinuria occur in about 40% of patients, usually within 3–5 years of diagnosis. Overall, at 20 years after diagnosis about one-third of patients will have developed ESRD, about one-third will be in remission, and about one-third will have varying levels of persisting proteinuria and renal function. Among those who undergo remission either spontaneously or with drugs, about 67% remain in remission, while the rest either have recurrent relapses without progression to renal failure (20%) or progress to renal insufficiency (13%).

NEPHRITIC SYNDROME

Glomerulonephritis is defined as acute inflammation of the glomerular compartment. Nephritis results from injury to one or more of the cell types or structures that comprise the glomerulus—endothelial, epithelial, or mesangial cells or the basement membrane. Injury can be categorized into several different pathological patterns, which are broadly grouped into nonproliferative or proliferative types. The etiology of these different types of nephritis can be either primary causes, i.e., ones that are intrinsic to the kidney, or secondary causes, which are associated with certain infections (bacterial, viral, or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis), or diabetes (box 62.2). Serological testing for autoantibodies and evaluation of the pattern of hypocomplementemia are usually very helpful in the workup of patients (table 62.1). Ultimately, however, renal biopsy is often necessary to make a definitive diagnosis.

    The nephritic syndrome is characterized by hematuria, red cell casts, azotemia, variable proteinuria, lipiduria, edema, and hypertension.

Box 62.2 CAUSES OF NEPHRITIS

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