a. Pathophysiologic mechanism. While the nephrotic syndrome is mediated by damage to the podocyte (an epithelial cell) and the glomerular basement membrane (GBM), nephritic syndrome occurs as a result of inflammatory damage to the renal endothelium. The main causes share intraglomerular inflammation and include vasculitis, antibody-mediated damage, and immune complex disease.
b. Clinical manifestations of nephritic syndrome. Nephritic syndrome features a constellation of glomerular hematuria, proteinuria (typically in the subnephrotic range), rise in serum creatinine (indicating decreased glomerular filtration or acute kidney injury), and systemic hypertension.
i. Glomerular hematuria and pyuria. The urine sediment must be examined to delineate between glomerular hematuria and hematuria that may relate to problems in the tubular or collecting system. The presence of dysmorphic red blood cells (most classically acanthocytes) or red blood cell casts is always indicative of glomerular hematuria and is the hallmark of the nephritic syndrome. White blood cells (WBCs) or WBC casts may also appear in the urine as a sign of inflammation. When glomerular hematuria, pyuria, or red or white cell casts are present, the urine sediment is often referred to as being “active.”
1. Hematuria may be microscopic but is often macroscopic (patients complain of dark or “smoky” urine).
ii. Proteinuria is typically present in the subnephrotic range.
iii. Renal dysfunction is also typically present and evident by an increased serum creatinine and oliguria, although the degree at presentation and rate at which it changes are variable.
iv. Hypertension and edema may occur from sodium and water retention.
c. Chronicity and terminology. Nephritic syndrome typically presents acutely and in this case may be called an acute glomerulonephritis. If renal function (as measured by the glomerular filtration rate [GFR]) deteriorates over a period of days to weeks, a rapidly progressive glomerulonephritis (RPGN) may be present and is typically associated with crescents on renal biopsy. Some nephritic syndromes can smolder over months to years with no change in the renal function and are thus referred to as a chronic glomerulonephritis.
B. Causes of Acute Nephritic Syndrome
a. Immune complex diseases. Activation of the complement system by immune complexes is usually a cause of low complement (C3 and/or C4 and C1q) levels. This accounts for about half of all cases of RPGN.
i. Systemic diseases
1. Postinfectious glomerulonephritis (most commonly due to streptococcal infection) is the prototype for acute glomerulonephritis. Nephritis usually occurs 1–2 weeks after a pharyngeal or cutaneous infection with a group A (β-hemolytic) streptococcus. Ninety percent of patients will make a full recovery.
2. Systemic lupus erythematosus (SLE). Complement levels are decreased in 75%–90% of patients with SLE. Other manifestations of lupus are usually present as well.
3. Subacute bacterial endocarditis. More than 90% of patients have low complement levels. Blood cultures can usually confirm the diagnosis.
4. Hepatitis C. Most patients have low complement levels, and more than 90% have serum cryoglobulins; hepatitis C antibody is positive in all patients.
5. “Shunt” nephritis is usually caused by infection of a ventriculoperitoneal shunt used to relieve hydrocephalus. As with bacterial endocarditis, sustained bacteremia is the cause of nephritis. Complement levels are low as in bacterial endocarditis.
6. Immunoglobulin A (IgA) nephropathy (Berger’s disease), is an immune complex disease with normocomplementemia. IgA protein complex deposition is the mechanism of renal impairment seen with Henoch-Schönlein purpura.
a. IgA nephropathy can present as gross hematuria (lasting 2–6 days) that occurs a few days after an upper respiratory tract or gastrointestinal infection (termed “synpharyngitic”), as opposed to the hematuria that occurs with postinfectious glomerulonephritis (after 7–21 days).
b. Progression to renal failure occurs in up to one-third of patients within 20 years. Up to one-third of patients will fully recover renal function. Renal function in the last one-third typically remains stable.
Most, but not all, causes of immune complex-associated nephritic syndrome can be identified by complement activation and consumption. These causes of hypocomplementemic nephritic syndrome can be remembered by the (admittedly silly) mnemonic, “She Saw Sally Cook Poisoned Macaroni.”
MNEMONIC: (“She Saw Sally Cook Poisoned Macaroni”)
Subacute bacterial endocarditis
Cryoglobulinemia in the setting of hepatitis C
ii. Renal causes
1. Membranoproliferative glomerulonephritis (MPGN) is a disease of children and young adults and is relatively rare.
a. It is classified by specific findings on light microscopy: type I (the most common type, usually with subendothelial deposits), type II (dense deposit disease associated with a higher incidence of hypocomplementemia), or type III (prominent subepithelial and subendothelial deposits).
b. MPGN can also present as nephrotic syndrome and has a generally progressive clinical course with poor outcome.
b. Pauciimmune diseases. These account for approximately 40% of cases of RPGN. These diseases appear as necrotizing glomerulonephritis on renal biopsy but without immune complexes. They frequently involve lung (pulmonary renal syndromes), although can be renal limited. These patients are always normocomplementemic.
i. Small vessel vasculitis syndromes (see Chapter 75). Granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis), Churg-Strauss syndrome, and microscopic polyangiitis can cause acute glomerulonephritis. More than 90% of these patients will have a positive test for antineutrophil cytoplasmic antibody (ANCA) or antibodies directed against proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA).
ii. Primary ANCA-associated glomerulonephritis. While these patients usually present without systemic manifestations, some progress and develop a systemic vasculitis.
c. Anti-GBM–associated diseases account for about 10%–15% of cases of RPGN; patients are always normocomplementemic.
i. Systemic diseases. Goodpasture’s syndrome is characterized by the presence of anti-GBM antibodies, pulmonary hemorrhage, and acute glomerulonephritis. It is caused by serum antibodies that react with glomerular and alveolar basement membranes. The classic clinical presentation is hemoptysis with hematuria.
ii. Renal disease. Anti-GBM associated disease can also be limited to the kidneys.
C. Approach to the Patient
a. Diagnosis. The most important aspect of making the diagnosis of acute glomerulonephritis (after taking the history and performing a physical examination) is to personally examine a freshly voided urine specimen. A spot urine protein-to-creatinine ratio is also important to gauge severity; a ratio of 1 is equivalent to 1 g/day of proteinuria.
b. Categorize the glomerulonephritis. After the diagnosis is made, the search for the underlying cause begins.
i. Laboratory studies. The serum complement (C3 and C4) levels allow classification of the glomerulonephritis as hypocomplementemic or normocomplementemic. Other tests may be useful depending on the clinical setting and include anti–streptolysin O (ASO), antinuclear antibody (ANA), anti-GBM antibody, ANCA titers, serum cryoglobulin, blood cultures, liver function tests, hepatitis serologies (B and C). Remember, Churg-Strauss syndrome is usually associated with eosinophilia.
ii. Renal biopsy is the definitive procedure for diagnosing acute glomerulonephritis. Anticoagulation tests and a complete blood count are necessary before the biopsy.
Acute glomerulonephritis is a medical emergency!
a. Inflammatory renal disorders should be treated with immunosuppressive agents, which typically include immunosuppression with steroids, mTOR inhibitors (e.g., sirolimus), and cytotoxic drugs. Nephritic syndrome due to preformed antibodies may benefit from having those antibodies removed by plasmapheresis, especially in the setting of pulmonary hemorrhage. Newer treatment strategies, such as monoclonal antibodies directed at B cells, have shown promise. If the glomerulonephritis is secondary to a systemic disease, the primary disorder should be treated as well.
b. Indications for hemodialysis are listed in Chapter 37.
c. The patient’s electrolyte status (including blood urea nitrogen [BUN] and creatinine levels), volume status, and blood pressure should be monitored frequently. Hypertension should be treated aggressively to prevent renal injury.
Suggested Further Readings
Chadban SJ, Atkins RC. Glomerulonephritis. Lancet 2005;365:1797–806.Find this resource:
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Workgroup. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:139–274.Find this resource:
Madaio MP, Harrington JT. The diagnosis of acute glomerulonephritis. N Engl J Med 1983;309:1299–302. (Classic Article.)Find this resource: