Nephritic Syndrome

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This patient's case presents the problem of rapidly deteriorating renal function, terminating in uremia with coexistent pulmonary hemorrhage and hemoptysis. The presence of erythrocytes in the urine indicated hemorrhage into the urinary tract. Whereas hemorrhage may occur at any point from the glomerulus to the urethra, the presence of erythrocyte casts localizes the process within the kidney, most likely high in the nephron. Additional evidence of reduced glomerular filtration rate (GFR), namely, rising serum urea nitrogen and creatinine, oliguria, and acidosis (decreased total CO2 and increased anion gap) supports the inference that the glomeruli are the site of injury. The combination of hematuria with manifestations of reduced GFR constitutes the nephritic syndrome, which is the result of diffuse injury to the glomeruli.

Most glomerulopathies are the result of immunological injury of either the immune complex type or antibody-dependent type. The injury may be either a primary manifestation of a disease or part of a systemic process such as Goodpasture's disease.

A hallmark of glomerulonephritis is severe injury to the glomerular filtration apparatus such that erythrocytes are lost into Bowman's space and then appear in the urine. Less severe forms of glomerular injury may allow loss of protein but not of cellular elements. If protein loss is massive, the nephrotic syndrome may result.

Other features of glomerulonephritis are a reduction of blood flow through the glomeruli and a reduction in GFR because of compromise of the capillaries by the inflammatory process. If the injury involves only a few glomeruli, the result is generally asymptomatic hematuria and proteinuria. Alternatively, if the injury is diffuse, the nephritic syndrome results. The nephritic syndrome consists of hematuria plus evidence of reduced GFR. Reduced GFR is accompanied by hypertension, edema, azotemia, oliguria, and electrolyte and acid-base disturbances, most commonly metabolic acidosis and hyperkalemia.

When injury to the glomeruli is particularly severe, activated clotting factors enter Bowman's space with resulting deposition of fibrin. The fibrin appears to stimulate a proliferative response from the parietal epithelial cells and infiltrating macrophages. The capsular proliferation may compress the glomerulus or obstruct the opening into the proximal renal tubule. In either case, severe compromise of nephron function is the result.

Some patients present with the clinical and laboratory findings of acute nephritis and suffer a progressive loss of renal function over a matter of weeks. The clinical term rapidly progressive glomerulonephritis (RPGN) is then used. Frequently these patients have severe oliguria or even anuria. Electrolyte disturbances, particularly hyperkalemia, may become an urgent problem, and metabolic acidosis may develop as seen in this patient.

In early glomerulonephritis, tubular function may remain relatively unchanged, and the urine and serum biochemical pattern can resemble prerenal causes of azotemia with concentrated, low-sodium urine and an increased serum urea nitrogen/creatinine ratio due to tubular reabsorption of Na+ and urea. As injury progresses, the urine becomes more isosthenuric (specific gravity of urine similar to that of unmodified glomerular filtrate, 1.010 + 0.002), and the serum urea nitrogen/creatinine ratio becomes more typical of intrinsic renal disease.

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome with many causes. These may be divided into three groups: postinfectious RPGN, RPGN associated with systemic disease, and idiopathic RPGN. The most common form occurring after infection is poststreptococcal. Common systemic diseases associated with RPGN include systemic lupus erythematosus, Wegener's granulomatosis, vasculitis, and Goodpasture's syndrome.1 The pulmonary findings of linear fluorescence along alveolar basement membranes confirm that this patient had Goodpasture's syndrome. Goodpasture's syndrome is associated with antibodies to a component of the a3 chain of type IV collagen preferentially expressed in basement membranes of pulmonary alveoli and renal glomeruli.2,3 This antibody explains the clinical picture of RPGN with associated pulmonary hemorrhage. In both organs there is an acute necrotizing inflammatory lesion resulting in loss of basement membrane integrity with subsequent hemorrhage.

Approximately 50-70% of patients with Goodpasture's syndrome present with pulmonary symptoms. A smaller percentage of patients, as in this case, have initial renal findings. Therapy includes plasmapheresis and immunosuppressive drugs.4 Despite good responses to plasma exchange, some patients, as in this case, may still eventually require dialysis or transplantation. Transplantation may be delayed until anti-GBM titers have been negative for 6-12 months to reduce the risk of recurrent disease posttransplantation. The diagnosis of Goodpasture's is based on the finding of a linear fluorescent pattern in pulmonary or glomerular basement membrane. The demonstration of antiglomerular basement membrane (anti-GBM) antibodies, present in over 90% of patients in peripheral blood,5 is generally the initial laboratory test.

The uremic syndrome is the result of extensive loss of nephron function including both glomerular and tubular components. The typical uremic syndrome is generally seen when GFR is less than 20-25% of normal. The cause is inadequate functional renal mass. It may be regarded as loss of the kidney's normal excretory, regulatory, and endocrine functions.

Failure of excretory function results in retention of nitrogenous wastes, most commonly measured as serum urea nitrogen and creatinine concentrations. There is also failure to excrete the daily endogenous acid load with a resulting metabolic acidosis. This acidosis usually results in an elevated anion gap acidosis secondary to diminished NH3 production; it is reflected in a decreased serum bicarbonate and pH. The patient may exhibit constitutional symptoms and compensatory hyperventilation. Retention of additional, presently uncharacterized wastes probably contributes to gastrointestinal ulceration; abnormal skin coloration and itching; neuromuscular abnormalities ranging from peripheral neuropathy to seizures, stupor, or coma; and episodes of pleuritis and pericarditis. There is also an acquired deficit of platelet function that may give rise to a prolonged bleeding time and may contribute to gastrointestinal hemorrhage.

Regulatory failure is manifested by failure to regulate electrolytes and water, blood pressure, and acid-base status. Inability to concentrate or dilute the urine adequately leads to inability to handle either a salt load or free water load. An increased salt load results in volume expansion with aggravation of hypertension, edema, and possibly congestive heart failure. An increased free water load causes hyponatremia and may contribute to edema and volume overload. Failure to regulate electrolytes may lead to life-threatening hyperkalemia. Inability to concentrate may give rise to hypovolemia with salt and water deprivation. Poor regulation of the renin-angiotensin system, with resulting salt and water retention and hypervolemia, contributes to hypertension, which is common in the uremic syndrome. Hypertension contributes to further renal injury.

Last, failure of important endocrine function also occurs in chronic renal failure with uremia and may help to separate it clinically from acute renal failure. Inadequate secretion of erythropoietin causes a normochromic, normocytic anemia with low reticulocyte count. The uremia may be aggravated by gastrointestinal hemorrhage. Failure of proper synthesis of 1,25-dihydroxyvitamin D and hyperphosphatemia give rise to hypocalcemia with consequent stimulation of parathyroid glands, which ultimately culminates in the complex metabolic bone disease called renal osteodystrophy (see Cases 10 and 29). The anatomical features of renal osteodystrophy resemble a combination of osteomalacia and osteitis fibrosa cystica.

In summary, this patient presented with acute nephritis with a rapidly progressive course and associated pulmonary hemorrhage. A renal biopsy showed a crescentic glomeru-lonephritis but indeterminate immunofluorescent staining. A subsequent lung biopsy revealed linear immunofluorescent staining for immunoglobulins characteristic of Goodpasture's syndrome. Although the patient responded initially to plasma exchange, she ultimately developed end-stage renal disease with uremic syndrome and required hemodialysis; she now awaits renal transplantation.

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