Chapter 87: Specific Renal Syndromes

• Edema, hematuria, and oliguria suggest acute glomerulonephritis

• Children with nephrotic syndrome are usually immunocompromised and are at risk for life-threatening infection

• Patients with hemolytic uremic syndrome are at risk for hypertension and seizures

• Hemodialysis may be needed for fluid overload in patients with acute renal failure who are refractory to medical management

Glomerulonephritis is a histopathologic diagnosis acutely associated with clinical findings of hematuria, edema, and hypertension. It commonly follows a skin or throat infection caused by a nephritogenic strain of Group A β-hemolytic Streptococcus in children between 3 and 7 years of age. Patients younger than 2 years are rarely affected. Timely treatment ofpharyngitis does not clearly decrease the incidence of acute glomerulonephritis.

Glomerulonephritis probably results from the deposition of circulating immune complexes in the kidney. These immune complexes are deposited on the basement membrane causing glomerular inflammation and injury and thereby reducing glomerular filtration.¹

Diagnostic Findings

There is usually a preceding streptococcal infection or exposure 1 to 2 weeks before the onset of glomerulonephritis. An interval of less than 4 days may imply that the illness is an exacerbation of preexisting disease rather than an initial attack. Skin infections may have a latent period of 3 to 6 weeks. Henoch–Schönlein purpura, nephritis associated with subacute bacterial endocarditis or shunt infection may also be causative. Fever, malaise, abdominal pain, and decreased urine output are often noted.

The physical findings reflect the duration of illness. Initial findings may be mild facial or extremity edema only, with a minimal rise in blood pressure. Patients uniformly develop fluid retention and edema and commonly have hematuria (90%), hypertension (60%–70%), and oliguria (80%). Fever, malaise, and abdominal pain are frequently reported. Anuria and renal failure occur in 2% of children. Circulatory congestion, as well as hypertensive encephalopathy, may be noted.

Urinalysis reveals microscopic or gross hematuria. Erythrocyte casts are present in 60% to 85% of hospitalized children. Proteinuria is generally less than 2 g/m² per 24 hours. Hematuria (Fig. 87-1) and proteinuria (Fig. 87-2) may present independently and require a specific evaluation.^2–4 Leukocyturia and hyaline and granular casts are common. If the diagnosis and etiology are unclear, renal biopsy may be indicated to exclude other diagnoses.

The fractional excretion of sodium as a reflection of renal function may be reduced (Table 87-1). The blood urea nitrogen (BUN) level is elevated disproportionately to the creatinine level.

Total serum complement and specifically C₃ is reduced in 90% to 100% of children during the first 2 weeks of illness, returning to normal within 4 to 6 weeks. Ongoing low levels suggest the presence of chronic renal disease. The streptozyme test, measuring five different streptococcal antibodies, is positive in 95% of patients with pharyngitis and 80% of those with skin infections. The antistreptolysin (ASO) level may be low or negative in patients with skin infections. Anemia, hyponatremia, and hyperkalemia may be present.

Management

Fluid and salt restriction is essential to normalize intravascular volume. Diuretics are often required. Elevated blood pressure may require specific pharmacologic management. Specific complications, such as congestive heart failure, renal failure, and hyperkalemia, must be anticipated and treated. Recovery is usually complete. More than 80% of patients recover without residual renal damage. Children without evidence of hypertension, congestive heart failure, or azotemia may be followed closely at home; although a nephrologist is usually consulted. Fortunately, recurrence is rare.

Historically known as lipoid nephrosis, childhood nephrosis, foot process disease, nil disease, minimal change nephrotic syndrome, and idiopathic nephrotic syndrome; nephrotic syndrome is associated with increased glomerular permeability, which produces massive proteinuria. Hypoalbuminemia results, producing a decrease in the plasma osmotic pressure. The shift of fluids from the vascular to interstitial spaces shrinks the plasma volume, thereby activating the renin–angiotensin system and enhancing sodium reabsorption. Edema develops.

The etiology is generally idiopathic, but has been associated with diffuse foot process effacement on electron microscopy with glomerular lesions Seventy-five percent of children have minimal change disease. Intoxications, allergic reactions, infection, and other entities have also been associated with the syndrome (Table 87-2). It may be a primary pathologic process or associated with a systemic disease.

Males are affected more frequently, but this equalizes in adulthood. Primary nephrotic syndrome occurs more commonly in children younger than 5 years whereas secondary nephrotic syndrome is more common in older children.

The renin–angiotensin–aldosterone system produces increased reabsorption of sodium chloride and worsens the edema state. Serum cholesterol levels rise and remain high even after resolution of urinary protein loss.^5,6

Patients frequently have edema, often with a history of a preceding flu-like syndrome. Edema initially is present periorbitally and may become generalized, associated with weight gain. Ascites may be caused by edema of the intestinal wall, often associated with abdominal pain, nausea, and vomiting. Pleural effusion or pulmonary edema may occur. Malnutrition may be noted secondary to protein loss.

Blood pressure may be decreased if the intravascular volume is depleted or increased in the presence of significant renal disease. Blood pressure is elevated in approximately 5% to 10% of these patients. Renal failure may develop.

Infection is probably the most common complication, related to the increased risk of peritonitis and concomitant immunosuppression due to the steroid therapy. Immune protein levels, including IgG, are low due to urinary losses. Children's blood is hypercoagulable, leading to an increased risk of thromboembolism. Renal vein thrombosis is probably underrecognized but should be suspected if hematuria, flank pain, and decreased renal function occur.

Hypoalbuminemia is common, as well as proteinuria and hyperlipidemia. A 24-hour urine collection reveals a protein excretion of >3.5 g/1.73 m² per 24 hours. A spot protein: creatinine ratio of >3.0 or a urine protein excretion of >50 mg/kg/24 hours is noted. The BUN and creatinine levels are elevated in 25% of children. Serum complement is decreased. Plasma cholesterol carriers (low-density lipoprotein and very low-density lipoprotein) are increased. Elevated lipids result from increased synthesis, as well as catabolism of phospholipid. Imaging studies, especially ultrasound, should document normal renal structure.

A renal biopsy should be considered if the following poor prognostic signs are present:

• Age more than 10 to 12 years

• Azotemia

• Decreased complement

• Hematuria

• Persistent hypertension

• No response to steroids which occurs in about 10% to 20% of patients. Genetic testing is often indicated in such patients.⁷

Other causes of edema should be excluded, including congestive heart failure, vasculitis, hypothyroidism, starvation, cystic fibrosis, protein-losing enteropathy, and drug ingestions (such as steroids or diuretics).

Management

The majority of patients should be hospitalized initially, usually in consultation with a nephrologist. Treat hypovolemia with albumin and fluids. Monitor closely and treat hypertension if it occurs.

After diagnosis and stabilization, patients without complications (younger than 10–12 years, normal complement, no hypertension, marked elevation in creatinine, or gross hematuria, no large protein loss, or no extra renal findings such as malar rash or purpura) are started on prednisone at a dose of 2 mg/kg per 24 hours up to a maximum of 80 mg per 24 hours for 6 weeks followed by alternate day therapy of 1.5 mg/kg per 24 hours for another 6 weeks. Nearly 75% of patients will respond within 14 days. Limited response to initial steroid therapy is generally predictive of a poor outcome. Specific protocols exist for relapses or resistance to steroid management. Other pharmacologic agents may ultimately be needed. Salt and water restriction should be initiated.

Diuretics may be needed if there is pulmonary edema or respiratory distress. However, they must be used judiciously to avoid vascular volume depletion and electrolyte abnormality. Loop diuretics such as furosemide, 1 to 2 mg/kg/d, may be helpful to decrease edema in cases of mild hypertension. Severe fluid overload requires specific management.

Watch for signs of infection since these patients are considered immunocompromised. Avoid deep vein punctures if possible to avoid triggeringa deep vein thrombosis.

Nephropathy, microangiopathic hemolytic anemia, and thrombocytopenia are found in patients with hemolytic uremic syndrome (HUS). This syndrome commonly occurs in children younger than 5 years following an episode of gastroenteritis or respiratory infection. Siblings may also develop the disease due to a familial genetic component. The illness has an acute onset with rapid progression to renal failure and thrombocytopenia.⁸

HUS results from endothelial damage of the renal microvasculature. A microangiopathic hemolytic anemia develops as a result of mechanical damage and sequestration of red blood cells. Platelet aggregation may produce microthrombi and hypoxia in the kidney. Decreased C₃ may result from deposition of complement in the lumina of the glomeruli.

Associated infections can be found. Escherichia coli serotype 0157:H7 is the most commonly found organism, producing a Shiga toxin that inhibits protein synthesis leading to cell death in gastrointestinal organs.

Shigella, Salmonella, and Group A Streptococcus may be associated with HUS, as well as coxsackievirus, influenza, and respiratory syncytial virus (RSV).

Atypical HUS may have a genetic origin, causing a problem with the complement system.

Diagnostic Findings

Patients usually have a history of gastroenteritis with vomiting, bloody diarrhea, and crampy abdominal pain within 2 weeks of the onset of HUS. Children who develop HUS without a prodrome of gastroenteritis have a poor prognosis. Low-grade fever, pallor, hematuria, oliguria, and gastrointestinal bleeding occur. Central nervous system deterioration can occur with a spectrum from irritability to seizures or coma. About one-half of the cases occur from July to September.

There is a tremendous spectrum of severity of clinical disease ranging from mild elevation of BUN with anemia to total anuria due to acute nephropathy with severe anemia and thrombocytopenia.

Ultimately, patients may develop hypertension; anemia with pallor, petechiae, and easy bruising; hepatosplenomegaly; and edema. Hypertension occurs in up to 50% of patients. Irritability or lethargy may develop. Seizures occur in 40% of the cases. Hyponatremia and hypocalcemia are common. Acute abdominal conditions including intussusception, bowel perforation, and toxic megacolon can occur. Hepatic and pancreatic injury can occur in HUS. There may be cardiac involvement with cardiomyopathy, myocarditis, or high-output failure. Recurrences may occur, often without a prodrome, and may be associated with a high mortality rate.

Laboratory evaluation should include assessment of renal function including electrolyte, BUN, and creatinine levels; and urinalysis. Hematologic studies reveal low hemoglobin with a microangiopathic, hemolytic anemia. Burr cells are common. Platelets are usually decreased below 50,000/mm³. New tools can detect Shiga toxin in stool. Coagulation studies are usually normal.^9,10

Management

Initial stabilization is followed by admission to an appropriate medical center. Volume overload may occur secondary to anemia. Hypertension may occur and appears to be caused by increased renin levels. Treatment is recommended if the diastolic pressure is above 120 mm Hg. A variety of agents may be used, including nifedipine, labetolol, captopril, and hydralazine. Renal failure requires meticulous balancing of intake and output with specific treatment of hyperkalemia, acidosis, hypocalcemia, hyperphosphatemia, and other metabolic abnormalities. Dialysis is required in about 60% of patients, especially when the BUN is more than 100 or when congestive heart failure, encephalopathy, or hyperkalemia are present. Peritoneal dialysis is also indicated when anuria has been present for 24 hours.

A serum hemoglobin <5 g/dL or hematocrit <15% generally requires treatment with packed red blood cells, infused slowly. Platelet survival is shortened and platelet infusions may be required in children with active bleeding. Seizures require specific management and are usually caused by hypertension or uremia. Acute treatment includes stabilization and anticonvulsants, as well as a consideration of emergency dialysis. Heparin and streptokinase have been tried without significant success. Soliris may be helpful as adjunctive therapy in patients with atypical HUS.

Impairment of the kidney's ability to regulate urine volume and composition produces problems with hemostasis. This is usually associated with a decreased glomerular filtration rate (GFR).

The etiology of acute renal failure may be categorized on the basis of the type of renal injury. It may be prerenal (decreased perfusion of the kidney), intrarenal (damage to the actual nephron), or postrenal (downstream obstruction of the urinary tract; Table 87-1).¹¹

Prerenal patients have decreased perfusion of the kidney. Dehydration is usually the cause and may be secondary to vomiting, diarrhea, diabetic ketoacidosis, or decreased intravascular volumes associated with nephrotic syndrome, burns, or shock.

Intrarenal failure results from direct, intrinsic damage to the nephrons caused by glomerulonephritis (hematuria, proteinuria, edema, and hypertension), HUS, nephrotoxic exposures, crush injuries, sepsis, or disseminated intravascular coagulation.

Obstruction leads to postrenal failure and may be accompanied by symptoms, although blockage may be insidious and without symptoms. Causes of postrenal obstruction include posterior urethral valves, ureteropelvic junction abnormalities, renal stones, and trauma. Abdominal pain and an abdominal mass due to hydronephrosis may be noted.

Diagnostic Findings

The history may reflect the underlying disease and the category of renal failure. The physical examination will help determine the mechanism. It is essential to evaluate for hypovolemia, volume overload, hypertension, or obstruction.

Patients may have oliguria with urine output less than 1 mL/kg/h or be nonoliguric with an output excessive for the volume status. Azotemia may be noted.

Laboratory evaluation should include electrolytes, studies of renal function, urinalysis and a search for the underlying pathology. The creatinine clearance is a good measure of GFR and is useful in initial assessment and ongoing monitoring. A 24-hour urine is normally needed.

A rapid approximation can be made using the formula:

P = plasma concentration of creatinine (mg/dL);

Normal values are the following:

• Newborn and premature: 40 to 65 mL/min/1.73 m²

• Normal child: Female, 109 mL/min/1.73 m² or male, 124 mL/min/1.73 m²

• Adult: Female, 95 mL/min/1.73 m² or male, 105 mL/min/1.73 m²

A single-voided urine in adults has been of some use in assessing renal function. In patients with stable renal function, a spot protein:creatinine ratio of >3.0 represents nephrotic range proteinuria (a ratio of <0.2 is normal). The fractional excretion of sodium is useful in differentiating between prerenal and acute tubular disease. Ultrasonography is also important in the evaluation of these patients. Combining data from serum, urine, and ultrasonography helps differentiate among prerenal, intrarenal, and postrenal failure (Table 87-1).

Management

Initial management must focus on stabilization with correction of fluid imbalance (Fig. 87-3). If the intravascular volume is adequate or overloaded, urine output may be enhanced with furosemide, usually in an initial dose of 1 mg/kg increased up to 6 mg/kg/dose. Mannitol may be administered if there is no response to furosemide. The dose is 0.5 to 0.75 mg/kg/dose IV. Do not use these agents if obstruction is present.

In oliguric or anuric patients with decreased intravascular volume, fluid may be administered slowly, often in conjunction with monitoring of the central venous pressure. Low-dose dopamine occasionally may be used to increase renal blood flow and GFR. Those with high urine output must receive a significant amount of fluid to avoid hypovolemia.

Hypertension may be caused by fluid overload or high renin secretion. Children having acute hypertension with a diastolic pressure more than 100 mm Hg should be treated parenterally because of the risk of seizures, encephalopathy, and other sequelae. Only a mild reduction is needed, usually to the diastolic range of approximately 100 mm Hg. Nitroprusside and nifedipine are useful for reduction of pressure.

Hyperkalemia causes membrane excitability with possible cardiac dysrhythmias. A potassium level >6.5 mEq/L can cause elevation of the T wave. Specific and immediate treatment for a potassium level >7.0 mEq/L is required. Treatment may include calcium chloride, 20 to 30 mg/kg slowly; sodium bicarbonate, 1 to 2 mEq/kg/dose; or glucose and insulin infusion of 1 mL/kg of D₅₀W followed by 1 mL/kg of D₂₅W and 0.5 U/kg of regular insulin per hour to keep serum glucose between 120 to 300 mg/dL. Kayexalate at 1 g/kg/dose every 4 to 6 hours mixed with 70% sorbitol, orally or rectally, may be useful after initial stabilization. Other abnormalities that may need specific treatment include anemia, metabolic acidosis, hyponatremia, and hyperphosphatemia.

Dialysis may be required for unresponsive fluid overload, severe hyperkalemia, severe hyponatremia or hypernatremia, unresponsive metabolic acidosis, BUN >100 mg/dL, or altered level of consciousness secondary to uremia. Such patients obviously require hospitalization.