Pediatric Nephritis

In general, glomerulonephritis (GN; ie, nonsuppurative) is produced by antigen-antibody complexes (or some other unknown mechanism) trapped in the renal parenchyma. A process of inflammation and cell proliferation, in which endothelial, mesangial, or epithelial cells are stimulated to proliferate in varying degrees, is initiated, which damages normal renal tissue. If the inflammatory process is turned off, as in acute poststreptococcal GN, recovery occurs. If the inflammatory process continues unabated, progressive loss of glomeruli and nephrons occurs (eg, as in membranoproliferative GN).

In children with tubulointerstitial nephritis (TIN), some stimulus (eg, an infection, a drug, a metabolic abnormality) initiates a tubulointerstitial inflammatory process. TIN probably occurs as a result of humoral and cell-mediated immune reactions against a hapten-protein complex. Cytokines are released and recruitment/dysregulation of inflammatory cells continues, leading to injury out of proportion to the initial insult. The occurrence of mononuclear cell infiltrates in tubulointerstitial areas is the principal pathogenic process. Tubular dysfunction is out of proportion to glomerular dysfunction.

TIN is often clinically classified as acute or chronic based on the rapidity with which renal clearance function decreases. With acute TIN, treatment or removal of the stimulus leads to resolution. In chronic TIN, differing rates of progressive renal damage persist.

In the United States, the incidence and prevalence of glomerulonephritis (GN) in the pediatric population is unknown. Acute postinfectious (most often poststreptococcal) GN has diminished in recent years but is still the most frequent type of GN. Other conditions sometimes presenting with GN, such as Henoch-Schönlein purpura, immunoglobulin A (IgA) nephropathy,[1] Alport syndrome, and SLE, as well as membranoproliferative GN and mesangial proliferative GN, occur infrequently.

Acute tubulointerstitial nephritis (TIN) in the United States may account for 5-10% of acute renal failure, and chronic TIN may account for 20% of chronic renal failure in children. TIN is purely a biopsy diagnosis, thus the previous estimates of TIN may be underrepresentations. Most cases of acute TIN in children are virus or medication related. Most cases of chronic TIN in children are related to chronic infection, vesicoureteral reflux, or metabolic disease (eg, oxalosis, Crohn disease).

The incidence and prevalence of glomerulonephritis and TIN on a worldwide basis are unknown. Industrialized countries tend to produce more reports.

Nephritic syndrome may occur in people of all races. The race of the child is not generally helpful in determining the primary etiology of GN. No racial differences have been reported for the incidence of TIN in children.

Acute poststreptococcal GN and IgA nephropathy occur more frequently in males than in females. SLE is more frequent in females. TIN occurs with equal frequency in both sexes.

Age-related differences in incidence

Age is not usually very helpful in determining the pathobiology of glomerulonephritis. Acute postinfectious GN usually occurs in children older than age 2 years. IgA nephropathy is rare before adolescence. Henoch-Schönlein purpura and membranoproliferative GN tend to occur in children older than age 8 years. SLE can occur in people of any age but is more frequent in adolescents.

TIN is very rare in children younger than age 5 years. Acute TIN can potentially occur in people of any age. Chronic TIN tends to occur late in childhood or adolescence with obstructive uropathy or reflux. Chronic TIN may occur in younger patients with inherited metabolic diseases.

The overall prognosis for survival in children with all forms of nephritis is good. A child with glomerulonephritis (GN) might die of potential complications of severe hypertension (eg, cerebral hemorrhage) or complications of renal failure (eg, hyperkalemia). Generally, fatal outcome in the United States is rare. Children with postinfectious GN usually have complete recovery. Children with chronic GN may develop morbidity secondary to hypertension, chronic renal failure, complications of end-stage renal disease, or complications of the primary disease (eg, SLE).

Over the last 3 decades, an important increase in the survival of children with SLE has been observed, especially in those patients with renal involvement. Management with immunosuppressive drugs (eg, intravenous [IV] cyclophosphamide, mycophenolate mofetil, rituximab, tacrolimus, and azathioprine) has changed the prognosis in these children.[2, 3] Children with SLE have increased life expectancy but are now faced with new types of morbidity because of the sequelae related to the disease.

When tubulointerstitial nephritis (TIN) leads to acute or chronic renal failure, associated morbidity may occur. TIN is an unusual cause of death in children. The prognosis for complete recovery from acute renal failure in TIN is excellent. The prognosis for recovery with chronic TIN depends on the primary disease.

Nonetheless, in a case series of children with acute TIN, 70% of patients had an estimated glomerular filtration rate of <  90 mL/min/1.73m2 at their last follow-up visit. Thus, they may be at risk for hypertension or progression of chronic kidney disease later in life.[4]

Complications

Primary complications associated with hypertension include:

• Seizure

• Encephalopathy

• Stroke

• End-organ damage

• Posterior reversible encephalopathy syndrome[5, 6]

Primary complications associated with kidney failure include:

• Fluid overload

• Electrolyte abnormality

• Uremic symptoms

• Anemia

• Abnormal bone mineralization

• Poor growth

• Anorexia

• Endocrine abnormalities

When considering Alport syndrome, family history is important, especially to identify other family members with nephritis or renal failure. When considering poststreptococcal glomerulonephritis (GN), elicit a history of streptococcal throat or skin infection. Inquire about symptoms of swelling and facial, perioral, or pedal edema or ascites. Symptoms of pulmonary edema or congestive heart failure (eg, dyspnea with exertion, orthopnea, shortness of breath) may be present. Gross hematuria (eg, dark, rust colored, coke colored, tea colored) may be present. With severe hypertension, identify nosebleed, headache, or encephalopathy. The parent may note decreased urine frequency. Nonspecific symptoms, such as malaise, fever, anorexia, or weakness, may be present.. 

A recurrent history of gross hematuria triggered by infections may point to IgA nephropathy. Hearing loss may suggest Alport syndrome. 

For children with tubulointerstitial nephritis (TIN) who present with allergic manifestations, most have fever (80-100%) and many have maculopapular rash (25-50%). These symptoms often occur with arthralgias and malaise. When considering the diagnosis of TIN, attempt to obtain a history of a known etiology (eg, bacterial, viral, drug-related, metabolic). In patients with TIN, a history of polyuria, rather than oliguria, is obtained.

Elevated blood pressure is an important physical finding. Look for edema. The child may have a pale appearance because of dilutional anemia. Tachypnea, dyspnea, hepatic congestion, and gallop rhythm suggest fluid overload with congestive heart failure. If a secondary form of glomerulonephritis (GN) is suspected, seek physical findings of the condition (eg, vasculitis in SLE).

With tubulointerstitial nephritis (TIN), physical findings include maculopapular rash, joint pain (with flexion and extension), and fever. Rarely, the patient may present with uveitis as part of tubulointerstitial nephritis and uveitis syndrome (TINU).[7, 8]

The most helpful laboratory studies include the following:

• Electrolyte, creatinine, and blood urea nitrogen (BUN) levels

• Complete blood count (CBC)

• Urinalysis

• Urine culture

• Lupus serologies

• Measurement of complement components (ie, C3, C4)

• Antistreptolysin-O (ASO) titer

• Anti-DNAase B

• Perinuclear antineutrophil cytoplasmic antibody (P-ANCA) measurement

• Cellular antineutrophil cytoplasmic antibody (C-ANCA) assessment

• Serum IgA measurement[1]

If the child has a history consistent with acute poststreptococcal glomerulonephritis (GN), such as low C3, positive ASO, and anti-DNAase B, a provisional diagnosis of this disorder can be made. Supportive care and observation for improvement within 10-14 days is reasonable. If a diagnosis of acute poststreptococcal GN seems unlikely, a percutaneous renal biopsy is the single most effective mechanism to arrive at a pathologic diagnosis.

Laboratory findings in tubulointerstitial nephritis (TIN) include hematuria, eosinophilia, sterile pyuria, low-grade proteinuria, eosinophiluria, and urinary white blood cell casts. A percutaneous renal biopsy is the criterion standard for diagnosing TIN. With TIN, the hallmarks of GN (ie, edema, hypertension, sodium chloride retention) are not present. Tubular dysfunction is the predominant feature.

The pattern of tubular dysfunction that develops in TIN depends on the tubular segment(s) involved. Proximal tubular lesions result in aminoaciduria, glucosuria, phosphaturia, uricosuria, beta2 microglobinuria, and bicarbonaturia, often producing proximal renal tubular acidosis.[8] Lesions involving the distal tubule result in an inability to acidify urine (distal renal tubular acidosis), to regulate sodium balance, and to secrete potassium. Lesions affecting the medulla and papilla result in an inability to concentrate urine.

These tubular functions may be tested by calculating the fractional excretion of phosphate or bicarbonate, measuring the urinary glucose excretion, and measuring the urine pH and osmolality with fasting.

Imaging studies

Renal ultrasonography is usually performed to exclude other causes of hypertension and hematuria, such as renal artery stenosis (ie, small, abnormal kidney on one side), anatomic abnormalities, a tumor, and stones. The kidneys are frequently echodense when GN is present. The kidneys may be abnormally large or small.

No imaging tests are sensitive or specific for TIN. Renal ultrasonography may show large kidneys with normal echogenicity. 

Renal biopsy

If a specific diagnosis is needed for a child with hematuria, proteinuria, edema, and hypertension (ie, nephritis), a percutaneous renal biopsy usually is the criterion standard for identifying a specific pathology. Kidney biopsy findings are diagnostic for TIN.

In glomerulonephritis (GN), light microscopy usually reveals infiltration of the kidney by lymphocytes, polymorphonuclear leukocytes, or both. Immunofluorescence microscopy may reveal IgG, IgA, IgM, or complement in mesangial or vascular distribution, depending on the type of GN. Electron microscopy may reveal deposits in mesangial, subendothelial, or subepithelial tissue or in a combination of tissues, depending on the type of GN present. Replacement of renal tissue by scar tissue (tubular atrophy and interstitial fibrosis) is the final common pathway for several types of GN.

For tubulointerstitial nephritis (TIN), light microscopy reveals focal interstitial infiltrates of edema that contain lymphocytes and eosinophils. Tubular injury is usually greater than glomerular or vascular injury.

Medical care for glomerulonephritis (GN) is usually divided into 2 major components: treatment of primary pathology and supportive care. In renal diseases, supportive care involves managing hypertension and fluid and electrolyte abnormalities and managing decreased renal function.

The treatment of primary pathology ranges from watchful waiting, as in postinfectious GN, to treatment with immunosuppressive medication, such as steroids or cyclophosphamide in lupus. To discuss the primary treatment of all forms of nephritis is beyond the scope of this article. In the case of some etiologies for GN, for example, IgM nephropathy, no definitive therapy is known.

Hypertension can be managed with antihypertensives, such as calcium channel–blocking agents, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor–blocking agents, peripheral vasodilators, and diuretics. The most common fluid abnormality, hypervolemia, is managed with fluid restriction and diuretics or with dialysis if renal function is too poor to respond to diuretics. Hyponatremia is usually dilutional and responds, at least partially, to removal of excess fluid. Hypocalcemia may respond to oral or IV calcium, depending on severity. Mild metabolic acidosis may be present but rarely requires primary treatment.

Some recommend a short course of steroids or cyclophosphamide for tubulointerstitial nephritis (TIN). Prednisone may speed up the recovery from renal symptoms of TIN.[9] However, these drugs are usually not necessary. Most often, stopping the offending agent leads to recovery.

Consultations

Primary care physicians can usually manage children with poststreptococcal GN unless dialysis is imminent. If dialysis access is necessary, consultation with a surgeon may be required. Refer children with other forms of GN or TIN to a pediatric nephrologist.

Inpatient care

Inpatient care is usually necessary only to manage severe hypertension or complications of acute or chronic renal failure (eg, dialysis access, uremic syndrome, congestive heart failure, electrolyte abnormalities such as hyperkalemia and pericardial effusion). These problems are infrequent in the general pediatric population.

Children with renal failure should be cared for by a physician with experience in managing pediatric renal failure. In the United States, such doctors are frequently found at a tertiary facility.

Outpatient monitoring and care

Outpatient care may be as simple as observation in a child with tubulointerstitial nephritis (TIN) or resolving poststreptococcal glomerulonephritis (GN), or it may involve the use of antihypertensives, diuretics, and diet modification, as in a child with IgA nephropathy or membranoproliferative GN and preserved renal function. Outpatient therapy may involve dialysis in a child who develops end-stage renal disease.

In children with acute renal failure secondary to glomerulonephritis (GN) who have lost the ability to excrete a water load, fluid restriction may prevent fluid overload. Tubulointerstitial nephritis (TIN) usually produces nonoliguric acute renal failure. Fluid restriction of 300 mL/m2/d plus losses may allow management of acute renal failure for 2-3 days without dialysis. In patients with hypertension, sodium restriction to the recommended daily allowance (RDA) of 2-4 mEq/kg/d may aid in management. In children with renal failure, potassium restriction is justified to prevent hyperkalemia. Calcium supplementation is useful to maintain normal serum calcium.

In patients with hypertension and renal failure, discourage strenuous activity; however, walking, playing, and other activities are acceptable.

The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative made the following recommendations for each class of childhood-onset lupus nephritis based on the International Society of Nephrology/Renal Pathology Society 2003 classification system.[10]

• Class I: Treatment should be guided by other symptoms.
• Class II: Should be treated initially with low-dose prednisone, a disease-modifying antirheumatic drug should only be added after three months of persistent proteinuria or prednisone dependency.
• Class III/IV: Treatment with mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment MMF and/or azathioprine for at least three years.
• Class V: MMF with low-dose prednisone can be used as induction, MMF as maintenance treatment.

Medications used to treat patients with glomerulonephritis (GN) generally fall into 3 categories: antihypertensives, diuretics, and anti-inflammatories or immunosuppressives.

Pharmacotherapy may include numerous drug classes that have antihypertensive effects and possess different pharmacologic actions. Thiazide diuretics and beta blockers have been the mainstay of drug therapy for hypertension. The availability of other drugs (eg, calcium channel blockers, ACE inhibitors, alpha blockers, angiotensin II receptor antagonists) now allows regimens to be customized to the population treated and permits enhanced compliance and an improved ability to tolerate treatment. (For more information, see Pediatric Hypertension and Neonatal Hypertension.)

As previously mentioned, some recommend a short course of steroids or cyclophosphamide for tubulointerstitial nephritis (TIN), but these drugs are usually not necessary. Most often, stopping the offending agent leads to recovery.

Class Summary

These agents are used to remove excess fluid in children with edema secondary to renal disease and as an adjunct to manage hypertension.

Furosemide (Lasix)

Furosemide is a loop diuretic. It is often effective in removing fluid even when the glomerular filtration rate is reduced secondary to nephritis. This agent increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide (HCTZ) acts on the distal nephron to impair sodium reabsorption, enhancing sodium excretion. It has been in use for more than 40 years and is generally an important agent for the treatment of essential hypertension.

Class Summary

These agents reduce the systemic arterial blood pressure, reducing injury caused by elevated blood pressure. They may not only reduce cardiovascular risk but also slow progression of renal failure. ACE inhibitors may also slow progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms.

A dry cough is a common adverse effect of ACE inhibitors. If the cough occurs with one ACE inhibitor, it is likely to occur with another. A reasonable substitute for an ACE inhibitor if a cough develops is an ARB, such as losartan, valsartan, or candesartan.

Captopril

Captopril, a competitive ACE inhibitor, prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, increasing levels of plasma renin and reducing aldosterone secretion. It has been clinically used for more than 20 years and is effective in experimental radiation nephropathy. Captopril may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms.

Enalapril (Vasotec)

A competitive ACE inhibitor, enalapril reduces angiotensin II levels, decreasing aldosterone secretion. The drug lowers systemic arterial blood pressure, reducing injury caused by elevated blood pressure. It may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms. Enalapril may be used every day or twice per day, which may improve compliance in comparison with a 3-time-per-day medication, such as captopril.

Lisinopril (Prinivil, Qbrelis, Zestril)

Class Summary

ARBs antagonize the action of angiotensin II at the type 1 receptor, reducing systemic arterial blood pressure and blunting the intrarenal effect of angiotensin II. If ACE inhibitors cause cough, ARBs may be substituted.

Losartan (Cozaar)

Losartan is a prototype ARB. It is specific for the type 1, as opposed to type 2, angiotensin receptor. It may induce more complete inhibition of the renin-angiotensin system than do ACE inhibitors. Losartan does not appear to affect bradykinin and is less likely to be associated with cough and angioedema. Use it in patients who are unable to tolerate ACE inhibitors.

Valsartan (Diovan)

Valsartan is a prodrug that directly antagonizes angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Valsartan may induce more complete inhibition of the renin-angiotensin system than do ACE inhibitors. It does not affect bradykinin and is less likely to be associated with cough and angioedema. Valsartan is for use in patients who are unable to tolerate ACE inhibitors.

Class Summary

Antihypertensive agents other than or in addition to ACE inhibitors and ARBs may be needed for blood pressure control in many subjects with hypertension and chronic renal failure. The same is true for subjects with radiation nephritis. No evidence indicates that one type of calcium channel blocker is preferred over another for radiation nephritis. However, one should avoid verapamil, because the use of this drug in a subject with hyperkalemia may cause atrial arrest.

Nifedipine (Procardia, Adalat, Nifedical XL)

Like other calcium channel blockers, nifedipine causes peripheral arterial vasodilation by inhibiting calcium influx across vascular smooth-muscle cell membranes. Long-acting formulations are used for control of blood pressure.

Amlodipine (Norvasc)

Class Summary

These agents inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation

Esmolol (Brevibloc)

An ultra–short-acting beta-1-blocker, esmolol is particularly useful in patients with elevated arterial pressure, especially if surgery is planned. It may be useful as a means to test beta-blocker safety and tolerance in patients with history of obstructive pulmonary disease who are at uncertain risk for bronchospasm from beta-blockade. The elimination half-life of esmolol is 9 min.

Labetalol (Trandate)

Labetalol blocks alpha-1 beta 1-, and beta 2-adrenergic receptor sites, decreasing BP.

Propranolol (Inderal, InnoPran XL)

A class II antiarrhythmic nonselective beta-adrenergic receptor blocker, propranolol has membrane-stabilizing activity and decreases automaticity of contractions. Propranolol is not suitable for emergency treatment of hypertension. Do not administer IV in hypertensive emergencies.

Metoprolol (Lopressor, Toprol-XL)

Metoprolol is a selective beta 1–adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor BP, heart rate, and ECG. When considering conversion from IV to oral (PO) dosage forms, use the ratio of 2.5 mg PO to 1 mg IV metoprolol.