AUTHOR INFORMATION

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Authored by Sahar Fathallah-Shaykh, MD, Assistant Professor in Pediatric Nephrology, Northwestern University Feinberg School of Medicine; Consulting Staff, Division of Kidney Diseases, Children's Memorial Hospital

Coauthored by Richard Neiberger, MD, PhD, Director of Pediatric Renal Stone Disease Clinic, Associate Professor, Department of Pediatrics, Division of Nephrology, University of Florida College of Medicine and Shands Hospital

Sahar Fathallah-Shaykh, MD, is a member of the following medical societies: American Society of Nephrology

Edited by Uri S Alon, MD, Director of Research and Education, Children's Mercy Hospital of Kansas City; Professor, Department of Pediatrics, Division of Pediatric Nephrology, University of Missouri at Kansas City; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Frederick J Kaskel, MD, PhD, Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine; Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Professor, Department of Pediatrics, Division of Nephrology, Albert Einstein College of Medicine; and Craig B Langman, MD, Professor, Department of Pediatrics, Northwestern University School of Medicine; Head, Division of Kidney Diseases, Children's Memorial Hospital of Chicago

Author's Email:	Sahar Fathallah-Shaykh, MD
Editor's Email:	Uri S Alon, MD

eMedicine Journal, June 6 2006, VOLUME 7, Number 6

INTRODUCTION

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Background: Nephritis is an older term used to clinically denote a child with hypertension, decreased renal function, hematuria, and edema. Technically, nephritis suggests a noninfectious inflammatory process involving the nephron; glomerulonephritis (GN) generally is a more precise term.

Diseases producing GN are usually classified as primary (ie, diseases in which the kidney is the primarily effected organ) and secondary (ie, systemic disorders that involve the kidneys in addition to other organs, such as systemic lupus erythematosus [SLE]).

Currently, most children with hematuria and decreased renal function who do not have a presentation consistent with postinfectious GN receive a renal biopsy, leading to a specific pathologic diagnosis. The general terms GN and nephritis are not specific enough to be very useful for treatment or prognosis.

For a more complete discussion of poststreptococcal GN, see Acute Poststreptococcal Glomerulonephritis.

A second use of the term nephritis is to describe tubulointerstitial nephritis (TIN). TIN is a group of unrelated inflammatory disorders that affect mainly the interstitium and renal tubules initially.

Pathophysiology: In general, nephritis (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 (ie, 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, such as in acute poststreptococcal GN, recovery occurs. If the inflammatory process continues unabated, progressive loss of glomeruli and nephrons occurs (eg, in membranoproliferative GN).

In children with TIN, some stimulus (eg, infection, drug, metabolic abnormality) initiates a tubulointerstitial inflammatory process, leading to a mononuclear cell infiltrate. TIN is often classified clinically as acute or chronic based on the rapidity with which decreased renal clearance function develops. With acute TIN, treatment or removal of the stimulus leads to resolution. In chronic TIN, differing rates of progressive renal damage persist.

Frequency:

• In the US: Incidence and prevalence of nephritis in the pediatric population is not known. Acute postinfectious (most often poststreptococcal) GN has diminished in recent years but still is the most frequent. Other conditions sometimes presenting with nephritis, such as membranoproliferative GN, mesangial proliferative GN, Henoch-Schönlein purpura, immunoglobulin A (IgA) nephropathy, Alport syndrome, and SLE are infrequent.

  Acute TIN 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, so 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).

• Internationally: Incidence and prevalence of nephritis and TIN on a worldwide basis is not known. Industrialized countries tend to produce more reports.

Mortality/Morbidity:

• A child with nephritis 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). In the last three decades, we have seen an important increase in the survival of children with SLE, especially in those patients with renal involvement. Management with immunosuppressive drugs, such as IV cyclophosphamide or azathioprine has changed the prognosis in these children. Children with SLE have increased life expectancy but are now faced with new types of morbidity because of the sequelae related to the disease itself.

• When TIN leads to acute or chronic renal failure, the associated morbidity may occur. TIN is an unusual cause of death in children.

• The prognosis for complete recovery of acute renal failure in TIN is excellent. The prognosis for recovery with chronic TIN depends on the primary disease.

Race: 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.

Sex: 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:

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

• TIN is very rare in children younger than 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.

CLINICAL

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History:

• When considering Alport syndrome, family history is important, especially to identify other family members with nephritis or renal failure. When considering poststreptococcal GN, elicit an antecedent 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.

• 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, other).



• In patients with TIN, a history of polyuria rather than oliguria is obtained.

Physical:

• 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 GN is suspected, seek physical findings of the condition (eg, vasculitis in SLE).



• With 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).

Causes:

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



• TIN probably occurs as a result of humoral and cell-mediated immune reactions against a haptin-protein complex. Cytokines are released and recruitment/dysregulation of inflammatory cells continues, leading to injury out of proportion to the initial insult. Mononuclear cell infiltrates in tubulointerstitial areas is the principal pathogenic process. Tubular dysfunction is out of proportion to glomerular dysfunction. With acute TIN, removal of the stimulus usually results in resolution of the inflammatory process.

DIFFERENTIALS

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Acute Poststreptococcal Glomerulonephritis
Anti-GBM Antibody Disease
Antiphospholipid Antibody Syndrome
Escherichia Coli Infections
Goodpasture Syndrome
Hematuria
Hemolytic-Uremic Syndrome
Hemorrhagic Fever With Renal Failure Syndrome
Hepatorenal Syndrome
Hypercalcemia
Hypertension
IgA Nephropathy
MELAS Syndrome
Medullary Sponge Kidney
Multicystic Renal Dysplasia
Nephrotic Syndrome
Oliguria
Polycystic Kidney Disease
Proteinuria
Pyelonephritis
Renal Cortical Necrosis
Rhabdomyolysis
Sarcoidosis
Systemic Lupus Erythematosus
Systemic Sclerosis
Tumor Lysis Syndrome
Ureteropelvic Junction Obstruction
Uric Acid Stones
Urinary Tract Infection
Urolithiasis
Wilms Tumor
Wilson Disease
Xanthinuria

Other Problems to be Considered:

GN
Takayasu disease
Membranoproliferative glomerulonephritis

Conditions that produce hematuria, decreased clearance, and, sometimes, hypertension include all specific types of GN, anatomic abnormalities of the kidneys, renal stones, tumors, drugs, and infection.

WORKUP

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Lab Studies:

• The most helpful laboratory studies include electrolytes, creatinine, BUN, CBC, urinalysis, urine culture, lupus serologies, complement components (ie, C3, C4), antistreptolysin-O (ASO) titer, anti-DNAase B, perinuclear antineutrophil cytoplasmic antibody (P-ANCA), cellular antineutrophil cytoplasmic antibody (C-ANCA), serum IgA.


• • If the child has a history consistent with acute poststreptococcal GN (eg, low C3, positive ASO, anti-DNAase B), a provisional diagnosis of acute poststreptococcal GN 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 with 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 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. Lesions involving the distal tubule result in inability to acidify the urine (distal renal tubular acidosis), to regulate sodium balance, and to secrete potassium. Lesions affecting the medulla and papilla result in inability to concentrate the 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, 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. Gallium scanning may show increased uptake.

Procedures:

• 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.



• The kidney biopsy findings are diagnostic for TIN.

For TIN, light microscopy reveals focal interstitial infiltrates of edema containing lymphocytes and eosinophils. Tubular injury is usually greater than glomerular or vascular injury.

TREATMENT

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Medical Care: Medical care for GN is usually divided into 2 major components, which are treatment of primary pathology and supportive care. With renal diseases, supportive care involves managing hypertension and fluid and electrolyte abnormalities and managing decreased renal function.

Treatment of primary pathology ranges from watchful waiting, as in postinfectious GN, to treatment with immunosuppressive medication, such as steroids or cyclophosphamide in lupus or tubulointerstitial nephritis (TIN). To discuss the primary treatment of all forms of nephritis is beyond the scope of this article. In some causes, 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 is hypervolemia managed with fluid restriction and diuretics or dialysis if renal function is too poor to respond to diuretics. Hyponatremia usually is dilutional and responds, at least partially, to removal of excess fluid. Hypocalcemia may respond to oral or intravenous calcium depending on severity. Mild metabolic acidosis may be present but rarely requires primary treatment. For dosages of the above medications see Medication.

The primary treatment for TIN is to stop the offending agent.

Surgical Care: If dialysis access is necessary, consultation with a surgeon may be required.

Consultations: Primary care physicians can usually manage children with poststreptococcal GN unless dialysis is imminent. Refer children with other forms of GN or TIN to a pediatric nephrologist.

Diet: In children with acute renal failure secondary to GN who have lost the ability to excrete a water load, fluid restriction may prevent fluid overload. TIN usually produces nonoliguric ARF. Fluid restriction of 300 mL/m²/d plus losses may allow management of acute renal failure for 2-3 days without dialysis. In hypertensive patients, sodium restriction to recommended daily allowances (RDA) of 2-4 mEq/kg/d may aid in management. In children with renal failure, potassium restriction is justified to prevent hyperkalemia. A short-term high-carbohydrate diet may prevent catabolism of body protein as an energy source. Calcium supplementation is useful to maintain normal serum calcium.

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

MEDICATION

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Medications used to treat patients with GN generally fall into 3 categories, which are antihypertensives, diuretics, and anti-inflammatory or immunosuppressives.

Some recommend a short course of steroids or cyclophosphamide for tubulointerstitial nephritis. These drugs are usually not necessary. Most often, stopping the offending agent leads to recovery.

Pharmacotherapy may include a number of drug classes that have antihypertensive effects. They possess different pharmacological actions. Thiazide diuretics and beta-blockers have been the mainstay of drug therapy for hypertension. Recently, the availability of other drugs (eg, calcium-channel blockers, ACE inhibitors, alpha-blockers, angiotensin II receptor antagonists), allow regimens to be customized to the population treated and allow enhanced compliance and improved ability to tolerate treatment. For complete information, see the following pediatric topics Hypertension and Neonatal Hypertension.

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

Drug Name	Furosemide (Lasix) -- A loop diuretic. Often effective in removing fluid even when GFR is reduced secondary to nephritis. Increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.
Adult Dose	20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states
Pediatric Dose	1-2 mg/kg PO/IV up to 6 mg/kg/d
Contraindications	Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions	Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently with this medication
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

FOLLOW-UP

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Further 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.

Further Outpatient Care:

• Outpatient care is an extension of inpatient care.



• Outpatient care may be as simple as observation in a child with tubulointerstitial nephritis or resolving poststreptococcal GN, or it may involve antihypertensives, diuretics, and diet modification as in a child with IgA nephropathy or membranoproliferative GN and preserved renal function.



• Outpatient care may involve dialysis and transplantation in a child who develops end-stage renal disease.

In/Out Patient Meds:

• No specific change in medications is necessary for transition from inpatient to outpatient care.

Transfer:

• A physician who has experience in managing renal failure in children should care for children with renal failure. In the United States, this frequently is at a tertiary facility.

Deterrence/Prevention:

• No effective methods of deterrence or prevention are known.

Complications:

• Primary complications associated with hypertension


• • Seizure
  
  
  
  • Encephalopathy
  
  
  
  • Stroke
  
  
  
  • End-organ damage
  
  
  
• Primary complications associated with kidney failure


• • Fluid overload
  
  
  
  • Electrolyte abnormality
  
  
  
  • Uremic symptoms
  
  
  
  • Anemia

  • Abnormal bone mineralization

  • Sexual dysfunction

  • Poor growth

  • Anorexia

  • Endocrine abnormalities
  
  
  

Prognosis:

• The overall prognosis for survival in children with all forms of nephritis is good.

Patient Education:

• Education about the specific nephritis is helpful.



• Encourage medication compliance and a healthy lifestyle (eg, ideal body weight, no smoking, exercise, avoidance of risk behaviors).



• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center . Also, see eMedicine's patient education article Blood in the Urine.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to consider the diagnosis in a child with nephritis may delay diagnosis and treatment, which may allow progression to end-stage renal disease and allow complications, such as hypertensive seizures, to occur. A provider might be held responsible.

TEST QUESTIONS

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CME Question 1: Which of the following occurs more frequently in boys than in girls?

A: Acute poststreptococcal glomerulonephritis (GN)
B: Immunoglobulin A (IgA) nephropathy
C: Alport syndrome
D: Systemic lupus erythematosus
E: A, B, and C

The correct answer is E: Alport syndrome, acute poststreptococcal GN, and IgA nephropathy all occur more frequently in boys than in girls. The reason is unknown.

CME Question 2: Which of the following is the most frequent primary glomerulonephritis (GN) in children?

A: Immunoglobulin A (IgA) nephropathy
B: Acute poststreptococcal GN
C: Alport syndrome
D: Membranoproliferative GN
E: Mesangial proliferative GN

The correct answer is B: Acute poststreptococcal GN far exceeds other causes of nephritis in children.

Pearl Question 1 (T/F): Children with acute renal failure should be provided adequate carbohydrate calories in their diet to prevent protein breakdown.

The correct answer is True: Breakdown of body protein as an energy source occurs when inadequate carbohydrate calories are provided.

Pearl Question 2 (T/F): The primary treatments for a child with dilutional hyponatremia and acute nephritis include fluid restriction and diuretics.

The correct answer is True: If renal function is adequate, diuretics, fluid restriction, or both correct dilutional hyponatremia in most patients. Otherwise, dialysis may be indicated.

Pearl Question 3 (T/F): Supportive care for a child with acute poststreptococcal glomerulonephritis (GN) includes blood pressure control.

The correct answer is True: Hypertension frequently is the major problem in children during the early phase of acute GN.

Pearl Question 4 (T/F): Nephritis is an older term used to denote hypertension, edema, hematuria, and reduced renal function.

The correct answer is True: Nephritis is an older term used to clinically denote a child with hypertension, decreased renal function, hematuria, and edema. Technically, nephritis suggests a noninfectious inflammatory process involving the nephron; glomerulonephritis generally is a more precise term.

BIBLIOGRAPHY

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• Adler SG, Cohen AH, Glassock RJ: Secondary glomerular diseases. In: Brenner BM, ed. The Kidney. 5th ed. Philadelphia, Pa: WB Saunders Co; 1996: 1498-1596.
• Balow JE, Austin HA: Treatment of proliferative lupus nephritis. Am J Kidney Dis 2004 Feb; 43(2): 383-5[Medline].
• Bargman JM: Management of minimal lesion glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 1999 Jun; 70: S3-16[Medline].
• Cattran DC: Evidence-based recommendations for the management of glomerulonephritis. Introduction. Kidney Int Suppl 1999 Jun; 70: S1-2[Medline].
• Eddy AA: Mechanisms of immune glomerular injury. In: Barrett TM, Avener EV, Harmon H, eds. Pediatric Nephrology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999: 641-668.
• Eknoyan G: Tubulointerstial nephritis. In: Massry SG, Glassock RJ, eds. Massry and Glassock's Textbook of Nephrology. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: 746-758.
• Flanc RS, Roberts MA, Strippoli GF, et al: Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2004 Feb; 43(2): 197-208[Medline].
• Glassock RJ, Cohen AH, Adler SG: Primary glomerular diseases. In: Brenner BM, ed. The Kidney. 5th ed. Philadelphia, Pa: WB Saunders Co; 1996: 1392-1497.
• Goda C, Kotake S, Ichiishi A, et al: Clinical features in tubulointerstitial nephritis and uveitis (TINU) syndrome. Am J Ophthalmol. 2005; 140(4): 637-41[Medline].
• Gonzalez B, Hernandez P, Olguin H, et al: Changes in the survival of patients with systemic lupus erythematosus in childhood: 30 years experience in Chile. Lupus 2005; 14(11): 918-23[Medline].
• Lee JW, Kim HJ, Sung SH, Lee SJ: A case of tubulointerstitial nephritis and uveitis syndrome with severe immunologic dysregulation. Pediatr Nephrol. 2005; 20(12): 1805-8[Medline].

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