A 7 year old male presents to his primary care physician with the chief complaint of dark "cola colored" urine, facial puffiness and abdominal pain for the past 2 days. He had been in his usual state of good health until 14 days ago when he had a sore throat and fever. His sore throat and fever resolved. He was not seen by a physician at that time. Over the past 2 days facial puffiness has been noted, but no swelling of his hands or feet. He has had some nonspecific abdominal pain that comes and goes which does not seem to be related to eating or bowel movements. There is no nausea or vomiting. His urine is dark brown and he has not been voiding as much as usual, only 2 times in the past 24 hrs. There is no urinary frequency, urgency, dysuria or foul smell to the urine. His appetite has been poor although he is still drinking fluids well. He is also complaining of some back pain in the flank area that he describes as a dull pain that comes and goes and does not seem to be related to activity. His energy level is down and he has not felt up to going to school for the past 2 days. He is also complaining of a dull generalized headache that has not been relieved with acetaminophen.

Review of systems is negative for recent skin infection, skin rash, cough, rhinorrhea, seizure activity, fever, arthralgia or weight loss. His past medical history, family history and social history are unremarkable.

Exam: VS T 37, P 100, RR 20, BP 120/75, oxygen saturation 100% in RA. Height and weight at 50th %tile. He is tired appearing but in no acute distress. Pupils are equal and reactive. Optic disc margins are sharp. Sclera are white and conjunctiva are clear. Mild periorbital is edema noted. TMs are normal. Throat, oral mucosa and nose are normal. His neck is supple without lymphadenopathy. Heart is regular without murmurs. Lungs are clear. Abdomen is diffusely tender (mild), without guarding or rebound. Bowel sounds are normal. No organomegaly is noted. Mild CVA tenderness is present. His extremities are warm, with strong pulses. Capillary refill is less than 2 seconds. No edema is noted in his legs, feet or hands. No skin rashes or impetigo scars are noted. His genitalia are normal. No scrotal edema is present. Neurologic exam is normal.

Lab: His urine is tea colored. UA shows an increased specific gravity. A dipstick is positive for a large amount of blood and moderate protein. RBCs are too numerous to count. 5-10 WBCs per HPF. RBC casts are present. CBC with diff is normal. Throat swab is sent for culture. ASO titer is elevated. Serum complement C3 level is low. Serum electrolytes are normal. BUN 23 and Cr 0.8.

Clinical Course: He is diagnosed with acute poststreptococcal glomerulonephritis. He is initially hospitalized for treatment of oliguria/volume overload with furosemide, and monitoring of his modest hypertension. He has a good urine output with the furosemide, however he later requires a calcium channel blocker to control worsening hypertension. He is placed on a fluid and sodium restricted diet. His throat culture later returns positive for group A beta hemolytic streptococci (GABHS), so he is given a course of penicillin. He is discharged after 3 days of hospitalization. His hypertension resolves over the next 2 weeks. He is followed closely by his primary physician and his proteinuria and gross hematuria resolve early. His C3 level normalizes two months after the onset of illness. Microscopic hematuria is expected to persist for months so this will be rechecked in 3 to 6 months. He does not develop any long term complications.

Acute glomerulonephritis (GN) presents with hematuria, oliguria, hypertension and volume overload (edema), which are the findings of the classic "nephritic syndrome". Acute GN (AGN) is associated with inflammation and proliferation of the glomerular tuft. Most AGN is immunologically mediated. In acute poststreptococcal glomerulonephritis (APSGN), immune complexes form with streptococcal antigens, localize on the glomerular wall, activate the complement system, and initiate a proliferative and inflammatory response. AGN may be rapidly progressive (RPGN). Chronic GN (CGN) implies that permanent damage has occurred.

Acute poststreptococcal glomerulonephritis (APSGN) is the most common form of glomerulonephritis in children. APSGN can occur in all ages but is most frequent in males between 5 and 15 years. APSGN can occur after either an upper respiratory tract or skin infection due to GABHS. It is more common after an infection of the throat. CGN occurs more often in teenagers and adults. There are genetic predispositions for familial GN (Alport, X-linked) and autoimmune etiologies (e.g., SLE-lupus nephritis). Goodpasture's disease (anti-basement membrane autoantibodies) also presents with a classic nephritic syndrome in conjunction with hemoptysis, but this condition is rare.

Important questions to ask the patient/caregiver include history of macroscopic (gross) hematuria (tea or cola colored urine, or red colored urine), sore throat, impetigo, prior URI at least 1 week previously or skin sores (impetigo) in the preceding 3-4 weeks (suggestive of APSGN), URI in the preceding few days (suggestive of IgA nephropathy), reduced urine output, dyspnea, fatigue, lethargy, headache or seizures (hypertensive encephalopathy). Also, symptoms of a systemic disease such as fever, vasculitic rash (especially on the buttocks and legs posteriorly), arthralgia and weight loss may be present. On physical exam, pay particular attention to hypertension, pallor, signs of volume overload (edema, jugular venous distention, hepatomegaly, crackles in the lung bases), impetigo and rash. For PSGN, edema (specifically, facial edema involving the periorbital area) is the most frequent presenting symptom. Dark colored or bloody urine is frequently not noticed by patients because the abnormal color is only visible when the urine is collected in a cup. The abnormal color is not noticeable in a urine stream unless the urine color is very dark.

Many patients with APSGN are asymptomatic and do not seek medical care. Mild hypertension is often asymptomatic. The classic dark urine is often not noticed. Screening urinalysis may often identify persistent microhematuria which eventually resolves months later. Many of these cases are felt to be resolving APSGN cases which never presented for medical attention during the acute nephritis phase.

Throat culture for GABHS will be positive in 15-20% of patients with APSGN. CBC is normal in AGN and with chronic renal insufficiency a normocytic normochromic or hypochromic microcytic anemia will usually be found. Serum chemistries will reflect the degree of renal failure (BUN, creatinine, potassium and phosphate are all elevated, while calcium is decreased), which is usually mild. The ASO titer will be positive in 60% of patients with APSGN. The complement C3 serum level will be low in APSGN and in other causes of GN described below. Urine microscopy shows RBC casts and crenated RBCs in AGN. EKG, CXR and renal ultrasound are other tests that should be considered. RBC casts indicate the presence of acute nephritis. WBC casts can also be seen in APSGN, interstitial nephritis and pyelonephritis.

During convalescence from APSGN, complement C3 levels return to normal within 6-8 weeks. Persistently low C3 levels indicate an etiology other than APSGN. Gross hematuria will generally resolve within 1 to 2 weeks. Microscopic hematuria may persist for a year or more.

The differential diagnosis for glomerulonephritis includes infectious etiologies such as GABHS, pneumococcus, mycoplasma, mumps and EBV. Glomerulonephritis may also be related to hepatitis B and C as well as syphilis infections. IgA nephropathy, membranoproliferative GN, autoimmune GN, familial GN, acute interstitial nephritis, hemolytic uremic syndrome and pyelonephritis should all be on your differential diagnosis list. One way to sort out the etiology of the glomerulonephritis is to look at the complement level and whether evidence of systemic or renal disease is present. For a patient with low serum complement level and systemic disease consider vasculitis and autoimmune disease (SLE), subacute bacterial endocarditis, shunt nephritis and cryoglobulinemia. For a patient with low serum complement level and evidence of renal disease consider APSGN and membranoproliferative glomerulonephritis (types 1,2, and 3). In a patient with normal serum complement level and evidence of systemic disease consider polyarteritis nodosum, Wegener vasculitis, Henoch-Schonlein purpura and hypersensitivity vasculitis. In a patient with normal serum complement and evidence of renal disease consider IgA nephropathy, idiopathic RPGN and immune complex disease. A renal tumor (e.g., Wilms) will occasionally present with gross hematuria so an imaging study may be indicated to rule this out.

APSGN is a self-limiting disease. Treatment is symptomatic. Restricted fluid and sodium diets are initially beneficial. Potassium and phosphate may also need to be restricted. Medication may be required for management. Loop diuretics (e.g., furosemide) are the first choice for volume overload, hypertension and hyperkalemia control. Vasodilators such as calcium channel blockers are also used to manage hypertension. IV antihypertensives may also be required to treat severe refractory hypertension. In severe hyperkalemia serum potassium lowering agents and IV calcium may be needed. Immunosuppressive agents are used in the treatment of vasculitis associated GN, membranoproliferative GN and RPGN. Plasmapheresis may be used to treat RPGN.

Most patients with APSGN do not need hospitalization. Indications for hospitalization include: an uncertain diagnosis, significant hypertension, anticipated poor follow-up, cardiovascular or cerebrovascular compromise, etc. The diagnosis can usually be firmly established as an outpatient. An imaging study may be necessary to rule out a Wilms tumor. If the patient's blood pressure is normal or only mildly elevated, most parents can be taught to measure the child's blood pressure at home using an automated blood pressure measurement device which is easily available at most stores. Parents must notify the physician when the blood pressure exceeds the parameters given by the physician. If the parents are deemed to be unreliable, or are not capable of measuring the child's blood pressure, then hospitalization should be considered.

Prognosis is excellent for APSGN and variable for other causes of GN in children. Complications of AGN include acute renal failure, hyperkalemia, hypertension, volume overload (congestive heart failure, pulmonary edema, hypertension) and chronic renal failure.

Questions

1. When does the complement C3 level return to normal in APSGN?

2. What is the significance of finding red cell casts in the urine?

3. What is the significance of finding white cell casts in the urine?

4. How long does hematuria persist in APSGN?

5. Describe some indications for hospitalization of patients with APSGN.

6. What are the clinical elements of the nephritic syndrome?

7. What are classic causes of the nephritic syndrome?

8. A 5 year old boy has a screening urinalysis as part of a general physical exam. The UA shows microscopic hematuria. History suggests that he has impetigo periodically. What a likely cause for the microscopic hematuria?

References

1. Ruley EJ. Chapter 230 - Nephritis. In : Hoekelman RA(ed). Primary Pediatric Care, 2nd edition. 1992, St. Louis: Mosby-Year Book, Inc., pp. 1379-1386.

2. Bergstein JM. Chapter 18 - The Urinary System, Nephrologic Diseases. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 14th edition. 1992, Philadelphia: W.B. Saunders Company, pp. 1323-1336.

3. Travis LB. Chapter 19.6 - Glomerulonephritis. In: Rudolph AM (ed). Rudolph's Pediatrics, 20th edition. 1996, Stamford, CT: Appleton and Lang, pp. 1351-1366.

Answers to questions

1. C3 levels return to normal within a 6-8 week period in APSGN. Persistently low C3 levels suggest a cause other than APSGN.

2. The presence of red cell casts on urinalysis almost always indicates the presence of glomerulonephritis. They can also be seen after strenuous exercise and renal trauma.

3. The presence of white cell casts on urinalysis can be seen in APSGN, interstitial nephritis and pyelonephritis.

4. Gross hematuria resolves within days to weeks. Microhematuria may persist for months.

5. An uncertain diagnosis, significant hypertension, anticipated poor follow-up, cardiovascular or cerebrovascular compromise, etc.

6. Gross hematuria, oliguria, hypertension, edema (usually mild).

7. APSGN and Goodpasture's. Other causes of nephritis include SLE nephritis, MPGN, RPGN, Alport's, etc.

8. Convalescing APSGN.