Dark Urine - Case 20-4: 7-Year-Old Girl
I. History of Present Illness
A 7-year-old African-American girl with glucose-6-phosphate dehydrogenase (G6PD)
deficiency was in good health until 5 days before admission, when she developed
cough, rhinorrhea, abdominal pain, and a fever to 40.6
°C. Her abdominal pain worsened on the day before admission, and she developed
emesis. The family described the emesis as bilious but not bloody. She had had
some relief of her pain and fever with ibuprofen. On the day of admission, the
patient
's symptoms of upper respiratory tract infection had largely resolved, but she
was not drinking well and had persistent fevers. She was brought to the
emergency department, where she was noted to have bloody urine.
II. Past Medical History
She had had pneumonia at 4 years of age. She did not have any true allergies to
medicine, but because of her G6PD deficiency she avoided drugs associated with
hemolysis in G6PD deficiency. Her only medication was ibuprofen.
III. Physical Examination
T, 38.5°C; RR, 35/min; HR, 104 bpm; BP, 157/112 mm Hg; SpO2, 93% in room air
Weight, 20.8 kg
On examination, the patient was alert and comfortable. Her sclerae were
nonicteric, her nose had no discharge, and her oropharynx was clear with moist
mucous membranes. Her tonsils were 2+. Her neck was supple and exhibited shotty
cervical and submandibular lymphadenopathy. Her lungs had decreased breath
sounds at the bases, with scattered rales and mild end-expiratory wheezing
diffusely. Her cardiac examination revealed a hyperdynamic precordium and a
II/VI flow murmur at the left lower sternal border. She had no gallop. Her
abdomen was soft. Her extremity examination was normal, with no evidence of
edema. She had no rash, and her neurologic examination was normal.
IV. Diagnostic Studies
A complete blood count revealed 11,600 WBCs/mm3, with 1% band forms, 78% segmented neutrophils, 15% lymphocytes, and 4%
monocytes. The hemoglobin was 10 g/dL, and the platelet count was 297,000/mm
3. The mean corpuscular volume was 75.8 fL. Her blood urea nitrogen and
creatinine concentrations were normal at 8 and 0.6 mg/dL. The remainder of her
electrolytes also were normal. A urinalysis revealed moderate ketones, large
blood, and 4+ protein. Urine microscopy showed red blood cells too numerous to
count, 10 to 20 WBCs per high-power field, and cellular casts. Urine culture
was ultimately negative. A complement component C3 level was low at 33 mg/dL
(normal range, 88 to 155 mg/dL). A throat swab rapid antigen test was negative
for group A
Streptococcus.
V. Hospital Course
The patient's hypertension was managed with nifedipine. A renal ultrasound study
demonstrated mildly enlarged kidneys with increased cortical echogenicity. She
had decreased urine output on the second day of hospitalization that required
furosemide therapy. A chest radiograph (Fig. 20-1) suggested a diagnostic
category that was confirmed by additional testing.
Discussion: Case 20-4
I. Differential Diagnosis
When this patient presented to the emergency department, the initial concern
focused on her fever, cough, and abdominal pain. However, the presence of
bloody urine quickly complicated the problem. Attempts to combine all of her
symptoms into a single diagnosis led to consideration of her respiratory tract
illness as a prodrome. Fever, cough, and abdominal pain could all be the result
of a group A
Streptococcus infection in a school age child. Poststreptococcal glomerulonephritis could
then be the cause of bloody urine in this patient. However, glomerulonephritis
typically follows the prodrome by 10 days, so the time course does not fit in
this case. IgA nephropathy and benign recurrent hematuria can both be triggered
by respiratory tract infections. Both are recurrent illnesses, and this patient
had never experienced these symptoms before. The patient has G6PD deficiency,
and a severe hemolytic event could lead to free hemoglobin in the urine. Such
urine, however, is classically cola or tea colored, not frankly bloody. It is
possible that the patient has developed hemorrhagic cystitis caused by the same
pathogen that led to her other symptoms. However, she had not complained of any
change in voiding pattern such as increased frequency or urgency. In addition,
the blood and cellular casts on urinalysis strongly supported a diagnosis of
glomerulonephritis. High fever, cough, and abdominal pain in a school age child
is a classic presentation for pneumonia. The patient
's chest radiograph confirmed this suspicion, and so the remaining problem was
trying to connect pneumonia with glomerulonephritis. A literature search showed
a few case reports of glomerulonephritis associated with
Mycoplasma infection.
II. Diagnosis
The chest radiograph (Fig. 20-1) showed diffuse bilateral interstitial
involvement consistent with an atypical pneumonia.
Mycoplasma pneumoniae was detected from the nasopharynx by polymerase chain reaction. The low
complement level and casts on urinalysis support a diagnosis of
glomerulonephritis. Renal biopsy demonstrated a membranoproliferative
glomerulonephritis. Specific testing excluded systemic lupus erythematosus,
hepatitis B and C, endocarditis, human immunodeficiency virus, and sickle cell
disease as possible causes of the glomerulonephritis. The antibiotics were
changed to azithromycin. Her respiratory condition improved, and she was
discharged on azithromycin and furosemide with plans to follow-up with a blood
pressure determination in 1 week.
The diagnosis is membranoproliferative glomerulonephritis and pneumonia caused
by
M. pneumoniae.
III. Incidence and Epidemiology
In 1998, Said et al. reported a case series of six children with M. pneumoniae-associated nephritis. At that time, 24 total cases had been reported in the
literature. The authors suggested that this entity may be more common that the
literature would indicate. They reported that between 1991 and 1994, 27% of
patients referred to them with acute glomerulonephritis had evidence of
M. pneumoniae documented by the persistence of anti-M. pneumoniae IgM and IgG. Of patients who underwent renal biopsy, the majority had glomerular
lesions including membranoproliferative glomerulonephritis, minimal change
glomerulonephritis, and endocapillary and extracapillary glomerulonephritis.
Other pathologic conditions included tubular interstitial nephritis and acute
tubular necrosis. One patient progressed to renal failure, but all other
patients quickly regained a normal glomerular filtration rate.
Acute postinfectious glomerulonephritis has been associated with a number of
other infections in addition to the classic group A streptococcal disease.
Staphylococcus aureus, S. pneumoniae, coxsackievirus B4, echovirus 9, influenza A and B, and mumps virus have all
been implicated. The mechanism is not clear, but in general it is thought that
immune complexes localize to the glomerular wall and activate the complement
system, initiating a proliferative and inflammatory response.
IV. Clinical Presentation
Children with M. pneumoniae respiratory tract infection may initially develop malaise, myalgias, headache,
and fever
—symptoms indistinguishable from those caused by influenza and other viruses that
produce respiratory tract disease. Over the next few days, however, the cough
worsens, the constitutional symptoms begin to resolve, and the patient begins
to feel subjectively better. At this time, auscultation of the chest reveals
both wheezing and crackles, leading to the term
“walking pneumonia.”
Extrapulmonary manifestations of Mycoplasma infections include exanthems, hemolysis, central nervous system disease,
cardiac disease, hepatitis, pancreatitis, and glomerulonephritis. Renal
involvement after
M. pneumoniae infection is rare. Symptoms of typical M. pneumoniae respiratory tract infection, as described previously, generally precede the
renal involvement. The glomerulonephritis manifests most commonly with abrupt
onset of edema and hematuria. In extreme cases, a patient may experience
oliguria, edema, hypertension, azotemia, proteinuria, and hematuria from days
to weeks after the initial infection. At least half of children with nephritis
remain asymptomatic, with only changes in urinalysis as evidence of kidney
involvement. At least half of those who require hospitalization have gross
hematuria. This may manifest as grossly bloody, smoky, cola-colored,
tea-colored, or rust-colored urine. The hypertension may be severe.
Constitutional complaints including malaise, lethargy, anorexia, fever,
abdominal pain, and headache are also common.
V. Diagnostic Approach
Immunology. Serum samples may be sent for determinations of IgG and IgM specific to M. pneumoniae, which may be detected by immunofluorescence or enzyme linked immunosorbent assay
(ELISA). The IgM is more specific to active current infection, but, in the
absence of evidence of other recent infection, IgG may be evidence of the
causative agent for glomerulonephritis a few weeks after the initial prodromal
illness.
Cold agglutinins. Cold-agglutinating antibodies, or cold agglutinins, are IgM autoantibodies
directed against the I-antigen on human red blood cells. They appear within 7
to 10 days after the respiratory tract infection and disappear after
approximately 3 weeks. Cold agglutinins are neither sensitive nor specific for
M. pneumoniae infection. They may be found in other causes of atypical pneumonia. For example,
cold agglutinins were detected in 18% of military recruits with adenovirus
pneumonia.
M. pneumoniae polymerase chain reaction. This test is available at some institutions to detect M. pneumoniae infection. Nasopharyngeal samples are generally positive in affected children.
This test has been attempted as a means of detecting
M. pneumoniae in other tissues (e.g., cerebrospinal fluid, renal biopsy specimens) with
varying levels of success.
Complement levels. Approximately 80% to 92% of patients with postinfectious glomerulonephritis have
low C3 levels. Many also have low C4 levels.
Urinalysis. Urine dipstick tests are positive for blood and usually are positive for
protein. Microscopy reveals red blood cells and cellular casts, as well as
hyaline casts.
Renal biopsy. Biopsy is performed infrequently, but in a confusing case the findings of large
swollen glomerular tufts, proliferation of mesangial and epithelial cells, and
invasion of neutrophils make the diagnosis. IgG and C3 granular deposits may
also be seen.
Blood urea nitrogen and creatinine. Both values may be elevated in the acute setting, and they provide vital
information in monitoring renal function.
VI. Treatment
The initial approach to treatment focuses on management of severe hypertension.
Intravenous hydralazine at 0.15 to 0.3 mg/kg per dose, or oral nifedipine at
0.2 to 0.3 mg/kg per dose, can help to quickly bring blood pressure down. A
dose of Lasix as high as 2 mg/kg can be given at the same time. If there is
evidence of renal impairment, fluids should be restricted to replace only
insensible losses. These fluids should not contain potassium until renal
function has improved. The patient should also be placed on a low protein and
low sodium diet in the acute phase. The majority of patients recover. Once the
patient is discharged to home, blood pressure and hematuria should be evaluated
every 4 to 6 weeks for 6 months. If the patient continues to improve, these
follow-up studies can be done 3 to 6 months until symptoms resolve. A normal C3
value should be documented approximately 3 months after the acute event.
VII. References
1. Eddy AA. Glomerular disorders. In: Rudolph CD, Rudolph AM, Hostetter MK, et
al.
Rudolph's pediatrics, 21st ed. New York: McGraw-Hill, 2003:1677–1699.
2. George RB, Ziskind MM, Rasch JR, et al. Mycoplasma and adenovirus pneumonias: comparison with other atypical pneumonias in a
military population.
Ann Intern Med 1966;65:931–942.
3. McMillan JA, Weiner LB. Mycoplasma pneumoniae. In: Long SS, Pickering LK, Prober CG. Principles and practice of pediatric infectious diseases, 2nd ed. New York: Churchill Livingstone, 2003:1005–1010.
4. Said MH, Layani MP, Colon S, et al. Mycoplasma pneumoniae-associated nephritis in children. Pediatr Nephrol 1999;13:39–44.
5. Tunnessen WW Jr. Signs and symptoms in pediatrics, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.
6. Westrhenen R, Weening JJ, Krediet RT. Pneumonia and glomerulonephritis
caused by
Mycoplasma pneumoniae. Nephrol Dialysis Transplant 1998;13:3208–3211.
