Acute Kidney Injury in a Patient with Trisomy 21.

Abstract

A 5-year-old former 34-week girl with trisomy 21, hypothyroidism, and obstructive sleep apnea presents to the emergency department with a chief complaint of fever. She initially presented to her pediatrician 3 weeks earlier with sore throat and was diagnosed as having group A streptococcal pharyngitis. She completed 10 days of amoxicillin with resolution of sore throat. Now for the past 3 days she has had fever, chest pain, decreased enteral intake, and emesis. Review of systems is negative for diarrhea, gross hematuria, dysuria, polyuria, polydipsia, edema, weight loss, rash, arthralgia, arthritis, oral ulcers, epistaxis, and hemoptysis. She has had normal growth. She takes levothyroxine and took several doses of ibuprofen for fever over the past several weeks. There is no family history of kidney disease. She had no recent travel or sick contacts.On physical examination her weight is 45.2 lb (20.5 kg) (65th percentile); height, 46.1 in (117 cm) (62% percentile); temperature, 100.8°F (38.2°C); heart rate, 110 beats/min; respiratory rate, 24 breaths/min; oxygen saturation, 100% on room air; and blood pressure, 92/42 mm Hg (systolic 31st and diastolic 9th percentiles for age and sex). There is no pharyngeal injection or exudate. She appears well-hydrated, including moist mucous membranes. Lungs are clear to auscultation. Her abdomen is soft, nontender, and nondistended. There is no edema, and she has brisk capillary refill. She has no rash or joint swelling, erythema, or warmth. Laboratory evaluation includes a white blood cell count of 15,310/µL (15.31×109/L) with 83.6% neutrophils and 0.8% bands; hemoglobin level, 8.1 g/dL (81 g/L); platelet count, 474×103/µL (474×109/L); and elevated C-reactive protein level, 21.3 mg/dL (213 mg/L; reference range, <0.5 mg/dL [<5 mg/L]) to assess for signs of infection/inflammation. A metabolic panel is obtained given the patient’s history of decreased intake and emesis and shows the following levels: sodium, 132 mEq/L (132 mmol/L); potassium, 7.5 mEq/L (7.5 mmol/L); carbon dioxide, 20 mEq/L (20 mmol/L); blood urea nitrogen (BUN), 69 mg/dL (24.6 mmol/L); creatinine, 6.5 mg/dL (495.6 µmol/L); and albumin, 3.4 g/dL (34 g/L). Urinalysis has specific gravity 1.012, 2+ protein, negative glucose, small hemoglobin, negative nitrites, large leukocyte esterase, 170 white blood cells per high-power field, 6 red blood cells per high-power field, and a urine protein to creatinine ratio of 0.94 mg protein/mg creatinine. There are no urinary casts. Fractional excretion of sodium is calculated to be 2.1%. Blood and urine cultures are obtained. Given the elevated creatinine level and abnormal urine test results, ultrasonography is performed, which shows large hyperechoic kidneys for age without hydronephrosis (right kidney, 9.9 cm; left kidney, 10.4 cm) and a normal bladder. There are no renal calculi or masses. There is normal renal arterial and venous Doppler flow. A chest radiograph obtained to evaluate for pneumonia given chest pain in the setting of fever shows a left upper lobe opacity. She has a normal echocardiogram. Of note, she had normal levels of electrolytes, BUN, and creatinine (0.36 mg/dL [31.82 µmol/L]) 5 months earlier during an emergency department visit for a respiratory tract infection.This 5-year-old girl with trisomy 21 presented with a markedly elevated serum creatinine level after 3 days of fever, chest pain, and emesis a few weeks after having had successfully treated streptococcal pharyngitis. She had normal blood pressure. Additional laboratory findings included severe hyperkalemia, elevated white blood cell count and C-reactive protein level, and moderate proteinuria without significant hematuria. The normal serum creatinine level of 0.36 mg/dL (31.82 µmol/L) several months earlier, structurally normal kidneys on ultrasonography, and normal growth are most suggestive of acute kidney injury (AKI) as opposed to previously undiagnosed chronic kidney disease (CKD). Potential causes of AKI in this patient include prerenal AKI, acute tubular necrosis, acute interstitial nephritis, acute glomerulonephritis (GN), and shunt nephritis.Prerenal AKI is possible given her reported history of decreased enteral intake and emesis. However, she did not appear dehydrated on physical examination. An elevated fractional excretion of sodium value also argues against a prerenal etiology, although this test must be interpreted with caution in the setting of tubular injury. The BUN to creatinine ratio was 10. However, this ratio may not be reliable in differentiating dehydration from intrinsic renal injury with this degree of AKI. Acute tubular necrosis as a result of prolonged renal hypoperfusion, enhanced by exposure to nonsteroidal anti-inflammatory drugs, is another possible cause of AKI in this patient. Acute interstitial nephritis as a result of nephrotoxin exposures, including amoxicillin and ibuprofen, should also be considered.The history of antecedent streptococcal pharyngitis raises the possibility of acute postinfectious GN. However, acute postinfectious GN was thought to be less likely in this patient given minimal hematuria and no hypertension, although some patients with acute postinfectious GN can have more mild phenotypes. Other etiologies of acute GN to consider include immunoglobulin (Ig) A nephropathy, pulmonary-renal syndromes such as antineutrophil cytoplasmic antibody (ANCA) vasculitis and Goodpasture syndrome given the focal consolidation seen on chest radiography, and systemic lupus erythematosus (SLE). However, she had no other clinical features suggestive of vasculitis or SLE. To further evaluate for potential causes of GN, additional laboratory studies were sent, including complement levels, antinuclear antibody, and ANCA. Complement 3 and 4 levels were in the normal range, making acute postinfectious or SLE nephritis less likely. Antinuclear antibody and ANCA were negative.Finally, given the increased incidence of congenital heart disease in children with trisomy 21, endocarditis with secondary immune complex (shunt) nephritis should be considered. However, she had a normal echocardiogram and no other physical signs to support endocarditis, so this diagnosis was thought to be less likely.Hyperkalemia was acutely managed with intravenous calcium gluconate, sodium bicarbonate, insulin/glucose, and oral sodium polystyrene sulfonate. Albuterol was not used in this patient, but this is another option for managing hyperkalemia because β-agonists temporarily shift extracellular potassium to the intracellular space. Despite medical therapy for 12 hours, she had persistent hyperkalemia, so a temporary central venous catheter was placed for initiation of hemodialysis. Her creatinine level peaked at 8.6 mg/dL (760.24 µmol/L).A kidney biopsy was performed given severe AKI of unclear etiology. Light microscopy included 18 glomeruli per section. All glomeruli were normal, with no evidence of proliferation, inflammation, or thrombosis. There was extensive tubulointerstitial inflammation, which consisted primarily of neutrophils with occasional lymphocytes (Fig 1). The tubular lumens were full of neutrophils with disruption of normal tubular architecture (Fig 2). Immunofluorescence showed nonspecific mesangial staining close to the glomerular vascular pole for IgG 2-3+, IgA 2-3+, C1q 2-3+, kappa 2-3+, lambda 2-3+, with trace staining for C3 and negative staining for IgM. Electron microscopy showed normal glomeruli with normal thickness and texture of glomerular basement membranes and no podocyte foot process effacement. Weigert stain showed gram-positive organisms within the intratubular casts (Fig 3). These findings were suggestive of extensive acute pyelonephritis.On hospital day 2, her blood culture grew group A Streptococcus pyogenes. Given the left upper lobe opacity seen on chest radiography, the bacteremia was thought to be possibly secondary to pneumonia. Her urine culture returned negative. Despite negative urine culture, her biopsy showed histologic evidence of pyelonephritis with Gram-stain positivity for gram-positive organisms. In the setting of a positive blood culture and histologic evidence of pyelonephritis, she was diagnosed as having acute pyelonephritis due to hematogenous seeding by group A S pyogenes. She was treated with intravenous ceftriaxone. She required hemodialysis for 2 days and then had improvement in urine output and stabilization in hyperkalemia. Her creatinine level steadily improved over the next 9 days to 1.1 mg/dL (97.24 µmol/L) at the time of hospital discharge. She completed a total of 3 weeks of antibiotics, including intravenous ceftriaxone followed by oral amoxicillin. Four weeks after hospital discharge her creatinine level had returned to her previous baseline of 0.5 mg/dL (44.20 µmol/L).Given her severe AKI requiring dialysis, the patient should be followed longitudinally to monitor for CKD. With severe AKI, it is possible to have nephron loss due to scarring, even if the serum creatinine level returns to normal. (1) The risk of CKD is particularly high in patients who have recurrent episodes of AKI. (2) In a retrospective study of 359 patients hospitalized from 2000 to 2010 with a previous episode of AKI, 250 AKI episodes were observed among 122 patients. Of those with recurrent AKI, the hazard of CKD was 2.2 times greater in those who had recurrent AKI than in those who did not have recurrent AKI (P < .005). (3)Pyelonephritis is an infection of the upper urinary tract. (4) When pyelonephritis occurs secondary to infection from the lower urinary tract, the urine culture is typically positive. The patient in this case had a negative urine culture, which may have occurred for several reasons. One possibility is that she had pyelonephritis due to hematogenous seeding from bacteremia as evidenced by the Weigert stain on biopsy showing gram-positive organisms. A study of kidney transplant patients with acute graft dysfunction in whom urine cultures and biopsies had been performed reported a prevalence of 19% (5 of 26 persons) with biopsy findings consistent with pyelonephritis and a negative urine culture. These patients also reported no lower urinary tract symptoms. (5) Urine culture results can also be negative in the setting of pyelonephritis if the urine sample was collected after antibiotic administration. The patient did receive a 10-day course of amoxicillin within a month of presentation with AKI. Finally, urine culture results can be negative in the setting of renal parenchymal infection if the infection is localized, such as in the case of renal abscesses and struvite stones, which can harbor bacteria in a matrix of minerals and biofilm. (6)(7)The prevalence of pyelonephritis varies based on age group. Urinary tract infections are estimated to occur in 1% to 3% of school-age children. (8) AKI may occur in the context of pyelonephritis related to acute tubulointerstitial inflammation, dehydration, and concurrent nephrotoxin exposure. However, the incidence of severe AKI requiring dialysis in the setting of pyelonephritis is rare. In a study of adults, 12.3% of patients admitted to the hospital with urinary tract infections were noted to have AKI. Of those patients, only 0.5% required dialysis. (9)