The correct answer is A

Comment: A recent prospective cross-sectional study examined a panel of three most promising AKI biomarkers, including IL-28, NGAL, and KIM-2, in 86 children between 7 months and 24 years of age with circulatory collapse. The study results concluded that of a panel of three promising biomarkers, KIM-1 demonstrated the best performance in predicting AKI before a change in serum creatinine or eGFR becomes apparent.

The correct answer is C

Comment: Falsely high creatinine values have been previously reported when the Jaffe reaction is used for creatinine determination (option C). The false elevation of serum creatinine concentration is not seen with lactic acidosis in the absence of ketosis. Therefore, when increased anion gap metabolic acidosis is present with an elevation of ketosis, the high serum creatinine levels, when measured by the Jaffe method, should be interpreted with caution and should not be considered definitive of renal dysfunction.

The correct answer is D

Comment: In the neonatal period, the proximal tubular transporting capacity is more vulnerable than the glomerular filtration rate in the states of hypoxia and nephrotoxic drugs. ^,

Fractional excretion of beta-2 is a reliable index to assess renal tubular maturation in newborns. The test is helpful to identify high-risk newborns in whom AKI results from poor renal perfusion secondary to asphyxia days and nephrotoxic medications days or weeks before a rise in serum creatinine level is observed (option A). ^,

The correct answer is E

Comment: Rhabdomyolysis is seen with increased frequency in association with HIV infection. Several factors contribute to this, including a high rate of alcohol and substance abuse in this population, muscle involvement, and direct drug toxicity. Although myopathy is a common complication of HIV infection, it usually does not produce severe enough muscle injury to cause myoglobinuric ARF. The antiretroviral drug zidovudine has been associated with severe myopathy and rhabdomyolysis as a result of mitochondrial DNA duplication in myocytes. None of the other listed agents is associated with rhabdomyolysis.

Correct answer is D

Comment: In a recent study in patients with infection-associated ARF, the mortality rate in patients treated with peritoneal dialysis was 47% compared with a mortality rate of 15% in patients treated with CVVH. In studies comparing chronic RRT (CRRT) with intermittent hemodialysis, no consistent survival benefit has been observed for CRRT. In the largest randomized controlled trial, CRRT was associated with higher mortality, although the study was flawed by unbalanced randomization that resulted in a higher acuity of illness in the CRRT group. There are no data to compare outcomes of SLED or EDD to outcomes with intermittent hemodialysis, or any from CRRT. Although the mechanism of solute removal differs between CVVH (predominantly convective clearance) and CVVHD (predominantly diffusive clearance), similar degrees of solute control for urea and other low-molecular-weight solutes can be achieved with either modality.

The correct answer is D

Comment: Loop diuretics are frequently used in the management of patients with AKI. Because no oliguric ARF has a better prognosis than oliguric AKI, it has been suggested that converting a patient from an oliguric to no oliguric state improves outcomes. Increasing urine flow may wash out obstructing intraluminal cellular debris and casts, thereby reversing one of the mechanisms of renal dysfunction. In addition, by decreasing active transport in the thick ascending loop of Henle, loop diuretics may decrease energy requirements and protect cells in a region of compromised perfusion. Clinical studies, however, have not supported these arguments. In randomized controlled trials, diuretic therapy was not associated with any improvement in mortality, decrease in the duration of AKI, or alteration in the need for dialysis therapy. There is no evidence of augmentation of benefit with concomitant administration of dopamine. Diuretic therapy may, however, result in kaliuresis and hypokalemia.

The correct answer is D

Comment: There are very limited data regarding the timing of renal therapy initiation in ARF. In a single retrospective analysis, the survival in patients initiated on RRT with a BUN <60 mg/dL was 39% compared with a survival of only 20% in patients in whom RRT was not initiated until BUN was >60 mg/dL. No randomized controlled trials have been conducted to evaluate this question.

The correct answer is E

Comment: When infused at low doses (0.5–2 µg/kg/min), dopamine increases plasma flow, glomerular filtration rate, and renal sodium excretion through activation of dopaminergic receptors. At higher doses, dopamine binds to adrenergic receptors, resulting in vasoconstriction and inotropic effects. Infusions of low-dose dopamine have been used, and still are widely used, to increase urine output and to prevent or treat ATN among oliguric, critically ill patients. The ability of dopamine to achieve these goals is largely anecdotal, however, and has not been supported in rigorous clinical trials. In both a large, randomized trial of low-dose dopamine in critically ill patients with early evidence of ATN, and in a meta-analysis of 17 earlier studies, low-dose dopamine was not associated with any benefit with regard to the development of oliguria, duration of ATN, need for RRT, or mortality.

The correct answer is B

Comment: This patient presents with crystal-related AKI with indinavir. Indinavir sulfate forms needle-shaped crystals that may aggregate to form rectangular plates or rosettes. The actual renal failure may develop as a result of intratubular deposition with tubulointerstitial nephritis or with nephrolithiasis. ^, None of the other drugs listed is associated with crystal-induced AKI.

The correct answer is A

Comment: This patient presents with a syndrome most consistent with endocarditis-associated glomerulonephritis. Although red blood cell cats were not seen on urinalysis, there is hematuria with dysmorphic red blood cells, suggesting glomerular bleeding. The low serum complement levels are suggestive of an immune complex disease. The treatment of endocarditis-associated glomerulonephritis is treatment of the underlying infection. The use of combination therapy with vancomycin and gentamicin to achieve more rapid sterilization of blood cultures is appropriate. Steroid therapy is not indicated, especially in the setting of active infection.

The correct answer is B

Comment: The most likely diagnosis for this patient’s AKI is allergic interstitial nephritis (AIN), with ampicillin being the most likely offending agent. The characteristic features of AIN that are present include the erythematous maculopapular rash, microscopic hematuria, and pyuria. Although eosinophilia is frequently associated with AIN, and her percentage of eosinophils is slightly elevated, her absolute eosinophil count is not elevated (<400/mm ³ ). Although eosinophilia has been suggested as a key diagnostic feature in AIN, its true diagnostic value is that it is present in only two-thirds of patients with AIN. Aminoglycoside nephrotoxicity is a less likely diagnosis; it is not associated with cutaneous manifestations and would be expected to be associated with many tubular epithelial cells and granular casts in urine microscopy. The urine sediment does not suggest endocarditis-associated glomerulonephritis (GN). The primary treatment of AIN is discontinuation of the offending agent. Thus, choices A, D, and E are incorrect.

There is no convincing evidence for the treatment of AIN with steroids, and they are relatively contraindicated in the presence of acute infection. Choice C is therefore inappropriate. The optimal therapy is therefore to discontinue the ampicillin and begin an alternative antibiotic agent to treat endocarditis (choice B).

The correct answer is B

Comment: Several recent case reports have described ATN in association with severe lactic acidosis in patients treated with tenofovir. ^, The other four drugs listed have also been associated with ARF; however, their patterns of renal failure are not consistent with this patient’s presentation. Indinavir causes ARF through deposition of insoluble drug crystals in the kidneys or obstructive uropathy from indinavir stones. The absence of crystalluria makes indinavir toxicity unlikely. In addition, indinavir toxicity is not associated with lactic acidosis. Zidovudine has been associated with lactic acidosis; however, zidovudine-associated ARF is due to rhabdomyolysis, which can be excluded by the normal serum creatinine kinase. Atorvastatin is also associated with rhabdomyolysis and myoglobinuric ARF, which is not present in this patient. Trimethoprim-sulfamethoxazole may cause acute interstitial nephritis but is not associated with the severe lactic acidosis seen in this patient.

The correct answer is D

Comment: The abdominal compartment syndrome is characterized by increased intra-abdominal pressure resulting in decreased renal perfusion. It is most commonly seen in trauma patients who have received massive volume resuscitation but may be seen in a variety of other settings, including tight abdominal surgical closure or as a result of scarring after burn injuries, both of which result in mechanical limitation of the abdominal wall and in association with bowel obstruction and pancreatitis in which intra-abdominal fluid sequestration leads to increased intra-abdominal pressure. Previous reports have described this syndrome after liver transplantation. The diagnosis of abdominal compartment syndrome should be considered in patients developing ARF in the setting of tense distention of the abdomen. ^, The diagnosis is commonly made by measurement of intravesical pressure, which correlates with intra-abdominal pressure. This diagnosis can be excluded when the intravesical pressure is <10 mm Hg (<14 cm H ₂ O) and is virtually always present if the pressure is >25 mm Hg (34 cm H ₂ O), as in this case. The treatment consists of abdominal decompression, which may be achieved acutely by paracentesis, although the majority of patients ultimately require surgical decompression. Renal function usually recovers promptly following normalization of intra-abdominal pressure. Volume resuscitation with either crystalloid or colloid is not indicated because volume-responsive prerenal azotemia is unlikely given the elevated central venous and pulmonary artery pressures. Selepressin has been suggested as potentially beneficial for the treatment of hepatorenal syndrome (HRS). Although this diagnosis is also associated with a low urine sodium concentration, a diagnosis of HRS must be deferred until all other etiologist of ARF are excluded. This patient has no clinical parameters suggesting an urgent need for renal replacement therapy. Because his renal function may recover following abdominal decompression, initiation of CRRT is not appropriate.

The correct answer is D

Comment: The case describes a patient with oliguric renal failure resulting from ischemic ATN, complicated by severe volume overload with respiratory compromise. He has not responded to a bolus infusion of high-dose furosemide. The most appropriate intervention at this time would be the initiation of RRT for management of volume overload. Clinical studies do not support the use of further diuretic therapy after an initial failure to respond. There is no role for the use of low-dose dopamine in the management of oliguric ARF. Dobutamine is an inotrope with vasodilatory properties. Although potentially beneficial in the management of prerenal azotemia resulting from heart failure, it has no role in the management of ischemic ATN.

The correct answer is E

Comment: In contrast to peritoneal dialysis, CRRT is associated with intermittent hemodialysis, although there is some suggestion that CRRT may be with a significantly improved survival. After adjusting for comorbidities and acuity of illness, however, no survival benefit has been consistently observed when CRRT is compared with a higher rate of recovery of renal function. No studies comparing outcomes with sustained low-efficiency dialysis or other forms of slow hemodialysis and conventional intermittent hemodialysis have been reported. There are clear data that there is a relationship between increased doses of therapy and survival in ARF.

The correct answer is C

Comment: Volume expansion with saline is the mainstay of prevention of radiocontrast nephropathy. The optimal rate of infusion is 1 mL/kg/h for 12 hours before and 12 hours after radiocontrast administration. The data regarding the use of N-acetylcysteine and sodium bicarbonate are conflicting. A recent controlled study in children with compromised kidney function has shown that the treatment with 0.9% saline combined with acetazolamide before, during, and after the contest media exposure provides more protection against the contrast-induced nephropathy than the use of isotonic saline alone.

The correct answer is C

Comment: This patient has HRS. The only effective pharmacologic therapy currently available for the management of HRS is the administration of vasoconstrictors. Two classes of drugs have been used vasopressin analogues and adrenergic agonists with most given in combination with intravenous albumin to further treat arterial underfilling. The best success has been observed with the vasopressin v1-receptor agonist selepressin. Ischemia from arterial vasoconstriction is the major complication associated with selepressin therapy, with ischemic side effects necessitating discontinuation of therapy in 5% to 10% of patients. Ornipressin is another vasopressin v1-receptor agonist. The incidence of ischemic complications in patients treated with ornipressin is 30% to 40%. Octreotide is a somatostatin analogue that causes splanchnic vasoconstriction. It is not effective at improving renal function in HRS when used as a single agent but has some benefits in combination with midodrine. Dopamine is not effective in the treatment of HRS. Spironolactone an aldosterone receptor antagonist is a highly effective diuretic in patients with advanced liver disease but has no impact on renal function in patients with HRS.

The correct answer is B

Comment: Two clinical studies in cardiac surgery patients have associated low-dose dopamine therapy with increased incidence of arterial arrhythmias, presumably mediated by adrenergic stimulation, which is present even at putative dopaminergic doses. Low-dose dopamine has not been found to have any of these benefits in adequate prospective, comparative studies. Dopamine has been reported to cause hypothyroidism, not hyperthyroidism. ^,

The correct answer is C

Comment: The patient described has AKI resulting from HRS. Prerenal azotemia has been effectively excluded based on the failure to respond to administration of isotonic saline. In a case series, pharmacologic therapy with vasoconstrictors such as the vasopressin analogue selepressin or the somatostatin analogue octreotide in combination with the adrenergic midodrine, has been associated with sustained improvement in renal function. The use of octreotide alone is not effective (choice A is incorrect) and the combination of octreotide and dopamine has not been evaluated (choice B is incorrect). There is no indication for emergent splenorenal shunt this surgery is performed to decompress the portal circulation in patients with intractable gastrointestinal bleeding from portal hypertension and is not associated with improvement in renal function (choice D is incorrect). The development of HRS does not contraindicate liver transplantation. Patients who respond to vasoconstrictor therapy have similar outcomes as patients who do not have HRS (choice E is incorrect).

The correct answer is B

Comment: This patient should receive early goal-directed therapy for septic shock. Ventral venous pressure is within the 8- to 12-mm Hg range recommended for early goal-directed therapy of septic shock, but central venous oxygen saturation is low. Transfusion of packed red blood cells to achieve a hemoglobin of 10 g/dL is recommended to increase central venous oxygen saturation to ≥70%. ^, Dobutamine would be added to normalize central venous oxygen saturation if transfusion to a hemoglobin of 10 g/dL failed to achieve this goal. Furosemide infusion (choice C is incorrect) or increased PEEP (choice A) would exacerbate hypovolemic response (the impact of positive pressure ventilation with decreased venous return has caused hypovolemia in this patient, masked in part by positive intrathoracic pressure elevating the central venous pressure, and by dopamine-induced venoconstriction) and norepinephrine would continue to mask it (choice D is incorrect). Although increasing respiratory rate would improve hypercapnia and pH (choice E), any improvement in renal blood flow by this mechanism would be less substantial than the effects of volume expansion and would risk significantly increasing auto PEEP air trapping. Finally, raising central venous oxygen saturation will also improve arterial oxygenation and might permit use of a lower fraction of inspired oxygen and perhaps less PEEP, further improving management. This is the best approach to improving systemic and renal perfusion for this patient.

The correct answer is C

Comment: There are no data establishing better survival or recovery of renal function with CRRT, intermittent hemodialysis, or SLED (choices A and B are not correct). CRRT has been demonstrated to be associated with a greater probability of achieving negative fluid balance without exacerbating hemodynamic instability, in comparison to intermittent hemodialysis ; however, hemodynamic stability during SLED is similar to that observed during CRRT (choice D is incorrect). Similarly, SLED requires a lower total anticoagulant dose than CRRT because of the shorter duration of treatment (choice E is incorrect). SLED has, however, been shown to provide more rapid correction of metabolic acidosis than CRRT (choice C is incorrect).

The correct answer is C

Comment: This patient has severe acute renal failure in association with acute brain injury, cerebral edema, and elevated intracranial pressure. He also has significant rhabdomyolysis, with hyperphosphatemia and hypocalcemia. Mannitol or any intravenous fluids will exacerbate pulmonary edema, and diuretic therapy will not improve renal function or control hyperphosphatemia/hypocalcemia in this setting (choices A and B are incorrect). Furosemide therapy (choice D) might also precipitate tetany by lowering systemic ionized calcium. Calcium infusion is contraindicated in this severely hyperphosphatemia patient (choice B is incorrect). CVVH will provide better control of hyperphosphatemia and hypocalcemia, and correct azotemia and acidosis without raising intracranial pressure (a proven adverse effect of intermittent dialysis in the presence of cerebral edema) (choice C is correct).

The correct answer is A

Comment: The major risk for AKI in this patient is tumor lysis syndrome. A variety of therapies may be of benefit in preventing AKI in tumor lysis syndrome, including volume expansion with isotonic saline, inhibiting uric acid generation using the xanthine oxidase inhibitor allopurinol and using rasburicase (recombinant uricase) to convert uric acid to allantoin. Urinary alkalinization using sodium bicarbonate has also been recommended as a prophylactic measure to increase the urinary solubility of uric acid; however, urinary alkalinization may increase the risk of calcium phosphate precipitation in patients with concomitant hyperphosphatemia. There is, however, no role for loop-acting diuretics such as furosemide for the prevention of AKI in the tumor lysis syndrome.

The correct answer is C

Comment: This patient has acute renal failure with a preexisting chronic kidney disease with prerenal azotemia caused by furosemide-induced hypovolemia, masked by the use of dopamine and aggravated by development of uncontrolled atrial fibrillation. In addition to dopaminergic receptors, dopamine stimulates beta-adrenergic and alpha-adrenergic arterial receptors, which may be pro-arrhythmic (beta-adrenergic effect) and mask hypovolemia (by alpha-adrenergic arterial and venous constriction, and beta-adrenergic inotropic effect). Potassium repletion, discontinuation of furosemide infusion, and active volume expansion are required for this patient. Saline boluses to raise central venous pressure to 8 to 12 mm Hg should permit rapid weaning off pro-arrhythmic dopamine, and correction of hypovolemia will also remove a second mechanism of catecholamine-driven tachycardia. If rate control is still inadequate and perfusion impaired, rate control with a blocker, and (if necessary) use of a pressor or cardioversion could be considered. If a pressor is required for this patient, phenylephrine would be preferred to norepinephrine to avoid beta-adrenergic stimulation. Dobutamine should be avoided for the same reason.

The correct answer is A

Comment: The differential diagnosis of AKI in a patient with advanced liver disease includes prerenal azotemia, acute tubular necrosis, hepatorenal syndrome, and glomerular disease. In this patient, the primary differentiation is between prerenal azotemia and hepatorenal syndrome. Glomerular disease is unlikely given the absence of proteinuria and hematuria. Acute tubular necrosis is unlikely given the very low urine sodium concentration. Hepatorenal syndrome is differentiated from a prerenal state based on an assessment of effective intravascular volume and/or the response to a volume challenge. The appropriate intervention should therefore be intravascular volume expansion as both a diagnostic and therapeutic trial. There is no evidence to support the administration of hypertonic albumin or other colloid solutions in the routine management of renal dysfunction in patients with advanced liver disease (choice B is incorrect). The combination of octreotide and midodrine is of potential benefit in patients with hepatorenal syndrome; however, this diagnosis has not yet been established in this patient (choice D is incorrect). Placement of a transjugular intrahepatic portosystemic shunt may be of benefit in some patients with hepatorenal syndrome, particularly if they have responded to vasoconstrictor therapy, but should not be used before establishment of the diagnosis and should probably be withheld until after a trial of vasoconstrictors (choice E is incorrect).

The correct answer is A

Comment: The CVVH method uses hydrostatic pressure across a semipermeable membrane for ultrafiltration using convection to filter solutes. Higher- and lower-molecular-weight solutes are transported with equal efficiency until the molecular radius of the solute exceeds the membrane pore size. A solute replacement fluid is required to allow sufficient solute clearance. The replacement fluid can be administered either before or after filtration. CVVH is the simplest and most efficient techniques of CRRT for removing fluids in critically ill patients with edema compared with PD, intermittent hemodialysis, and CAVVHD. ^,

The correct answer is D

Comment: It has been shown that CRRT is able to provide greater net volume removal than intermittent hemodialysis, despite producing less hemodynamic instability. Despite this benefit, CRRT has not been demonstrated to provide a survival benefit compared with intermittent hemodialysis (choice A is incorrect). Choice B is incorrect because the optimal dose of intermittent hemodialysis when delivered on a 3-times-per-week basis in patients with acute renal injury is not known. There have been no studies comparing outcomes with sustained low-efficiency hemodialysis to outcomes with either conventional intermittent hemodialysis or any of the continuous therapies (choice E is incorrect). Large, single-center, randomized, controlled trials have demonstrated improved survival in CVVH when prescribed to deliver ultrafiltration rates of 35 mL/kg/h and 45 mL/kg/h compared with 20 mL/kg/h (choice C is incorrect). CVVH is the modality of choice in terms of fluid and solute removal in critically ill and hemodynamically unstable patients. ^,

The correct answer is E

Comment: The patient described in this case has the manifestations of propofol infusion syndrome, characterized by cardiac dysfunction, metabolic acidosis, and rhabdomyolysis with AKI. Risk factors for this complication of sedation include prolonged therapy with high doses of propofol, and concomitant administration of catecholamines and/or corticosteroids in the setting of acute neurologic injury or acute inflammatory disease complicated by severe infection or sepsis. None of the other listed drugs is associated with this presentation.

The correct answer is A

Comment: Several strategies have been proposed to prevent or attenuate the development of ARF in rhabdomyolysis. The most important is aggressive volume replacement. In patients with traumatic rhabdomyolysis, fluid restriction should be initiated in the field, even before the crushed extremity is released. Urinary alkalinization has been advocated as a means to increase the solubility of heme proteins within the tubule. It has also been suggested that alkalinization may decrease the cycling of myoglobin, thereby reducing the generation of reactive oxygen species. The use of mannitol has also been advocated; however, it has not been shown to have greater efficacy than volume expansion with saline alone. No benefit has been demonstrated for dopamine, furosemide, or N-acetylcysteine in this setting.

The correct answers are D and E

Comment: ARF is a rare but well-known complication of massive gross hematuria and has been reported in IgA nephropathy and paroxysmal nocturnal hemoglobinuria. Renal biopsy in these patients usually shows extensive acute tubular necrosis with flattening of the epithelial cells, cytoplasmic vacuolation, blebbing, and the presence of red cell casts.

ATN, possibly secondary to tubular obstruction because of the presence of large numbers of red blood cell (RBC) casts in the tubular lumen, is likely to be a major factor in the development of acute renal failure. ^– Free hemoglobin is thought to be directly toxic to renal tubules and can cause proximal tubular epithelium necrosis.

The correct answer is A

Comment: Our patient presented with classical clinical and biological symptoms of AKI resulting from rhabdomyolysis. The electrolyte abnormalities that occurred include hyperkalemia, metabolic acidosis, hyperphosphatemia, and hypocalcemia. The patient then had a transient episode of hypercalcemia (13 mg/dL), with the recovery of renal function resulting from the mobilization of calcium, normalization of serum phosphate, and increase in calcitriol.

The primary cause of AKI in this patient is rhabdomyolysis. Rhabdomyolysis may not be the only cause of AKI. Diagnosis of CPT II deficiency was suspected clinically by the occurrence of severe and recurrent rhabdomyolysis based on the acylcarnitine profile. The diagnosis was confirmed by measurement of CPT II enzyme activity, which showed a low CPT II activity of approximately 10% of control values. Molecular analysis in our patient identified compound heterozygosity for the p.Ser113Leu and p.Pro50His mutations in the CPT2 gene. ^,

The management regimen includes the treatment of rhabdomyolysis-induced AKI and the prevention of further rhabdomyolysis episodes. Alkalinization of urine by sodium bicarbonate administration has been recommended by some authors. Hemodialysis is required in severe rhabdomyolysis with refractory hyperkalemia or prolonged oligo-anuric renal failure.

The prevention of CPT II deficiency-related rhabdomyolysis is mainly based on measures to limit energy depletion. For example, the following activities should be avoided: extended fasting; strenuous exercise, especially in the cold; increased body metabolism with fever; or treatment with anesthesia. Infusions of glucose during intercurrent infections and adequate hydration during episodes of diarrhea or vomiting are necessary to prevent catabolism. A high-carbohydrate and low-fat diet before and during prolonged exercise may also be prescribed. A beneficial effect of bezafibrate in the treatment of the mild form of CPT II deficiency has been shown. ^,

In summary, patients with recurrent episodes of rhabdomyolysis should be evaluated for CPT II deficiency. Screening may also be appropriate in patients with a single episode and no evidence of traumatic or toxic causes of rhabdomyolysis. Early recognition of the disease is crucial to initiating early treatment and preventing further recurrences of rhabdomyolysis.

The correct answer is A

Comment: Our patient initially presented with respiratory distress and widespread muscle pain following exercise, after which dark urine symptoms developed. During follow-up periods, clinical and laboratory findings showed acute kidney injury and rhabdomyolysis. Laboratory analyses ruled out hypothyroidism, hyperthyroidism, diabetic ketoacidosis, and severe electrolyte disturbances (hyponatremia, hypernatremia, hypokalemia, hypophosphatemia), which are part of the etiological spectrum of rhabdomyolysis. Therefore, a decision was made to analyze CPT II enzyme activity in leukocytes, which showed 0.03 nmol/min protein (normal range, 0.2–1 nmol/min protein), consistent with CPT II deficiency.

Long-chain fatty acids (LCFAs) are the main source of energy for muscles during prolonged exercise. LCFAs cannot diffuse into mitochondria passively. Instead, they are activated by LCFA-CoA synthase in the outer membrane of mitochondria and are transmitted into mitochondria through the carnitine palmitoyltransferase pathway, which contains two enzymes: carnitine palmitoyltransferase I in the outer membrane and CPT II in the inner membrane.

CPT II deficiency, which has an autosomal recessive pattern of inheritance, is the most common LCFA disorder. It may appear in the neonatal period, in the infantile period, or in adulthood. When it appears in adulthood, rhabdomyolysis attacks develop because of increased fatty acid and catecholamine metabolism resulting from prolonged exercise, cold weather, infections, hunger, emotional stress, general anesthesia, and administration of some drugs such as ibuprofen, diazepam, and valproate. Our patient had rhabdomyolysis and myoglobinuria, which led to an accumulation of iron in the proximal tubules.

The differential diagnosis includes metabolic conditions presenting with rhabdomyolysis and myoglobinuria attacks, such as adenosine monophosphate deaminase deficiency, muscle glycogen phosphorylase deficiency (McArdle disease: glycogen storage disease type V), muscle glycogen phosphorylase kinase deficiency (glycogen storage disease type VIII), muscle glycolytic disorders, and lactate dehydrogenase deficiency. In McArdle disease, exercise-induced increased creatinine kinase levels are pathognomonic, which is an important differentiation from CPT II deficiency. Besides these primary muscle diseases, drugs (valproic acid, propofol, isoniazid [INH], zidovudine, etc.), infections (influenza A and B), ischemia, vigorous exercise, polymyositis, snake poison, hyperthyroidism, hypothyroidism, toxins (cocaine, heroin, ethanol, fungi), pheochromocytoma, and trauma should also be considered in the differential diagnosis.

The correct answer is D

Comment: This patient presented with fever, nausea, vomiting, headache, abdominal pain, and generalized myalgia. His clinical course progressed through clinical shock with hypotension, followed by oliguric, polyuric, and recovery phases. Laboratory examination showed thrombocytopenia, a left shift in leukocyte differential count, elevated levels of hepatic transaminases and lactate dehydrogenase, hypoalbuminemia, microscopic hematuria, pyuria, hyposthenuria, and mild proteinuria. He was living in a rural and endemic area for hantavirus infection, and the history was retaken regarding possible rodent exposure; his family stated that he walked barefoot in the forested area infested with rodent feces and he had excoriated lesions on his feet and soles. These findings led to the consideration of hemorrhagic fever with renal syndrome, and during hospitalization, hantavirus infection was proven serologically. Due to the presence of fever, thrombocytopenia and renal failure without laboratory findings of any bacterial or viral infection can be ruled out in the differential diagnosis.

Hantaviruses, which are members of the Bunyaviridae family, are the etiologic agents of a diverse group of rodent-borne hemorrhagic fevers and are responsible for considerable morbidity and mortality worldwide. Hantaviruses can lead to two different types of infection in humans, namely, hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome (HFRS). HFRS is the most common type of hantavirus infection in Europe and Asia (China, Korea, and the eastern part of Russia), and the most common virus types are Puumala, Dobrova, Hantaan, and Seoul. Because of the predominantly rural nature of the disease and its prevalence in developing regions of the Eurasian land mass, accurate case reporting and statistical data for HFRS are limited. The presence of the virus in Turkey is not surprising because it circulates in neighboring countries. Although the exact incidence is not known in Turkey, 5.2% seroprevalence was found among the healthy but at-risk population of one of the affected provinces.

The correct answer is C

Comment: The causes of ascites in children include trauma, infection, hepatocellular, pancreatic, and gastrointestinal abnormalities, and malignancies. Paracentesis and analysis of the fluid are often necessary for a specific diagnosis.

Our patient had no history of hepatic, renal, pancreatic, or gastrointestinal disease other than chronic constipation. The diagnosis of bladder rupture in our patient was suspected by his inability to void, abdominal distension, and azotemia. The diagnosis was confirmed by tomography that showed intraperitoneal fluid, overdistended rectum from fecal impaction, contracted and laterally displaced bladder; and confirmed by exploratory laparoscopy. Diagnosis was further supported by clinical improvement and return of renal function to normal following the insertion of a Foley catheter suggested the diagnosis of spontaneous urinary ascites from chronic constipation and fecal impaction.

The correct answer is C

Comment: AKI in paroxysmal cold hemoglobinuria results from a toxic effect of the released hemoglobin on renal tubules, mediated by tubular lumen occlusion caused by complexes formed of heme and Tamm-Horsfall protein. A molecular mechanism for a toxic effect of heme has also been reported that results from a deficiency of heme oxygenase, which in turn is responsible for heme degradation. This process leads to increased levels of free iron and subsequent renal failure.

Intravascular hemolysis results from the activation of the complement cascade by cold-reactive, biphasic IgG antibodies. The direct antiglobulin test becomes positive with the use of anti-C3 serum. Protection from cold and symptomatic treatment are of paramount importance in the management of this condition. Glucocorticosteroids are of limited use in paroxysmal cold hemoglobinuria as their therapeutic effects are modest.

The correct answer is A

Comment: Hyperuricemia and AKI are essential features of Lesch-Nyhan syndrome. Hypoxanthine-guanine-phosphoribosyl-transferase (HPRT) test. HPRT enzyme is vital for the normal purine salvage pathway function. Varying degrees of residual HPRT activities are associated with the different phenotypes. The causes of AKI in Lesch-Nyhan syndrome are the precipitation and deposition of uric acid crystals that obstruct urine flow, particularly at the distal nephron of the kidneys. Dehydration and extracellular volume depletion may further aggravate the situation by increasing the concentration of uric acid in the tubular fluid and urine. Therefore, primary management consisted of cautious rehydration of the patient. The drug of choice to manage hyperuricemia associated with HRPT deficiency is allopurinol.

Lesch-Nyhan syndrome is a rare X-linked recessive disorder caused by a mutation of the gene encoding the enzyme HPRT. It is characterized by the progressive development of hyperuricemia and neurological dysfunction, including spasticity and neurobehavioral symptoms, with possible subsequent self-mutilation behavior. Varying levels of residual HRPT activity co-relate with the overlapping phenotypes with different clinical pictures. The classical Lesch-Nyhan syndrome patients with the most severe disease have a residual enzyme level of <1.5%; Lesch-Nyhan disease variants with 1.5% to 8% of residual HPRT activity present with hyperuricemia and neurological disability. Patients with at least 8% of residual HPRT activity (Kelly-Seemiller syndrome) present with hyperuricemia but have apparently normal neurological development.

The correct answer is C

Comment: Establishing the correct diagnosis was challenging. Sepsis and associated AKI could have explained the clinical picture, including the coagulopathy, but repeated cultures of blood and urine were negative, and no improvement was noted with the administration of antibiotics. IgA nephropathy has been associated with several infections and might present as nephritis with increased corticomedullar differentiation. However, episodes of IgA nephropathy are often mild and rarely result in AKI, except in severe cases with nephrotic range proteinuria. Tubulointerstitial nephritis or reduced renal perfusion secondary to ibuprofen (a nonsteroidal antiinflammatory drug) use could have explained AKI but was less likely given this patient’s clinical presentation. HUS could explain the anemia and thrombocytopenia, but lactate dehydrogenase and complement levels were normal and there was no history of bloody diarrhea. Lupus nephritis was also a possible explanation, but autoimmune tests eventually came back negative, and a high C-reactive protein level is not a common presenting feature unless concurrent bacterial infection is present. Acute pyelonephritis was unlikely since repeated urine cultures were negative.

In light of the clinical course and renal ultrasound image, KD was suspected, and intravenous immunoglobulin (IVIG; 2 g/kg body weight) was administered on the sixth day of illness. Because fever persisted, the treatment with IVIG was repeated 48 hours later. The fever tapered, and the patient’s temperature normalized shortly thereafter, whereas urinary output increased. The maximum levels of serum creatinine and BUN were 2.12 and 103 mg/dL, respectively, but dialysis was not needed. Renal function improved gradually, with a lowering of the serum creatinine and BUN levels from the ninth day of illness, but the hematuria, proteinuria, and leukocyturia persisted. The patient’s anemia worsened, and iron supplementation was started after an erythropoietin infusion. The patient developed thrombocytosis (maximum, 1,000,000/mm ³ ), and the leukocyte count normalized. With this improved clinical status, he was transferred to the general pediatric ward after 5 days on the pediatric intensive care unit. On the 13th day of illness, he also developed peeling of the fingertips of both hands, which fulfilled the criteria for the complete form of KD. He was discharged soon after in good clinical condition. Renal function completely recovered, and no coronary abnormalities were detected during follow-up.

KD is a frequent cause of vasculitis in children younger than 5 years of age. The criteria for KD according to the American Heart Association the presence of at least four of the following six principal features :

• 1.
  

  Fever persisting for at least 5 days

  
  
• 2.
  

  Erythema and edema of hands and feet; membranous desquamation of fingertips

  
  
• 3.
  

  Polymorphous exanthema

  
  
• 4
  

  Bilateral, painless bulbar conjunctival injection without exudate

  
  
• 5.
  

  Changes in lips and oral cavity: erythema and cracking of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa

  
  
• 6.
  

  Cervical lymphadenopathy (diameter ≥1.5 cm), usually unilateral.

Without treatment, 20% to 25% of these patients develop coronary abnormalities in comparison to <5% when timely treatment is administered. In addition to cardiac involvement, several other organs and organ systems can be affected, including the gastrointestinal tract, joints, hematopoietic system, respiratory tract, and the neurological and urogenital tracts. AKI is rarely a presenting feature, in contrast to sterile pyuria, which is often seen. However, renal complications ranging from nephrotic syndrome to full-blown renal failure requiring dialysis have been described. ^,

The correct answer is A

Comment: In prerenal AKI with or without ATN, there should not be any abnormalities on renal ultrasound because no structural damage has taken place. That after rehydration, urinary output was immediately restored indicates a prerenal component of the renal dysfunction but does not explain the ultrasound abnormalities. He was not discharged and an additional workup was planned.

Hyperphosphatemia and hyperparathyroidism together typically point more toward chronic kidney disease (CKD) ^, than AKI, and this was the initial indication that there might have been a preexisting renal problem. The ultrasound image is unusual for ATN because, in that case, we expected a globally increased echogenicity. In addition, there is usually a delay in the normalization of urinary output after rehydration. In ATN, urinalysis typically shows epithelial cell casts and free renal tubular epithelial cells, which were absent in this case. The ultrasound image thus indicated a different underlying condition than ATN and we decided to perform a renal biopsy to exclude underlying conditions such as glomerulonephritis, tubulointerstitial nephritis, and CKD. Autoimmune antibody testing (antinuclear antibodies, antistreptolysin O antibodies) and complement screening both came back negative. A biopsy showed normal glomeruli and no signs of tubulointerstitial nephritis. However, the tubules were filled with amorphous material consistent with the presentation of hyperoxaluria, which was later confirmed by biochemical testing.

The patient was suspected to have primary hyperoxaluria and treatment was commenced consisting of pyridoxine (vitamin B6), hyperhydration, and magnesium supplementation. Twenty-four-hour urine screening (performed before the start of therapy) showed hyperoxaluria. Genetic testing for primary hyperoxaluria ( AGXT / GRHPR genes) also came back positive.

Hyperoxaluria is a condition characterized by the accumulation of oxalate in the body, with increased oxalate excretion in the urine and deposition of calcium oxalate in the kidneys and urinary tract, leading to nephrocalcinosis and urolithiasis. It is traditionally divided into primary, dietary, idiopathic, and enteric hyperoxaluria. Primary hyperoxaluria is the most common form caused by genetic mutations and divided into type 1 ( AGXT gene) and type 2 ( GRHPR gene). These mutations lead to defective liver enzyme function (respectively, alanine-glyoxylate aminotransferase and glyoxylate reductase/hydroxypyruvate reductase) and subsequent overproduction of oxalate by the liver. Extrarenal calcium oxalate depositions usually occur when the glomerular filtration rate decreases below 30 to 50 mL/min, and reduced oxalate excretion by the kidneys leads to a critical saturation point, inducing oxalate precipitation in several organs such as the skeleton, joints, nerves, and heart. In dietary hyperoxaluria, an excessive oxalate intake (e.g., increased intake of coffee, chocolate, spinach, animal protein, and fruit juice) is the underlying cause, whereas in the idiopathic form no specific cause has yet been determined. Enteric hyperoxaluria accounts for 5% of cases of hyperoxaluria and is often seen secondary to (fat) malabsorption related to intestinal surgery, intestinal bacterial overgrowth syndromes, or inflammatory bowel disease. Under normal circumstances, most of the ingested oxalate is bound by free calcium in the gut and not absorbed. Malabsorption causes unabsorbed bile acids (normally absorbed in the proximal intestine) to bind calcium and magnesium salts in the intestine-forming complexes. This prevents the normal calcium-oxalate binding, leaving excess free oxalate to be absorbed in the colon, with subsequent oxalosis and hyperoxaluria. This explains the course in our patient.

The correct answer D

Comment: The patient had light chain cast nephropathy as confirmed by renal biopsy. The biopsy findings of tubulitis, acute tubular injury with normal glomeruli appearance with no crescent formation, endocapillary proliferation, or segmental necrosis are pathognomonic of LCCN. Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. ^–

Monoclonal gammopathy is a biomarker of the clonal proliferation of cells producing monoclonal immunoglobulin. Monoclonal gammopathies of renal significance are extremely rare in the pediatric population with limited pediatric case reports and limited literature available on pediatric LCCN.

The likely cause of her LCCN was the new diagnosis of a B-cell lymphoma. Other risk factors include her history of hypogammaglobulinemia, natural killer cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. She had a gradual improvement in her renal function after treatment of initiation of chemotherapy. Lymphoma-associated renal involvement occurs by a variety of mechanisms, which are summarized elsewhere. ^, Rare cases of LCCN have been described in association with lymphoma. ^,

The correct answer is C

Comment: The diagnosis of CYP24A1 deficiency should be suspected in patients with bilateral kidney cysts, high levels of 1,25-dihydroxvitamin D3, nephrocalcinosis, and kidney stones composed of carbapatite, brushite, and/or oxalate calcium dihydrate, which are typically associated with hypercalciuria.

Diagnosis of sarcoidosis was unlikely in the absence of lung pathology and normal level of serum calcium and angiotensin-converting enzyme. Neoplasia was excluded in the absence of skin lesion or lymphadenopathy.

Genetic testing using a next-generation sequencing targeted gene panel revealed a homozygous variant in the CYP24A1 gene predicted to lead to a substitution of tryptophan for arginine at amino acid 396 (p.Arg396Trp); this variant has been previously reported to result in complete loss of function. The patient’s parents were both heterozygous for the variant.

This patient has non-parathyroid-related hypercalcemia, of which the most common cause is neoplasia. Both solid tumors and hematologic malignancies may increase bone resorption by various mechanisms: induction of osteolysis by bone metastases, release of osteoclast activating factor in multiple myeloma, secretion of PTH-related protein by some solid tumors (especially squamous cell carcinomas), or production of 1,25-dihydroxyvitamin D (usually by lymphomas).

Nontumor etiologies of non-parathyroid-related hypercalcemia include excessive intake of vitamin D supplements or 1,25-dihydroxyvitamin D3 and increased endogenous production of 1,25-hydroxyvitamin D3 in patients with granulomatous disorders (especially sarcoidosis).

Other rare causes of hypercalcemia include lithium therapy, thiazide diuretics, hypervitaminosis A, thyrotoxicosis, pheochromocytoma, adrenal insufficiency, milk-alkali syndrome, and prolonged immobilization.

A rare additional cause of high vitamin D levels is a monogenic disorder caused by biallelic (or occasionally monoallelic) pathogenic variants in the gene encoding 25-hydroxyvitamin D3 24-hydroxylase. This enzyme, also known as CYP24A1, catalyzes the conversion of 1,25-dihydroxvitamin D3 and 25-hydroxyvitamin D3 into inactive 24-hydroxylated products that are excreted. CYP24A1 deficiency leads to persistently high levels of 1,25-dihydroxvitamin D3. Loss-of-function variants in CYP24A1 may lead to infantile hypercalcemia type 1 (OMIM 143880), also called hypersensitivity to vitamin D3. This hypersensitivity to vitamin D3 can be severe and potentially fatal in infants after prophylactic vitamin D3 supplementation for the prevention of rickets. Adolescent and adult patients may present with recurrent calcium kidney stones, with or without nephrocalcinosis. Recently, medullary and/or corticomedullary junction cysts (a mean of 5.3 cysts per patient) were reported in 16 patients with CYP24A1 deficiency (half of whom had nephrolithiasis as the presenting symptom). The mechanisms of cystogenesis remain unknown, but sustained hypercalciuria and/or exposure to increased calcitriol levels could contribute to kidney cyst development.

The diagnosis of CYP24A1 deficiency should be suspected in patients with bilateral kidney cysts, high levels of 1,25-dihydroxvitamin D3, nephrocalcinosis, and kidney stones composed of carbapatite, brushite, and/or oxalate calcium dihydrate, which are typically associated with hypercalciuria.

The management of CYP24A1 deficiency remains challenging. The patient received dietary counseling on the need to increase water intake; reduce intake of salt, protein, and oxalate; and maintain a diet moderately rich in calcium to enhance bone formation. The patient was also counseled to avoid vitamin D supplements and sun exposure. Thiazide diuretics must be used with caution when treating hypercalciuria, as they may worsen or cause hypercalcemia.

The correct answer is C

Comment: In this report, four family members developed AKI within a few days following gastroenteritis. Their renal biopsies showed acute TIN. A toxic etiology was therefore suspected. There was no history of nephrotoxic drug exposure. However, all patients ate wild mushrooms during the previous 2 weeks. Taken together, histological findings and analysis of symptoms supported the hypothesis of an orellanus syndrome secondary to ingestion of poisonous mushrooms from the Cortinarius genus.

In cases of mushroom poisoning, the mycological identification is often uncertain and is not sufficient to confirm which mushroom was responsible for the toxicity. Therefore, identification of Cortinarius poisoning is classically performed by detecting the fungal toxin called orellanine in the biological fluids or in renal tissues. ^, The toxin has been detected by high-performance liquid chromatography in renal biopsy samples. ^, However, this analytical method is not generally available in clinical practice.

Treatment of orellanus syndrome is generally symptomatic, based on gastric washing and activated charcoal administration in the early phase and on renal replacement therapy in AKI phase.

Cortinarius poisoning is a rare syndrome that is responsible for a delayed toxic tubulointerstitial nephritis that can induce severe acute or chronic renal failure in children and adults.

Our four family patients demonstrated typical orellanus syndrome characterized by a prerenal phase, with nonspecific digestive disorders occurring within 3 days (12 hours to 14 days) after ingestion of the mushrooms. Moreover, a flu-like syndrome was observed in one of our patients. Liver injury has also been described but was not observed in our patients. Sometimes, because of the large duration of the asymptomatic phase, mushroom consumption is repeated in several meals, as in patients in this family. The renal phase was delayed (4–15 days, with a median of 8.5 days after the first mushroom meal).

In our report, all individuals presented with AKI, with variable degrees of severity. When the renal function is normal, a latent TIN may not be suspected in the absence of microscopic hematuria and leukocyturia. The tubular epithelium is the toxin’s target, with a direct dose-dependent toxicity that explains the severity of tubulointerstitial injury in the case of the child in our report. The prognosis of Cortinarius poisoning is poor, and about 50% of patients present with acute renal failure that evolves into chronic renal failure. In children, a very poor outcome had been described in previous published cases, indicating that all of the five reported cases rapidly developed acute renal failure requiring renal replacement therapy and kidney transplantation in one of them.

The correct answer is D

Comment: Our patient presented with classical clinical and biological symptoms of AKI resulting from rhabdomyolysis. The electrolyte abnormalities that occurred include hyperkalemia, metabolic acidosis, hyperphosphatemia, and hypocalcemia. Hypocalcemia might be due to calcium entering the ischemic muscle cells and the precipitation of calcium-phosphate complexes in necrotic muscle. The patient then had a transient episode of hypercalcemia (3 mmol/L), with the recovery of renal function resulting from the mobilization of calcium, normalization of serum phosphate, and increase in calcitriol. The urine and plasma organic acid profile, rise in lactic acid, plasma carnitine levels, and acylcarnitine levels suggested a CPT II deficiency in our patient.

Diagnosis of CPT II deficiency was suspected clinically by the occurrence of severe and recurrent rhabdomyolysis and based on the acylcarnitine profile. The diagnosis was confirmed by the measurement of CPT II enzyme activity and subsequent molecular analysis.

Molecular analysis in our patient identified compound heterozygosity for the p.Ser113Leu and p.Pro50His mutations in the CPT2 gene. There is a correlation between genotype and phenotype; both of these mutations are considered to be common mutations in patients with the mild form of CPT II deficiency, and inheritance of these mutations is not associated with the more severe infantile or neonatal forms of the disease.

Rhabdomyolysis is facilitated by the fact that mild myopathic CPT II deficiency is characterized by a thermolabile mutant enzyme protein. As such, these patients show susceptibility to high temperature, therefore explaining how myopathic episodes can be triggered by febrile illness. Some drugs, such as valproic acid, diazepam, or ibuprofen, may also trigger attacks of rhabdomyolysis in CPT II-deficient patients. Our patient carefully followed the instructions and did not show any recurrence of rhabdomyolysis at 18 months after the acute episode.

In conclusion, patients with recurrent episodes of rhabdomyolysis should be evaluated for CPT II deficiency. Screening may also be appropriate in patients with a single episode and no evidence of traumatic or toxic causes of rhabdomyolysis. The biochemical diagnosis relies on the plasma (or blood spotted onto filter paper) acylcarnitine profile, which has to be performed during rhabdomyolysis or, at some interval between these episodes, in the fasting state. Early recognition of the disease is crucial to initiating early treatment and preventing further recurrences of rhabdomyolysis.

The primary cause of AKI in this patient is the rhabdomyolysis. Rhabdomyolysis may not be the only cause of AKI. Indeed, our patient also presented with diarrhea and occasional vomiting and was probably dehydrated. Finally, a cumulative dose of 60 mg/kg body weight of ibuprofen was given as self-medication 1 day before admission. All of these elements may have contributed to a deterioration of the renal function resulting from hypoperfusion and/or vasoconstriction.

The management regimen includes the treatment of rhabdomyolysis-induced AKI and the prevention of further rhabdomyolysis episodes. Supportive treatment of rhabdomyolysis consists of the early and aggressive repletion of fluids. Alkalinization of urine by sodium bicarbonate administration has been recommended by some authors, but evidence supporting its clinical benefit is weak. Hemodialysis is required in severe rhabdomyolysis with refractory hyperkalemia or prolonged oligo-anuric renal failure. The prevention of CPT II deficiency-related rhabdomyolysis is mainly based on measures to limit energy depletion. For example, the following activities should be avoided: extended fasting, strenuous exercise, especially in the cold, increased body metabolism with fever, or treatment with anesthesia. Infusions of glucose during intercurrent infections and adequate hydration during episodes of diarrhea or vomiting are necessary to prevent catabolism. A high-carbohydrate and low-fat diet before and during prolonged exercise may also be prescribed. A beneficial effect of bezafibrate in the treatment of the mild form of CPT II deficiency has been shown.

The correct answer is D

Comment: The parents of our patient denied any medication use. Blood and biopsy analysis did not reveal eosinophilia. Thus, drug-induced AIN was highly unlikely in this young girl. Neither the clinical presentation nor the radiographic, laboratory, or histological findings supported a diagnosis of autoimmune disease. Tubulointerstitial nephritis and uveitis syndrome were excluded because the ophthalmic examination showed no signs of uveitis. Normal results for complement and immunoglobulin studies refuted other rate etiologies. ^–

Our patient had a low-grade fever, a sore throat, a red tongue, and bilateral purulent conjunctivitis a week before presentation, likely as a result of streptococcal infection. There are three mechanisms by which streptococcal infection can conduce to AKI. First, APSGN may result from scarlet fever or group A streptococcal skin infections. Inasmuch as the glomerular structure appeared to be unaffected in the renal biopsy specimen, hypertension was absent and serum complement levels were normal, APSGN was not the cause of AKI in this young girl. Second, fulminant streptococcal sepsis is commonly associated with ischemic ATN because of poor renal perfusion. Although this may have contributed to the deterioration of renal function in our patient, it was probably not the main cause because tubular epithelial cell shedding was not found in the renal biopsy specimen. Third, and more rarely, AKI may be the consequence of group A Streptococcus -related AIN, ^– as was the case in our patient. Distinguishing among these three entities is important because they have different course, treatment, and prognosis.

Patients with AIN are usually normotensive. AIN is biochemically characterized by a varying degree of AKI, (tubular) proteinuria, hematuria, leukocyturia, hyposthenuria, tubular dysfunction, ranging from isolated glucosuria to Fanconi syndrome, (non-) hemolytic anemia, and eosinophilia/eosinophiluria. This latter finding is commonly associated with an allergic reaction underlying drug-induced AIN. Renal ultrasound may show normal-sized or enlarged kidneys with hyperechogenicity. The histological hallmarks of AIN are interstitial inflammation with a predominant mononuclear cell and eosinophil infiltrate, interstitial edema with or without fibrosis, tubulitis, minimal or absent glomerular alterations, and normal renal vessels. Given the nonspecific nature of clinical signs and symptoms, a kidney biopsy is required for a definitive diagnosis of AIN. ^–

Treatment mainly consists of the removal of the offending agent and supportive care with dialysis if needed. The role of corticosteroids in the treatment of AIN is controversial, ^– except for cases with underlying autoimmune disease, with small retrospective studies showing therapeutic benefits. However, evidence from randomized controlled trials is lacking. Nevertheless, many clinicians opt for steroid treatment when confronted with severe renal failure and use a regimen similar to the one used in our case, namely, methyl-prednisolone pulses on 3 consecutive days, followed by oral prednisone tapered over several weeks. With appropriate management, AIN has an excellent prognosis in the majority of children, with complete convalescence of renal function and normalization of the urinary sediment within several weeks to months. ^– Clinical and/or histopathological parameters consistently predicting renal outcome in AIN have not yet been established. Consequently, life-long follow-up is recommended for all AIN patients. ^,

Although the literature on AIN secondary to streptococcal infection is relatively scarce, several reports have documented this association, both in adults ^, and children. In fact, AIN was first described as a clinical entity in patients with scarlet fever. ^, We feel confident that our patient represents a further case of group A Streptococcus -associated AIN because she presented with scarlet fever and her blood culture was positive for Streptococcus pyogenes . Additional support for the causative role of streptococci in the genesis of AIN can usually not be derived from the histopathological (i.e., light microscopic) findings because clues for a specific etiology are generally lacking in renal biopsy specimens. With immunofluorescence staining, the renal interstitium can be assessed for deposition of complement and immunoglobulins. Immunofluorescence studies were negative in our patient.

Hemorrhagic interstitial nephritis can be caused by (hyper)acute humoral rejection, renal infarction, invasive procedures (e.g., needle biopsy), and various infections, among which are leptospirosis, rickettsiosis, hantavirus-associated HFRS and other hemorrhagic fever viruses (Marburg, Ebola, and Flaviviridae). With the noteworthy exception of hantavirus, all of these infectious agents seemed unlikely in the present case. Hantavirus was first considered to be the culprit in our patient for the following reasons: (1) HFRS is a well-known and relatively frequent cause of acute hemorrhagic interstitial nephritis ; (2) all five phases of HFRS were discernible in our patient, with a period of polyuria before full recovery ^– ; (3) anti-hantavirus IgM antibodies were initially (weakly) positive; and (4) the young girl lives in a region of The Netherlands where hantavirus-infected rodents occur, ^, and direct contact with these animals is not a prerequisite for human infection because transmission of disease takes place via inhalation of aerosols contaminated by virus-infected rodent excreta. ^, However, HFRS was eventually discarded as a diagnosis because certain clinical manifestations (e.g., thrombocytopenia) were absent, and, more importantly, IgG for hantavirus remained negative. ^{, –} Whereas specific serum antibodies may incidentally be lacking in hantavirus-infected patients, an attempt to detect hantaviral antigen in the renal biopsy specimen was undertaken using reverse transcription PCR. Negative results were also obtained with this test. Streptococci are not listed among the causes of hemorrhagic interstitial nephritis.

The correct answer B

Comment: In light of the clinical course and renal ultrasound image, KD was suspected, and IVIG (2 g/kg body weight) was administered on the sixth day of illness. Since the fever persisted, the treatment with IVIG was repeated 48 hours later. The fever tapered, and the patient’s temperature normalized shortly thereafter, whereas urinary output increased. The maximum levels of serum creatinine and BUN were 2.12 and 103 mg/dL, respectively, but dialysis was not needed. Renal function improved gradually, with a lowering of the serum creatinine and BUN levels from the ninth day of illness, but the hematuria, proteinuria, and leukocyturia persisted. The patient’s anemia worsened, and iron supplementation was started after an erythropoietin infusion. The patient developed thrombocytosis (maximum 1,000,000/µL), and the leukocyte count normalized.

KD is a frequent cause of vasculitis in children younger than 5 years of age. The criteria for KD according to the American Heart Association are (1) fever persisting at least 5 days and the presence of at least four of the following five principal features; (2) changes in extremities: erythema and edema of hands and feet; membranous desquamation of fingertips; (3) polymorphous exanthema; (4) bilateral, painless bulbar conjunctival injection without exudate; (5) changes in lips and oral cavity: erythema and cracking of lips, strawberry tongue, and diffuse injection of oral and pharyngeal mucosae; and (6) cervical lymphadenopathy (diameter ≥1.5 cm), usually unilateral.

KD occurs in all ethnic groups, with the highest incidence is found in Asian countries, particularly Japan (137.7 cases per 100,000 children aged <5 years), and a lower incidence in White children. It is slightly more common in boys, with a male to female ratio of 1.3:1. The etiology of KD is still uncertain, although infectious and autoimmune causes have been suggested. The most frequent and feared cardiac complications involve coronary aneurysms, which in turn are associated with myocardial infarction and sudden death. KD has been recognized as the leading cause of acquired heart disease in children in the United States and Japan. Treatment within 10 days of disease onset with IVIG is associated with a significant reduction of mortality because of cardiac complications. ^,

Without treatment, 20% to 25% of these patients develop coronary abnormalities in comparison to <5% when timely treatment is administered. In addition to cardiac involvement, several other organs and organ systems can be affected, including the gastrointestinal tract, joints, hematopoietic system, respiratory tract, and the neurological and urogenital tracts. AKI is rarely a presenting feature, in contrast to sterile pyuria, which is often seen. However, renal complications ranging from nephrotic syndrome to full-blown renal failure requiring dialysis have been described. ^,

Establishing the correct diagnosis in this case proved to be quite challenging. Sepsis and associated AKI could have explained the clinical picture, including the coagulopathy, but repeated cultures of blood and urine were negative, and no improvement was noted with the administration of antibiotics. IgA nephropathy has been associated with several infections and might present as nephritis with increased corticomedullar differentiation. However, episodes of IgA nephropathy are often mild and rarely result in AKI, except in severe cases with nephrotic range proteinuria. Tubulointerstitial nephritis or reduced renal perfusion secondary to ibuprofen (a nonsteroidal antiinflammatory drug) use could have explained AKI but was less likely given this patient’s clinical presentation. HUS could explain the anemia and thrombocytopenia, but lactate dehydrogenase and complement levels were normal and there was no history of bloody diarrhea. Lupus nephritis was also a possible explanation, but autoimmune tests eventually came back negative, and a high C-reactive protein level is not a common presenting feature unless concurrent bacterial infection is present. Because repeated urine cultures remained negative, it was believed that acute pyelonephritis was unlikely. Patients with tumors of the hematopoietic and lymphoid tissues can present with high fever and AKI secondary to tumor lysis syndrome or leukemic infiltration of the kidneys. However, because uric acid levels were normal and the results of ultrasound imaging were indicative of renal vasculitis, we considered that acute leukemia/lymphoma was not likely to be the underlying condition. Traditional renal ultrasonography, performed to exclude obstructive causes in AKI, provided an important clue in this case. The ultrasound image showed significantly enlarged kidneys with increased corticomedullary differentiation. This increased corticomedullary differentiation is caused by hyperechogenicity of the cortex in combination with a hypoechogenic medulla and is typically associated with renal vasculitis. ^{, –} Renal ultrasound images in septic AKI are highly variable, ranging from kidneys with a normal appearance to those showing global parenchymal hyperechogenicity with a loss of corticomedullary differentiation. ^,

Our young patient also had high urinary α1-microglobulin levels (maximum, 64 mg/L), which suggested tubular injury. He eventually developed severe pyuria (9600 leukocytes/µL), but repeated urine cultures remained negative. Watanabe et al. studied sterile pyuria in patients with KD but were unable to determine whether the pyuria represented sterile urethritis or whether it originated from the kidney. Respiratory symptoms can accompany KD, often caused by a concurrent upper respiratory tract infection. An association between viral infections and KD has previously been reported, but no causal relationship has yet been established. Coagulopathies secondary to increased consumption of clotting factors have been described in KD and are associated with a complicated course of the disease. We did not perform a biopsy in light of this coagulopathy and that, in our opinion, this would not have provided sufficient benefit to the patient to justify the procedure.

Treatment for KD usually consists of a combination of IVIG and high-dose aspirin. We chose not to administer aspirin because of the potential deleterious effect on the already compromised renal function and the coagulopathy. IVIG was administered even though at the time the patient did not yet completely fulfill the criteria for KD (fever ≥5 days and four principal features) because the risk of coronary artery lesions in incomplete KD is at least as high as in patients with complete KD.

At the time of treatment initiation, the diagnosis was far from being clear-cut but the decision to administer IVIG proved to be the right one. This case highlights the need for timely treatment when there is a suspicion of KD, with treatment strongly recommended before the 10-day window of treatment efficacy closes since late treatment (≥10 days after illness onset) has proven to be ineffective in preventing coronary artery lesions.

The correct answer is B

Comment: Ureteritis is a rare complication of Henoch-Schönlein purpura. It typically presents with severe symptoms. It results from ureteral vasculitis. As demonstrated in our cases, there was marked edema at a vesicoureteric junction on the left side, which resolved with corticosteroids. Only about 16 cases have been reported in the medical literature. It is important to remember that pain in the abdomen in Henoch-Schönlein purpura may also be due to ureteritis causing inflammation, spasm, or obstruction secondary to clot formation.

There is a variable response, from self-remitting ureteritis, good response to surgical management, and even progression to end-stage renal disease. There is also a report of ureteritis progressing to diffuse immune complex glomerulonephritis on follow-up.