The correct answer is C

Comment: The clinical features of hypercalcemia in infants may range from polyuria, hypovolemia, weakness, hypotonia, and impaired consciousness to seizure attacks. Early recognition of hypercalcemia is critical to prevent catastrophic events. In general, the heterogeneous causes of hypercalcemia can be divided into three categories ^, :

• 
  

  Increased renal tubular calcium reabsorption (reabsorptive hypercalcemia)

  
  
• 
  

  Accelerated bone calcium resorption (resorptive hypercalcemia)

  
  
• 
  

  Enhanced gastrointestinal calcium absorption (absorptive hypercalcemia)

Detailed patient history and complete physical examination, measurement of the urinary calcium excretion rate, serum iPTH, and 1,25(OH) ₂ vitamin D ₃ levels provide a rapid differentiation of these three categories. The patient’s marked hypercalciuria, low serum iPTH, but inappropriately high serum 1,25(OH) ₂ vitamin D ₃ concentration pointed to absorptive hypercalcemia. He did not receive exogenous vitamin D supplements, such as fortified milk formulas, the most common cause of hypercalcemia in children.

The pathological findings from the biopsy of subcutaneous neck nodules showed he had subcutaneous fat necrosis causing absorptive hypercalcemia. He was treated with intravenous hydration and furosemide with oral potassium citrate. His serum calcium level was normalized within 5 days, followed by the resolution of subcutaneous nodules 3 weeks later and improvement of medullary nephrocalcinosis during a 6-month follow-up.

The correct answer is B

Comment: ^99m Tc-DMSA is a renal cortical imaging agent. Static renal scintigraphy using ^99m Tc-DMSA obtains information about the overall morphology of the functional renal unit and split renal function and detects parenchymal abnormalities. It is a highly useful imaging technique for identifying renal cortical scarring or defects. ^99m Tc-DMSA is a dithiol and localizes to the renal cortex by binding to sulfhydryl groups in the proximal tubules. Renal uptake of ^99m Tc-DMSA approximates the functional renal cortical mass, which depends on renal blood flow and proximal tubular membrane transport function. Renal scintigraphy using ^99m Tc-MAG3 is a dynamic scan. It allows simultaneous investigation of renal perfusion and the presence of any obstruction. To have a complete absence of uptake of ^99m Tc-DMSA despite a normal ^99m Tc-MAG3, there must be a defect in the transport mechanism into the proximal tubular cells of ^99m Tc-DMSA in this child. This DMSA abnormality led to the early diagnosis of Dent disease in this child before any symptoms appearing.

The differential diagnosis in this case includes idiopathic autosomal-dominant idiopathic Fanconi syndrome, mitochondrial disorder, and iatrogenic secondary to aminoglycoside use. Patients with idiopathic tubular proteinuria present with asymptomatic low-molecular-weight proteinuria with normal renal function and show similar poor renal accumulation of ^99m Tc-DMSA.

Lowe syndrome was unlikely because the patient did not have the other features of bilateral congenital cataracts, renal Fanconi syndrome, and intellectual disability. Tubular proteinuria secondary to aminoglycoside treatment is usually transient. Cytotoxic agents including ifosfamide and cisplatin can cause renal tubular injury that can present with reduced uptake of ^99m Tc-DMSA before clinical deterioration.

Dent disease is part of a spectrum of hereditary renal tubular disorders known as X-linked hypercalciuric nephrolithiasis. These include Dent disease, X-linked recessive nephrolithiasis, X-linked recessive hypophosphatemic rickets, and low-molecular-weight proteinuria, and are caused by mutations in the CLCN5 gene. It was first described by Dent and Friedman in 1964. Dent disease causes a renal Fanconi syndrome with proximal renal tubular defects, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis/nephrocalcinosis, metabolic bone disease, and progressive renal failure. Female carriers are asymptomatic but have low-molecular-weight proteinuria, and approximately half have hypercalciuria. Low-molecular-weight proteinuria is uniformly present in disorders of proximal tubular function such as Dent, and its absence excludes the diagnosis.

Subsequent genetic analysis in our patient has revealed a mutation p.Gly57Arg in the CLCN5 gene, confirming the diagnosis. This mutation has not been described before but is believed to be pathogenic because pGly57Val has previously been identified as a pathogenic mutation.

The CLCN5 gene encodes for the voltage-gated chloride channel and chloride/proton exchanger (CIC-5). CIC-5 is predominantly expressed in the proximal tubule of the kidney, where it is thought to be involved in endosomal acidification. Nonsense and missense mutations in the CLCN5 gene reduce or abolish CIC-5 chloride currents. CIC-5 knockout mice have been shown to have reduced levels of two apical cell surface receptors, megalin and cubilin. These receptors are involved in the uptake of proteins into the cells of the proximal tubule by endocytosis and reduced recycling of megalin and cubilin leads to low-molecular-weight proteinuria. Dent patients have been shown to be deficient in urinary megalin.

It has been proposed that ^99m Tc-DMSA is filtered in the glomeruli and then reabsorbed by megalin and cubilin endocytosis in the proximal renal tubule. This explains the reduced ^99m Tc-DMSA uptake seen in Dent patients. ^99m Tc-DMSA has a molecular size of 24 to 28 kDa, which is within the range of low-molecular-weight proteins.

Calcium crystals are removed from the collecting duct apical cell surface by endocytosis. This is impaired in Dent patients because of an increase in plasma membrane annexin A2, a crystal-binding molecule. This may be why Dent patients may develop nephrocalcinosis even in the absence of hypercalciuria.

Treatment with thiazide diuretics has been proven to improve the hypercalciuria, but it is uncertain whether this improves renal survival, although they are associated with adverse events including hypovolemia and electrolyte abnormalities particularly at higher doses. Future therapeutic options may include reduction of inflammation and immunomodulation, but this has not been established. The use of an angiotensin-converting enzyme inhibitor may also delay the reduction in renal function as in other tubulopathies, although the value in normotensive patients is uncertain.

The correct answer is A

Comment: Eosinophilic cystitis is an inflammatory disorder caused by eosinophilic infiltration of the bladder wall. Immunological factor associated with EC is thought to be the IgE-mediated formation of antigen-antibody complex that attacks eosinophils at the bladder wall. Many etiologies have been proposed including allergy; asthma; drugs such as cyclophosphamide, sulfonamides, warfarin, nonsteroidal antiinflammatory drugs (NSAIDs), antihistamines, and penicillin; and UTI and vesicoureteral reflux. ^,

The presenting symptoms of EC is similar to those of UTI, such as frequency, urgency, dysuria, gross hematuria, and suprapubic pain. Some patients have microscopic hematuria, urinary retention, and nocturia. Urinalysis in EC commonly shows proteinuria and microscopic hematuria. Urine cultures are usually sterile.

Diagnosis of EC requires tissue biopsy for histological examination, which will reveal eosinophilic infiltration of the lamina propria and muscularis in the acute phases and variable degrees of fibrosis in more long-standing disease. ^,

The correct answer is B

Comment: The coexistence of hypoparathyroidism, oral candidiasis, dental enamel hypoplasia, and subclinical Hashimoto disease in our patient is strongly suggestive of autoimmune polyglandular syndrome type 1. ^, One of the clinical implications of this diagnosis is the high probability of future occurrence of adrenal insufficiency, emphasizing the importance of maintaining a high level of suspicion with the onset of symptoms such as weakness, fainting, hypotonia, or hyperkalemia. Addison disease would in fact represent quite a challenge in terms of the future management of this patient.

The correct answers are A, B, and D

Comment: The renal manifestation in JS is similar to patients with NPHP. NPHP patients typically present with polyuria and polydipsia, and NPHP ultimately leads to progressive renal failure, usually within the first three decades of life. The predominant form of NPHP is juvenile, although a much rarer infantile form also exists. The typical features revealed by ultrasonography are normal or reduced kidney size (note that normalized kidneys in end-stage renal disease is unusual), loss of corticomedullary differentiation, and small cysts at the corticomedullary junction. On renal biopsy, structural tubulointerstitial abnormalities are seen including tubular atrophy, interstitial fibrosis, and tubular basement membrane defects. In infantile NPHP, there can be enlarged kidneys on the ultrasound scan, and renal biopsy findings include cortical microcysts and normal tubular basement membrane.

Patients with JS present with developmental delay, hypotonia, abnormal ocular movement, colobomas, and cerebellar vermis agenesis evolving into ataxia. ^, Subsequently, a neuroradiological mid-hindbrain malformation, known as the “molar tooth sign,” was identified. This malformation is caused by hypoplasia of the cerebellar vermis with fourth ventricle deformity and a sagittal vermian cleft from incomplete vermis fusion. Elongated and thickened superior cerebellar peduncles with a widened interpeduncular fossa are also present. The absence of a normal vermis results in a midline cleft between the cerebellar hemispheres, resulting in the “bat wing” sign on an MRI scan.

In general, juvenile NPHP presents with biopsy findings of severe chronic tubulointerstitial changes with secondary tubular dilatation but with minimal inflammation. Conversely, TIN usually shows marked interstitial inflammation with minimal chronic change. In this boy’s biopsy, there was extensive lymphocytic infiltration of tubules and a dense interstitial inflammatory infiltrate of lymphocytes, presenting a histological picture of acute TIN rather than the expected picture of chronic change one would expect in NPHP.

The correct answers are A, B, C, and D

Comment: The presence of reddish urine discoloration with a positive dipstick test for hemoglobinuria after walking and after exclusion of other causes of hemoglobinuria, and otherwise normal erythrocytes, is most likely secondary to march hemoglobinuria. ^,

The repetitive reddish discoloration of the urine in his patient was associated with hemoglobinuria or myoglobinuria, based on the positive dipstick test and the absence of RBCs on microscopic urine examination. The normal levels of serum blood muscle enzymes, creatine kinase, and alanine aminotransferase ruled out the diagnosis of myoglobinuria.

A detailed laboratory evaluation ruled out other causes of hemoglobinuria, such as paroxysmal nocturnal hemoglobinuria (presence of CD55 and CD59 on peripheral erythrocytes by flow cytometry), cold agglutinin disease and paroxysmal cold hemoglobinuria (negative direct antiglobulin test, absence of cold agglutinins and Donath-Landsteiner antibody), glucose-6- phosphate dehydrogenase deficiency (normal levels of the enzyme), and congenital unstable hemoglobinopathies (normal hemoglobin electrophoresis).

Erythrocyte membrane disorders, such as hereditary spherocytosis, stomatocytosis, and ovalocytosis, were excluded by osmotic fragility testing, and the results of the flow cytometric eosin-5′-maleimide-binding test and the spectrin/band3 and ankyrin/band3 ratios were within the normal range. Pyrimidine 5′ nucleotidase deficiency was also ruled out with the use of a specific screening test (OD260/OD280 absorbance ratio). The levels of other enzymes involved in erythrocyte metabolism were within the normal range (i.e., hexokinase, glucose phosphate isomerase, phosphofructokinase, glyceraldehyde-P-dehydrogenase, phosphoglycerate kinase, pyruvate kinase, 6-phosphogluconate dehydrogenase, and adenylate kinase).

Because of the presence of reddish urine discoloration with a positive dipstick test for hemoglobinuria after walking, exclusion of other causes of hemoglobinuria, and otherwise normal RBCs, the most likely diagnosis is march hemoglobinuria.

The patient was advised to avoid long walks, to take frequent rest breaks even during short walks, and to use appropriate footwear for walking. No other episodes of urine discoloration occurred during the next 8 months.

The correct answer is D

Comment: Our patient had xanthine stones with hypouricemia and hypouricosuria. The genetic analysis by next-generation sequencing of our patient revealed a homozygous missense variation in exon 2 of the MOCS2 gene (c.45T>A) that resulted in the amino acid substitution of arginine for serine at codon 15 (p.Ser15Arg; ENST00000450852). ^– Xanthine renal stones are uncommon in infants and children, out of which hereditary renal xanthiuria (HX) type I and HX type II contribute to a majority of their etiology.

The correct answer is A

Comment: Differential diagnosis must consider potential causes of left lumbar and flank pain of severe intensity including (1) nephrourologic diseases, such as acute pyelonephritis, urolithiasis, cystic kidney diseases, and renal vascular alterations; (2) infectious, traumatic, or tumoral disorders involving spinal column; (3) gynecological diseases such as endometriosis, and pelvic inflammatory disease; (4) abdominal inflammation or ischemia, including inflammatory bowel disease and acute intermittent porphyria; and (5) psychosomatic problems. ^–

The finding of a retroaortic LRV is a condition known as nutcracker anatomy. This anatomical position of the LRV not leading to symptoms is called the nutcracker phenomenon, but the presence of symptoms and signs related to LRV outflow obstruction defines the nutcracker syndrome. LRV entrapment may be of two types: anterior or posterior. The anterior one is more common and corresponds to the entrapment of the LRV between the abdominal aorta and superior mesenteric artery.

Clinical manifestations include hematuria (microhematuria or macroscopic); orthostatic proteinuria; left flank pain; abdominal pain; varicocele; dyspareunia; dysmenorrhea; fatigue; orthostatic intolerance; and symptoms of autonomic dysfunction such as hypotension, syncope, and tachycardia. The pain can be strong and prolonged and become relentless, and the use of chronic narcotics may be required for adequate analgesia.

The correct answer is A

Comment: The observation of green urine in this child raised further concerns about a recto-urethral fistula; however, this hypothesis was made unlikely by the lack of findings during cystoscopy, despite the irrigation of the rectum with a large amount of methylene blue. The differential diagnosis of green urine was therefore advocated.

Congenital conditions potentially responsible for greenish discoloration of urine (namely Hartnup disease, blue diaper syndrome) were easily ruled out based on the sudden occurrence of the phenomenon in adolescent age. Biliverdinuria and urinary tract infections were excluded by the normal urinalysis results. Among the different drugs potentially involved, propofol was taken into account: however, very low induction doses were used in this child, who had been sedated with propofol before without displaying any similar findings. Finally, a dye-related urine discoloration was considered: based on previous reports, the occurrence of green urine in this child was attributed to the administration of methylene blue through a rectal enema. As expected, the urine discoloration eventually faded over few days. The history of recurrent cystitis was attributed to severe constipation.

The diagnosis of dye-related urine discoloration is clinical and does not require any additional test. Urinalysis can assist in the exclusion of urinary tract infections, potentially responsible for the urine of greenish hue. The awareness of the benign nature of this condition prevented this child from undergoing further unnecessary invasive investigations. ^–

The correct answers are A, B, C, and D

Comment: In cases of CTIN, the causes of systemic and chronic inflammation must be reviewed. Drug use is the leading chronic cause. Antibiotics, NSAIDs, analgesics, proton pump inhibitors, calcineurin inhibitors, and chemotherapeutic agents are the most common underlying factors. Heavy metals such as lead, bismuth, cadmium, and aristolochic acid can cause CTIN. Infection-related causes including chronic pyelonephritis, malakoplakia, and xanthogranulomatous pyelonephritis are among the other common causes of CTIN. In addition, systemic diseases such as dysproteinemias, lymphoproliferative diseases, sickle cell disease, inflammatory bowel disease, cystinosis, and atheroembolic diseases; metabolic diseases such as oxalate nephropathy, uric acid nephropathy, nephrocalcinosis, and hypokalemic nephropathy; autoimmune diseases including Sjögren syndrome, sarcoidosis, systemic lupus erythematosus, tubulointerstitial nephritis and uveitis (TINU), and scleroderma; and IgG4-related disease are among the other differential diagnoses of CTIN.

To evaluate these diseases, medical history, anti-nuclear-antibody (ANA), anti-dsDNA, C3 and C4, p-antineutrophil cytoplasmic antibody (ANCA), c-ANCA, immunoglobulin levels, urine electrolytes, urine cultures, ophthalmologic examination, and abdominal US should be performed in such a patient as the first step. These were performed and resulted in normal ranges in our patient. There was no drug use or known toxic substance exposure.

The IgE levels in our patient were remarkably high, with 26,400 IU/mL at admission and 31,000 IU/mL in the control. In such a case with severely high levels of IgE without eosinophilia, primary and secondary causes of immune deficiencies, and systemic diseases including allergic, skin, infectious, inflammatory, and although rare in children, neoplastic problems including gammopathies should be ruled out. There was no evidence suggesting primary or secondary immunodeficiency in his medical history or flow cytometric lymphocyte panel. Serum immunofixation electrophoresis demonstrated no paraprotein associated with IgD or IgE. Contrast-enhanced thoracal and abdominal tomography revealed no tumoral mass in any cavity of the body.

High IgE levels, CTIN, and glomerular pathologies with crescents pointed at IgG4-related disease as the underlying cause. The patient serum IgG4-related disease was 2.42 g/L (normal, 0.012–1.699). Accordingly, immunohistochemical IgG4 staining of the biopsy specimens resulted in more than 10 IgG4 (+) plasma cells per HPF.

High IgG4 levels and lymphoplasmacytic infiltration with IgG4 (+) plasma cells >10/HPF in the kidney biopsy were suggestive of IgG4-related kidney disease.

The correct answers are A, B, C, and D

Comment: The patient has eosinophilic cystitis, which developed because of eosinophilia triggered by celiac disease. Under normal conditions, eosinophils are mainly found in the bone marrow, lymphoid organs, the mucosa of the gastrointestinal tract, and the uterus, but very rarely in other organ tissues. Secondary (reactive) eosinophilia is mainly driven by cytokines, whereas primary (clonal) forms of eosinophilia are mostly caused by tyrosine kinase gene fusions, involving the coding genes for platelet-derived growth factor receptor alpha ( PDGFRA ), beta ( PDGFRB ), or fibroblast growth factor receptor 1 ( FGFR1 ). Secondary (reactive) eosinophilia has multiple causes, such as allergy, drugs, parasitic disease, and respiratory, gastrointestinal, and rheumatologic disorders.

Regardless of its cause, prolonged or marked activation of eosinophils may lead to migration of eosinophils into other organ tissues, such as the heart, lung, skin, or urinary tract, resulting in tissue and subsequent end-organ damage. Therefore, evaluation for the presence of other end-organ damage is essential. Based on individual signs and symptoms, chest x-ray, electrocardiogram, echocardiography, abdominal US, tissue biopsies, and other evaluations should be performed. ^,

The correct answers are A, B, and C

Comment: The cause of AKI in this child could be a granulomatous infection of the kidneys causing progressive derangement of the kidney function tests and enlarged kidneys. In this clinical setting of an immunocompromised child who has been on multiple antibiotics for a prolonged period, deep-seated fungal infection or infection with Mycobacterium appears to be a strong possibility.

Our child had pancytopenia and hemophagocytosis with no evidence of lymphocytic infiltration of organs when he presented with a bacterial infection and developed a secondary fungal infection. Hemophagocytosis and pancytopenia in this case could be secondary to severe infection because no evidence of lymphocytic infiltration of any organ was evident. The kidney biopsy also showed granulomatous interstitial nephritis without lymphocytic infiltration and, as mentioned earlier, was secondary to an infectious cause.

Our patient developed GIN most likely due to fungal infection or tuberculosis. Renal tuberculosis is rarely reported in infants, but given the background of the child’s immunocompromised status, it merits consideration. Drug-induced GIN is also reported rarely in pediatric cases and has been usually shown to respond to steroid therapy, but in this case, it will be a diagnosis of exclusion as discussed earlier. ^.

The correct answers are A, B, and C

Comment: Conditions that cause hypercalciuria in the presence of normocalcemia include distal renal tubular acidosis, loop diuretic use, medullary sponge kidney and hyperalimentation. Dent disease is an example of hypercalciuria with low-molecular-weight proteinuria.

The hypercalcemic states associated with hypercalciuria that causing nephrolithiasis include primary hyperparathyroidism, hypervitaminosis D, sarcoidosis and other granulomatous diseases, prolonged immobilization, milk-alkali syndrome, and malignancy. Of all the aforementioned causes, primary hyperparathyroidism and hypervitaminosis D constitute the most important etiologies for hypercalcemia causing urolithiasis in children.

In our patient, hypercalcemia and hypophosphatemia prompted us to investigate for primary hyperparathyroidism. Serum PTH level in our index case was elevated (249 ng/mL [normal, <64 ng/mL]), which was responsible for hypercalcemia and hypophosphatemia. The 25-hydroxy-cholecalciferol level was 33.1 ng/mL (normal for age), thereby ruling out hypervitaminosis D as the underlying etiology of urolithiasis in our patient. The patient did not have any features suggestive of sarcoidosis or other chronic granulomatous conditions that could produce a hypercalcemic state by increased production of calcitriol. Other etiologies such as prolonged immobilization, milk-alkali syndrome, and malignancy were not forthcoming in this case. Hence, primary hyperparathyroidism was the most likely etiology of hypercalcemia and urolithiasis. In view of the elevated PTH levels, further workup was done to unveil the underlying cause. Ultrasonography of the neck revealed a 10 × 6-mm well-defined hypoechoic lesion with polar vessels from the inferior thyroid artery noted in the corresponding site, which indicated a possibility of adenoma or hyperplasia. Contrast-enhancing CT of the neck revealed a well-defined hypodense enhancing soft tissue lesion in the right tracheaesophageal groove anterior to C7 vertebra measuring 7 × 4 mm, consistent with an adenoma. A ^99m Tc scan was done for the parathyroid gland, which showed ectopic right superior parathyroid adenoma. As a part of the workup for primary hyperparathyroidism, evaluation for the involvement of other endocrine organs was carried out.

Blood glucose and serum T3, T4, and thyroid-stimulating hormone were normal. Contrast-enhancing CT of the abdomen was done to rule out pancreatic involvement as in multiple endocrine neoplasia type 1. Clinical exome sequencing was also done, which was normal. The patient was finally diagnosed with primary hyperparathyroidism secondary to a parathyroid adenoma. A biopsy report of the parathyroid gland (after excision) confirmed parathyroid adenoma. ^–

The correct answer is C

Comment: TINU is a rare form of bilateral anterior uveitis found in patients with acute kidney inflammation. The uveitis is usually mild and the nephritis is self-limited. However, cases of chronic uveitis and renal failure have been reported.

Although the cause of TINU is unknown, research has revealed various associations. Certain HLA genotypes increase the relative risk of developing TINU in certain populations. Medications such as NSAIDs and antibiotics have also been implicated, the drug causing hypersensitivity reaction or hapten-induced cytokine production and immune reaction. Another possibility links dysfunction or targeted disruption of similar enzymes in the renal tubule and ciliary epithelium.

TINU occurs predominately in young females. The median age of onset is 15 years old with patient’s ages ranging from 9 to 74. It affects both sexes, with an overall predominance of females but a trend toward a male predominance in younger age groups.

Patients will usually present with typical anterior uveitis symptoms including eye pain, redness, decreased vision, photophobia, fever, malaise, fatigue, and flank pain.

In addition to ophthalmology findings, increased levels of serum and blood urinary beta-2 microglobulin, pyuria, hematuria, glycosuria, and presence of eosinophils may be noted. However, a definitive diagnosis of TIN can only be made with renal biopsy. Pathology will demonstrate eosinophilic and mononuclear cellular infiltrates with glomerular sparing. Blood urea nitrogen and creatinine are elevated in renally compromised patients.

A number of other conditions can present with both renal manifestations and uveitis. These include systemic lupus erythematosus, Sjögren syndrome, syphilis, sarcoidosis, granulomatosis with polyangiitis (formerly Wegener), Behcet disease, Epstein-Barr virus-associated infectious mononucleosis, tuberculosis, toxoplasmosis, brucellosis, histoplasmosis, and hyper-IgG4 disease.

Standard treatment for anterior uveitis with topical steroids can be effective. However, with the high frequency of recurrent disease, long-term follow-up is recommended for these patients. If kidney functions do not quickly normalize, a short course of high-dose intravenous or oral steroids is often used. Steroid-sparing immunomodulatory therapy may be needed for severe inflammation.

Long-term ocular complications are rare.

Uveitis will often persist longer than the nephritis and may require long-term local therapy, rarely lasting more than a year. Recurrence of uveitis can occur in patients with TINU, as high as 40%. Most recurrences occur within the first few months of stopping therapy but have occurred as late as 2 years later. Renal outcomes are also generally good, with nephritis often spontaneously resolving, but there have been cases of chronic renal failure following TINU. In contrast to uveitis, nephritis rarely recurs.

The correct answer is D

Comment: TIN and TINU syndrome is a rare disease. The renal prognosis is generally thought to be better in children with TINU syndrome than in adults.

The median age at diagnosis of TINU syndrome is from 15 to 17 years, but the exact incidence and prevalence remain undetermined and are probably underestimated, as the condition could be underdiagnosed.

Patients with TINU syndrome have been treated successfully with corticosteroids, but the use of systemic steroids may be restricted in patients with significant tubulointerstitial injury. However, uveitis must be treated because of its poor prognosis. Some patients require additional immunosuppressive drugs such as azathioprine, methotrexate, cyclosporine, or rituximab if steroid resistance, recurrence of uveitis, or significant steroidal side effects occur.

The correct answer is C

Comment: The pathogenesis of TINU is likely multifactorial, with contributions from genetic, infectious, autoimmune, and iatrogenic factors. The nephrology literature has made the most headway in exploring the links between these factors and acute interstitial nephritis. Work in this field has identified a role for allergy-mediated immune mechanisms in drug-induced interstitial nephritis and mutations in genes encoding the “tubulointerstitial nephritis antigen” leading to chronic disease. However, the mechanistic links underlying the ocular disease or tying together the nephritis and uveitis remain largely unknown. Two promising areas of investigation are focused on understanding the dysregulation of cell-mediated immunity and humoral immunity in patients with TINU. ^–

Loss of T-cell tolerance in the pathogenesis of TINU is suggested by multiple studies identifying a strong link between TINU and certain class II HLA subtypes, such as HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01, with a relative risk as high as 167.1 for HLA-DRB1*0102. The latter HLA gene is an independent risk factor for TINU, particularly of younger onset. These HLA subtypes confer variable risks based on the population studied. Because HLA class II molecules are involved with exogenous antigen presentation to CD4+ T-helper cells, molecular mimicry between exogenous infectious antigens and ocular antigens could explain the HLA association with this disease. Other potential mechanisms could include an insufficient or poorly functioning antigen-specific regulatory T-cell population. However, there is controversy about the role of regulatory T cells in autoimmune uveitis and no TINU-specific studies have been reported. ^–

The role of humoral immunity in TINU pathogenesis has been suggested by the identification of autoreactive antibodies directed against renal and ocular antigens in TINU patients. One study identified elevated titers of anti-monomeric C-reactive protein (anti-mCRP) antibodies in the serum of patients with active TINU. Serum from healthy subjects, and from active patients with isolated acute interstitial nephritis (AIN, idiopathic or drug-related), ANCA-vasculitis, IgA-nephropathy, minimal change disease, Sjögren syndrome, or amyloidosis was also tested. This study found that elevated titers of anti-mCRP antibodies were not unique to patients with TINU, but the percentage of patients with elevated titers was significantly higher in the TINU group (9/9, 100%) when compared with all other groups. The only disease category with more than two patients that also demonstrated an elevated titer was AIN (4/11, 36%). It is not known if these patients with AIN were screened for eye disease, their follow-up course, or if any did ultimately proceed to TINU, but it is interesting that other forms of kidney disease other than interstitial nephritis did not lead to the development of anti-mCRP antibodies. This suggests that these antibodies may have disease-specific relevance. In addition to elevated serum anti-mCRP antibodies, the authors also showed an increase in the extent of mCRP found in kidney biopsies by immunohistochemistry when compared with normal kidneys. ^–

In the eye, mCRP was identified in normal human iris and ciliary body collected at the time of trabeculectomy by immunohistochemistry. Serum obtained from patients with active TINU colocalized with mCRP staining in these normal tissues further suggests a mechanistic link between this protein and disease pathogenesis. mCRP is the dissociated monomer of the parent acute phase reactant pentamer (C-reactive protein) and is involved in the activation and regulation of the complement pathway, but no tissue-specific role for the protein has been identified. Therefore, it is not clear if mCRP is truly a specific antigen involved in ocular and renal disease, or if these findings represent an autoantibody that develops to this acute phase reactant as a result of chronic inflammation as has been reported previously in lupus nephritis. Understanding the role of humoral immunity in uveitis has become more important as we try to explain the success of rituximab, a B-cell–depleting biologic therapy, on certain forms of recalcitrant uveitis. A more thorough understanding of TINU pathogenesis may also uncover an important role for humoral immunity in other forms of uveitis. ^–

Another interesting question in TINU pathogenesis is whether the disease is a sequential process where an initial renal (or potentially uveal) insult incites an inflammatory cascade with secondary effects on the other organ, or if both tissues share a common target for a single underlying mechanism. However, there is evidence to suggest that the kidney is the primary target. One study found that in patients with AIN, elevated anti-mCRP antibodies were predictive of subsequent uveitis development. Thus, a reasonable hypothesis for disease pathogenesis begins with exposure of the kidney to an inciting agent that stimulates a HLA class II response that targets the immune system to a common antigen in both organs. Most likely this antigen is a native protein in the uvea and renal interstitium that shares a common epitope. However, the mCRP data also suggest the antigen could be an acute phase reactant that deposits in the eye and kidney. Experimental animal models will be required to address these possible hypotheses. ^–

The correct answer is A

Comment: Allergic reaction to a drug is the most common cause of acute tubulointerstitial nephritis is an allergic reaction to a drug. Antibiotics such as penicillin and sulfonamides, diuretics, and NSAIDs, including aspirin, may trigger an allergic reaction. Options B, C, and D are other causes of both acute and chronic forms of tubulointerstitial nephritis.

The correct answer is C

Comment: Light microscopy showed diffuse interstitial inflammation with lymphocytes, edema, tubulitis, and atrophic tubules with the presence of an epithelioid, nonnecrotic, noncaseating granuloma leading to the diagnosis of GIN. Two of the 12 glomeruli available for analysis were sclerotic, whereas the others appeared normal. No immune deposit was detectable by immunofluorescence. ^,

The correct answer is A

Comment: Tubulointerstitial nephritis often results in kidney failure. It may be caused by various diseases, drugs, toxins, or radiation that damages the kidneys. Damage to the tubules results in changes in the electrolytes with the kidney’s ability inability to concentrate urine, resulting in urine that is too diluted. ^,

Problems concentrating urine causes an increase in daily urine volume (polyuria) and difficulty maintaining the proper balance of water and electrolytes in the blood.

The most common cause of acute tubulointerstitial nephritis is an allergic reaction to a drug. Antibiotics such as penicillin and the sulfonamides, diuretics, and NSAIDs, including aspirin, may trigger an allergic reaction. The interval between the exposure to the allergen that caused the reaction and the development of acute tubulointerstitial nephritis varies usually from 3 days to 5 weeks.

Drugs can also cause tubulointerstitial nephritis through nonallergic mechanisms. For example, NSAIDs can directly damage the kidney, taking up to 18 months to cause chronic tubulointerstitial nephritis.

UTIs can also cause acute or chronic tubulointerstitial nephritis.

Tubulointerstitial nephritis may be caused by immunologic disorders that primarily affect the kidney, such as antitubular basement membrane antibody-associated interstitial nephritis.

When tubulointerstitial nephritis develops suddenly, the urine may be almost normal, with only a trace blood or protein, but often the abnormalities are striking. The urine may show large numbers of WBCs, including eosinophils. Eosinophils do not normally appear in the urine, but when they do, a person may have acute tubulointerstitial nephritis caused by an allergic reaction. In such cases, blood tests may show that the number of eosinophils in the blood is increased.

When tubulointerstitial nephritis develops gradually, the first symptoms to appear are those of kidney failure, such as itchiness, fatigue, decreased appetite, nausea, vomiting, and difficulty breathing. BP is normal or only slightly above normal in the early stages of the disease. Most patients manifest polyuria, nocturia, hypokalemia, and hyponatremia with elevated BUN and serum creatinine concentrations.

The main causes of GIN include drugs, infections, and immune disorders. In our patient, recent antibiotic therapy and pantoprazole treatment were considered as potential causative agents, and proton pump inhibitor treatment was withdrawn. Extensive serologic testing for bacteria, parasites, fungi, viruses, and immune disorders returned negative results. Ziehl-Nielsen staining, Lowenstein culture, and DNA polymerase chain reaction (PCR) on kidney biopsy and three independent urinary samples found no evidence of Mycobacterium tuberculosis infection.

However, tumor necrosis factor α–blocking agents such as adalimumab facilitate the progression from latent to active tuberculosis (TB) and are associated with a 5- to 25-fold increase in risk for TB infection stressing the need for additional investigations in our patient. Interferon γ release assay was suggestive of either latent or active TB infection, and positron emission tomography showed hypermetabolic lymph nodes in the abdomen and retroperitoneum. A biopsy of a retrogastric lymph node was performed, and a diagnosis of infection caused by Mycobacterium tuberculosis was made based on both culture and PCR results.

Although classic renal TB is characterized by unilateral gross tissue scarring and calcification of the kidneys and urinary and genital tracts. TB-related GIN was recently identified as an emerging alternative presentation of mycobacterial kidney disease.

This insidious and progressive form of renal TB is characterized by bilateral involvement, absence of calcification, and lesions of GIN.

The correct diagnosis is challenging and frequently delayed; in the vast majority of cases, mycobacteria are undetectable by Ziehl-Nielsen staining of the kidney biopsy, culture, and PCR testing. However, the high frequency (∼50%) of extrarenal lesions may provide an opportunity for diagnosis and timely initiation of treatment, especially in high-risk patients.

The correct answer is A

Comment: Modern anti-TB treatment, based on an initial induction period of three to four drugs including rifampicin, followed by a continuation phase, is effective for the treatment of renal TB, including GIN. However, the optimal duration of treatment and potential role of a short course of corticosteroids is not established. In our patient, a 10-month standard regimen led to significant improvement in kidney function (serum creatinine, 1.07 mg/dL; eGFR, 63 mL/min/1.73 m ² ) and normalization of positron emission tomography imaging. Secukinumab, a human monoclonal antibody selectively targeting interleukin 17A, which has not been associated with TB reactivation, was introduced because of persistence of severe psoriasis. ^,

The correct answers are A and B

Comment: Our patient was diagnosed with acute interstitial nephritis likely caused by the use of pantoprazole. The key features leading to this diagnosis were acute renal failure from a renal cause with associated proteinuria and eosinophiluria, as well as a renal biopsy that showed interstitial inflammation and a lack of evidence for other causes of renal failure.

Treatment included volume repletion and discontinuation of pantoprazole. The patient was prescribed high-dose oral prednisone (1 mg/kg daily) with stepwise tapering. ^, After 6 weeks on steroid treatment, the patient’s creatinine level had decreased and plateaued at 0.8 mg/dL and his BP was normal. Prednisone was discontinued at this point.

Esophagogastroduodenoscopy was performed to evaluate the patient’s reflux disease. The results suggested severe esophagitis with a benign lower esophageal ulcer. The patient was given both ranitidine and domperidone, and he was instructed not to take any proton pump inhibitors or NSAIDs, except for acetylsalicylic acid (81 mg daily). As of the patient’s last visit, his reflux was controlled with ranitidine (300 mg twice daily) and calcium carbonate tablets (750 mg twice daily).

The correct answer is A

Comment: Infection-associated AIN is likely to develop during the course of many systemic infections from bacterial, viral, and parasitic organisms. It has a variable clinical presentation depending on the causative organism along with renal impairment ranging from mild self-limiting renal dysfunction to progressive renal impairment resulting in CKD. Laboratory results are usually nonspecific. Renal biopsy showing interstitial edema and predominant lymphocytic interstitial infiltrates remains the definitive test for diagnosis for any type of AIN. Infection-associated AIN shows prominent neutrophilic infiltration and tends to be negative on immunofluorescence microscopy. Extensive interstitial damage can result in irreversible tubulointerstitial fibrosis leading to the progression of AKI into CKD. ^,

Basic principles of management in infection-associated AIN are similar to other cases of AKI, which is mainly renal supportive therapy with a special focus on limiting the inflammatory damage by controlling the causative infection and by achieving immunosuppression.

Steroid therapy started early in the course likely limits the inflammatory cellular infiltration and edema, thereby preventing the fibrosis and scarring and promoting faster recovery of renal function without long term complications. ^,

In summary, it is essential to consider AIN in the differential for unexplained AKI. Initial management should include conservative therapy by withdrawing any suspected causative agent. Renal biopsy is needed for confirmation in cases where kidney function fails to improve within 5 to 7 days on conservative therapy. A trial of corticosteroids can be started in biopsy-proven patients with AKI for <3 weeks. Steroid therapy is usually maintained for 4 to 6 weeks and dosage is tapered over the next 4 weeks.

The correct answers are A, B, C, D, and E

Comment: AIN represents a frequent cause of AKI, accounting for 15% to 27% of renal biopsies performed because of this condition. By and large, drug-induced AIN is currently the most common etiology of AIN, with antimicrobials and NSAIDs being the most frequent offending agents. Pathogenesis is based on an immunologic reaction against endogenous nephritogenic antigens or exogenous antigens processed by tubular cells, with cell-mediated immunity having a major pathogenic role. The characteristic interstitial infiltrates, mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, experience a rapid transformation into areas of interstitial fibrosis. A significant proportion of AIN has an oligosymptomatic presentation, although specific extrarenal symptoms such as fever, skin rash, arthralgias, and peripheral eosinophilia have important roles in orientating clinical diagnosis. Identification and removal of the offending drug are the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment.

The correct answers are A and B

Comment: Corticosteroids have been a mainstay of therapy for tubulointerstitial nephritis, but mycophenolate mofetil may also have a role. Ultimately, however, treatment depends on the underlying etiology.

Most patients presenting with renal insufficiency, proteinuria, and/or acid-base electrolyte disorders require consultation with a nephrologist. These patients may require inpatient care until stabilization or resolution.

Hypertensive patients should be on a low-sodium diet. For all patients with early renal disease, recommend general guidelines for a healthy diet (i.e., a low-fat [low-cholesterol] diet rich in fresh fruits and vegetables such as the Dietary Approaches to Stop Hypertension [DASH] diet).

Provide patients with acute interstitial nephritis with follow-up care until resolution. Patients who do not recover renal function and those with chronic tubulointerstitial nephritis should receive long-term follow-up care to ensure that optimal control of BP is achieved and to protect kidneys from further potentially nephrotoxic therapies and/or interventions.

The correct answer is B

Comment: Kidney biopsy is the definitive test for diagnosing acute allergic interstitial nephritis, particularly in cases in which the clinical diagnosis is difficult. Because the differential diagnosis of acute tubulointerstitial nephritis encompasses multiple etiologies, consider kidney biopsy when the diagnosis is not obvious.

Kidney biopsy shows mononuclear and often eosinophilic cellular infiltration of the renal parenchyma with sparing of the glomeruli. Sometimes, interstitial changes such as fibrosis and atrophy are also present.

The renal cortex shows a diffuse interstitial, predominantly mononuclear, inflammatory infiltrate with no changes to the glomerulus. Tubules in the center of the field are separated by inflammation and edema, compared with the more normal architecture in the right lower area.

Findings on kidney biopsy in chronic tubulointerstitial nephritis usually show varying degrees of interstitial fibrosis, tubular atrophy, fibrosis, arteriolar sclerosis, and, occasionally, patchy mononuclear cell infiltration. Often, the findings are nonspecific and the etiology is not discernible from the biopsy; some diseases, such as sarcoidosis, show noncaseating granulomas, and, in viral diseases, immunostaining can yield clues to the cause.

The correct answer is F

Comment: Tubulointerstitial diseases of the kidney encompass diverse etiologies and pathophysiologic processes, and the patient can present with acute or chronic conditions. Many forms of tubulointerstitial injury involve exposure to drugs or other nephrotoxic agents such as heavy metals and, rarely, infection. By far the most common form of tubulointerstitial inflammation is a hypersensitivity reaction to medications, termed allergic interstitial nephritis.

The following are the causes of tubulointerstitial disease:

• 1.
  

  Any drugs can cause acute allergic and hypersensitivity reactions involving the kidney.

  
  
• 2.
  

  Immunologic diseases (e.g., lupus, Sjögren syndrome, primary glomerulopathies, sarcoidosis, vasculitis, ANCA-associated vasculitis)

  
  
• 3.
  

  Metabolic diseases such as hyperglycemia, hypercalcemia, and hypokalemia

  
  
• 4.
  

  Infectious diseases

  
  
• 5.
  

  Neoplasia

  
  
• 6.
  

  Genetics (medullary cystic disease, Alport syndrome)

  
  
• 7.
  

  Heavy metals exposure

  
  
• 8.
  

  Obstructive uropathy

  
  
• 9.
  

  Nephrolithiasis

  
  
• 10.
  

  Vesicoureteral reflux

In a study by Maripuri et al., kidney biopsies in 24 patients with primary Sjögren syndrome who also had kidney dysfunction revealed that 17 individuals had tubulointerstitial nephritis as the primary lesion and 11 of those 17 patients had the chronic form of this nephritis. The investigators suggested these results support the notion that in patients with primary Sjögren syndrome, chronic tubulointerstitial nephritis is the most frequent cause of renal impairment found through kidney biopsy.

Similarly, a prospective study by Jain et al. of renal involvement in 70 patients with primary Sjögren syndrome reported that tubulointerstitial nephritis was the most common disorder found on kidney biopsy. Tubulointerstitial nephritis was identified in 9 of 17 biopsies in this study.

Correct answer is D

Comment: Urinary β2-microglobulin and serum creatinine levels are sensitive and relatively simple diagnostic screening tools for detecting renal dysfunction to diagnose tubulointerstitial nephritis in young patients with uveitis.

The correct answer is A

Comment: Lymphoma, a cancer of the lymphatic system, is more common in people with Sjögren syndrome than in the general population. People with Sjögren syndrome develop non-Hodgkin lymphoma at 40 times the normal rate. Options B, C, and D: These cancers are not more common in people with Sjögren syndrome.

Correct answer is A

Comment: AKI is common among hospitalized patients with COVID-19, with the occurrence of AKI ranging from 0.5% to 80%. Both live kidney biopsies and autopsy series suggest acute tubular necrosis as the most commonly encountered pathology. Collapsing glomerulopathy and thrombotic microangiopathy are other encountered pathologies noted in both live and autopsy tissues. Other rare findings such as anti-neutrophil cytoplasmic antibody vasculitis, anti-glomerular basement membrane disease, and podocytopathies have been reported.

The correct answer is B

Comment: TIN is a frequent cause of AKI that can lead to CKD. TIN is associated with an immune-mediated infiltration of the kidney interstitium by inflammatory cells, which may progress to fibrosis. Patients often present with nonspecific symptoms, which can lead to delayed diagnosis and treatment of the disease.

The etiology of TIN can be drug-induced, infectious, idiopathic, genetic, or related to a systemic inflammatory condition such as TINU syndrome, inflammatory bowel disease, or IgG4-associated immune complex multiorgan autoimmune disease. It is imperative to have a high clinical suspicion for TIN to remove potential offending agents and treat any associated systemic diseases. Treatment is ultimately dependent on underlying etiology. Although there are no randomized controlled clinical trials to assess treatment choice and efficacy in TIN, corticosteroids have been a mainstay of therapy, and recent studies have suggested a possible role for mycophenolate mofetil. Urinary biomarkers such as alpha1-microglobulin and beta2-microglobulin may help diagnose and monitor disease activity in TIN. ^, Screening for TIN should be implemented in children with inflammatory bowel disease, uveitis, or IgG4-associated multiorgan autoimmune disease.

The correct answer is A. ^,

The correct answer is B. ^,

The correct answers are C and E. ^,

The correct answers are B, D, and E. ^,

The correct answers are A, B, C, D, F, H, J, K, and L

Comment: Nephrolithiasis is a common health problem across the globe with a prevalence of 15% to 20%. Idiopathic hypercalciuria is the most common cause of nephrolithiasis, and calcium oxalate stones are the most common type of stones in idiopathic hypercalciuric patients. Calcium phosphate stones are frequently associated with other diseases such as renal tubular acidosis type 1, UTIs, and hyperparathyroidism. Compared with flat abdominal film and renal sonography, a noncontrast helical CT scan of the abdomen is the diagnostic procedure of choice for the detection of small and radiolucent kidney stones with sensitivity and specificity of nearly 100%. Stones smaller than 5 mm in diameter often pass the urinary tract system and rarely require surgical interventions.

The main risk factors for stone formation are low urine output, high urinary concentrations of calcium, oxalate, phosphate, and uric acid compounded by a lower excretion of magnesium and citrate. A complete metabolic workup to identify the risk factors is highly recommended in patients who have passed multiple kidney stones or those with recurrent disease. Calcium oxalate and calcium phosphate stones are treated by the use of thiazide diuretics, allopurinol, and potassium citrate. Strategies to prevent kidney stone recurrence should include the elimination of the identified risk factors and a dietary regimen low in salt and protein, rich in calcium and magnesium, with adequate fluid intake. ^,

The correct answer is C

Comment: Kidney stones can be classified broadly into two categories: radiopaque and radiolucent. Calcium- and uric acid–containing calculi are the most common types of radiopaque and radiolucent stones, respectively. Imaging studies such as KUB radiography, abdominal sonography, intravenous urography, and non-contrast CT help separate the density, size, location, and obstruction of stones. The formation of various kidney stones also is influenced strongly by urinary pH. Alkaline urine (pH 7) suggests calcium phosphate or struvite stones, whereas acidic urine (pH 5.3) can produce pure uric acid or cystine stones.

In this patient, radiologic studies showed radiolucent lesions on KUB radiograph, but hyperechoic lesions with acoustic shadow on abdominal sonography and relatively alkaline urine (pH 6.5). This profile made pure uric acid or cysteine stones less likely.

With relatively alkaline urine, high urate excretion, and negative urine anion gap suggestive of ammonium, but low urine sodium excretion and the morphologic finding of brown-tinged radially striated spherical crystals, a clinical diagnosis of ammonium urate stones was made and then confirmed by infrared spectrophotometry.

The cause of ammonium urate stones can be endemic or sporadic. Endemic cases often occur in developing countries where a diet is enriched in grain (rice) and low in animal protein. Sporadic cases are prevalent in patients with inflammatory bowel disease, ileostomy diversion, laxative abuse, or urinary infection. In this patient, low urine potassium (potassium-creatinine ratio 0.08 0.15 mEq/mg) and sodium (6 mEq/L) excretion, combined with relatively high chloride (58 mEq/L) and ammonium levels suggested electrolyte losses through the colon. The patient admitted to using a stimulant laxative (bisacodyl) habitually for weight control for 7 years, with an increase to 10 to 15 tablets daily during the preceding 4 months. Laxative abuse, especially with bowel stimulant (diphenylmethane derivatives [bisacodyl] and anthraquinones [senna and cascara]), increasingly has been reported to cause ammonium urate stones. The resulting hypokalemia with proximal tubular intracellular acidosis increases ammonium excretion, increases urinary pH, and decreases citrate excretion in urine. The low urinary sodium excretion resulting from volume depletion in the relatively alkalized urinary milieu contributes to stone formation.

The management of laxative-associated ammonium urate stones with obstructive pyelonephritis is aimed at controlling infection, relieving obstruction, and preventing recurrence. The supersaturation and crystallization of ammonium urate can occur rapidly, in as short a period as 1 day. Given its rapidly forming characteristics, recurrent ammonium urate stones may promptly encrust and obstruct stents, leading to obstruction and recurrent infection. Volume repletion with sufficient potassium supplementation and complete cessation of stimulant laxatives are needed to avoid recurrence and complication.

The correct answer is C

Comment: Virtually any disease that causes urolithiasis can cause crystal nephropathy. The histochemical reaction known as von Kossa stain is specific for phosphates. Absence of reaction with the von Kossa stain indicates that the crystals do not contain calcium phosphate salts, but there are several different potential causes of von Kossa–negative stones. Adult-onset congenital metabolic defects cannot be ruled out as a primary cause. Primary hyperoxaluria and cystinuria are frequently associated with kidney stones. Although stones from primary hyperoxaluria are sometimes von Kossa positive, stones formed of most pure oxalates are negative by means of von Kossa stain. Stones associated with disorders of purine metabolism are phosphate free and have a characteristic shape. Stones associated with acute hyperoxaluria caused by ethylene glycol or ascorbic acid intoxication also are possibly negative by means of von Kossa stain. An increased incidence of kidney stones and renal failure in infants has been reported in China, believed to be associated with the ingestion of infant formula contaminated with melamine. To the best of our knowledge, no biopsy specimens have been obtained from human cases, but melamine and cyanuric acid intoxication was found to cause rather circular von Kossa–negative crystal formation in animals. Drugs, such as acyclovir or protease inhibitors, as well as infection, also can cause crystals.

In addition to patient history, stone analysis is necessary for the diagnosis; however, not enough urinary stones were obtained from our patient. Instead, a urinary analysis was performed by using gas chromatography and mass spectrometry for a broad screening of congenital metabolic defects. Urine samples from our patient showed marked increases in adenine and its metabolite, 2,8-dihydroxyadenine (2,8-DHA). Subsequent genetic examination showed that the patient was homozygous for the APRTQ0 allele, that is, the null allele of the adenine phosphoribosyltransferase gene. The patient therefore was identified as having a type I APRT deficiency. APRT deficiency is an autosomal recessive inherited disorder of purine metabolism. Age at diagnosis has ranged from 5 months to 74 years, and this disease affects only the kidney and urinary tract. Two types of APRT deficiency have been described. Patients with type I, predominantly White, feature undetectable enzyme activity in erythrocyte lysate and are either homozygotes or compound heterozygotes for a variety of null alleles, collectively referred to as APRTQ0. The inability to salvage adenine in APRT deficiency results in the accumulation of its alternative metabolite, 2,8-DHA, by means of xanthine dehydrogenase. This extremely insoluble and nephrotoxic product generates crystals in affected individuals. In addition to adenine restriction and hydration, allopurinol is used as a treatment for this condition. Tubular crystal deposition in patients with APRT deficiency is not a well-known cause of acute kidney injury or chronic kidney disease. APRT deficiency usually is identified by the detection of urinary stones, whereas urinary stones have not been detected in some patients with chronic kidney disease, possibly because of diminished clearance of 2,8-DHA.

The correct answer is D

Comment: Staghorn calculi are a specific type of lithiasis in which the calculus occupies the pelvis and renal calyces, taking the form of a coral. ^, Staghorn nephrolithiasis is characterized as a disease of rapid growth that, if not treated, will possibly evolve into destruction of the affected kidney and sepsis. ^,

In the pediatric patient, the clinical picture of the disease can be nonspecific, which requires much attention, because just a minority will clinically exteriorize the urinary calculus as classical renal colic. Considering its significant morbidity and mortality, this disease demands early evaluation and treatment. The gold-standard treatment for staghorn calculi is surgery and aims at obtaining a stone-free collecting system, besides preserving renal function. PCNL is the treatment of choice for staghorn calculi with the best treatment rates.

Staghorn calculi chemical condition is variable: it can be formed of calcium oxalate, uric acid, cystine, and struvite. Struvite staghorn calculi are composed of magnesium, ammonium, and phosphate and are closely related to UTIs. The infections that mostly associate to the pathogenesis of staghorn calculi are those caused by organisms producing the urease enzyme, promoting the generation of ammonia and hydroxide from urea such as Proteus , Klebsiella , Pseudomonas , and Staphylococcus . This relationship occurs because of the dependent coexistence of pH 7.2 and ammonia for the crystallization of struvite in urine. There is another mechanism for which UTI can induce the formation of those calculi: association with increased adherence of crystals; yet, this thesis is still not fully clarified. Such a hypothesis justifies the fact that E. coli is related to 13% of the struvite calculi, although that bacterium causes 85% to 90% of UTIs. Staghorn calculi are uncommon in the pediatric population and pose challenges and singular difficulties for surgical treatment. This illness can occur in patients of any age, with the mean age at diagnosis among children being 7 to 10 years. Those calculi represent a substantial concern because the combination of infection and the increased potential obstruction can induce damage to renal parenchyma. Around 75% to 85% of children with urolithiasis present risk factors, such as metabolic disorders, recurrent infections, and/or congenital abnormalities of the urinary tract. Staghorn calculus, in turn, is associated with delay in diagnosis and treatment of UTI. This happens because the recognition of these infections in the child can be difficult, as symptoms are nonspecific or absent, especially in infants. In this group, fever is the main manifestation and many times the only sign. When diagnosis of urinary lithiasis is made due to a casual finding, the metabolic study of the patient must be conducted, because it is a risk factor for the development of urolithiasis. In the presence of this occasional finding in the reported patient, we continued with metabolic investigation, which did not show significant results. Besides, one must readily evaluate and treat nephrolithiasis, especially because of the importance and the severity of staghorn calculus. Removal, eradication of infection, and correction of eventual metabolic disorders and anatomical abnormalities causing urinary stasis are the bases for treatment. This can be clinical, interventional, or demand association with other therapies. The clinical approach must be considered in combination with surgery for those patients with prohibitive surgical risk, because conservative treatment presents a mortality rate of 28% in 10 years and 36% risk of developing severe kidney failure.

The interventional treatment includes ECL, endoscopic lithotripsy using the ultrasound, open pyelolithotomy, and PCNL. The intervention is chosen according to the calculus location and its effects on the kidneys. Moreover, decisions must be individualized, considering aspects related to the age and health status of each patient. With the development of minimally invasive surgeries, the number of open surgeries decreased, especially in pediatric patients. At a large series, PCNL for the treatment of staghorn calculus revealed rates of partial and complete removals of 98.5% and 71%, respectively. In spite of the high popularity of this surgical technique, there are just two randomized clinical essays that assess its therapeutic value and prove the superiority of PCNL over ECL, so the first is recommended as the preferential treatment for struvite staghorn calculi. Pyeloplasty is the indicated treatment for correction of ureteropelvic junction stenosis. Such stenosis is characterized as the ureter narrowing in its cranial portion, close to the renal pelvis, which, by causing urinary stasis, can develop into progressive hydronephrosis. Pictures of hydronephrosis are not rare in children and, in their majority, occur because of congenital uropathies. ^– Pyelolithotomy is the removal of calculus by means of an incision in the posterior face of the renal pelvis. This practice became obsolete after the appearance of CL and PCNL. However, in the case of our patient, the adoption of these procedures was not possible. Although nowadays open surgery is not frequently used, it is recommended for complex cases. Among its indications for the treatment of urinary lithiasis, the main recommendations are cases of large staghorn calculi in patients with complex collecting systems, as in the described clinical case. Its morbidity is related to the incision, surgical infection, and vascular and parenchymal lesions, which can cause renal atrophy. Ureteral obstruction is a frequent complication in renal surgeries because of local inflammation that can occur with adherence of ureteral walls. For such, the insertion of a double-J catheter ^– is indicated. The adequate and early treatment is directly associated with the maintenance of renal function; therefore, the information presented here is very useful to avoid complications, such as kidney failure in children.

The correct answer is D

Comment: Children presenting with acute renal failure usually exhibit a number of clinical symptoms. Laboratory findings relative to recent medical history enable the clinician to differentiate between acute glomerulonephritis and systemic disease, mainly lupus nephritis and ATIN. ^, Very often, renal biopsy is mandatory for diagnosis. Renal biopsy findings of interstitial mononuclear cellular infiltration with eosinophils, interstitial edema, and changed tubular cells but intact vessels and glomeruli are characteristic of ATIN. Drugs represent the most frequent cause of ATIN, most commonly in association with beta-lactams and NSAIDs, even in children. ^, Typical clinical signs of drug-induced ATIN, such as fever and skin rash, are not always present. Renal manifestations range from completely asymptomatic urinary abnormalities to acute renal failure with tubular dysfunction. The magnitude of renal damage depends on the localization and extent of interstitial inflammation affecting different segments of nephrons. In children, isolated glycosuria, mild tubular proteinuria, and hyposthenuria seem to be the only constant manifestations of tubular dysfunction. Peripheral eosinophilia and eosinophiluria, although nonspecific findings, usually support the clinical diagnosis of drug-induced ATIN. However, the definite diagnosis of ATIN has to be based on renal biopsy findings, with a clear distinction between acute and chronic changes characterized by tubular atrophy and interstitial fibrosis.

Despite the abundance of clinical elements correlating with ATIN caused by drugs in our patient, the drug directly responsible for actual renal damage could not be identified, and heavy metal intoxication was suspected.

Heavy metal analyses of serum and urine were normal, except for the high urinary excretion of cadmium. Cadmium excretion was 13.52 µg/24 hours (normal, <2 µg/24 h), which was sixfold higher than the normal range. A serum cadmium concentration of 1.7 µg/L (normal, <1.5 µg/L) was slightly elevated but insignificant according to our laboratory. In an attempt to explain the presence of such high levels of urinary cadmium, the assessment of cadmium in four herbal preparations that she had consumed was undertaken. The analyzed plants were Hypericum perforatum , Melissa officinalis , Achillea millefolium , and Plantago media . The estimated cadmium concentration of analyzed herbs ranged from 0.034 to 0.36 mg/kg (limits of detection up to 0.02 mg/kg) and was assigned to the category of high metal concentration but considered insignificant according to low-average consumption. Two weeks following admission and after she stopped taking the herbal mixtures, her impaired renal function remained unchanged. According to renal biopsy findings consistent with drug-induced ATIN, therapy with pulse methylprednisolone (three pulses) was introduced, followed by prednisolone 1 mg/kg per day. Her serum creatinine normalized promptly within 3 weeks, followed by normalization of ESR, negative C-reactive protein, and disappearance of glycosuria, phosphaturia, and uricosuria after 4 weeks. Mild proteinuria, elevated ß2-MG, and elevated urinary cadmium persisted for 6 months. After normalization of serum creatinine, her steroid regimen was changed to alternate-day therapy, with tapering of the dose for the next 2 months. Closely followed for the next 3 years, her renal function remained stable. Control urinary cadmium was 10.7, 1.8, and 0.7 µg/24 h after 3 months, 6 months, and 3 years, respectively. Currently, the girl is asymptomatic, in good health, and not receiving any therapy.

The published data about the safety of azithromycin led us to consider a possible adverse reaction to acetaminophen (paracetamol), despite a relatively short period of treatment and no evidence of nephrotic syndrome, as has been reported sporadically in children receiving NSAIDs.

Besides drugs, our vegetarian patient had been consuming different “homemade” herbal mixtures composed of some local plants. Reports dealing with herbal mixtures point to the dangers of misidentification, adulteration, and contamination. Based on the plants listed in this particular case, poisoning from natural chemistry was not likely, although individual susceptibility depending on age, state of health, and the concomitant use of other drugs could not be excluded. The unexpected finding of elevated urinary cadmium led us to consider possible contamination of consumed herbs. Any herbal product can be contaminated during production and processing, especially by insecticides, fungicides, or heavy metals, including cadmium. ^, Cadmium as an environmental or occupational toxin can cause severe toxicity in a variety of organs, with the kidney as the principal target. The renal toxicity of cadmium documented in highly exposed populations in occupational settings is characterized by irreversible tubular and glomerular dysfunction and the tendency to disease progression even after a reduction in environmental cadmium exposure. In a recently published Cadmibel study, increased cadmium body burden resulting from environmental pollution was not associated with progressive renal dysfunction. As reported, the renal effects of cadmium ranged from weak, stable, and reversible changes after reduced exposure. The intake of cadmium through food varies geographically and is generally low in most European countries (1–2 µg/day). However, slight cadmium-induced renal effects on the kidney have been reported in Germany and Sweden. Predisposing factors such as dietary habits, including contaminated vegetables and low body iron stores, enhance the absorption of cadmium from the gastrointestinal tract. The signs of cadmium toxicity rarely give rise to symptoms and clinical disease, even if different segments of the nephron are affected by cadmium. Because urinary concentrations associated with renal effects vary, besides an increased excretion of low-molecular-weight proteins, urinary β2-MG and NAG excretion have been proposed as indirect but sensitive biological indicators of cadmium accumulation in the kidney. However, the mechanism underlying the increased excretion of these markers and the mechanisms by which cadmium leads to multiple tubular abnormalities remain uncertain. Irrespective of the causative agent of ATIN, the recommended therapy is still controversial. Reported benefits from steroid therapy in drug-induced ATIN are not generally approved. In certain situations, when the simple exclusion of the offending drug has no influence on the compromised renal function, a trial of steroids has to be undertaken.

The kidney is especially susceptible to toxic injury, either from drugs or other toxins. In cases of ATIN occurring in patients treated by more than one potentially nephrotoxic agent, it is sometimes difficult to discern which one is responsible for renal damage, as in the presented case of drug-induced ATIN and the simultaneous occurrence of elevated urinary cadmium. A search of the relevant literature did not reveal a single report of environmental exposure to toxic metals or cadmium-induced reversible renal failure in children. The cadmium-induced renal damage in our patient was documented by elevated urinary cadmium, ß2-MG, and NAG excretion. These findings cannot be considered accidental, but rather a complementary cause of drug-induced ATIN. The presence of cadmium in the urine and all analyzed herb preparations, despite the low concentrations, had to be regarded as responsible for the actual renal damage. If renal effects of cadmium in cases of low environmental exposure are reversible, why should this not be the case with temporary consumption of herbal preparations containing cadmium in concentrations defined as high but harmless because of low average consumption? In any case, the multiple tubular dysfunction may not be solely attributed to drugs but also to cadmium in patients with vegetarian habits.

The correct answer is A

Comment: This patient had a reduced GFR, borderline diabetes mellitus, multiple small kidney cysts bilaterally, and pancreatic hypoplasia. He also had a family history of diabetes and kidney cystic lesions, which are HNF1B-associated phenotypes, and genetic analysis revealed a novel variant of HNF1B. The kidney biopsy demonstrated not only tubulointerstitial fibrosis but also abnormal mitochondrial morphology in tubular cells. These findings represent autosomal dominant tubulointerstitial kidney disease (ADTKD)-HNF1B and genetic analysis revealed a missense variant of HNF1B. ^,

ADTKD is a chronic tubulointerstitial kidney disease caused by a gene variant. The subtype hepatocyte nuclear factor 1β (HNF1B) is caused by a variant in the HNF1B gene and is referred to as ADTKD-HNF1B. This subtype has a variety of extrarenal manifestations, such as pancreatic hypoplasia, hyperparathyroidism, hypomagnesemia-like Gitelman syndrome, and genital tract malformation, as well as kidney cysts, unilateral kidney agenesis, and hypoplasia. ^, It is closely related to early-onset diabetes mellitus with a familial history, in particular maturity-onset diabetes of the young type 5 (MODY5). Cystic formation is present in 73% of patients with ADTKD-HNF1B; cysts are usually small and often arise within the kidney cortex. However, previous reports have not described the pathology of the kidney in ADTKD-HNF1B.

Medullary cystic kidney disease, which is characterized by cyst formation in the corticomedullary and medullary areas, is a morphologic classification based on radiologic features. Genetic analyses of medullary cystic kidney and related disease have revealed variants of five different genes, including MUC1 , uromodulin ( UMOD ), REN , HNF1B , and more rarely, SEC61A1 . ^– Kidney Disease: Improving Global Outcomes redefined the disease concept of medullary cystic kidney disease as ADTKD, which involved a change from morphologic classification to genetic classification of the disease.

In individuals with ADTKD-HNF1B, hypoplasia of the pancreatic body and tail and a slightly atrophic pancreatic head are involved in the development of diabetes. Diabetes with onset before the age of 25 years in families with this autosomal dominant inheritance is called MODY, and the type caused by the variant of HNF1B is called HNF1BMODY (MODY5). In 2014, Faguer et al. ^, described an HNF1B score that can be calculated from clinical, imaging, and biological variables. The cutoff threshold for a negative predictive value to rule out HNF1B variants is 8 points. Our patient scored at least 20 points, indicating that our diagnosis of ADTKD-HNF1B was correct.

Although ADTKD is defined as tubulointerstitial nephropathy, few reports have described the kidney biopsy and pathologic features of ADTKD. Ayasreh Fierro et al. reported that kidney specimens of patients with ADTKDUMOD showed interstitial fibrosis, tubular atrophy, normal glomeruli, and tubular dilatation with tubular microcystis. However, kidney biopsy of ADTKD-HNF1B has not been reported.

The findings in the kidney biopsy of this patient may support previous findings. For example, Connor et al. showed that variants in mitochondrial DNA also caused tubulointerstitial kidney disease. Furthermore, Casemayou et al. reported that HNF1B regulated transcription factor peroxisome proliferator-activated receptor-γ expression and regulated mitochondrial morphology and respiration in proximal tubule cells in mice.

Through genetic analysis, a novel heterozygous missense variant of HNF1B (NM_000458.3: c.865A>C, p.(Asn289- His)) was detected in both the individual and his daughter. Faguer et al. reported a variant (NM_000458.2: c.865A>G, p.(Asn289Asp)) and submitted the variant to the Human Gene Mutation Database (CM117494). This patient showed the same site variant. According to American College of Medical Genetics and Genomics guidelines, this variant meets PM1, PM2, PP1, and PP3 so that this variant is “likely pathogenic” of ADTKD-HNF1B. In conclusion, this patient presented with both kidney cystic lesions and diabetes and had a family history of kidney cystic lesion and diabetes, which are HNF1B-associated phenotypes, and genetic analysis revealed a novel variant of HNF1B.

This patient presented with both kidney cystic lesions and diabetes and had a family history of kidney cystic lesion and diabetes, which are HNF1B-associated phenotypes, and genetic analysis revealed a novel variant of HNF1B. We performed a kidney biopsy of his cystic kidney, and this is the first report of the kidney biopsy on ADTKD-HNF1B. This case also showed tubulointerstitial fibrosis and abnormal mitochondrial morphology in tubular cells.

The correct answer is B

Comment: Acute tubulointerstitial nephritis (ATIN) is characterized histologically by inflammation of the renal interstitium, with relative sparing of glomeruli. ^. This lesion may account for 10% to 15% of cases of unexplained acute renal failure investigated with renal biopsy. ^, Acute tubulointerstitial nephritis be caused by drugs, infections, or systemic disease, but sometimes no cause is found. Because cases of ATID are rarely diagnosed, clinical experience with them is limited and optimal therapy is unknown. In particular, whereas steroid therapy has been used with apparent success, ^– its true value remains unproven. This report will review the clinical and pathologic features of acute idiopathic tubulointerstitial nephritis and report two additional cases. Our patients presented with severe azotemia and evidence of generalized proximal tubular dysfunction. Both patients responded dramatically to steroid therapy.

Acute idiopathic tubulointerstitial nephritis must be considered in the differential diagnosis of acute renal failure. Although there is a predominance of females, both sexes and all ages are affected. In the majority of cases, there is a prodrome consisting of nonspecific constitutional symptoms, and a few patients experience flank or abdominal pain. Unlike drug-induced acute interstitial nephritis, fever and skin rash are usually absent. There is no history of preceding drug or toxin exposure, nor are there signs or symptoms of a specific systemic disease. However, some cases have been associated with uveitis and bone marrow and lymph node granulomas. ^–

Patients often present with moderate to severe renal failure, which is usually nonoliguric. BP is almost always normal. There is usually mild anemia, and the ESR is almost always elevated, but routine cultures and serologic markers of rheumatologic and infectious disease are negative. Complement levels are usually normal. Eosinophilia is seen only in a minority of patients, and IgE levels, when measured, have been either normal or increased. Proteinuria is generally <2g/24 h, and only occasional RBCs, WBCs, and granular casts are seen on urinalysis. Only four patients with heavy proteinuria have been reported, and all had glomerular involvement on biopsy. The kidneys are of normal size and are not obstructed. Our patients presented with severe renal failure and evidence of generalized proximal tubular dysfunction, with impaired reabsorption of glucose, amino acids, uric acid, and phosphorus. The recognition of proximal tubular dysfunction is more difficult when the glomerular filtration rate is reduced ; however, renal failure alone cannot explain all the findings in our patients. Both patients had marked elevations of the fractional excretion of uric acid, much greater than that associated with renal failure alone. Moreover, both patients had marked renal glycosuria and generalized aminoaciduria, useful markers of proximal tubular dysfunction, which are not features of renal failure alone. ^, During an exacerbation, case 2 demonstrated full Fanconi syndrome, including a hypokalemia hyperchloremic acidosis, hypophosphatemia, hypouricemia, renal glycosuria, and generalized aminoaciduria. Although there are only two previous reports of generalized proximal tubular dysfunction and Fanconi syndrome in acute idiopathic tubulointerstitial nephritis, many other cases have had glycosuria on routine urinalysis. Many of these patients would have manifested other features of the Fanconi syndrome had these been sought. As previously suggested, the finding of glycosuria in the presence of a normal blood glucose is an important clue to the diagnosis of acute tubulointerstitial nephritis, but its absence does not exclude the diagnosis. Histologically, an intense inflammatory interstitial infiltrate is seen, with relative sparing of the glomeruli. The majority of infiltrating cells are lymphocytes and plasma cells-eosinophils are prominent only occasionally. Lymphocytes may be seen between the basement membrane and tubular cells, so-called tubulitis. There may be tubular necrosis, loss of tubular basement membrane, and varying degrees of interstitial edema and fibrosis. In most cases, immunofluorescence has been negative or has shown only nonspecific staining, and electron microscopy confirms tubular injury and has usually not revealed deposits. The prognosis of acute idiopathic tubulointerstitial nephritis has generally been favorable with or without steroid therapy. Only one patient has been described who required permanent dialysis, although several patients have required dialysis during the acute illness. Many patients reported were left with some degree of renal impairment. However, their ultimate outcome is unclear because follow-up was short. The etiology of this condition is unknown. Its frequent prodrome raises the possibility of an infectious origin. In fact, in our first case, other family members had similar symptoms. However, attempts to demonstrate viral, bacterial, and fungal infections have been unsuccessful in all reported cases. Similarly, no systemic disease has emerged during follow-up of these patients. The lack of specific immunofluorescence and the demonstration that the majority of infiltrating cells are T-lymphocytes suggest a role for cell-mediated immunity in this disorder. If cell-mediated immunity is responsible for the injury pattern, then steroids would be rational therapy. In several cases, steroids were used and led to dramatic improvements of renal function, ^– usually within 1 to 2 months. However, because there have been reports of spontaneous recovery, ^– the value of steroids remains open to question. Our two cases shed further light on this issue. Both patients’ renal function improved dramatically after steroid therapy was begun. Moreover, our second case is the first reported in which renal function initially improved on steroids, deteriorated when steroids were withdrawn, and then improved a second time with reinstitution of steroid therapy. This leaves little doubt that steroids were both effective and instrumental in reversing the tubulointerstitial nephritis in this patient. Similarly, Frommer et al. described a patient who was on dialysis for 31 months before a renal biopsy demonstrated interstitial nephritis; the creatinine decreased to 2 mg/100 mL after the institution of steroid therapy. Thus, although the prognosis of acute idiopathic tubulointerstitial nephritis is generally good with or without therapy, steroids are effective and may be necessary to improve renal function in some patients. Therefore, in the absence of contraindications, we believe a short course of high-dose steroid therapy is indicated in patients with severe renal failure. During follow-up, markers of proximal tubular dysfunction should be monitored in addition to the serum creatinine. In our second case, despite near normalization of serum creatinine, glycosuria persisted after the first course of steroid therapy; such findings signal the need for close observation and perhaps continued therapy. Finally, we emphasize that such cases demonstrate the value of renal biopsy in acute renal failure of obscure origin. Although gallium scanning may be suggestive, only through biopsy can acute tubulointerstitial nephritis be diagnosed definitively. Left undetected, this potentially treatable lesion can lead to end-stage renal disease.