Correct answers are A, B, C, and D

The correct answer is A

The correct answer is B

Comment: Constellation of polyuria, polydipsia, generalized aminoaciduria, hyponatremia, hypokalemia, and non-gap metabolic acidosis is consistent with the diagnosis of renal Fanconi syndrome.

Constipation secondary to dehydration has also been described both in the infantile and juvenile forms of cystinosis.

Although cystinosis is the most common identifiable cause of the inherited renal Fanconi syndrome in children, other metabolic diseases (tyrosinemia, galactosemia, glycogen storage diseases), Wilson disease, Dent disease, and Lowe syndrome should also be considered in the differential diagnosis of the renal Fanconi syndrome. Some cystinosis patients with atypical presentations may also be initially diagnosed as nephrogenic diabetes insipidus.

Three clinical forms of cystinosis have been described on the basis of severity of symptoms and age of onset: infantile cystinosis, characterized by renal proximal tubulopathy and progression to end-stage renal disease before 12 years of age; juvenile form, with a markedly slower rate of progression; and adult form, with only ocular abnormalities. Slit-lamp examination of the cornea showing cysteine crystal deposits is considered the best initial test to confirm the diagnosis of cystinosis.

Complete Fanconi syndrome often does not develop in late-onset cystinosis, but renal function deteriorates as in infantile nephropathic cystinosis, and patients often experience end-stage renal failure within a few years of diagnosis.

Pregnant women with cystinosis should not be treated with cysteamine because of its teratogenic effects on developing fetus, particularly in the first trimester. ^,

Studies in animals have shown reproductive toxicity, including teratogenesis and fetotoxicity, at doses less than the recommended human maintenance dose. Observed teratogenic findings were cleft palate, kyphosis, heart ventricular septal defects, microcephaly, and exencephaly. No study has been performed during pregnancy or breast-feeding, so it should not be used by pregnant or breast-feeding women (option A).

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

The correct answer is A

Comment: This patient is not presenting with full-blown nephrotic syndrome. Mildly low serum albumin and heavy proteinuria are concerning for a primary podocytopathy, especially focal segmental glomerulosclerosis (FSGS).

It is recommended to wait for EM findings to look for the extent of foot process effacement and the appearance of glomerular basement membrane (GBM) on EM (option C). ^–

For now, we should start ACE inhibitors/angiotensin receptor blockers and (option D) and would not do steroids or any other immunosuppression at this stage.

We also should consider doing genetic testing including NPH2 , WT1 , and CLCN5 (option B) ^, and ask for evaluation of hypercalciuria and low-molecular-weight proteinuria such as beta-2 microalbuminuria to rule out Dent disease (option E).

In Dent disease, the EM shows no or minimal podocyte effacement with FSGS histopathology.

Should EM reveal minimal change disease (MCD) or primary FSGS (negative genetic results), we should start steroids alone, and if the steroids fail to achieve remission following 6 weeks of therapy, we should then consider this case as steroid-resistant nephrotic syndrome (SRNS) and begin treatment with rituximab (RTX; induction therapy) plus mycophenolate mofetil (MMF; maintenance therapy).

In a recent randomized controlled trial, Assadi et al. compared the efficacy and safety of RTX-cyclosporine A (CsA) MMF (n = 32) vs. RTX-CsA (n = 34) in 66 children with SRNS (MC, n = 15; FSGS, n = 47; and diffuse mesangial hyperplasia (DMH), n = 4) between the ages 2 and 6 years and found RTX-MMF was superior to RTX-CsA both in maintaining the remission and causing fewer adverse events in all cases of renal histology lesions. ^–

The correct answer is E

Comment: Guidelines from the International Study of Kidney Disease in Children, Kidney Disease: Improving Global Outcomes (KDIGO) and, more recently, from the International Pediatric Nephrology Association have been modified and adopted across the world, depending on the availability of medications and preferences by parents and physicians. A review of country-specific guidelines shows that despite minor differences, there is reasonable consensus on the management of both steroid-sensitive and steroid-resistant nephrotic syndrome in children. Harmonizing guidelines and considering region-specific preferences will be useful for uniform guidance for physicians, parents, and patient groups, as well as for allowing comparisons of outcome.

Several randomized controlled trials (RCTs) have investigated the duration and dose of corticosteroid therapy for the initial episode of nephrotic syndrome. Findings from four multicenter trials on more than 800 patients that compared standard (8–12 weeks) to prolonged (16–26 weeks) initial prednisone therapy consistently favor limiting initial therapy to 8 to 12 weeks.

An updated meta-analysis comparing 2 months versus 3 months or longer was not associated with increased risk of relapse.

Individual patient data analyses of two European studies suggest that initial therapy for 12 weeks was better than 8 weeks in terms of delaying the time to first relapse and fewer relapses on short-term follow-up. Furthermore, prolonged therapy in young children might reduce the risk of first relapse but not frequent relapses. Similar findings were reported in a recent RCT on patients with onset of disease before age 4 years, which showed that extending the duration of initial therapy beyond 12 weeks postponed the time to first relapse without altering the risk of frequent relapses.

Based on the results of these trials, the International Pediatric Nephrology Association recommends that initial therapy should comprise 6 weeks each of daily and alternate-day prednisone therapy. KDIGO guidelines recommend that physicians could either follow 8 weeks or 12 weeks of initial treatment, with empiric advice to prefer the former in patients with rapid (<7 days) remission or comorbidities such as obesity or hypertension, and consider prolonged (26–24 weeks) therapy in young patients with delayed remission.

The correct answer is C

Comment: We recommend kidney biopsy be obtained at the onset of nephrotic syndrome to establish a histological diagnosis to determine the treatment plan in patients (1) whose age is younger than 1 year or older than 6 years, (2) with persistent hematuria and frank hematuria, (3) with hypertension and renal dysfunction, (4) with hypocomplementemia, and (5) with extrarenal symptoms (e.g., rash, purpura) because these patients are likely to have other histological types than minimal-change disease. ^,

Kidney biopsy is also recommended in patients showing steroid resistance and in patients given long-term calcineurin inhibitor therapy, even without renal dysfunction at 2 to 3 years into the therapy to assess for any nephrotoxicity.

The correct answer is A

Comment: FSGS is a histological pattern of glomerular injury, rather than a single disease, that is caused by diverse clinicopathological entities with different mechanisms of injury with the podocyte as the principal target of lesion. It is considered the most common glomerular cause leading to end-stage renal disease (ESRD).

Primary FSGS, which usually presents with nephrotic syndrome, is thought to be caused by circulating permeability factors that have a main role in podocyte foot process effacement.

Secondary forms of FSGS include maladaptive FSGS secondary to glomerular hyperfiltration such as in obesity or in cases of loss in nephron mass, virus-associated FSGS, and drug-associated FSGS that can result in direct podocyte injury.

Genetic FSGS has increasingly been recognized and a careful evaluation of patients with atypical primary or secondary FSGS should be performed to exclude genetic causes.

Unlike primary FSGS, secondary and genetic forms of FSGS do not respond to immunosuppression and tend not to recur after kidney transplantation.

Distinguishing primary FSGS from secondary and genetic causes has a prognostic significance and is crucial for an appropriate management. In this review, we examine the pathogenesis, clinical approach to distinguish between the different causes, and current recommendations in the management of FSGS. ^,

The correct answer is E

Comment: In a recent RCT, Assadi et al. compared the efficacy and safety of maintenance mycophenolate versus cyclosporine following rituximab in children with steroid-resistant nephrotic syndrome with FSGS and found that a combination of rituximab plus mycophenolate in maintaining remission was superior to rituximab plus cyclosporine with fewer adverse effect in 12 months of follow-up.

The correct answer is A

Comment: In a large prospective study of 1205 renal biopsies reviewed at The Hospital for Sick Children, Toronto, 14 patients had a clinicopathologic diagnosis of idiopathic membranous glomerulopathy. Typical thickening of glomerular capillary basement membranes, a spike-and-dome pattern, and subepithelial electron-dense deposits were noted. Strong deposits of immunoglobulin G (IgG) and weaker deposits of C3, IgM, and IgA were present in glomeruli. Stages of membranous glomerulopathy on EM were I in one biopsy, II in nine biopsies, and III in four biopsies.

At presentation, 11 patients had nephrotic syndrome, 7 had hypertension, and 8 had hematuria. Now four are in remission, seven have active disease with normal renal function, and three have renal failure.

Patients with hypertension, presence of nephrotic syndrome, hematuria, and being younger than age 6 years at the onset tended to do worse. Administration of steroids or immunosuppressive drugs did not adversely affect outcome. Furthermore, clinical outcome did not correlate with stage of disease. Hence, pathologic and most clinical features do not predict long-term prognosis in children with membranous glomerulopathy. Based on these observations, a conservative and less aggressive therapeutic approach is recommended for children with normal renal function and normal BP. ^,

The correct answer is C

Comment: Despite the continuing development of immunomodulatory agents and supportive care, the prognosis associated with lupus nephritis (LN) has not improved substantially in the past decade, with end-stage kidney disease still developing in 5% to 30% of patients within 10 years of LN diagnosis.

Modalities that better preserve kidney function and reduce the toxicities of concomitant glucocorticoids are needed in the development of therapeutics for LN. In addition to the conventional recommended therapies for LN, there are newly approved treatments as well as investigational drugs in the pipeline, including the newer generation of calcineurin inhibitors and biologic agents. In view of the heterogeneity of LN in terms of clinical presentation and prognosis, the choice of therapies depends on a number of clinical considerations. Molecular profiling, gene-signature fingerprints, and urine proteomic panels might enhance the accuracy of patient stratification for treatment personalization in the future.

Immunosuppressive therapy in patients with class I/II LN should be guided by extrarenal disease manifestations unless the patients have nephrotic syndrome resulting from lupus podocytopathy, which is managed as a minimal change disease.

The initial treatment of active proliferative (± membranous) LN is glucocorticoids plus either MMF or low-dose (Euro-Lupus) intravenous cyclophosphamide.

Although glucocorticoids have generally been given in high doses for LN, emerging data suggest that lower doses may be equally effective but with fewer short- and long-term toxicities.

Following initial therapy of proliferative LN, mycophenolate mofetil is the preferred immunosuppressive and should be continued for at least 36 months.

Class V lupus nephritis is managed with RAS blockade, BP optimization, hydroxychloroquine, and the addition of immunosuppression in patients who develop nephrotic range proteinuria. ^,

The correct answer is A

Comment: At this stage of kidney tissue involvement, not only will immunosuppression be ineffective, but its use may be associated with serious adverse effects and high risk of morbidity and mortality. ^,

The correct answers are A and B

Comment: Microscopic hematuria without proteinuria is a common clinical finding. When urological causes are excluded, usual findings on renal biopsy are IgA nephropathy, Alport syndrome, or thin basement membrane nephropathy (which has an excellent prognosis).

Urinary microalbumin is a sensitive and noninvasive biomarker to discriminate between the IgA and thin basement membrane disease.

Urinary microalbumin excretion was assessed in 76 children with asymptomatic microscopic hematuria in whom the presence of proteinuria, hypertension, reduced renal function, hypercalciuria, urinary tract infection, or structural abnormality of the urinary tract had been excluded. MA/Cr µg/mg was <4. Twenty-two (29%) patients had microalbuminuria (MA/Cr >30 µg/mg) and 54 (71%) had normal albumin excretion.

Of those with normoalbuminuria, 38 (70%) had normal renal tissue, 15 (28%) thin glomerular basement membrane (TGBM) disease, and 1 (2%) IgA nephropathy. In contrast, 20 (91%) of those with microalbuminuria had IgA nephropathy and 2 (9%) had TGBM disease.

Statistical analysis showed no significant differences between the mean MA/Cr ratio for children with TGBM disease and those with normal glomerular findings. Fourteen of the 20 children with IgA nephropathy who also had microalbuminuria were treated with an ACE inhibitor. Over a mean follow-up of 51 months, none developed overt proteinuria; hematuria resolved and microalbuminuria returned to normal in eight (57%) during therapy with the ACE inhibitor. In contrast, hematuria persisted and proteinuria developed in the other untreated children. None of the children with TGBM disease developed overt proteinuria after a mean of 51 months. Hematuria was persistent in children with TGBM disease, but often resolved in those whose biopsies were completely normal.

These data suggest that determination of urinary microalbumin excretion is warranted in the routine examination of children with isolated microscopic hematuria. Routine screening for microalbuminuria may help identify a subgroup of patients with IgA nephropathy who are at high risk for progressive kidney disease and need more intensive therapy and closer follow-up.

The correct answer is A

Comment: Histological features of HIV-associated nephritis (HIVAN) include collapsing FSGS as a result of podocyte proliferation and tubular dilatation with atrophy and flattening of tubular epithelial cells. Interstitial edema and lymphocyte infiltration often accompany interstitial fibrosis in patients with HIVAN.

Kidney biopsy is contraindicated in HIV patients with small and contracted kidneys, single kidney, polycystic kidney disease, hydronephrosis, and presence of urinary tract infection. ^,

To distinguish HIVAN from other forms of renal disease (e.g., immune complex glomerulonephritis, IgA nephropathy), patients who are seropositive for HIV require a kidney biopsy. The typical practice is to obtain a biopsy specimen if the patient’s daily protein excretion is greater than 1 g. ^,

The correct answer is C

Comment: Approaches to treatment of idiopathic membranoproliferative glomerulonephritis (MPGN) have included immunosuppression, inhibiting platelet-induced injury with aspirin and dipyridamole, minimizing glomerular fibrin deposition with anticoagulants, and use of steroidal and nonsteroidal anti-inflammatory agents. ^,

Only a handful of RCTs have been published with sufficient power to determine the benefits of therapy for MPGN. The use of variable end points (e.g., reduction in proteinuria, renal function measured using variable techniques) further confounds the data.

Thus, the optimal treatment of idiopathic MPGN is not clearly defined. Specific therapies should be reserved for patients with MPGN who have one or more of the following indications:

Proteinuria exceeding 3 g/d, active interstitial or glomerular disease (crescents) on biopsy, impaired renal function at presentation, and a progressive decline in renal function. ^,

The correct answers are B and D

Comment: Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.

Tumor lysis syndrome is a metabolic and oncologic emergency frequently encountered in clinical practice. This condition is prevalent in both adult and pediatric patients undergoing chemotherapy. Most of the symptoms seen in patients with tumor lysis syndrome are related to the release of intracellular chemical substances that cause impairment in the functions of target organs. This can lead to acute kidney injury, fatal arrhythmias, and even death.

Because this condition is so lethal, it is imperative to identify patients at high risk for developing tumor lysis syndrome and start early preventive therapy. Quick and early recognition of the renal and metabolic derangement associated with tumor lysis syndrome and initiation of treatment can save the patient’s life.

Rhabdomyolysis is a complex process associated with morbidity and mortality. Although the condition is often caused by direct traumatic injury, other potential etiologies are drugs, toxins, infections, muscle ischemia, electrolyte and metabolic disorders, genetic disorders, exertion or prolonged bed rest, and temperature-induced states such as neurologic malignant syndrome (NMS) and malignant hyperthermia. Rhabdomyolysis is exhibited by a triad of symptoms including myalgia, weakness, and myoglobinuria, with an elevation in creatinine kinase level being the most sensitive test for muscle injury–induced rhabdomyolysis. All clinicians should be aware of common causes, diagnosis, and treatment options.

The correct answer is D

Comment: In its most florid form, calcific vasculopathy may be manifested as calciphylaxis. A small fraction of patients with ESRD, particularly those treated with dialysis, develop deep skin ulcerations in association with calcification of subcutaneous arterioles. Uremic peripheral neuropathy is a distal, symmetrical, mixed sensorimotor. It occurs more commonly in men and is independent of the underlying disease. There is no specific myopathy associated with uremia.

Arthralgia and myalgias characterize diffuse scleroderma. Early diffuse cutaneous systemic sclerosis includes arthritic symptoms. A specific myopathy is not seen.

Recurrent HSP does not manifest a specific myopathic picture, as seen in this case.

The correct answer is D

Comment: Sevelamer hydrochloride (Renagel) significantly lowers serum phosphorous in hemodialysis patients but with minimal effects on serum calcium in comparison to treatment with standard calcium-based phosphate binders. Patients with the highest PTH levels (>300 pg/mL) experienced the greatest reduction in PTH. The effect on PTH levels, however, may be inconsistent.

The correct answer is D

Comment: Hyperphosphatemia is the strongest predictor of calciphylaxis in patients receiving hemodialysis treatment. There is a 3.5-fold increase in the risk of calciphylaxis associated with each 1-mg/dL increase in the serum phosphate concentrations. Body mass index, diabetes, hypertension, hypomagnesemia, aluminum, and higher dosages of erythropoietin and iron dextran are not independent predictors of calciphylaxis.

The correct answer is A

Comment: This patient’s clinical picture is consistent with low turnover bone disease; therefore, aluminum toxicity must be considered. In the presence of significant aluminum exposure, bone biopsy seems indicated in the following cases: before parathyroidectomy and before starting long desferrioxamine treatment, given the risks of deafness and fatal mucormycosis as complications of treatment. Bone alkaline phosphatase is not sensitive enough to distinguish between low and normal turnover. Procollagen-icarboxy-terminal propeptide is not a specific indicator of bone disease because it is not well controlled with bone histology.

The correct answer is C

Comment: The indications for parathyroidectomy, two of which apply to this patient, have classically included: (1) hypercalcemia and hyperphosphatemia in the presence of very high PTH levels (>800 pg/mL), as in this patient, with concurrent resistance to pharmacologic control; (2) fractures and tendon avulsions; (3) when the estimated weight of a parathyroid gland exceeds 1 g; and (4) calcific arteriolopathy, which some experts have considered to be an absolute indication.

The correct answer is C

Comment: Green et al. studied the mechanism of posttransplant hypophosphatemia and found that sera from hypophosphatemic posttransplant patients inhibited PO ₄ transport in vitro in a PTH-independent mechanism. This finding is consistent with the concept that there are PTH-independent humoral agents (phosphating) that dramatically reduce PO ₄ reabsorption, and they may underline disorders of phosphate transport, as seen in oncogenic osteomalacia.

Cyclosporine does not produce phosphate wasting, nor does 1,25 (OH)2 D3. Glucocorticoids are phosphaturic but do not produce the severe degree of phosphate wasting seen in this case.

The correct answer is C

Comment: Any evaluation of dietary phosphorus adequacy should consider not only the content of phosphorus in food but also the bioavailability of phosphorus because most phosphorus in plants is in the form of phytate. Because humans do not have the phytase enzyme that is required to degrade phytate and to release phosphorus, phytate is poorly digested in the human gastrointestinal tract and therefore limits phosphorus absorption from plant sources. Phosphorus in meat is well absorbed because it is found mostly as intracellular organic compounds that are easily hydrolyzed in the gastrointestinal tract, releasing inorganic phosphorus for absorption.

The correct answer is A

Comment: The indications for percutaneous ethanol injection include serum PTH >800 pg/mL, symptoms such as severe itching or bone pain, evidence of high-turnover bone disease, exclusion of aluminum bone disease by desferrioxamine, resistance to medical therapy including calcitriol pulse therapy, and the long axis of the target parathyroid gland detected by ultrasonography exceeding 5 mm and shown to have a positive blood flow by power-Doppler ultrasonography. Patients failing to have adequately sized glands will likely require surgical removal. Increasing calcium in the dialysate or increasing vitamin D intake would be inappropriate in this hypercalcemic patient. Calcimimetic agents would be ineffective in this patient with the enlarged parathyroid mass greater than 5 mm in length.

The correct answer is A

Comment: This patient has developed skin necrosis associated with calcific vasculopathy. This syndrome is called calciphylaxis. Because he demonstrates hypercalcemia with therapeutic doses of vitamin D, he likely has adynamic bone disease as well. The association of the two conditions has been reported and is linked by the role of recurrent episodes of hypercalcemia. Hyperphosphatemia does play a role, but the elevation of serum phosphate is typically persistent. Hyperparathyroidism is frequently found associated with calciphylaxis, but in this case the iPTH level is below that associated with the full picture of symptomatic hyperparathyroidism including accelerated bone turnover and hypercalcemia with small doses of vitamin D. Vasculitis and atheroembolic disease are important entities in the differential diagnosis of calciphylaxis but are not associated with the tendency to hypercalcemia found in this patient.

The correct answer is D

Comment: Low doses of active vitamin D and calcium partially prevent bone loss at the lumbar spine and proximal femur during the first 6 months after renal transplantation. Recently, prophylactic bisphosphonate treatment has shown promise, but the exact indications for its use in this setting remain to be determined. Steroid therapy contributes to bone loss, but not cyclosporine or mycophenolate.

The correct answers are B and D

Comment: Calcimimetics are calcium receptor agonists that act on the parathyroid gland by increasing the sensitivity of the receptor to calcium. Treatment with cinacalcet HCl causes significant decreases in PTH without elevating serum calcium or phosphate levels.

The correct answer is D

Comment: The indications for parathyroidectomy include (1) hypercalcemia and hyperphosphatemia in the presence of very high PTH level (>800 pg/mL) with failure to lower PTH levels after 6 to 8 weeks of vitamin D analog and/or calcimimetics therapy; (2) fractures and tendon avulsions; (3) calcific arteriolopathy; and (4) hypertrophied gland and weight >4.0 g as determined by ultrasonography.

The correct answer is A

Comment: Gadodiamide binds with colorimetric agents used in assaying serum calcium and produces a spurious hypocalcemia. Parathyroid infarct is a rare event. Gadopentetate does not produce the same effect. Barium administration is associated with hypokalemia, and barium sulfate used in radiologic studies does not enter the circulation. A defective laboratory instrument is always possible, but gadodiamide predictably produces this artificial finding.

The correct answer is C

Comment: Green et al. studied the mechanism of posttransplant hypophosphatemia and found that sera from hypophosphatemic posttransplant patients inhibited PO ₄ transport in vitro in a PTH-independent mechanism. This finding is consistent with the concept that there are PTH-independent humoral agents (phosphating) that dramatically reduce PO ₄ reabsorption, and they may underline disorders of phosphate transport, as seen in oncogenic osteomalacia.

Cyclosporine does not produce phosphate wasting, nor does 1,25 (OH)2 D3. Glucocorticoids are phosphaturic but do not produce the severe degree of phosphate wasting seen in this case.

The correct answer is C

Comment: Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3-ANCA positive, or ANCA-negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or renal-limited vasculitis.

Immunomodulatory and immunosuppressive therapies are used to induce remission, maintain remission, and treat relapses. Over recent years, there have been major advances in optimizing treatment by minimizing toxic therapy and using more targeted therapy.

In the present case study, patient’s renal function and laboratory findings have substantially improved after switching to cyclophosphamide to azathioprine. The best approach at this point is to continue azathioprine with close follow-up (option C).

The correct answers are A, B, and C

Comment: The finding of a positive ANCA in association with HSP has been described in both pediatric and adult cases. ^, The presence of IgA ANCA has been found in anywhere between 28% and 79% of patients with HSP, and it has been suggested to be able to help confirm the diagnosis of childhood HSP. Also, the presence of ANCA in HSP has been associated with a more severe course in adults. On the other hand, the presence of IgG ANCA in HSP is still unclear and of unknown significance.

The positive IgG anti-proteinase 3 C-ANCA (PR3-ANCA) in our patient allowed for a working diagnosis of HSP but brought further consideration of ANCA-associated vasculitis. ANCA-associated vasculitis includes Churg-Strauss (eosinophilic granulomatosis with polyangiitis), Wegener granulomatosis (granulomatosis with polyangiitis), and microscopic polyangiitis, among others.

Because of the consideration of other etiologies, a renal biopsy was performed, which showed pauci-immune necrotizing and crescentic glomerulonephritis with global glomerulosclerosis, interstitial fibrosis, and tubular atrophy. The glomerulonephritis demonstrated mild activity and moderate chronicity. There was no evidence of immune complex–mediated disease, and it represented an ANCA-mediated glomerulonephritis.

Based on renal biopsy and being ANCA positive, the patient was given pulse methylprednisolone, mycophenolate mofetil, and rituximab.

The correct answer is A

Comment: Systemic lupus erythematosus is a typical autoimmune disease characterized by multiple system involvement and is associated with anti-phospholipid antibody syndrome in approximately 36% of patients. Anti-phospholipid antibody syndrome is associated with recurrent arterial and venous thrombosis, fetal loss, and thrombocytopenia. Thrombosis resulting in various clinical manifestations can occur in any small or large vessel in the body. The thrombosis of the intrahepatic proportion of the inferior vena cava, called Budd-Chiari syndrome, secondary to anti-phospholipid antibody syndrome has been noted in previous reports. A previous study of 43 patients with anti-phospholipid antibody syndrome-associated Budd-Chiari syndrome showed that two-thirds of these patients were girls, and the first clinical appearance of anti-phospholipid antibody syndrome, despite the absence of the other clinical systemic lupus erythematosus findings, was Budd-Chiari syndrome.

In anti-phospholipid antibody syndrome, thrombosis can develop anywhere in the body or in any organ, ranging from 29% to 69% and results in different clinical manifestations depending on the organ involved and the location/degree of the involvement.

Similarly, the liver dysfunction that occurs in Budd-Chiari syndrome varies according to the rate and degree of venous hepatic occlusion and ranges from an asymptomatic state to fulminant hepatic failure.

Many studies have shown that anti-phospholipid antibodies, including lupus anticoagulant and anti-cardiolipin antibodies, positive patients are prone to recurrent thrombosis and spontaneous fetal loss episodes, which is termed anti-phospholipid antibody syndrome , classified as either primary or secondary.

Budd-Chiari syndrome can develop in the clinical course of systemic lupus erythematosus and should be considered in the differential diagnosis when such a patient develops abdominal pain, nausea, vomiting, hepatomegaly, ascites, and massive lower extremities edema. Systemic lupus erythematosus patients should be screened for anti-phospholipid antibody syndrome, even if there is not any clinical sign of thrombosis.

The correct answer is D

Comment: Schimke immunoosseous dysplasia (SIOD) is characterized by short stature, spondyloepiphyseal dysplasia, nephropathy, and T-cell immune deficiency. The diagnosis of SIOD is usually based on clinical findings, especially in patients with nephrotic syndrome. Genetic analysis can confirm the diagnosis and lead to early interventions that may prevent the fatal outcome of SIOD patients.

SIOD is a rare autosomal recessive disorder that manifests as disproportionate short stature, facial dysmorphic features, spondyloepiphyseal dysplasia, SRNS progressing to ESRD, and T-cell deficiency.

Additionally, lymphopenia, anemia, thrombocytopenia, neutropenia, cerebrovascular events (transient ischemic attack, stroke, headache), hyperpigmented macules, hypothyroidism, developmental delay, and occasionally non-Hodgkin lymphoma have been reported. ^, In the case presented here, clinical findings were suggestive for the diagnosis, which was ascertained at the initial evaluation. The present patient had homozygote c.1606_1701delinsTTCCC mutations at exon 10 of the SMARCAL1 gene. Treatment is symptomatic. Nephropathy has been reported as steroid resistant, and although transient partial response to calcineurin inhibitors has been reported, renal pathology has always progressed to ESRD. Renal transplantation when possible has been effective for the ESRD. Growth hormone therapy for short stature has been reported as ineffective.

The correct answer is B

Comment: There are many disorders that may present with nephrocalcinosis, including Bartter syndrome, disorders of calcium sensing receptors, idiopathic calcium and kidney stone diseases, disorders of vitamin D metabolism resulting from CYP24A1 mutations presenting as idiopathic infantile hypercalcemia type 1 (HCINF1) or type 2 because of mutations of sodium, phosphate co-transporter (NaPi 2a) (SLC34A1), hypervitaminosis D, and primary distal renal tubular acidosis. However, chronic kidney disease (CKD) is not seen in these disorders.

Our patient had anemia, elevated urea, and creatinine with an eGFR of 31 mL/min/1.73 m ² (CKD stage 3) with hyperparathyroidism, and normal calcium and vitamin D levels and hypomagnesemia with hypercalciuria and hyperuricemia and subnephrotic proteinuria, which rule out calcium-sensing receptor and vitamin D metabolism defects.

Clinical disorders associated with nephrocalcinosis that lead to CKD at an early age are Dent disease, cystinosis, FHHNC, cystinuria, and primary hyperoxaluria.

The presence of low-molecular-weight proteinuria, hypercalciuria, and kidney stones or nephrocalcinosis with stage 5 CKD should raise the suspicion of Dent disease. In these disorders, the proximal tubular dysfunction may also cause phosphaturia, glycosuria, and metabolic acidosis (Fanconi-Bickel syndrome). The progression to CKD occurs by age 30 to 50 years, and sometimes even later. The diagnosis of Dent disease may be confirmed on genetic analysis by looking for the presence of OCRL1 or CLCN5 mutations. In the given case, however, no metabolic acidosis was present and features of proximal tubular dysfunction such as phosphaturia and glycosuria were absent. The screen for β ₂ -microglobulin was negative. Slit-lamp examination ruled out deposits of cysteine in the cornea, and the absence of Fanconi-Bickel syndrome completely ruled out cystinosis. ^–

FHHNC is a rare autosomal recessive disorder that presents with loss of magnesium and calcium, thereby causing magnesium wasting, hypercalciuria, nephrocalcinosis, and kidney failure. There may not be significant protein excretion, but early presentation with loss of magnesium in urine and hypomagnesemia is characteristic of the disease. Most children would develop kidney failure in adolescence or early adulthood resulting from a progressive CKD setting from early in life. A defect in claudins that are present at the tight junctions of the thick ascending limb of the loop of Henle (encoded by CLDN16 or CLDN19 ) is implicated in the development of FHHNC.

The kidney manifestations resulting from both mutations are identical, but with CLDN19 there is severe ocular involvement, which may present with myopia, pigment retinitis, macular coloboma, strabismus, astigmatism, nystagmus, macular scars, macular degeneration, anisocoria, and retinochoroiditis. The clinical features in the current context make the diagnosis of FHHNC type 2 highly likely. This was confirmed by next-generation sequencing. An autosomal recessive homozygous missense mutation in exon 4 of the CLDN19 gene transcript was detected, which was a novel pathogenic variant.

This child was initiated on hydrochlorothiazide, magnesium supplements, and potassium citrate (to combat hypercalciuria and repress crystallization) and advised large-volume fluid intake.

The presence of dense unilateral or bilateral radiopaque stones like those from calcium oxalate should also raise the suspicion of primary hyperoxaluria. This is highly likely if the child presents early in life and has persistent nausea and vomiting, leading to failure to thrive or progressive CKD even without a history of passing stones. They may present with reduced kidney function over a period of time, and more than 65% present before the age of 10 years with stone disease.

Children with cystinuria will present with recurrent urinary tract stones in childhood. The individuals may be hypotonic at birth, presenting with delayed growth early in life, and may have hyperphagia and excessive weight gain later on. The average age at stone detection is early teenage years. A significant proportion of adults may develop CKD later in life. The diagnosis may be confirmed by detecting cysteine, ornithine, lysine, and arginine in a urine sample.

The correct answers are A, B, and C

Comment: Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) was diagnosed in the kidney biopsy of the patient who presented with arthralgia, microscopic hematuria, severe proteinuria, high serum creatinine level, and positive ANA in the granular pattern.

IC-MPGN has been accompanied with many infections such as hepatitis B, hepatitis C, autoimmune diseases, ^, and monoclonal gammopathies. Some of these diseases are extremely rare in childhood, such as SS.

Because our patient had arthralgia, positive ANA (with granular pattern), and IC-MPGN on kidney biopsy, we considered systemic autoimmune diseases including SLE, SS, and RA in the differential diagnosis.

For the differential diagnosis of associated diseases: hepatitis B surface antigen, hepatitis C antibody, and HIV screens were found to be negative. The presence of a monoclonal gammopathy was excluded with normal serum and urine protein electrophoresis. Lymphoma and leukemia were not considered in the patient because she had a normal physical examination. Also, no atypical cells were found in her peripheral blood smear.

Our patient did not have any of the clinical findings suggestive of SLE. Serum complement levels of C3 and C4 were normal, anti-dsDNA was negative, and therefore she did not fulfill the diagnostic criteria of SLE. RA was not considered because the duration of her complaint was as short as 2 weeks and rheumatoid factor (RF) was in the normal range.

An extremely rare cause of IC-MPGN in children is SS. Although our patient did not complain about dry mouth and/or eyes, the ophthalmological evaluation revealed she suffered from dry eyes. Schirmer test showed decreased tear secretion (≤5 mm in 5 minutes). Although she had no history of swelling in the salivary glands, the biopsy showed focal lymphocytic sialoadenitis, with a focus score of 5 per 4 mm ² of glandular tissue.

Primary SS (pSS) is diagnosed using the American College of Rheumatology/European League Against Rheumatism criteria in adults. There are no criteria established for children and adolescents.

Ocular dryness was present in her examination, although she did not complain about it at admission. Moreover, her Schirmer test was ≤5 mm/5 minutes (decreased tear secretion) and her focus score was 5 foci/4 mm ² on minor salivary gland biopsy. The complaint of ocular dryness appeared 2 weeks later. Therefore, she fulfilled the criteria of SS according to American College of Rheumatology/European League Against Rheumatism criteria. Additionally, the presence of granular pattern ANA positivity supported the diagnosis of pSS because this type of positivity is seen when the target antigens are nRNP/Sm, SS-A, and SS-B in the cell nucleus. The diagnosis was accepted as pSS.

The correct answer is B

Comment: Hydroureteronephrosis is classified based on the presence or absence of reflux and obstruction. The variant with reflux but no obstruction is high-grade vesicoureteral reflux with a dilated ureter. In primary VUR, there is a failure of this anti-reflux mechanism because of a congenitally short intravesical ureter. Secondary VUR is frequently associated with an anatomic obstruction (for example, posterior urethral valves) or a functional bladder obstruction (for example, bladder bowel dysfunction and neurogenic bladder). The severity of VUR can be influenced by the degree and chronicity of obstruction.

If progression in hydronephrosis is observed in patients with hydroureteronephrosis for a known cause such as VUR, intra-abdominal tumors should be kept in mind, including signet ring cell carcinoma (SRCC), a rare and rapidly progressing tumor in this age group capable of compressing the ureter.

After a histopathologic diagnosis of SRCC, chemotherapy was started as a modified FOLFOX 6 regimen that includes oxaliplatin 85 mg/m ² day 1, leucovorin 400 mg total dose over 2 hours day 1, fluorouracil 400 mg/m ² bolus day 1, followed by 2400 mg/m ² over 46 hours, and panitumumab 6 mg/kg every 2 weeks, was started. The patient is well after 3 months of follow-up. After chemotherapy, the creatinine level decreased to 0.7 mg/dL and hydroureteronephrosis of the right kidney regressed, whereas hydroureteronephrosis in the left kidney persisted.

The correct answer is A

Comment: The histological findings on the kidney biopsy are consistent with membranous glomerulonephritis. The cause of membranous nephropathy in this case was penicillamine treatment, which was confirmed with the resolution of proteinuria after switching the penicillamine treatment to trientine hydrochloride.

Membranous nephropathy is a rare cause of proteinuria in the pediatric age group (about 5%), and secondary causes such as infections (hepatitis B virus, hepatitis C virus, syphilis) and drugs are more common in children compared with adults. Routine urine analysis during follow-up of children with WD is essential for the diagnosis of kidney involvement because of the disease itself or as a side effect of penicillamine treatment. In children, who develop proteinuria under penicillamine treatment, membranous nephropathy must be kept in mind, and switching of penicillamine to trientine hydrochloride should be preferred.

Kidney involvement in WD mainly manifests as tubulopathy with findings of renal tubular acidosis, glucosuria, phosphaturia, aminoaciduria, proteinuria (i.e., low molecular weight), hypercalciuria, and nephrolithiasis. Copper is mainly deposited in the epithelium of proximal and distal convoluted tubules in the kidney, which induces cell swelling and degeneration. Acute kidney injury resulting from acute hemolytic anemia at the first presentation has also been reported.

Glomerular involvement as microscopic hematuria (11%) and microalbuminuria (34%) has been reported in pediatric WD cases, which were resolved after penicillamine treatment. In the same report, transient microscopic hematuria and microalbuminuria have also been reported during penicillamine treatment. Glomerulonephritis in patients with WD (without penicillamine treatment) is rarely reported. Immunoglobulin A nephropathy (IgAN) was reported in a patient with a known WD. Inversely, it is also reported that patients whose first presentation was immunoglobulin A nephropathy were diagnosed as having WD concomitantly or during follow-up with WD.

The correct answer is A

Comment: This girl with a solitary kidney had urinary incontinence and constipation since birth along with recurrent urinary tract infections, resulting in the development of CKD stage IV (eGFR 22 mL/min/1.73 m ² by modified Schwartz formula). She was underweight with short stature and had hypertension, anemia, metabolic acidosis, vitamin D deficiency, and hyperparathyroidism, which are manifestations of CKD. The solitary right kidney did not show compensatory hypertrophy and had loss of poor corticomedullary differentiation with hydroureteronephrosis in the absence of vesicoureteric reflux. These findings and increased bladder wall thickness on ultrasound suggested presence of concomitant bladder dysfunction probably from anatomical or functional obstruction. A patulous anus and characteristic “Christmas tree” appearance of urinary bladder with irregular contours were suggestive of a neurogenic bladder. Both ovaries and uterus were absent. As the patient was phenotypically female, this prompted us to consider 46, XY disorders of sexual development like androgen insensitivity syndrome (OMIM 300068). She was in her early adolescence; hence, we could not comment on the development of secondary sexual characteristics. Patients with androgen insensitivity syndrome usually do not have extragenital anomalies. The presence of genitourinary abnormalities, abnormal thumb of the left hand with loss of thenar prominence, and probable neurogenic bladder raised the suspicion of multisystem structural involvement. Patients with Kallmann syndrome may rarely have solitary kidney with genital and skeletal abnormalities, but they have associated anosmia and a family history of delayed or absent puberty. Hence, we revisited our differential diagnosis to a syndrome that involved müllerian duct agenesis, congenital anomalies of kidney and urinary tract, and the skeletal system. We further evaluated the patient for Mayer-Rokitansky-Küster-Hauser syndrome.

The correct answer is C

Comment: Hypoxanthine-guanine phosphoribosyl-transferase deficiency is an X-linked disorder that results in the overproduction of uric acid. The patient’s female gender and the absence of neurological symptoms, history of nephrolithiasis, or urate granulomas on renal biopsy argued against partial hypoxanthine-guanine phosphoribosyltransferase deficiency. On the other hand, renal ultrasound did not demonstrate renal cysts; therefore, the diagnosis of medullary cystic kidney disease type 2 was ruled out. The most likely etiology of the hyperuricemic chronic renal disease could be familial juvenile hyperuricemic nephropathy. This clinical picture is an autosomal dominant disorder characterized by hyperuricemia, low fractional renal urate excretion, progressive chronic interstitial nephritis, and chronic renal failure. Renal impairment usually appears between 15 and 40 years of age, leading to ESRD within 10 to 20 years. ^–

Familial juvenile hyperuricemic nephropathy is caused by mutations in the uromodulin gene ( UMOD ) located at 16p11.2-12 that encodes for uromodulin or Tamm-Horsfall glycoprotein, the most abundant protein in normal urine. Several mutations in the UMOD gene have been identified in some families. Thus, to achieve exact diagnosis, the patient was tested for UMOD mutations by polymerase chain reaction (PCR) amplification of genomic DNA and bidirectional automated DNA sequencing of all exons in the coding region of the UMOD gene.

The correct answer is A

Comment: Taking into account the end-stage CKD, retinitis pigmentosa (RP), cone-shaped epiphyses (CSE), and coxofemoral findings, the most likely diagnosis is Mainzer-Saldino (conorenal) syndrome in our patient. ^, Genetic analysis to demonstrate an IFT140 or IFT172 mutation would be the next step to confirm the diagnosis.

Mainzer-Saldino syndrome (MSS) or conorenal syndrome is a rare autosomal recessive ciliopathy that is characterized by CSE, CKD, RP, and radiographic abnormalities of the proximal femur. ^– The clinical entity was first described in two siblings (a 14-year-old girl and a 10-year-old boy) in the same family. Both patients had nephropathy characterized by failure to concentrate and acidify the urine, suggesting a dysfunction in distal tubules and collecting ducts along with RP, CSE, and cerebellar ataxia. The younger patient had femoral neck abnormalities as well. ^,

In our patient, we have observed all of the four components. However, she never showed any sign of cerebral ataxia, and head circumference was normal. The most striking finding in MSS is the CSE, which is described as a projection of the distal surface of an epiphysis beyond the proximal border of its diaphysis. The CSE in the feet, at the distal phalanx of the thumb or middle phalanx of the fifth finger of the hand is usually seen as variants of normal. However, CSE located at the proximal phalanges or at the middle phalanges of fingers 3 and 4 of the hands are more likely to be associated with a malformation syndrome. In our patient, CSE was observed in all phalanges of the hands. The CSE may be associated with many syndromes including trichorhinophalangeal syndrome, metaphyseal chondrodysplasias, and familial brachydactyly subtypes. In combination with nephronophthisis, the CSE has been reported in asphyxiating thoracic dystrophy, also known as Jeune syndrome. At the first admission of our patient, exclusion of urological problems, prominent short stature, and retinal findings were suggestive of Senior-Loken syndrome. However, because of end-stage kidney disease and renal atrophy, kidney biopsy could not be performed to show the findings of nephronophthisis. In addition, genetic analyses have not been conducted. When the CSE in the hands was realized in the follow-up, genetic testing was performed for MSS. Mutations in genes encoding intraflagellar transport complexes A (IFT-A) and B (IFT-B) proteins lead to ciliopathies, which are defined as a collection of complex developmental disorders of multiple organs and/or systems. Skeletal ciliopathies were found to be associated with mutations in genes mostly encoding IFT-A, and rarely in those encoding IFT-B complexes. ^, MSS has been suggestive of a ciliopathy with regard to retinal dystrophy, nephronophthisis, and skeletal findings, and because of the transmission profile, an autosomal recessive inheritance was assumed. Initially, candidate genes for IFT-A and IFT-B complexes were defined and mutations in IFT140 and IFT172 were found in patients with MSS. ^, IFT140 is an IFT-A protein that regulates retrograde protein transport in ciliated cells. IFT172 was found to be the only IFT-B protein shown to interact with IFT140 in mice and is involved in an interaction between IFT-A and IFT-B subcomplexes.

The correct answer is A

Comment: In view of the findings of the kidney biopsy, the patient was clinically and radiologically reassessed for all the features of NPS. Nails were unremarkable; the patient had normal patellae, and no pelvic horns were seen radiologically. Other than mild pectus excavatum and bilateral in-turned fifth toes, there were no remarkable stigmata. Joint examination, especially of the elbows, was normal.

The normal glomerular basement membrane is composed of a triple helical molecule of type IV collagen showing sieve-like arrangements. In NPS, abnormal banded collagen (type III) is detected in the lamina densa of the basement membranes.

Hereditary osteo-onycho-dysplasia or NPS is an autosomal dominant entity (OMIM 161200) characterized by absence of the patella, nail dystrophy, and renal abnormalities. The renal abnormality is seen in 35% to 45% of cases. It may be a late manifestation and is responsible for the morbidity and mortality of this condition. The diagnostic morphologic features are noted only using EM. ^,

A few reported cases have renal features typical of this syndrome in isolation, without the nail and skeletal anomalies. This entity has been called the nail-patella-like glomerulopathy (OMIM 256020).

The typical clinical presentation of nail-patella-like glomerulopathy is steroid-resistant proteinuria; hypertension is rarely associated with hematuria. Few patients present in renal failure and some progress to chronicity, suggesting a poorer prognosis. Light microscopy reveals nonspecific changes of focal and diffuse basement membrane thickening with mesangial widening. Immunofluorescence studies may be negative or show nonspecific deposits of granular IgM and C3. Both of these show no specific morphological changes, which may help establish the diagnosis. The diagnostic features are seen only with EM. These consist of lucent areas in the basement membrane with intramembranous inclusions of fibrillary collagen. The collagen may also be seen in the mesangium. The lamina densa is devoid of the basket-weave pattern or splitting or large vacuoles like those seen in Alport syndrome.

The only two conditions showing banded collagen in the basement membrane are NPS and nail-patella-like glomerulopathy. Banded collagen may be found in the other regions of the glomerulus (other than the basement membrane) in collagen fibrotic glomerulopathy. In fact, the lamina densa in cases of collagenofibrotic glomerulopathy are free of any collagen fibers. Rarely, very focal deposition of intramembranous collagen may be noted in advanced chronic glomerulopathies.

No specific treatment is available for NPS and nail-nail-patella-like glomerulopathy. The patients are managed only symptomatically. Patients of NPS treated with renal transplantation have not shown any recurrence of the disease.

The correct answer is A

Comment: CNS is usually caused by genetic defects affecting the glomerular filter. The most common defects are nephrin mutations, whereas defective WT1 , PLCE1 , LAMB2 , or NPHS2 gene products are less common. ^, Additionally, CNS has been described in association with metabolic diseases, such as respiratory chain deficiency. Variants in integrin α3 (ITGA3) are known to cause lung disease in combination with nephrotic syndrome. The most common nongenetic causes are infectious diseases, such as cytomegalovirus infection ^, and congenital syphilis.

CNS can also occur in congenital disorders of glycosylation (CDG). So far, it has been described in the subtypes PMM2-CDG, ALG1-CDG, and various cases of CDG-x (i.e., cases in which the subtype has not been identified).

Taking the dysmorphic and multiorgan presentation of the described patient into account, the differential diagnosis in the presented case consists of mitochondrial cytopathy, CDG, and ITGA3 disease. The most likely option with regard to the typical dysmorphic presentation (i.e., inverted nipples and facial dysmorphisms) is CDG.

The analysis of serum transferrin is the primary diagnostic tool for cases with suspicion of CDG. This group of diseases affects the glycosylation process and is known to cause a great variety of symptoms in almost all organ systems. There are two distinct pathologic patterns: the type 1 pattern with a decreased tetrasialo-fraction and increased di- and asialo-transferrin fractions; and the type 2 pattern, which shows an additional increase in the mono- and/or trisialo-transferrin bands.

Having obtained a pathological transferrin test, genetic analysis of the genes associated with CNS in CDG should be initiated. If this leads to no result, whole-exome sequencing is another option, which may facilitate the identification of the causative gene. However, this method has limitations, especially in consanguineous families where a vast number of variants and mutations is not unusual.

In the majority of cases, CNS is caused by underlying genetic defects leading to disruption of the glomerular filtration barrier resulting in proteinuria, hypoproteinemia, and generalized edema. ^{, ,} In the described patient, CNS was caused by a metabolic disease affecting the glycosylation of glycoproteins (ALG1-CDG). Sanger sequencing of the ALG1 gene was performed and the patient was found to be homozygous for the mutation c.773C>T [S258L] in the ALG1 gene (rs28939378), which results in a defect of β1,4-mannosyltransferase. The parents were heterozygous for this mutation. Renal manifestations of CDG other than CNS are rare.

The correct answer is D

Comment: In a patient with diabetes and proteinuria, the initial thought is often diabetic nephropathy. However, patients with diabetes are more likely to have conditions other than diabetic nephropathy. This is particularly true in patients with short duration of diabetes and good metabolic control. Our patient has diabetes, which is somewhat atypical for type 1 diabetes with negative autoantibodies and an unusually very low HbA1C levels. The renal biopsy showed FSGS, and she has other clinical features, including short stature, poor effort tolerance, and abdominal pain.

The patient had received large doses of analgesics, but the renal disease is unusual for analgesic nephropathy, which typically presents with papillary necrosis and reduced GFR. The association with drugs other than phenacetin remains speculative. Finally, the patient could have two or more unrelated conditions. Therefore, it is appropriate to consider genetic causes of diabetes that may account for some or all of these features.

Genetic testing revealed a mutation in mitochondrial DNA, m.3243A>G, which is the most common cause of maternally inherited diabetes and deafness (MIDD), a mitochondrial disorder characterized by maternally transmitted diabetes and sensorineural deafness. She was also found to be heterozygous for a missense variant of NPHS1, c.2746G>T; p (Ala916Ser). The patient therefore has MIDD, and the renal disease may be aggravated by the NPHS1 variant.

Maternally inherited diabetes and deafness has been previously reported. It is caused in the great majority of cases by an adenine to guanine substitution at position 3243 of the mitochondrial DNA (m.3243A>G) encoding the gene for leucine transfer RNA. MIDD is frequently misdiagnosed as type 1 or type 2 diabetes, depending on the age of the patient and mode of presentation. Approximately 1% of cases of diabetes are thought to be caused by mutations in mitochondrial DNA, and the m.3243A>G mutation accounts for about 85% of these. The key clinical features are diabetes and deafness and their presence in maternal relatives. As the case of our patient demonstrates, these are not always present. The diabetes usually presents insidiously, but in 20% of cases it presents acutely, with ketoacidosis present in 8% of the latter cases. Approximately 75% of diabetic patients with the m.3243A>G mutation have deafness, which is sensorineural and the result of cochlear disease. Renal disease is common in patients with MIDD, especially females. In one series of 74 patients with MIDD, proteinuria was greater in these patients than in control diabetic patients, and CKD stage 3 or greater was 4- to 6-fold higher despite lower HbA1C, lower blood pressure and a 3.7-fold lower incidence of diabetic retinopathy than controls. The most common histological pattern in patients undergoing renal biopsy is FSGS, but tubulointerstitial disease and renal cysts have also been described. The combination of nephropathy and deafness may lead to a mistaken diagnosis of Alport syndrome. Several other features present in this patient are also explained by the m.3243A>G mutation, including short stature, which is common and caused by a deficiency of growth hormone–releasing hormone. ^, Gastrointestinal complaints are also common, especially constipation and pseudoobstruction. The inability to play competitive soccer likely reflects impaired energy utilization and skeletal myopathy. Cardiomyopathy, retinal macular dystrophy, and stroke, features not present in our patient, are also described. Our patient had early onset of several features. This is likely to reflect high levels of heteroplasmy for the mutant mitochondrial DNA. The severity and early onset of renal disease may also be due to the presence of a heterozygous mutation in NPHS1 . This gene codes for nephrin, an important component of the glomerular slit diaphragm, and homozygous mutations cause Finnish type congenital nephrotic syndrome. A diagnosis of MIDD has several important implications for treatment. Metformin should not be used for treating the diabetes because of the increased risk of lactic acidosis. Antibiotics such as tetracyclines and chloramphenicol, which interfere with mitochondrial function, should also be avoided. Coenzyme Q10 has been shown to be beneficial in preventing hearing loss and delaying progression of diabetes. In patients who progress to end-stage renal failure, great caution should be exercised in using maternal relatives as kidney donors.

The correct answer is E

Comment: Sialidosis is a rare lysosomal storage disorder characterized by neuraminidase deficiency leading to proteinuria and kidney failure. Sialidosis may involve almost all organs and systems, either as a part of a systemic clinical picture or individually. The kidney is one of the target organs for inherited metabolic disorders, and a variety of IEMs present with different types of kidney disorders. Fanconi syndrome, proteinuria, renal tubular acidosis, nephrolithiasis, kidney cysts, acute kidney injury, and chronic kidney disease can be clinical manifestations of IEMs. Specific patterns of kidney involvement could be indicative of an underlying IEM. Kidney failure is a well-defined severe morbidity in Fabry disease, primary hyperoxaluria, cystinosis, and methylmalonic acidemia. Nephrosialidosis is a very rare subgroup of the lysosomal storage disorders leading to proteinuria and kidney failure. The patient has a life-limiting inherited metabolic disease and kidney failure because of this disorder. Genetic counseling and information about the condition should be given to the parents. To date, the age of symptom onset in all cases is before 2 years of age, and most patients have died before age 10 years. Our patient became dialysis-dependent at 8 years of age. In comparison with other cases reported before, the mild clinical phenotype in our patient may be associated with compound heterozygosity. It is difficult to say anything definite about the prognosis in this case.

It is caused by mutations in the NEU1 gene on chromosome 6p21. Neuraminidase deficiency affects glycoprotein degradation and leads to abnormal accumulation of sialyl oligosaccharides and glycoproteins. Sialidosis is divided into two groups: type 1 and type 2. Clinical severity is heterogeneous depending on the residual enzyme activity. Type 1 sialidosis is the milder form and usually presents in the second decade with neurological findings. Type 2 presents with earlier onset and mucopolysaccharide-like phenotype with dysostosis multiplex and organomegaly. Rarely, type 2 may affect the kidneys and lead to proteinuria progressing to nephrotic syndrome and chronic kidney disease.

The correct answer is C

Comment: The pathological features of the glomerular capillary loop thickening and subepithelial deposits of immune complexes typically indicate membranous nephropathy (MN). Inflammatory cell infiltration into the interstitium and mesangial deposits on EM are suggestive of secondary MN. IgG subclass staining revealed codominance of IgG1 and IgG2, and the M-type phospholipase A2 receptor staining was negative in her glomeruli, which also supported the diagnosis of secondary MN. The positive findings of ANA and anti-double-stranded DNA antibodies and the nephritis on kidney biopsy were consistent with SLE, according to the criteria of the Systemic Lupus International Collaborating Clinics, despite the patient being very young to be diagnosed with SLE and demonstrated no physical findings of SLE except for nephritis. No symptoms associated with lacrimal gland or salivary gland, suggestive of Sjögren syndrome, were found. No other cause of secondary MN was obvious during the follow-up.

Patients with nephrotic syndrome (NS) are at an increased risk of various complications including infections, kidney dysfunction, and thromboembolism (TE). Our patient was afebrile, and no inflammatory reaction or kidney dysfunction was observed on laboratory examinations. TE in patients with NS can occur in the renal vein or pulmonary artery, which can cause back and chest pain. Coagulation investigations and imaging findings such as ultrasonography (US) and contrast-enhanced CT are useful in the evaluation of thrombus formation. Lung perfusion scintigraphy could reveal the presence of pulmonary embolism (PE). The coagulation tests performed in this case were prothrombin time-international normalized ratio (PT-INR), 0.86; D-dimer, 11.8 µg/mL; fibrinogen, 233 mg/dL; and antithrombin III, 124.6%. Her activated protein C and protein S were normal. Her US and contrast-enhanced CT revealed a thrombus extending from the bilateral renal vein branch to the vicinity of the right atrium, and blood flow in the inferior vena cava (IVC) could not be confirmed using color Doppler US. Lung perfusion scintigraphy revealed decreased perfusion segmentally in the pleural lobes of both lungs, indicating multiple bilateral microemboli. The PE and TE in the renal vein and IVC were responsible for the tachycardia and back pain, respectively; decline of the venous return caused by IVC thrombus could have induced tachycardia during standing or sitting in the morning.

Heparin was administered as anticoagulant therapy with activated partial thromboplastin time to 60 to 80 seconds and was subsequently replaced by warfarin. The dose of warfarin was adjusted with PT-INR value between 2.0 and 3.0. After the initiation of the anticoagulant therapy, US revealed shrinking of the thrombi in the IVC and renal vein over time, followed by a dramatic improvement in tachycardia and back pain. Two months after the anticoagulant therapy, US and contrast-enhanced CT demonstrated the IVC and renal vein without evidence of residual thrombus, and lung perfusion scintigraphy showed normal findings. Complete remission was achieved 4 months after the initiation of CyA and lisinopril. The remission was maintained with the administration of CyA, lisinopril, and PSL (15 mg/m ² BSA) every other day. No recurrence of thrombosis was observed, continuing warfarin with PT-INR value between 1.5 and 2.0.

Patients with NS can have various complications, of which TE is one of the most serious severe. The development of NS-related TE has been attributed to the urinary loss of fibrinolytic and anticoagulant proteins, such as antithrombin III and protein S, and increased platelet aggregation and fibrinogen levels. ^, Other intrinsic and extrinsic factors including hemoconcentration, hyperlipidemia, dehydration, immobilization, intravascular catheter placement, and medications such as corticosteroids and diuretics have also been indirectly associated with thrombus formation in NS. ^{, ,} The incidence of TE in adults with NS is reported as approximately 25%. ^, Therefore, TE can always be assumed as a possible complication in adult patients with NS. In contrast, the incidence of TE in childhood NS has been reported as 2% to 9.2%, ^{, ,} which is less frequent than in adults. Age older than 12 years at onset has been a significant independent predictor of TE in children, suggesting that younger children are at a much lower risk of TE. These differences have been proposed to be attributed to several protective mechanisms against TE in children, including a reduced capacity to produce thrombin, an increased capacity of alpha-2 macroglobulin to inhibit thrombin, and enhanced antithrombotic capacity by the vessel wall. Membranous histology of MN and SLE class V is the greatest risk for TE in both adults and children, ^, although the mechanism is not yet clear. MN is a rare underlying cause of NS in children, which may contribute to the low frequency of TE. Responsiveness to steroids has also been implicated in the risk of developing NS-associated TE, with steroid-resistant NS being of a higher risk than steroid-sensitive NS. Consequently, although there are few reports of TE in younger children, our patient would have been at a relatively high risk of TE, considering the features of histology and steroid responsiveness. In cases with a higher risk of TE resulting from NS, the disease is most frequently seen in the veins of the lower extremities but is also common in the renal veins and pulmonary arteries, ^, of which PE can be the most potentially life-threatening. Accordingly, back pain, gross hematuria, impaired kidney function, chest pain, hypoxia, and dyspnea are well known as the main symptoms of TE. However, it is often overlooked that these symptoms are usually too subtle to trigger a diagnosis of TE, and occasionally the patients are even asymptomatic. In a review of 74 cases with renal vein thrombosis in adults with NS, asymptomatic patients outnumbered the symptomatic patients. Another report indicated that 84% of NS patients with PE were asymptomatic. Similarly, in our case, despite the large thrombi in the IVC and renal veins and multiple PE, the symptoms suggestive of TE or PE were mild during the course of the disease. TE may not be uncommon in childhood NS because it has simply been previously undetected. Thus, in pediatric patients as well as adults with NS, the development of NS-related TE should be carefully considered, regardless of the underlying disease.

Contrast-enhanced CT and scintigraphy, which can reliably detect TE, cannot be routinely performed in children because of the need for sedation, radiological exposure, and cost effectiveness. It is essential to identify children with NS at higher risk for TE and then proceed with more sensitive imaging studies in them. A previous report showed that as many as 30% of childhood NS patients with hemoglobin >16 g/dL, fibrinogen >400 mg/L, and serum total cholesterol >10 mmol/L had PE and TE in renal veins, indicating that a severe hypercoagulable state can be a risk. Additionally, an albumin level <2.8 g/dL, and severity of proteinuria were also suggested as risk factors for TE ^, in addition to age, histology, and steroid responsiveness as mentioned before. The close association between NS-related PE and D-dimer has been demonstrated, with a cumulative probability of PE in patients with NS of approximately 90% when D-dimer >8.9 mg/L was reached. US has also yielded promising results in the diagnosis of renal vein thrombosis. In our case, coagulation tests and abdominal US without overlooking mild symptoms led to more sensitive imaging studies of contrast-enhanced CT and lung perfusion scintigraphy, resulting in TE and PE detection.

Prophylactic anticoagulant therapy to prevent NS-related thrombosis in childhood NS has not been clearly established because of the lack of large and prospective RCTs to confirm the safety and efficacy of the therapy. International guidelines suggest NS patients with prominent hypoalbuminemia (<2.5 g/dL) and additional risks for TE should be considered for prophylactic anticoagulation with warfarin. However, prophylactic anticoagulation may be associated with an increased risk of bleeding events, ^, and warfarin can also be associated with kidney injury. ^, The timing of initiation or resumption of prophylactic anticoagulation would be hesitant in view of a kidney biopsy. Considering the underlying disease in our case, it would also be possible that we could have considered ways to introduce immunosuppressive agents other than steroids at an earlier stage for faster remission. Prophylactic anticoagulation could have been initiated, given the risk of TE in our case. However, the decision of prophylactic anticoagulation is always challenging because the expected benefits and adverse events must be carefully examined, considering the backgrounds of each patient, including the age and activity level, as well as the risk of developing TE. In the future, large and prospective randomized control trials on prophylactic anticoagulation for NS-related TE in children are expected to be conducted.

TE in pediatric NS is truly an “old and new” complication, although TE is a well-known complication of NS, the evidence on its prevention and treatment is sparse, especially in children. It should always be kept in mind that patients with NS can develop TE and PE, even younger children, and that the symptoms of NS-related TE are mild or often asymptomatic. Even for asymptomatic patients, routine noninvasive tests such as US and coagulation tests can lead to the detection of TE and PE. The treatment strategy for prophylactic anticoagulation in patients with NS should be determined by carefully examining each case for the risk of developing TE and the expected benefits and adverse events of this treatment.

The correct answer is A

Comment: Our patient presented with hypocomplementemic acute nephritic syndrome including reduced GFR, fluid overload, hematuria, leukocyturia, and proteinuria. Although the serum creatinine improved transiently with hemodynamic support, she subsequently manifested significant but nonnephrotic range proteinuria, further decrease in GFR, and anasarca from fluid retention, reflecting an evolving glomerulonephritis temporally associated with active systemic infection. The kidney biopsy findings of diffuse proliferative glomerulonephritis with many infiltrating neutrophils and hump-shaped subepithelial immune complex deposits of IgG and C3 resemble the changes seen in acute poststreptococcal glomerulonephritis. The patient, however, did not have any preceding sore throat or impetigo. A rapid streptococcal antigen test was negative at presentation; therefore, no throat culture was obtained. An elevated streptolysin titer together with a normal anti-DNase B level is a discordant antibody response. This serology in the setting of lack of preceding or current pharyngitis or skin infection provides evidence against a bona fide streptococcal infection.

Our patient presented with signs and symptoms consistent with disseminated gonococcal infection including fever, vasculitic petechia, tenosynovitis, arthralgias, and arthritis. Gonococcal DNA was detected in urine by PCR.

The most common presentation of sexually transmitted N. gonorrhoeae infection is cervicitis in women and urethritis in men. A history of recent symptomatic genital infection is uncommon in patients with disseminated gonococcal infection. The latter condition generally presents with abrupt onset of malaise, tenosynovitis, skin lesions of hemorrhagic macules, pustules or vesicles, polyarthralgia, and asymmetric polyarthritis. The skin lesions generally involve distal extremities and are often transient, as in our case. The risk of dissemination probably depends on microbial virulence as well as host immune factors.

In disseminated gonococcal infection, the blood culture is positive in fewer than half of cases and the skin culture is positive in 10% to 15% of cases. This is due to the fastidious nature of N. gonorrhoeae, as its viability is dependent on proper transport in a humid and carbon dioxide–rich atmosphere, as well as the proper use of chocolate blood agar for culture. By contrast, N. gonorrhoeae can be isolated from a mucosal site in about 80% of cases, as occurred in our patient.

Deficiencies in the complement system have been associated with disseminated disease. ^, Our patient had low C3, C4, C5, and C8 levels during the acute illness, but they normalized within 5 weeks, providing evidence against congenital complement deficiency and supporting active complement consumption associated with acute nephritis.

Most patients with poststreptococcal glomerulonephritis show only low serum C3, reflecting activation of the alternative complement pathway, whereas only a minority of patients also have low C4. Our patient had decreases in both C3 and C4. The C4 value returned to normal within 10 days, whereas the C3 value normalized later at 5 weeks, suggesting possible involvement of both the classical and alternative pathways of complement. In a recent study of acute infection-related glomerulonephritis, one-third of patients showed both low C3 and C4 levels similar to the findings in our patient.

The correct answer is B

Comment: Our patient was simultaneously vaccinated against diphtheria, tetanus, pertussis, polio, Hemophilus influenza type B, and Pneumococcus . Eighteen days after vaccination, he presented with clinical and laboratory signs of nephritic syndrome. Immune complex–mediated GN was histologically confirmed with predominant IgA and C3 deposits in immune complexes and no humps on electron microscopy. Specific antigens in glomerular immune complexes in glomerular immune complexes proved that the boy had formed specific antibodies in protective titers against all the received vaccines.

Genetic testing revealed two heterozygous mutations on gene for C2 component. The first one was 28-base pair deletion of genomic DNA, which results in a premature termination of transcription. The second was a missense mutation that changes glutamate into aspartate at position 298. The same mutations were found also in his older sister, whereas the parents refused to be tested, establishing the diagnosis of hereditary C2 complement GN.

Genetically determined C2 deficiency is the most common of inherited complement deficiencies. Homozygous or complete C2 deficiency can present with a variety of symptoms, from asymptomatic state to systemic lupus erythematosus-like illness, polymyositis, glomerulonephritis, Hodgkin lymphoma, vasculitis, HSP, and recurrent pyogenic infections with encapsulated bacteria, such as Streptococcus pneumoniae , Haemophilus influenza type b, and Neisseria meningitides . Patients may also have a combination of multiple autoimmune phenomena, especially various cutaneous manifestations and pyogenic infections. On the other hand, in most individuals, partial C2 deficiency has no clinical importance. ^{, ,}

Development of GN after vaccination has been reported earlier but as a very rare event and never in a patient with C2 deficiency. Postvaccine GN can present with a variety of clinical and histological pictures. It has been described after hyperimmunization with pertussis vaccine as a diffuse vasculitis and death, after influenza H1N1 vaccination as a membranous GN, after hepatitis B vaccine as a vaccine-related SLE, and after pneumococcal vaccination as a crescentic GN from anti-glomerular basement membrane disease. Nephrotic syndrome has been described after measles vaccination and after antirabies vaccine.

There was a question about the patient’s further vaccination. Because approximately 50% of C2-deficient patients have an increased susceptibility to bloodborne infections caused by encapsulated organisms (e.g., pneumococcus, H. influenza , and meningococcus), vaccination represents a treatment of choice against sepsis, meningitis, arthritis, and osteomyelitis. ^– On the other hand, they are at increased risk of developing SLE, glomerulonephritis, inflammatory bowel disease, dermatomyositis, anaphylactoid purpura, and vasculitis, ^– with all these conditions being possibly triggered by environmental factors like infection or vaccination.

The correct answer is D

Comment: CFGN is uncommon and carries the worst prognosis among FGN. Without electron microscopic study, CFGN is likely to remain undiagnosed. Electron microscopy and special immunohistochemical stains play a significant role in the diagnosis of rare glomerular diseases, especially deposition diseases. CFGN usually does not respond to available therapy and mostly progresses to ERSD. There is no consensus on the optimal treatment of fibrillary glomerulonephritis because of the paucity of clinical data.

FGN presents most commonly in five patterns in light microscopic evaluation. These are membranoproliferative, mesangial proliferative, membranous, diffuse proliferative, and diffuse global sclerosis pattern. Although uncommon, CFGN may present as crescentic GN as in this case. Prognosis is directly related to the histological pattern of the disease. The mesangial proliferative and membranous patterns have a milder course, whereas membranoproliferative and diffuse proliferative have poorer prognosis. FGN is considered primarily idiopathic, but infections, malignancies (particularly lymphoproliferative diseases), and autoimmune disorders are seen in up to one-third of cases.

Crescentic GN as defined by the presence of crescents in >50% of glomeruli has rarely been reported in FGN and has the worst prognosis, with the majority leading to ESRD within the next few months. The IF findings in FGN usually show intense staining for IgG usually accompanied by C3, kappa, and lambda, and sometimes also staining for IgM, C1q, and/or IgA. In 5% of cases of FGN, the IF shows monotypic pattern staining with IgG with for kappa or lambda light chain with or without circulating monoclonal protein, as in our patient.

After initial reporting of crescentic GN in biopsy, intravenous methylprednisolone 500 mg was given for 3 days followed by oral prednisolone 1 mg/kg/day and oral cyclophosphamide with dose adjustment. After confirmation of diagnosis as crescentic CFGN, we continued the same immunosuppressive treatment. Because the patient remained oliguric and continued to be dialysis-dependent even after 2 months of treatment, immunosuppressive drugs were withdrawn and supportive treatment was continued as for ESRD.

CFGN responds poorly to the treatment and optimum treatment remains largely unknown. The scarcity of clinical data makes it more difficult to make a guideline for the treatment. Most of the series used steroids with or without either cyclophosphamide or rituximab with variable success. The University of North Carolina (UNC) series showed one in nine patients treated with rituximab had a response, whereas Javaugue et al. reported partial remission in five of seven patients treated with rituximab. Hogan et al. treated 12 FGN patients with rituximab of which 5 reached ESRD. Those who responded to the treatment were having lower serum creatinine levels at presentation (three having baseline serum creatinine <1.2 mg/dL). Although adequate data are not available regarding posttransplant recurrence of FGN, Nasr et al. reported recurrence of FGN in 33% of 14 cases who underwent renal transplantation. Recent data by Mallett et al., exploring ANZDATA registry, reported outcomes similar to the overall transplant population and recurrence in one of 13 transplant patients who received renal allografts because of FGN-related ESRD.

The correct answer is A

Comment: Our patient presented with RPGN. His clinical presentation and findings on kidney biopsy were compatible with the diagnosis of MCTD. After induction therapy with cyclophosphamide, the patient started on azathioprine (2 mg/kg/day). He showed a significant improvement with serum creatinine decreasing to 1.2 mg/dL. Three months after the initial episode, the patient was asymptomatic. A continuous renal function improvement was evident (serum creatinine, 0.97 mg/dL; proteinuria, 335 mg/24 hours, with a normal urinary sediment), as well as an improvement in the respiratory symptoms and in the pulmonary function tests.

One of the most common causes of RPGN is pauci-immune CrGN. ^, In the majority of cases, this condition has a positive serologic marker, the ANCAs, but in approximately 10% there are no circulating ANCAs, and this subgroup has been known as the ANCA-negative pauci-immune CrGN.

In majority of cases, pauci-immune CrGN is associated with systemic small-vessel vasculitis, such as granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis, but also with renal limited vasculitis in a small number of cases. CrGN and RPGN share a common serologic hallmark, defined by the presence of ANCAs, and for this reason it is known as ANCA-associated vasculitis.

However, there is a small group of pauciimmune CrGN without ANCA positivity, representing about 10% of cases. Most of these cases are idiopathic and not associated with connective tissue diseases (MCTD). MCTD is defined as a syndrome that shares features of systemic sclerosis, polymyositis, and SLE. A laboratory characteristic of this syndrome is a high titer of anti-RNP antibodies and positive ANAs with a high-titer speckled pattern.

The antibodies to double-stranded DNA (dsDNA) Sm, Ro, and La might also be present, although not dominant or persistent. Renal involvement in MCTD is less common than in typical SLE. It occurs either as a membranous nephropathy or, less frequently, as mesangioproliferative glomerulonephritis or renal vasculopathy of scleroderma. Pauci-immune CrGN is a rare form of renal involvement in MCTD and is sparsely reported. The authors aim to describe a case of a pauci-immune CrGN, with negative ANCA, which was associated with MCTD.

MCTD is a rare syndrome with overlap features of rheumatic disorders, such as SLE, systemic sclerosis, and polymyositis with the serologic marker of high titers of anti-RNP antibodies. The Alarcon-Segovia and Kahn diagnostic criteria are the most used algorithms for establishing the diagnosis of MCTD. Both classifications include serological (high titers of anti-RNP antibodies) and clinical (swollen hands, synovitis, myositis, and Raynaud phenomenon) criteria. This patient presented with a higher titer of anti-RNP antibodies, swollen hands, synovitis, and Raynaud phenomenon, fulfilling the diagnosis criteria for MCTD. Although almost any organ can be involved in MCTD, severe renal involvement is infrequent, and it is hypothesized that high titers of anti-RNP antibodies may protect against the development of diffuse proliferative glomerulonephritis. ^– The most common presentations of renal disease in MCTD are membranous nephropathy and mesangioproliferative glomerulonephritis. Interstitial nephropathy and renal vasculopathy are less frequent and could lead to malignant hypertension as observed in scleroderma renal crisis. ^–

Specific therapeutic protocols for patients with CrGN and MCTD are not available because of the rarity of this association. The treatment for MCTD should be individualized depending on organ involvement and severity. In this case report, the therapeutic approach was based on the most commonly accepted strategy for pauci-immune CrGN because of the magnitude of the renal involvement and included cyclophosphamide in combination with high-dose steroids, followed by azathioprine. Successful use of azathioprine as maintenance therapy was reported in one case of pauci-immune CrGN associated with MCTD. Azathioprine has also been used on MCTD with good results, especially when there is pulmonary, articular, or neurologic involvement. As expected, the renal outcomes would have been better if the treatment started in the early stages of the disease. A favorable clinical outcome was observed, with renal function recovery, normalization of urinary sediment, significant proteinuria reduction, and substantial improvement in pulmonary function tests. This multiorgan improvement after immunosuppression consolidated the hypothesis of a common immune origin in both renal and pulmonary dysfunctions.

The correct diagnosis is C

Comment: Our patient presented with a 2-month history of malaise and joint pain and was found to have acute kidney injury, hematuria, and proteinuria. Initial immunological tests revealed positive anti-neutrophil cytoplasmic antibodies with a peri-nuclear pattern (pANCA). An ELISA for anti-MPO antibodies was also positive, leading to a tentative diagnosis of ANCA-associated small vessel vasculitis with renal involvement. Steroid treatment was commenced and an urgent kidney biopsy was performed. This showed crescentic glomerulonephritis but also demonstrated concurrent tubulointerstitial nephritis with a dominance of IgG4-producing plasma cells. Serum IgG4 levels were also elevated. The patient was initially treated with intravenous cyclophosphamide and steroids and then switched to rituximab. When last seen, she was well after one dose of rituximab, with kidney function, inflammatory parameters, and serum IgG4 levels returning to normal levels. The concurrent presentation of ANCA-associated vasculitis and IgG4 renal disease is rare, with only a few cases reported in the literature.

Histological identification of IgG4-producing plasma cells with concurrent crescentic glomerulonephritis in the presence of positive ANCA ELISA testing led to the diagnosis in the case presented here. Serum IgG4 is a sensitive marker for IgG4-related disease but is currently considered to lack diagnostic specificity. It is also worth considering the fact that both IgG4 immunohistochemistry in renal biopsies and serum IgG4 measurements are not easily accessible worldwide. The latter is certainly not currently part of routine blood tests in patients with unexplained renal impairment. Of note, elevated serum IgG4 levels are somewhat nonspecific and also seen in chronic inflammatory conditions (e.g., inflammatory bowel disease) and malignancies (e.g., lymphoma). It is therefore possible that some cases of this unusual presentation are not diagnosed and reported. Clinicians should be aware of the association, and use of IgG4 immunohistochemistry in renal biopsies and measurement of serum IgG4 should be employed in unusual cases of ANCA-associated vasculitis, for example when there is tubulointerstitial nephritis or fibrotic extrarenal disease. In summary, a high degree of suspicion is required to validate this unusual combination of diagnoses.

IgG4-related disease is a recently recognized syndrome that affects multiple organs through inflammation, fibrosis, or both. The concept of IgG4-related disease was initially described in 2001 by Hamano et al., who reported raised serum IgG4 levels in a subgroup of patients diagnosed with autoimmune pancreatitis. Since then, IgG4-related disease has been observed in the pancreas and biliary tract, salivary glands, lung, aorta and retroperitoneum, endocrine glands, and the kidney. The most common form of kidney involvement in IgG4-related disease is tubulointerstitial nephritis with both acute and chronic disease manifestations. IgG4-related membranous nephropathy is also seen. Concurrent IgG4-related disease and ANCA-associated vasculitis is very uncommon, and a distinct new syndrome has been proposed. We report a case of concurrent IgG4-related tubulointerstitial nephritis and ANCA MPO crescentic glomerulonephritis. We describe our case and provide a brief review of the literature in terms of pathophysiology, diagnostic recommendations, and management options based on current evidence.

Concurrent subacute presentation of IgG4-related kidney disease with ANCA-associated MPO crescentic glomerulonephritis is uncommon.

The evidence for treatment of this unusual presentation is weak simply because of the rarity of this presentation, and larger studies seem unlikely at present. Anecdotal reports consider cyclophosphamide combined with steroid therapy as a potentially effective treatment option for concurrent IgG4-related kidney disease and ANCA-associated vasculitis. Rituximab use has been described in the treatment of IgG4-related kidney disease because of its ability to deplete B cells and have a better side effect profile compared to cyclophosphamide combined with steroid therapy. It is tempting to think of rituximab as a potentially ideal drug in treating the concurrent presentation of IgG4 disease and ANCA-associated vasculitis, but this assumption will require further exploration.

The correct answer is D

Comment: Our patient with a history of chronic hepatitis B and C infections presented with acute kidney injury and E. faecalis IE. An elevated proteinase-3 (PR3)-ANCA and pauci-immune GN on renal biopsy were discovered, corresponding to ANCA-mediated GN.

Of the five cases of ANCA GN in the setting of IE reported in the literature, all had markedly elevated levels of PR3-ANCA, with either a subacute or chronic course of infection. Patients were treated with a combination of steroids and cyclophosphamide (2/5), steroids and antibiotics alone (1/5), or with valvular replacement (2/5). Renal function was recovered in 4/5 patients. Infection is a major etiologic player in the formation of ANCA; however, the role of PR3-ANCA in IE remains unclear. The development of GN during infection is associated with significant morbidity and mortality, and diagnosis requires a high index of clinical suspicion. Although antibiotics hasten renal recovery in immune-complex-mediated GN in IE, ANCA-associated renal vasculitis often requires treatment with immunosuppression through induction with either cyclophosphamide or rituximab.

Kidney biopsy is essential in differentiating IE-related GN resulting from infection and immune complex deposition versus ANCA-associated vasculitis. A paucity of reports on the development of GN in IE-associated ANCA vasculitis exists, highlighting the rarity of our case and lack of clear therapeutic strategies in a patient with active infection requiring immunosuppression. In this case, the patient’s chronic hepatitis B and C coinfection presented a unique challenge.

Various patterns of kidney injury have been described during the course of IE, including renal cortical necrosis in the event of septic emboli or thrombotic microangiopathy, acute interstitial nephritis, and tubular necrosis as a consequence of drugs, bacterial toxins, or intravascular volume depletion. GN represents a unique form of renal injury that might also complicate the course of SLE, ^, typically through circulating immune complex deposition within glomeruli.

Subacute and chronic inflammatory states including infection may also induce the formation of ANCAs ^, that may subsequently result in blood vessel damage leading to manifestations of vasculitis. ^, Unlike immune complex–mediated GN in which renal recovery parallels the resolution of infection, pauci-immune GN requires immunosuppression, posing a therapeutic challenge in the setting of bacterial sepsis.

The correct answer is D

Comment: Our patient’s renal biopsy demonstrated C3c-dominant deposition on immunofluorescence. The complement alternative pathway was overactivated with decreased plasma C3 and elevated plasma Bb, C3a, C5a, and sMAC levels. Thus, a diagnosis of C3 glomerulonephritis (C3G) was suspected. The electron microscopy further excluded the subtype of dense deposit disease (DDD), confirming the diagnosis of C3GN with an MPGN pattern.

The alternative pathway activation in C3GN was driven by either inherited or acquired defects. Acquired causes included C3Nef, anti-CFH autoantibodies, anti-C3b autoantibodies, or anti-CFB antibodies. Genetic factors included CFH , complement factor I ( CFI ), membrane cofactor protein ( MCP ), complement factor B ( CFB ), and C3 as well as CFH-related protein 5 ( CFHR5 ) internal duplication, CFHR1-3 hybrid, CFHR1 duplication, and CFHR2-5 hybrid. Genetic testing in our patient showed variants of CFH, THBD , and MBL2 and a novel variant of C2 mutant genes.

CFH is one of the key inhibitors of the alternative pathway. The CFH Val62Ile variant (rs800292) and Tyr402His variant (rs1061170), which locate within regions that bind C3b, heparin, and C-reactive protein, have been shown to confer susceptibility to DDD patients. Meanwhile, the Tyr402His variant had significant association with an increased risk of developing age-related macular degeneration, another complement-associated disease. Furthermore, the two variants have been reported in the postpartum atypical hemolytic uremic syndrome, which was also the result of inappropriate activation of the complement alternative pathway. Thus, we inferred that these two variants might result in a mutant CFH protein with reduced regulatory capacity to prevent complement overactivation. Thrombomodulin is an endothelial anticoagulant glycoprotein that can regulate the complement alternative pathway by enhancing factor I–mediated C3b inactivation after binding C3b and CFH. Based on a study in a large cohort demonstrating that the THBD Ala473Val variant could increase the probability of developing C3G, it was speculated that the mutant protein might reduce the binding capacity of C3b and CFH to inactive C3b, although the functional studies on THBD Ala473Val were lacking. In general, the common variants CFH Val62Ile, CFH Tyr402His, and THBD Ala473Val found in our patient might cause the dysregulation of the complement alternative pathway and increase susceptibility to C3GN.

Another CFH variant Glu936Asp (rs1065489) was previously demonstrated to be associated with host susceptibility to meningococcal disease in genome-wide association studies. CFH has been shown to be exploited by Neisseria meningitidis to escape host immune control. Binding of N. meningitidis to CFH would protect the bacterium from complement-mediated damage. Thus, we thought that this variant would increase the binding ability between CFH and N. meningitidis and then facilitate the escape of the bacteria from host immune responses. The MBL2 Gly54Asp variant (rs1800450) was found to decrease MBL2 protein stability and expression, which was supported by the lower plasma MBL level (342.89 ng/mL) in our patient that could be defined as partial MBL deficiency (50–1000 ng/mL). MBL is a soluble pattern recognition receptor that initiates the activation of the complement MBL pathway after binding to carbohydrate, and its deficiency was reported to increase the risk of various infections such as sepsis. Therefore, the common variants CFH Glu936Asp and MBL2 Gly54Asp might help explain our patient’s history of meningitis.

The renal prognosis of C3G is poor, and previous reports showed that approximately 50% of DDD patients progressed to ESRD in 10 years. C3GN had a better prognosis than DDD, although the latest study by Bomback et al. showed that there was no significant difference in renal prognosis between DDD and C3GN. Unfortunately, there were still no high-level randomized trials for the treatment of C3GN, and the therapy for the disease was mainly based on low-quality evidence consisting of case series, case reports, retrospective cohort studies, and expert opinion. General treatments include antihypertensive therapy and lipid-lowering therapy. Specific interventions include plasma infusion or exchange, immunosuppressive therapy, and eculizumab. Because our patient had genetic defects of circulating proteins without acquired autoantibodies, he received fresh frozen plasma infusion, and immunosuppressants were not initiated. He responded well with an elevated plasma C3 level, well-controlled proteinuria, and stable renal function. Moreover, anti-complement therapy (eculizumab) has been a novel and pathogenesis-based treatment method for the disease in recent years. C3G patients with deteriorating renal function, severe nephrotic syndrome, elevated sMAC levels, and active renal biopsy changes, might be more likely to benefit from this therapy based on previous studies.

The correct answer is E

Comment: Postinfectious GN is a form of GN that develops after an infection; it is especially common in children and in the elderly. ^– Often the infection is minor (e.g., pharyngitis) and has usually resolved by the time clinical evidence of an ongoing GN is manifested. The lag time between the start of the infection and the clinical manifestations can vary from a few days to weeks, and disease severity ranges from asymptomatic hematuria to an acute nephritic syndrome, renal failure, and fluid overload. On renal biopsy, postinfectious GN is characterized by proliferative GN on light microscopy, mesangial and/or capillary wall bright C3 staining with or without immunoglobulin on immunofluorescence microscopy, and subepithelial hump-like deposits on electron microscopy. ^, In some cases, there is no clinical or serologic evidence of a preceding infection, and the diagnosis of postinfectious GN is based solely on these renal biopsy findings. It should be also recognized that over the past 30 years, an important shift in epidemiology, bacteriology, and outcome of GN related to infection has occurred. A substantial number of cases now occur in adults, particularly the elderly, alcoholic persons, and patients who are immunocompromised. Because the presence of an infection is often ongoing at the time of renal biopsy, the term infection-related GN has been suggested as more appropriately describing this condition. In contrast to children, adults are more likely to have infection-related GN secondary to nonstreptococcal infections, particularly staphylococcal infection, and the overall prognosis in terms of renal and patient survival is poor.

The pathogenesis of acute postinfectious GN has been the subject of recent reviews. ^, It is important to recognize that no animal model can reproduce the classic findings of abundant neutrophil infiltration and subepithelial humps characteristic of human postinfectious GN. Nevertheless, it has been proposed that the initial phase of the process is characterized by deposition of bacterial antigens (e.g., streptococcal) in the glomeruli (planted). This phase is followed by production of antibodies that interact in situ with the planted antigens. ^, Antigens that enter the circulation after the antibody response is fully under way form immune complexes in circulation. Most of these immune complexes are cleared from the circulation by the liver and spleen, but those that escape the phagocytic system may deposit in the glomeruli and thus induce immune complex–mediated GN. Reduction in serum C3 complement levels is a constant feature during the initial phase of postinfectious GN. ^, The hypocomplementemia is due to activation of the alternative pathway (AP) of complement, whereas C1q, C2, and C4 complement levels (classic pathway) are usually normal. In some patients with poststreptococcal GN, low C3 levels have been associated with the transient expression of circulating autoantibodies against the C3 convertase complex (i.e., C3 nephritic factors). These antibodies result in stabilization of the enzyme, increase in convertase activity, and enhanced C3 cleavage by the AP of complement.

In most cases, GN resolves in a matter of weeks without specific treatment. Similarly, hypocomplementemia usually resolves within 8 weeks. However, in a minority of cases, urinary and complement abnormalities may persist or take longer to resolve, with some patients even progressing to ESRD. ^{, , , –} These cases have been labeled as “atypical,” “persistent,” or “chronic” postinfectious GN. Until recently, the cause of these atypical cases was unknown. A recent study postulates that cases of atypical postinfectious GN are due to a defect in the regulating mechanisms of the AP of complement that prevent downregulation of complement activation after resolution of the infection. As a consequence, there is excessive deposition of complement proteins and breakdown products in the glomeruli, resulting in persistence of the inflammatory response.

That study included 11 patients (5 women and 6 men; mean age, 35.1 years [range, 2–71 years]) who fulfilled the diagnostic criteria of atypical postinfectious GN, defined as (1) persistent hematuria and proteinuria, with or without history of preceding infection; (2) renal biopsy showing features of postinfectious GN; and (3) abnormalities of the complement AP. Five of the 11 patients had a history of upper respiratory tract infection or impetigo. In the remaining six, no antecedent illness was documented. Serum creatinine at presentation ranged from 0.5 to 3.1 mg/dL (mean, 1.4 mg/dL), with mean proteinuria of 5139 mg/24 hours (range, 500–15,760 mg/24 hours). C3 levels were low in seven patients, and C4 levels were normal in all patients. All biopsies showed proliferative GN; the most common pattern was diffuse endocapillary proliferative GN, followed by mesangial proliferative and membranoproliferative GN on light microscopy. On immunofluorescence microscopy, bright (3+) mesangial and capillary wall C3 staining was seen in all but one case, which showed mild (1+) C3 staining. Two cases also showed mild mesangial and capillary wall staining for IgG (1–2+). Electron microscopy showed the hallmark of postinfectious GN in all cases: hump-like subepithelial deposits, which were numerous in six patients. Ten of 11 patients also had mesangial and subendothelial deposits. Functional and genetic studies of the AP identified autoantibodies or mutations in complement genes in 10 of 11 patients. Seven patients were positive for C3 nephritic factors, which were associated with other functional abnormalities of the AP in six patients. Four patients had mutations of complement genes, including three patients with mutations in CFH and one patient with a mutation in CFHR5.

The study shows that patients with atypical postinfectious GN have an underlying defect in the complement AP. Results of the study are supported by recent case reports of patients initially diagnosed as having a postinfectious GN who subsequently were found to have a proliferative form of GN called C3GN. ^, Thus, it can be postulated that under normal circumstances, the activation of the AP by an infection is quickly brought under control once the infection abates. However, in patients with a defect in AP regulation, there is continual AP activation with deposition of complement proteins and their breakdown products in the glomeruli, even after resolution of the infection, leading to the development of atypical proliferative GN. If the defect is mild, AP control eventually occurs with resolution of the GN. If the defect in AP regulation is more severe, hematuria and proteinuria persist, often exacerbated by recurrent bouts of infection. Recent studies have shown that dysregulation of the AP also results in C3GN. C3GN is characterized by glomerular C3 deposition and the presence of numerous deposits in the mesangium and capillary walls, including subepithelial deposits. ^– Thus, there is considerable overlap in the biopsy findings of patients with atypical postinfectious GN and those with C3GN. This overlap is not surprising because both types are due to abnormalities of complement AP. Indeed, review of previous reports on prolonged hypocomplementemia in patients with poststreptococcal GN show kidney biopsy findings compatible with the diagnosis of C3GN. It is also likely that many cases of familial poststreptococcal GN represent undiagnosed C3 glomerulopathy. Therefore, atypical postinfectious GN should be considered a C3 glomerulopathy, and testing for abnormalities in the AP of complement in all patients with atypical postinfectious GN is recommended (option E).

The clinical presentation, laboratory evaluation, and renal biopsy findings of this case are not compatible with the diagnosis of systemic lupus erythematosus (option A) or cryoglobulinemic GN (option B). In lupus nephritis, immunofluorescence microscopy usually shows a “full house,” meaning that all or almost all immunoreactants (IgG, IgA, IgM, κ and λ light chains, C1q, C3) are present. This is unusual in other forms of GN. On electron microscopy evaluation, in addition to immune complex deposits (discrete electron dense immune-type deposits), a very common ultrastructural finding is the presence of tubuloreticular inclusions. On the other hand, in cryoglobulinemic GN, immunofluorescence microscopy typically shows diffuse, pseudo-linear peripheral capillary wall and mesangial staining for IgM, IgG, and C3, with a relatively stronger staining for IgM and κ (compared with λ) light chain, which reflects the typical clonal restriction of type II cryoglobulins. On electron microscopy, cryoglobulin deposits often display an organized substructure: short, curved, thick-walled tubular structures with a diameter of about 30 nm that appear annular on cross-sections.

Anti-DNase antibody testing (option C) detects antigens produced by group A streptococcus and is elevated in most patients with rheumatic fever and poststreptococcal GN. This test is often done concurrently with the antistreptolysin O titer, and subsequent testing is usually performed to detect differences in the acute and convalescent blood samples. Anti-DNase testing was not performed at presentation and will probably have negative results at this time. The first component of complement (C1) is composed of three subunits, designated as C1q, C1r, and C1s. C1q recognizes and binds to immunoglobulin complexed to antigen and initiates activation of the classic pathway of complement. Serum C1q levels (option D) are usually normal in conditions associated with abnormalities of the AP of complement (e.g., C3GN), although they may be mildly decreased early in the course of postinfectious GN.

The correct answer is E

Comment: Idiopathic MN is a common immune-mediated glomerular disease and remains the leading cause of nephrotic syndrome in White adults. Although in most patients the disease progresses relatively slowly, approximately 40% of patients eventually develop ESRD. Because of its frequency, it remains the second or third most common cause of primary glomerulopathy leading to ESRD. Patients with MN who remain nephrotic are at an increased risk for thromboembolic and cardiovascular ^– events. Available immunosuppressive therapies include the use of corticosteroids combined with cytotoxic agents, as well as calcineurin inhibitors. These therapies are at least partially successful in reducing proteinuria, but their use is controversial, is associated with significant adverse effects, and carries a high rate of relapse. To date, the best proven long-term therapy for patients with MN consists of the combined use of corticosteroids and cyclophosphamide—the Ponticelli protocol—and it was used in this patient. Proteinuria decreased substantially, but it never decreased to <4 g/24 hours and more recently has increased to 5.5 g/24 hours. The question to answer is: Does proteinuria in this patient reflect active immunologic disease or is it a consequence of renal damage? This question is clinically relevant and introduces the concept that immunologic remission should be added to clinical remission (based on proteinuria) and that both be used in judging treatment (conservative versus immunosuppressive) in MN.

Some qualitative aspects of proteinuria, such as urinary excretion of α1-microglobulin, β2-microglobulin, IgG, and IgM (option A), have been reported as strong predictors for renal disease progression. ^– However, little is known regarding factors that may predict response to therapy, and the only studies that have evaluated the use of urinary markers for this purpose concluded that neither absolute levels of urinary IgG, β2-microglobulin, or α1-microglobulin at baseline or 12 months nor the percentage of reduction between baseline and 12 months clearly predicted the occurrence of a remission, a relapse to nephrotic range proteinuria, or longer-term outcomes. ^, It is unknown whether the use of these markers could predict active immunologic disease.

IgG4-related disease represents a recently recognized group of multiorgan diseases characterized by hypergammaglobulinemia with elevated serum total IgG and/or IgG4 levels, a high level of serum IgG4, and dense infiltration of IgG4-positive cells into multiple organs. ^, The term IgG4-related sclerosing disease is also used for this entity because it results in a sclerosing lesion of multiple organs, including the kidney, with formation of pseudotumors. ^, Patients with renal involvement are often elderly men presenting with progressive renal failure. There are several other characteristics. Patients often have elevated serum total IgG and/or IgG4 levels or hypergammaglobulinemia. Kidney biopsy usually shows a tubulointerstitial nephritis (TIN) with moderate to marked increase in IgG4-positive plasma cells, with or without tubular basement membrane deposits. The term IgG4-related TIN has been proposed to describe this entity. A paucity of cases of IgG4-related TIN with MN has also been described (option B). ^, The absence of systemic organ involvement and TIN in this case make the diagnosis of an IgG4-related MN unlikely.

Renal ultrasonography with Doppler examination of renal veins (option D) is indicated to rule out renal vein thrombosis. Acute renal vein thrombosis is usually characterized by a recent episode of acute flank pain, macroscopic hematuria, flank tenderness at percussion, worsening proteinuria, and deterioration of renal function. Hypoalbuminemia, particularly a serum albumin concentration <2.8 g/dL, is the most significant independent predictor of venous thrombotic risk in patients with MN. In view of this, it is unlikely that our patient has developed acute renal vein thrombosis, although asymptomatic chronic renal vein thrombosis cannot be ruled out. However, there is no convincing evidence that chronic renal vein thrombosis is associated with worsening renal function or proteinuria.

Anti-PLA2R antibodies (option C) are present in 70% to 82% of patients with idiopathic MN but are not present in the serum of healthy controls or patients with other glomerular and autoimmune diseases. ^, Levels of anti-PLA2R correlate strongly correlated with disease activity and response to therapy: Disappearance of the antibody is associated with remission of proteinuria and reappearance of the antibody heralds a relapse of nephrotic syndrome. ^, Taken together, these observations suggest that detection and quantification of circulating anti-PLA2R levels may provide a tool for monitoring disease activity and treatment efficacy in patients with MN. On the other hand, low titers of anti-PLA2R have been detected in patients in remission, whereas the presence of high titers of anti-PLA2R antibodies did not preclude the development of spontaneous remission. Similarly, discrepancies between circulating anti-PLA2R antibodies and detectable PLA2R in glomerular deposits have been reported in a study of 42 consecutive patients with primary MN. ^– In 21 patients, anti-PLA2R antibodies were present in circulation and PLA2R was seen in glomerular deposits. However, three patients with high levels of circulating anti-PLA2R antibodies did not have detectable PLA2R in glomerular deposits, suggesting that antibodies were not nephritogenic or that epitopes were poorly accessible at the time of kidney biopsy; among the 18 patients with no detectable circulating anti-PLA2R antibodies, 10 had positive PLA2R glomerular staining. Debiec and Ronco suggest that these apparently discordant findings might be due to the rapid clearance of antibodies from the circulation and deposition in glomeruli or to patients with persistent proteinuria resulting from glomerular ultrastructural damage but immunologically inactive disease. Therefore, the persistence of proteinuria in some cases may be the consequence of an altered architecture of the filtration barrier because of long-standing disease and remodeling process in the glomerular basement membrane.

In the present case, serial anti-PLA2R testing was not available, and although a current negative test result would probably reflect immunologic remission, a single positive anti-PLA2R test result would not necessarily correlate with immunologic activity. As such, we believe the only way to accurately establish disease activity in this patient is to perform renal biopsy (option E).