Development of Urinary Diagnostic Biomarker for IgA Nephropathy by Lectin Microarray.

INTRODUCTION: The pathogenic roles of aberrantly glycosylated IgA1 have been reported. However, it is unexplored whether the profiling of urinary glycans contributes to the diagnosis of IgAN. METHODS: We conducted a retrospective study enrolling 493 patients who underwent renal biopsy at Okayama University Hospital between December 2010 and September 2017. We performed lectin microarray in urine samples and investigated whether c-statistics of the reference standard diagnosis model employing hematuria, proteinuria, and serum IgA were improved by adding the urinary glycan intensity. RESULTS: Among 45 lectins, 3 lectins showed a significant improvement of the models: Amaranthus caudatus lectin (ACA) with the difference of c-statistics 0.038 (95% CI: 0.019-0.058, p < 0.001), Agaricus bisporus lectin (ABA) 0.035 (95% CI: 0.015-0.055, p < 0.001), and Maackia amurensis lectin (MAH) 0.035 (95% CI: 0.015-0.054, p < 0.001). In 3 lectins, each signal plus reference standard showed good reclassification (category-free NRI and relative IDI) and good model fitting associated with the improvement of AIC and BIC. Stratified by eGFR, the discriminatory ability of ACA plus reference standard was maintained, suggesting the robust renal function-independent diagnostic performance of ACA. By decision curve analysis, there was a 3.45% net benefit by adding urinary glycan intensity of ACA to the reference standard at the predefined threshold probability of 40%. CONCLUSIONS: The reduction of Gal(ß1-3)GalNAc (T-antigen), Sia(α2-3)Gal(ß1-3)GalNAc (Sialyl T), and Sia(α2-3)Gal(ß1-3)Sia(α2-6)GalNAc (disialyl-T) was suggested by binding specificities of 3 lectins. C1GALT1 and COSMC were responsible for the biosynthesis of these glycans, and they were known to be downregulated in IgAN. The urinary glycan analysis by ACA is a useful and robust noninvasive strategy for the diagnosis of IgAN.

Management of corticosteroid-dependent eosinophilic interstitial nephritis: A case report.

INTRODUCTION: Drug-induced acute interstitial nephritis (DI-AIN) is an important cause of acute kidney injury. In renal biopsy specimens, tubulitis with eosinophilic infiltration is suggestive of DI-AIN. Although corticosteroid therapy and discontinuation of the offending drug can improve renal dysfunction in most cases of DI-AIN, some patients experience AIN recurrence, leading to corticosteroid dependency. Corticosteroid-dependent eosinophilic interstitial nephritis presents a difficult dilemma in diagnosis and information regarding optimum management is limited. PATIENT CONCERNS: A 25-year-old man, who received treatment with carbamazepine, zonisamide, valproate, and lacosamide for temporal lobe epilepsy, showed an increase in serum creatinine level from 0.98 to 1.29 mg/dL over a period of 6 months. Although he exhibited no symptoms, his serum creatinine level continued to increase to 1.74 mg/dL. DIAGNOSIS: Renal biopsy revealed tubulitis and interstitial inflammatory infiltrates with eosinophils. Immunological and ophthalmological examinations showed no abnormal findings, and thus, his renal dysfunction was presumed to be caused by DI-AIN. Although oral prednisolone (PSL) administration (40 mg/d) and discontinuation of zonisamide immediately improved his renal function, AIN recurred 10 months later. The increase in PSL dose along with discontinuation of valproate and lacosamide improved renal function. However, 10 months later, recurrent AIN with eosinophilic infiltration was confirmed by further biopsy. The patient was therefore diagnosed with corticosteroid-dependent eosinophilic interstitial nephritis. INTERVENTIONS: To prevent life-threatening epilepsy, carbamazepine could not be discontinued; hence, he was treated with an increased dose of PSL (60 mg/d) and 1500 mg/d of mycophenolate mofetil (MMF). OUTCOMES: MMF was well tolerated and PSL was successfully tapered to 5 mg/d; renal function stabilized over a 20-month period. LESSONS: The presence of underdetermined autoimmune processes and difficulties in discontinuing the putative offending drug discontinuation are contributing factors to corticosteroid dependency in patients with eosinophilic interstitial nephritis. MMF may be beneficial in the management of corticosteroid-dependent eosinophilic interstitial nephritis by reducing the adverse effects related to high-dose and long-term corticosteroid use.

Novel urinary glycan profiling by lectin array serves as the biomarkers for predicting renal prognosis in patients with IgA nephropathy.

In IgA nephropathy (IgAN), IgA1 molecules are characterized by galactose deficiency in O-glycans. Here, we investigated the association between urinary glycosylation profile measured by 45 lectins at baseline and renal prognosis in 142 patients with IgAN. The primary outcome was estimated glomerular filtration rate (eGFR) decline (> 4 mL/min/1.73 m2/year), or eGFR ≥ 30% decline from baseline, or initiation of renal replacement therapies within 3 years. During follow-up (3.4 years, median), 26 patients reached the renal outcome (Group P), while 116 patients were with good renal outcome (Group G). Multivariate logistic regression analyses revealed that lectin binding signals of Erythrina cristagalli lectin (ECA) (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.11-7.28) and Narcissus pseudonarcissus lectin (NPA) (OR 2.32, 95% CI 1.11-4.85) adjusted by age, sex, eGFR, and urinary protein were significantly associated with the outcome, and they recognize Gal(ß1-4)GlcNAc and high-mannose including Man(α1-6)Man, respectively. The addition of two lectin-binding glycan signals to the interstitial fibrosis/tubular atrophy score further improved the model fitness (Akaike's information criterion) and incremental predictive abilities (c-index, net reclassification improvement, and integrated discrimination improvement). Urinary N-glycan profiling by lectin array is useful in the prediction of IgAN prognosis, since ECA and NPA recognize the intermediate glycans during N-glycosylation of various glycoproteins.

A Patient with Type 3 Autoimmune Polyglandular Syndrome who Developed Systemic Lupus Erythematosus 8 years after the Diagnosis of Autoimmune Hepatitis.

Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored.

HIV-associated Immune Complex Kidney Disease with C3-dominant Deposition Induced by HIV Infection after Treatment of IgA Nephropathy.

A 57-year-old man was diagnosed with IgA nephropathy. Hematuria and proteinuria were improved by tonsillectomy plus methylprednisolone pulse therapy. Lymphadenopathy, hypocomplementemia and pancytopenia were observed six years later, and urinalysis abnormalities recurred. A biopsy revealed mesangial proliferative glomerulonephritis with C3-dominant deposition. Human immunodeficiency virus (HIV) antibody demonstrated positive conversion. He was diagnosed with HIV-associated immune complex kidney disease (HIVICK). The hematuria, proteinuria and hypocomplementemia were improved by reducing the HIV viral load through antiretroviral therapy. When C3-dominant deposition is observed on a renal biopsy, HIVICK must be differentiated.

A case of fatal osteolytic hypercalcemia complicated with IgG4-related ophthalmic disease leading to renal failure.

A 40-year-old male was hospitalized with renal impairment and severe hypercalcemia. His concentration of serum IgG4 was high, but serum whole PTH, 1-25(OH)2 vitamin D3 and PTHrP were not elevated. Computed tomography showed swelling of the bilateral lacrimal glands and systemic lymphadenopathy. The histological findings of lacrimal gland biopsy fulfilled the diagnostic criteria of IgG4-related ophthalmic disease (IgG4ROD). Bone scintigraphy showed increased ectopic uptake in the stomach, heart, lungs, and kidneys. He died on day 16 of admission, although the therapies for hypercalcemia were continued. Autopsy results showed an increase of osteoclasts in the bone marrow and metastatic calcification in multiple organs, and excluded from the differential diagnosis other disorders which present lymph-node swelling and hypercalcemia such as cancer, lymphoma, Castleman's disease, and sarcoidosis. He was given a diagnosis of IgG4ROD with osteolytic hypercalcemia.

Diffuse Alveolar Hemorrhage in IgA Vasculitis with an Atypical Presentation.

IgA vasculitis (IgAV) commonly occurs in young children, who present with a tetrad of purpura, abdominal pain, arthralgia and nephritis. Diffuse alveolar hemorrhage (DAH) is a rare complication of IgAV. We herein report an adult case of IgAV with a presentation of DAH and nephritis (pulmonary renal syndrome, PRS), but without other typical manifestations, such as purpura, abdominal pain and arthralgia. A 33-year-old man presented with hemoptysis and a low-grade fever and was diagnosed to have IgAV based on the results of a renal biopsy. Treatment with corticosteroids, cyclophosphamide, and plasmapheresis was effective. IgAV should therefore be considered in the differential diagnosis of adult PRS.

Acoustic radiation force impulse elastography of the kidneys: is shear wave velocity affected by tissue fibrosis or renal blood flow?

OBJECTIVES: The aim of this study was to identify the main influencing factor of the shear wave velocity (SWV) of the kidneys measured by acoustic radiation force impulse elastography. METHODS: The SWV was measured in the kidneys of 14 healthy volunteers and 319 patients with chronic kidney disease. The estimated glomerular filtration rate was calculated by the serum creatinine concentration and age. As an indicator of arteriosclerosis of large vessels, the brachial-ankle pulse wave velocity was measured in 183 patients. RESULTS: Compared to the degree of interobserver and intraobserver deviation, a large variance of SWV values was observed in the kidneys of the patients with chronic kidney disease. Shear wave velocity values in the right and left kidneys of each patient correlated well, with high correlation coefficients (r = 0.580-0.732). The SWV decreased concurrently with a decline in the estimated glomerular filtration rate. A low SWV was obtained in patients with a high brachial-ankle pulse wave velocity. Despite progression of renal fibrosis in the advanced stages of chronic kidney disease, these results were in contrast to findings for chronic liver disease, in which progression of hepatic fibrosis results in an increase in the SWV. Considering that a high brachial-ankle pulse wave velocity represents the progression of arteriosclerosis in the large vessels, the reduction of elasticity succeeding diminution of blood flow was suspected to be the main influencing factor of the SWV in the kidneys. CONCLUSIONS: This study indicates that diminution of blood flow may affect SWV values in the kidneys more than the progression of tissue fibrosis. Future studies for reducing data variance are needed for effective use of acoustic radiation force impulse elastography in patients with chronic kidney disease.