Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats.

Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent K+ channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/day. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that mitochondrial Ca2+ uniporter levels in glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through mitochondrial Ca2+ uniporter modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.NEW & NOTEWORTHY Our findings suggest that the mitochondrial Ca2+ uniporter may be an upstream regulator of manganese superoxide dismutase and indicate a biochemical basis for the interaction between the ATP-sensitive K+ channel and Ca2+ signaling. We believe that our study makes a significant contribution to the literature because our results indicate that the ATP-sensitive K+ channel may be a potential therapeutic target for podocyte injury and nephrotic syndrome.

Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3S433-P) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3S433-P dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3S433-P phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3S433-P levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3S433-P, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K+ induced calcineurin-dependent dephosphorylation of KLHL3S433-P These findings demonstrate that KLHL3S433-P is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.

Upregulation of renal Na-K-2Cl cotransporter 2 in obese diabetes mellitus via a vasopressin receptor 2-dependent pathway.

Na-K-2Cl cotransporter 2 (NKCC2) in thick ascending limb (TAL) in the kidney plays a central role in tubuloglomerular feedback (TGF) system by sensing NaCl delivery to the distal tubules. Although accumulating data indicate that dysregulated TGF contributes to the progression of diabetic complications, the regulation of NKCC2 in diabetes mellitus (DM) remains unclear. We here show that NKCC2 is overactivated via a vasopressin receptor 2 (V2R)-dependent mechanism in db/db mice, a mouse model of obese DM. Compared with db/+ mice, we found that both aquaporin 2 and NKCC2 levels were significantly increased in the kidney in db/db mice. Immunohistochemical analysis of V2R and NKCC2 in the kidney demonstrated that V2R is present in the TAL, as well as in the collecting duct. Moreover, the administration of tolvaptan, a selective V2R antagonist, sharply decreased aquaporin 2 and NKCC2 in db/db mice, confirming the causal role of V2R signaling in NKCC2 induction in this model. Although tolvaptan reduced aquaporin 2 abundance also in db/+ mice, its effect on NKCC2 was modest compared with db/db mice. In total kidney lysates, uromodulin expression was not altered between db/+ and db/db mice, suggesting that V2R signaling alters NKCC2 without altering uromodulin levels. These data implicate the dysregulation of NKCC2 in the pathophysiology of type 2 DM, and underscore the complex nature of fluid volume disorders in diabetic kidney disease.

Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice.

BACKGROUND: Mechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption via NaCl cotransporter (NCC). METHODS: We used the db/db diabetes mouse model to explore KLHL3's role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells. RESULTS: We observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3S433-P). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3S433-P and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3S433-P levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC's causal role in KLHL3S433-P and NCC induction. CONCLUSIONS: Dysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.

Uric Acid in the Follow-Up Determines 30% Decline in Estimated GFR Over 2 Years: a Propensity Score Analysis.

BACKGROUND/AIMS: Higher level of serum uric acid (SUA) predicts early entry to dialysis in chronic kidney disease (CKD) patients. However, a short-term effect of SUA remains to be elucidated using a novel surrogate endpoint. METHODS: Japanese CKD stage 3 to 4 patients were retrospectively examined (n= 701). The follow-up level of SUA was estimated as time-averaged uric acid (TA-UA). A propensity score for 6.0, 6.5 or 7.0 mg/dL of TA-UA was respectively calculated using baseline 23 covariates. The time-to-event analysis was performed for 30% decline in estimated GFR over 2 years. RESULTS: Incidence rates over 2 years were 90 of 440 in men and 36 of 261 in women (p = 0.03). Despite the negative result of baseline SUA, stratified Cox regression on the quintiles of the estimated propensity score showed that higher TA-UA of the three thresholds were all significant (crude HR 2.10 to 2.44) even after adjusting for the confounders. Kaplan-Meier analysis after propensity score matching likewise showed worse survival in the patients with the higher TA-UA (HR 3.11 to 4.26). CONCLUSION: Higher SUA increases likelihood of reaching a surrogate endpoint over 2 years. Early intervention for SUA less than 6.0 mg/dL is recommended for slowing CKD progression.

Time to target uric acid to retard CKD progression.

Uric acid (UA) remains a possible risk factor of chronic kidney disease (CKD) but its potential role should be elucidated given a fact that multidisciplinary treatments assure a sole strategy to inhibit the progression to end-stage renal disease (ESRD). In clinical setting, most observational studies showed that elevation of serum uric acid (SUA) independently predicts the incidence and the development of CKD. The meta-analysis showed that SUA-lowering therapy with allopurinol may retard the progression of CKD but did not reach conclusive results due to small-sized studies. Larger scale, randomized placebo-controlled trials to assess SUA-lowering therapy are needed. Our recent analysis by propensity score methods has shown that the threshold of SUA should be less than 6.5 mg/dL to abrogate ESRD. In animal models an increase in SUA by the administration of oxonic acid, uricase inhibitor, or nephrectomy can induce glomerular hypertension, arteriolosclerosis including afferent arteriolopathy and tubulointerstitial fibrosis. The ever-growing discoveries of urate transporters prompt us to learn UA metabolism in the kidney and intestine. One example is that the intestinal ABCG2 may play a compensatory role at face of decreased renal clearance of UA in nephrectomized rats, the trigger of which is not a uremic toxin but SUA itself. This review will summarize the recent knowledge on the relationship between SUA and the kidney and try to draw a conclusion when and how to treat asymptomatic hyperuricemia accompanied by CKD. Finally we will address a future perspective on UA study including a Mendelian randomization approach.

Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome.

BACKGROUND: Adult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist. METHODS: We performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI. RESULTS: Thirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-ß-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group. CONCLUSIONS: Proximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS patients.

Pathological implications of linear immunoglobulin G staining on the glomerular capillary walls in a case of infection-related glomerulonephritis.

We report a 32-year-old man with nephrotic syndrome and preceding symptom of infection. He had renal insufficiency, hypocomplementemia, and elevated titer of anti-streptolysin O. Renal biopsy showed mesangial hypercellularity and focal segmental endocapillary hypercellularity with double contour of the glomerular basement membrane (GBM). Immunofluorescence study showed granular C3 staining on the mesangial areas and glomerular capillary walls (GCWs) and linear immunoglobulin G (IgG) staining on GCWs. Electron microscopy revealed sporadic subepithelial humps, discontinuous small and thin deposits in the endothelial side of the GBM and mesangial deposits. He was diagnosed with infection-related glomerulonephritis (IRGN) with the striking finding of linear IgG staining, which is unusual in IRGN. The patient did not have diabetes mellitus or anti-GBM disease. The patient's serum seemed not to contain IgG, which can bind to GCW. He showed normalization of complement within two months after relief from infection symptoms and a trend toward improvement in proteinuria, hematuria and renal function over 14 months. We discuss the possible mechanisms of linear IgG staining in our case based on clinical and experimental studies on IRGN with cationic bacterial protein as antigen.

Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH.

BACKGROUND: Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model. METHODS: Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9). The rats were sacrificed to obtain kidney tissues 3 days after treatment. In addition to electrolyte metabolism, changes in expressions of the urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2 and NPT1 (SLC17A1) were examined by western blotting and immunohistochemistry. RESULTS: In the terlipressin-treated rats, serum uric acid (UA) significantly decreased and the excretion of urinary UA significantly increased, resulting in marked increase in fractional excretion of UA. Although no change in the expression of URAT1, GLUT9 expression significantly decreased whereas the expressions of ABCG2 and NPT1 significantly increased in the terlipressin group. The results of immunohistochemistry corroborated with those of the western blotting. Aquaporin 2 expression did not change in the medulla, suggesting the independence of V2 receptor stimulation. CONCLUSION: Stimulation of V1a receptor induces the downregulation of GLUT9, reabsorption urate transporter, together with the upregulation of ABCG2 and NPT1, secretion urate transporters, all changes of which clearly lead to increase in renal UA clearance. Hypouricemia seen in SIADH is attributable to V1a receptor stimulation.

Time-dependent risk factors associated with the decline of estimated GFR in CKD patients.

BACKGROUND: Targeting the modifiable risk factors may help halt the progression of CKD, thus risk factor analysis is better performed using the parameters in the follow-up. This study aimed to examine the time-dependent risk factors for CKD progression using time-averaged values and to investigate the characteristics of rapid progression group. METHODS: This is a retrospective cohort study enrolling 770 patients of CKD stage 3-4. Time-dependent parameters were calculated as time-averaged values by a trapezoidal rule. % decline of estimated GFR (eGFR) per year from entry was divided to three groups: <10% (stable), 10-25% (moderate progression), and ≥25% (rapid progression). Multivariate regression analyses were employed for the baseline and the time-averaged datasets. RESULTS: eGFR decline was 2.83 ± 4.04 mL/min/1.73 m(2)/year (8.8 ± 12.9 %) in male and 1.66 ± 3.23 mL/min/1.73 m(2)/year (5.4 ± 11.0%) in female (p < 0.001). % decline of eGFR was associated with male, proteinuria, phosphorus, and systolic blood pressure as risk factors and with age, albumin, and hemoglobin as protective factors using either dataset. Baseline eGFR and diabetic nephropathy appeared in the baseline dataset, while uric acid appeared in the time-averaged dataset. The rapid progression group was associated with proteinuria, phosphorus, albumin, and hemoglobin in the follow-up. CONCLUSION: These results suggest that time-averaged values provide insightful clinical guide in targeting the risk factors. Rapid decline of eGFR is strongly associated with hyperphosphatemia, proteinuria, and anemia indicating that these risk factors should be intervened in the follow-up of CKD.

Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy.

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

Combination of ACE inhibitor with nicorandil provides further protection in chronic kidney disease.

An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease.

Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease.

BACKGROUND: Uric acid (UA) remains a risk factor of chronic kidney disease (CKD). Therefore, it is important to clarify the mechanism of UA excretion in CKD. The specific mechanisms of extrarenal excretion from the intestine are unknown. We evaluated the expression of the UA transporter in the intestinal tract--the ATP-binding cassette transporter G2 (ABCG2)--in a 5/6 nephrectomy rat model of CKD. METHODS: Male Wistar rats (6 weeks old) were randomly assigned to the 5/6 nephrectomized (Nx) group or the sham-operated control group. Urine and blood samples were collected every 4 weeks. All the rats were killed at 8 weeks to obtain liver, duodenum, jejunum, ileum, and transverse colon tissues. Uricase activity was measured in the liver. Expression of ABCG2 in intestinal mucosa was measured with real time polymerase chain reaction (PCR). RESULTS: The Nx group showed significantly decreased urine UA excretion/body weight and UA clearance compared to the control group at 4 and 8 weeks after nephrectomy. In contrast, serum UA and uricase activity were not significant. The expression of ABCG2 in the ileum of the Nx group showed significantly increased upregulation, while no changes were seen in the intestines of the control group. CONCLUSIONS: The Nx rats exhibited lower excretion of urine UA and over-expression of ABCG2 in the ileum. The fact that serum UA did not increase despite the decrease in UA excretion suggests that an excretory pathway other than the kidney, probably the intestine, may operate in a complementary role that corroborates the increase in ABCG2 expression in the ileum.

An Elderly Case of Minimal Change Nephrotic Syndrome: Correlation between Renal Tubular Dysfunction and the Onset of Oliguric Acute Kidney Injury Requiring Hemodialysis.

Several theories have been proposed to explain the development of severe acute kidney injury (AKI) in patients with minimal change nephrotic syndrome (MCNS), but the exact mechanism remains unclear. We encountered an elderly patient with biopsy-proven MCNS who suffered from oliguric AKI, which required hemodialysis at the onset and during the first relapse of nephrotic syndrome. Throughout her relapse, we were able to monitor tubular injury markers, namely, urinary N-acetyl-ß-D-glucosaminidase and urinary alpha-1-microglobulin levels. This patient had hypertension. 8.5 years after achieving complete remission, she experienced a relapse of nephrotic syndrome accompanied by AKI, necessitating hemodialysis. The hemodialysis was discontinued after 7 weeks of corticosteroid therapy and cyclosporin A treatment. During this relapse, we observed a correlation between the sudden increase in renal tubular injury markers and proteinuria levels and the progression of severe AKI. Conversely, a reduction in renal tubular injury markers and proteinuria was associated with the resolution of AKI. The abrupt elevation of both tubular injury markers and proteinuria levels suggests a possible breakdown in protein endocytosis in proximal tubular cells. Moreover, it is less likely that the acute reduction in intra-glomerular pressure is the primary cause of tubular injury, as it might result in a decrease in both glomerular filtration rate and proteinuria levels. It is conceivable that massive proteinuria, in conjunction with the patient's clinical characteristics, may contribute to tubular injury, ultimately leading to severe AKI in this patient.

Effective Management of Hypertensive Emergencies with Aliskiren Treatment in a Patient Before and After Introducing Hemodialysis Secondary to Scleroderma Renal Crisis-like Condition Under Corticosteroid Treatment for Sjögren Syndrome-associated Multiple Mononeuropathy.

A middle-aged woman presented with hypertensive emergency after corticosteroid treatment for Sjögren syndrome-associated multiple mononeuropathy with suspected systemic sclerosis. Hypertensive heart failure with hyperreninemia improved with antihypertensives, including aliskiren; however, she became hemodialysis-dependent. Clinical findings and biopsy-proven thrombotic microangiopathy indicated conditions resembling scleroderma renal crisis (SRC). Severe hypertension and heart failure with hyperreninemia occurred after stopping aliskiren for hypotension due to diverticular bleeding, which improved after the reintroduction of aliskiren. Aliskiren appears to be effective in managing hypertensive heart failure in patients with SRC. Nevertheless, hemodialysis remained necessary in our case, and whether or not aliskiren can restore the renal function is unclear.

Tubulointerstitial B-cell infiltration and tertiary lymphoid tissue in adult-onset immunoglobulin A vasculitis with nephritis.

PURPOSE: This study aimed to examine tubulointerstitial B-cell infiltration in patients with adult-onset immunoglobulin A vasculitis (IgAV) and nephritis (IgAV-N), and to evaluate whether B-cell infiltration correlated with clinicopathological variables at kidney biopsy and with short-term renal outcomes. METHODS: Twenty patients with adult-onset IgAV-N and 10 control patients with thin basement membrane nephropathy (TBMN) were retrospectively examined. The lymphatic organization was graded based on B-cell infiltration and was classified into 4 groups: 0-T cells without B cells, 1-scattered B and T cells, 2-clustered B and T cells, and 3-nodular compartmentally arranged B- and T-cell aggregates, equivalent to tertiary lymphoid tissue (TLT). RESULTS: The B-cell infiltration grade was significantly higher in patients with IgAV-N than in patients with TBMN, and no age differences were observed. The B-cell infiltration grade in patients with IgAV-N was significantly correlated with age, serum IgA level, renal dysfunction, and tubulointerstitial injury parameters, but was not correlated with duration after purpura or glomerular injury parameters. Most patients with IgAV-N were treated with corticosteroids. The proteinuria level was significantly decreased, but renal function was not improved in 12 patients after the 24-month follow-up compared with the values at baseline. The B-cell infiltration grade was significantly correlated with renal dysfunction after 24 months of follow-up. CONCLUSIONS: The B-cell infiltration grade in patients with IgAV-N was associated with renal dysfunction and tubulointerstitial injuries but not with glomerular injury parameters. B-cell infiltration and TLT might have a pathologically significant role in irreversible renal dysfunction in patients with early phase adult-onset IgAV-N.

A Diagnostic and Therapeutic Dilemma Concerning Exostosin 1/Exostosin 2-associated Lupus-like Membranous Nephropathy with Positive Antinuclear Antibody in an Elderly Man with Various Immune Abnormalities.

Exostosin 1 (EXT1) and exostosin 2 (EXT2)-associated membranous nephropathy (MN) may be associated with active autoimmune disease. We encountered an elderly man who presented with EXT1/EXT2-associated lupus-like MN with full house immune deposits, monoclonal gammopathy of uncertain significance and Sjögren's syndrome. The patient exhibited various other immune abnormalities. Although he did not fulfill the criteria of clinical systemic lupus erythematosus (SLE), he met a stand-alone renal criterion of the Systemic Lupus International Collaborating Clinics (SLICC) 2012. Whether or not a stand-alone renal criterion with EXT1/EXT2 positivity, as in the present patient, can efficiently guide decisions regarding the diagnosis and treatment of SLE remains a clinical dilemma.

Slowly Progressive ANCA-associated Glomerulonephritis with Strong Mesangial MPO Deposits Following a Diagnosis of Interstitial Lung Disease: A Case Report.

An elderly woman showed positive conversion of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCAs) following the diagnosis of interstitial lung disease (ILD) and glomerular hematuria and subsequently experienced slowly progressive glomerulonephritis. A kidney biopsy revealed chronic damage and necrotizing crescentic glomerulonephritis with mesangial MPO deposits. After corticosteroid treatment, the patient's urinalysis results and MPO-ANCA titers almost normalized and her renal function stabilized. This case is similar to recently reported cases of slowly progressive ANCA-associated glomerulonephritis. ILD likely triggered the production of MPO-ANCAs, and the accumulation of MPO deposits in the glomeruli may have contributed to the progression of her renal disease.

IgA vasculitis with transient glomerular hematuria, diarrhea, and pericarditis following COVID-19 mRNA vaccination in a young patient with possible pre-existing ulcerative colitis.

Exacerbations or de novo autoimmune/autoinflammatory disease have been reported after COVID-19 vaccination. A young male presented with cutaneous IgA vasculitis with glomerular hematuria, diarrhea and pericarditis following his second COVID-19 mRNA vaccination. He also showed positivity for proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) and anti-cardiolipin antibody. Skin biopsy was compatible to IgA vasculitis. His purpura subsided and hematuria spontaneously disappeared. Treatment with anti-inflammatory medications and prednisolone resolved the pericarditis. He had a history of persistent diarrhea, and colonic biopsies showed possible ulcerative colitis without vasculitis. Kidney biopsy after prednisolone therapy revealed minor glomerular abnormalities without any immune reactants and did not show vasculitis. After prednisolone treatment, PR3-ANCA decreased in a medium degree despite of improvement of symptoms and inflammatory data, suggesting that his PR3-ANCA may be associated with ulcerative colitis. The cause of the transient glomerular hematuria was unclear, however, it might be caused by focal glomerular active lesions (glomerular vasculitis) due to vaccine-induced IgA vasculitis with nephritis. This case highlights that COVID-19 mRNA vaccination can activate multiple autoimmune/autoinflammatory systems. The conditions might help us better understand the mutual mechanisms of the relevant disorders.

Discontinuing Hemodialysis through Corticosteroid Treatment in a Patient with Cryofibrinogen-associated Glomerulonephritis.

Cryofibrinogen-associated glomerulonephritis (CryoFiGN) is rare, and its diagnosis is difficult while treatment is not established. We herein report an elderly woman with CryoFiGN who experienced recurrent purpura and nephritic features that subsequently progressed to nephrotic syndrome and required hemodialysis during the 18-month clinical course. The patient was treated with corticosteroids, which led to the discontinuation of hemodialysis. The diagnosis of CryoFiGN was based on the clinical presentation, characteristic glomerular deposits, and results of laser microdissection and liquid chromatography-tandem mass spectrometry of the glomeruli. This case highlights the potential utility of corticosteroids as a treatment option for patients with CryoFiGN, even after hemodialysis.