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.

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.

Blood pressure control and satisfaction of hypertensive patients following a switch to combined drugs of an angiotensin receptor blocker and a calcium channel blocker in clinical practice of nephrology.

BACKGROUND: Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood. METHODS: This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients' questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients' satisfaction with regard to combination drugs. RESULTS: Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients. CONCLUSION: Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints.

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.

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.

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.

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.

A Patient with Acute Kidney Injury Associated with Massive Proteinuria and Acute Hyperuricemia after Epileptic Seizures.

A 25-year-old man presented with acute kidney injury (AKI), massive proteinuria and hyperuricemia after epileptic seizures. His AKI improved along with the disappearance of proteinuria after corticosteroid treatment. A kidney biopsy revealed no significant glomerular abnormalities, but varying degrees of tubular injury, such as proximal tubular simplification, mild distal tubular proliferation, and Tamm-Horsfall protein-like material accumulation with extravasation into the interstitium, were noted. A further analysis revealed the intratubular depositions of uric acid crystals, indicating the involvement of acute uric acid nephropathy associated with seizures. Our patient's condition is rare, and the clinicopathological aspects of the diagnostic challenges are discussed.

Emergence of proteinase 3-antineutrophil cytoplasmic antibody-associated glomerulonephritis with mesangial immune deposition during the clinical course of IgG λ monoclonal gammopathy of uncertain significance.

Patients with monoclonal gammopathy of uncertain significance (MGUS) is sometimes associated with renal diseases, usually due to the deposition of secreted monoclonal immunoglobulin or a fragment thereof, a condition which is defined as monoclonal gammopathy of renal significance. Patients with MGUS appear to be at increased risk for various autoimmune conditions. We report the case of a 68-year-old man developed nephritic syndrome and mild renal insufficiency during the course of IgG λ MGUS. Laboratory findings showed hypocomplementemia, cryoglobulinemia, proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity and monoclonal proteins (λ light chain and λ-Bence-Jones protein) in the urine. A kidney biopsy revealed crescentic glomerulonephritis with mesangial immune deposits without paraproteins. Treatment with prednisolone for ANCA-associated glomerulonephritis, normalized urinalysis and decreased PR3-ANCA but MGUS persisted. This is a rare case of PR3-ANCA-associated glomerulonephritis with comorbid IgG λ MGUS with various pathological paraproteins. We highlight it as a clinical example with diagnostic and therapeutic implications.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Introduction: Impaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients. Methods: In this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index. Results: Of the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (ß = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 µg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables. Conclusion: Serum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

Pyuria without Casts and Bilateral Kidney Enlargement Are Probable Hallmarks of Severe Acute Kidney Injury Induced by Acute Pyelonephritis: A Case Report and Literature Review.

The patient was a 38-year-old man who had experienced nausea and fever for a few days and presented with back pain, oliguria, and pyuria, suggesting acute pyelonephritis (APN). He showed acute kidney injury (AKI) with bilateral kidney enlargement and was using nonsteroidal anti-inflammatory drugs (NSAIDs). AKI-induced by APN was confirmed by kidney biopsy. The AKI was successfully treated with antibiotic therapy. A search of the relevant literature for reports on histopathologically-proven APN-induced severe AKI revealed that the key characteristics were bilateral kidney enlargement with pyuria without casts. Oligoanuria was frequently associated with APN-induced severe AKI, and NSAID use may be a possible risk factor. Prompt antibiotic treatment based on the clinical characteristics of APN-induced AKI can improve the renal outcome.

A Ruptured Jejunal Arterial Aneurysm in a Young Woman Undergoing Chronic Hemodialysis Due to Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

A 21-year-old woman was admitted to our hospital because of massive intestinal bleeding. She started hemodialysis due to myeloperoxidase antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at 18 years of age. Her ANCA titers remained stable; however, her C-reactive protein increased on 5 mg/day prednisolone before admission. Computed tomography angiography revealed a ruptured jejunal arterial aneurysm. Transcatheter arterial embolization, blood transfusion and the reinforcement of steroid therapy resolved her symptoms of AAV. Our case of a young patient with AAV and medium-sized arterial vasculitis is rare and emphasizes that the ANCA titer does not always rise, especially in patients with nonrenal vasculitis flare-ups.

Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism.

Pendrin is a Cl-/HCO3- exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na+ channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.

A Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension.

A 51-year-old woman with rheumatoid arthritis presented with mild hypertension 20 months after tacrolimus treatment and developing proteinuria 24 months after the treatment. Tacrolimus was discontinued 27 months after the treatment, followed by heavy proteinuria, accelerated hypertension, and deteriorating renal function without ocular fundus lesions as a clinical sign of malignant hypertension. Renal biopsy revealed malignant nephrosclerosis characterized by subacute and chronic thrombotic microangiopathy (TMA), involving small arteries, arterioles, and glomeruli. Focal segmental glomerulosclerosis, probably secondary to chronic TMA, was identified as a cause of heavy proteinuria. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. The presence of nodular hyalinosis in arteriolar walls was indicative of tacrolimus-associated nephrotoxicity. Together with other antihypertensive drugs, administration of aliskiren stabilized renal function with reducing proteinuria. Owing to the preexisting proteinuria prior to severe hypertension and the complex renal histopathology, we postulated that chronic TMA, which was initially triggered by tacrolimus, was aggravated by severe hypertension, resulting in overt renal TMA.

A Patient with MPO-ANCA-positive IgA Nephropathy Diagnosed with the Clinical Onset of Macrohematuria.

A 21-year-old woman presented with renal dysfunction during macrohematuria. A kidney biopsy revealed IgA nephropathy with a small percentage of crescent formation and macrohematuria-associated tubular injury. Macrohematuria-associated acute kidney injury could explain her renal dysfunction. However, she was seropositive for myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) and showed fibrin deposition around one arteriole. Corticosteroids and mycophenolate mofetil were administered as for ANCA vasculitis, and the serum creatinine, abnormal urinalysis and MPO-ANCA titer all gradually ameliorated. The presence of extra-glomerular vasculitis, which was probably induced by ANCA, suggested that MPO-ANCA was an exacerbating factor for her prolonged renal dysfunction. This condition has so far only rarely been addressed in ANCA-positive IgA nephropathy.

Clinicopathological Implications of Proteinuria after Long-Term Isolated Hematuria due to Thin Basement Membrane Nephropathy and Focal Segmental Glomerulosclerosis.

A 45-year-old obese man presented with persistent hematuria for 21 years. At the age of 37, he developed hypertension and proteinuria which later increased up to 1.6 g/g creatinine. Kidney biopsy revealed thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS), which explained his urinary abnormalities. Although a subgroup of TBMN can be complicated by FSGS, his FSGS was associated with obesity because of its histological features. Reduction of body weight and increasing a dose of angiotensin-receptor blocker could transiently reduce the amount of proteinuria. Clinicopathological implications of proteinuria after long-term hematuria by TBMN and FSGS were further discussed.

Association of cholesterol efflux capacity with plasmalogen levels of high-density lipoprotein: A cross-sectional study in chronic kidney disease patients.

BACKGROUND AND AIM: Current research suggests that dysfunctional high-density lipoprotein (HDL) with low cholesterol efflux capacity may accelerate atherosclerosis, particularly in chronic kidney disease (CKD). We previously reported that serum levels of plasmalogens closely correlated with HDL concentration, and could serve as a novel biomarker for atherosclerosis. In the present study, we analyzed the association of cholesterol efflux capacity of HDL with clinical and biochemical parameters, including plasmalogens, in CKD patients. METHODS: We enrolled 24 mild-to-moderate CKD patients (CKD-3-4) and 33 end-stage renal disease (ESRD) patients nearing hemodialysis (CKD-5), and assessed physiological atherosclerotic scores, cholesterol efflux capacity, and plasmalogens levels in HDL. Furthermore, the effect of plasmalogen on cholesterol efflux capacity of HDL was examined by in vitro studies with re-constituted HDL (rHDL) and HDL prepared from CKD-5 patient (ESRD-HDL) with additional phospholipids. RESULTS: There were significant differences in many parameters between the two groups. In particular, plasmalogens levels and cholesterol efflux capacity of HDL were significantly reduced in the CKD-5 group compared to those in the CKD-3-4 group (-35.1%, p < 0.001, -36.8%, p < 0.001, respectively). Multivariate linear regression analyses revealed that ethanolamine plasmalogen levels of HDL were independently associated with cholesterol efflux capacity (p = 0.045) and plaque scores (p = 0.035). In vitro studies also indicated that additional plasmalogens augmented cholesterol efflux ability of HDL. CONCLUSIONS: High plasmalogens concentrations in HDL may correlate with acceleration of cholesterol efflux and their decreased levels may promote atherosclerosis in advanced CKD patients.

Remission of Refractory Ascites and Discontinuation of Hemodialysis after Additional Rituximab to Long-term Glucocorticoid Therapy in a Patient with TAFRO Syndrome.

Thrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a newly recognized but rare disease, and its treatment has not yet been established. We reported a 50-year-old woman with TAFRO syndrome diagnosed 2 years after the initial symptoms of a fever, fatigue, epigastric pain, edema, ascites, lymphadenopathy, thrombocytopenia and renal insufficiency. The patient showed refractory ascites and required hemodialysis under corticosteroid mono-therapy for suspected immune-mediated disease but was successfully treated with additive rituximab, resulting in improvement in her laboratory data, the withdrawal of hemodialysis and the disappearance of ascites. This case underscores the therapeutic utility of rituximab in patients with corticosteroid-resistant TAFRO syndrome, even long after the onset of the disease.