Prognostic Implications of Urinary Potassium to Creatinine Ratio in Patients With Predialysis Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Although a low or high serum potassium level in chronic kidney disease (CKD) is associated with worsening renal function and increased cardiovascular disease (CVD) events, urinary potassium excretion has been found to predict adverse health outcomes with conflicting results. We conducted a cohort study to determine whether urinary potassium to creatinine (K/Cr) ratio is an independent risk for further deterioration in renal function or increased CVD events. METHODS: We identified 650 predialysis patients with CKD hospitalized for an educational program regarding CKD between January 2010 and December 2018. The study outcomes were CKD progression and incident CVD events, with baseline urinary K/Cr ratio categorized into quartiles-Q1, < 19.8; Q2, 19.9-27.7; Q3, 27.8-37.9; and Q4, > 38.0. RESULTS: During follow-up (median, 35 months), 509 CKD progressions and 129 incident CVD events were identified. Sixty two patients died during follow-up. Multivariate Cox proportional hazard model showed that after adjustment for demographic factors and laboratory data, patients in Q1 had a 2.02-fold higher risk of worsening renal function than those in Q4 (95% confidence interval, 1.50-2.71; P < .001), whereas urinary K/Cr ratio had no association with the incidence of CVD events. Similarly, inverse probability weighting analysis showed an increased risk of CKD progression in the lowest quartile. Furthermore, the association between low fractional excretion of potassium and worsening renal function was confirmed. CONCLUSION: A low urinary K/Cr ratio is independently associated with worsening renal function but not with a risk of incident CVD event in predialysis patients with CKD.

The effect of sodium zirconium cyclosilicate on acid-base balance in chronic kidney disease.

Hyperkalemia is a common electrolyte abnormality in chronic kidney disease (CKD). Sodium zirconium cyclosilicate (SZC) is a novel selective cation exchanger that is used to treat hyperkalemia and may also capture ammonium, which is of a similar size to potassium. We investigated the effect of SZC on acid-base balance in CKD patients. This retrospective study surveyed 20 patients with CKD whose serum potassium levels were maintained within the normal range by treatment with polysulfonate resin, which was replaced with SZC during the clinical course. We compared clinical parameters before and after changing medications. Changing the potassium binder from polysulfonate resin to SZC increased serum bicarbonate (p = 0.016) and decreased blood urea nitrogen (p = 0.017). Serum potassium levels were maintained within the normal range. Urine pH, anion gap, and osmolality gap were unchanged during treatment. No gastrointestinal symptoms were noted during the observation period. Our data suggest that SZC may improve not only hyperkalemia but also metabolic acidosis by increasing the excretion of ammonium from the intestinal tract in patients with CKD. SZC could be a more suitable medication for CKD patients with hyperkalemia and metabolic acidosis.

Efficacy of corticosteroid therapy for IgA nephropathy patients stratified by kidney function and proteinuria.

BACKGROUND: Steroid therapy is one of the important therapies for IgA nephropathy (IgAN), but the features of the IgAN patients who have the benefit from this therapy remained unclear. METHODS: This retrospective observational study, using data of 874 patients with IgAN analyzed the proteinuria and kidney function of IgAN patients who had beneficial effect by steroid therapy. Two advantages of the present study were a large cohort and a long observational period. RESULTS: Corticosteroid therapy had ameliorated the kidney prognosis [incident rate ratio (IRR) 0.57 (95%CI 0.34-0.92), P = 0.029]. Because of interaction between kidney function and use of corticosteroid (P = 0.047), stratification analysis by kidney function revealed that prognosis of kidney function in IgAN patients whose eGFR was less than 60 ml/min/1.73m2 was ameliorated by corticosteroid therapy [IRR 0.50 (95%CI 0.26-0.97), P = 0.015); while, there was no change of kidney prognosis in IgAN patients whose eGFR was above 60 ml/min/1.73 m2. To make the target of corticosteroid therapy for IgAN patients more clear, IgAN patients, whose eGFR were less than 60 ml/min/1.73 m2, were stratified by proteinuria (1 g/day). In IgAN patients whose eGFR were under 60 ml/min/1.73 m2 and whose proteinuria were over 1.0 g/day, corticosteroid therapy seemed to ameliorate kidney function [IRR 0.39 (95%CI 0.19-0.86), P < 0.05]; while, there was obviously no change by corticosteroid therapy in IgAN patients whose eGFR were less than 60 ml/min/1.73 m2 and whose proteinuria were less than 1.0 g/day. CONCLUSION: Our results suggested that steroid therapy was especially effective for IgAN patients whose eGFR was less than 60 ml/min/1.73 m2 and whose proteinuria was more than 1.0 g/day.

New selectivity index calculated using protein fraction as a substitute for the conventional selectivity index.

BACKGROUND: Selectivity index (SI) of proteinuria, calculated using the clearance ratio of immunoglobulin G to transferrin, predicts the response to glucocorticoids in patients with nephrotic syndrome. However, there is disagreement regarding the suitability of SI. Therefore, alternate indices should be considered. This study investigated whether or not selectivity index protein fraction (SIPF) was inferior to SI for the prediction of the response to glucocorticoids. METHODS: Forty-nine patients with nephrotic syndrome were evaluated. On the basis of molecular weight and protein fraction, as an inexpensive substitute for SI, the clearance ratio of the albumin to γ fractions measured in serum and urine protein fractions was defined as SIPF. The quality of SIPF was examined. Moreover, the best cutoff value of SIPF was determined; and SIPF distribution, according to histopathological diagnosis by renal biopsy, was examined. RESULTS: SIPF was strongly correlated with SI (r = 0.79, P < 0.001). The area under the receiver operating characteristic (ROC) curve of SIPF and SI was not significantly different (P = 0.18). The best cutoff value of SIPF was 0.45. In the group with SIPF > 0.45, only two patients with minimal change disease (MCD) achieved complete remission. In the group with SIPF ≤ 0.45, all patients with MCD achieved complete remission, although eight patients with other histopathological diagnoses did not achieve complete remission. CONCLUSIONS: Analysis of protein fractions as a substitute for SI may be useful for predicting response to glucocorticoids in patients with nephrotic syndrome.

[Effectiveness of a practical protocol for the prevention of contrast-induced nephropathy: improved prevention of contrast-induced nephropathy].

BACKGROUND: In Japan, "Guidelines for iodinated contrast in a patient with chronic kidney disease (CKD) 2012" was published, but preventive protocols for specific contrast-induced nephropathy (CIN) have not been specified. Therefore, we developed a CIN preventive protocol, and validated its operation and renal protective effect. METHODS: In a retrospective cohort study, we determined eGFR within 3 months before contrast-enhanced computed tomography (CECT). We evaluated CKD stage 3b - 4 adult patients (eGFR 15 - 45 mL/min/1.73m2) who underwent CECT. We observed changes in renal function over 9 months and compared the changes between the pre-protocol group, which received CIN preventive measures from clinicians, and the post-protocol group, which received 500 mL 0.9% saline intravenously over 4 hours or drank 2,000 mL water over 36 hours. RESULTS: The numbers of CT and CECT patients after validation of the protocol were 5,450 and 2,037, respectively. Among the CECT patients, 310 (15.2%) and 77(3.8%)had eGFRs < 60 and 45 mL/min/1.73 m2, respectively. Among the CECT patients whose eGFRs were < 60 mL/min/1.73 m2, 74.5% were 70 years or older. Tumor scanning accounted for 77% of all CECT cases. The number of CECT patients after 3 months did not significantly differ between the groups (2,189 vs 2,037). The percentage of patients with CKD stage G3b - 4 showed no significant differences (3.3% vs 3.7%, p = 0.89). The proportion of patients whose eGFR did not deteriorate at 3, 6 and 9 months was significantly higher in the post-protocol group than in the pre-protocol group (p < 0.001), and the protocol was the only independently-significant predictor. CONCLUSIONS: Our protocol prevented CIN and provided a renal protective effect without reducing the number of CECT patients.

Effects of raloxifene on bone metabolism in postmenopausal women on chronic hemodialysis.

BACKGROUND: Postmenopausal women with end-stage renal failure are at an increased risk of fracture because of the effects of secondary hyperparathyroidism and postmenopausal osteoporosis. In the present study, we investigated the feasibility of using raloxifene to prevent fractures in postmenopausal women with end-stage renal failure on hemodialysis. METHODS: This study was conducted using a multicenter, single-arm, prospective design. Raloxifene was administered to postmenopausal women aged ≥50 years who were on maintenance hemodialysis and met any of the following criteria after a 24-week run-in period: an alkaline phosphatase level (bone formation marker) of ≥6.18 µkat/L (≥370 U/L), a bone-specific alkaline phosphatase (BAP; bone formation marker) level of ≥0.59 µkat/L (≥35.4 U/L), or a bone-derived tartrate-resistant acid phosphatase (TRACP-5b; bone resorption marker) level of ≥4.2 U/L. RESULTS: A total of 48 individuals were eligible for study inclusion. Of them, 30 individuals participated in this study. The BAP levels were significantly decreased at week 4, but returned to the baseline levels at week 24. Similarly, the TRACP-5b levels were significantly decreased at week 4, but returned to the baseline levels at week 24. The serum calcium value decreased consistently after the start of raloxifene therapy. The intact parathyroid hormone (iPTH) levels were likely increased at week 4. The ratio of BAP to iPTH levels and the ratio of TRACP-5b to iPTH levels both showed significant decreases over time. During the raloxifene therapy, no thrombosis or other drug-related adverse events developed. CONCLUSION: The study results indicated that raloxifene can transiently reduce the levels of bone metabolism markers and might be useful for preventing fractures in postmenopausal women with end-stage renal failure, although raloxifene use over the long term may not have adequate efficacy in the absence of appropriate concomitant active vitamin D therapy.

Effect of Dapagliflozin on Serum Uric Acid Levels in Patients with Advanced Chronic Kidney Disease.

Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are hypoglycemic agents, have been shown to be cardioprotective through a variety of mechanisms, and the effect of lowering uric acid (UA) levels may be one of the mechanisms. In the present retrospective study, we investigated the changes in serum UA levels in patients with chronic kidney disease (CKD) treated with SGLT2 inhibitors. Methods We included 31 patients with CKD who were newly started on dapagliflozin for renal protection and evaluated trends in various parameters, including serum UA levels and UA excretion from urine. Results The patients' median age was 71 years old, 20 patients were men, 7 patients had diabetes, and the median estimated glomerular filtration rate was 33.9 mL/min/1.73 m2 (CKD stage 3: 21 cases, stage 4: 10 cases). The differences in UA and fractional excretion of UA after three weeks and three months of prescription showed significantly decreased UA values and an increased fractional excretion of UA. Conclusion Our findings suggest that dapagliflozin can lower serum UA levels via increased UA excretion, even in patients with advanced CKD.

Voriconazole-associated salt-losing nephropathy.

A 74-year-old man was diagnosed with nephrotic syndrome due to focal segmental glomerulosclerosis, and steroid therapy was initiated. Subsequently, he was affected by deep mycosis, and hence, voriconazole (VRCZ) was administered. On the 16th day, he was transferred to our hospital because of somnolence and malaise. His systolic blood pressure was approximately 80 mmHg, and he showed decreased skin turgor, indicating volume depletion. Laboratory analysis revealed hyponatremia and liver dysfunction. Discontinuation of VRCZ and drip infusion of normal saline improved the consciousness disorder, hyponatremia, and liver dysfunction. The levels of antidiuretic hormone (ADH) and plasma renin activity were elevated. This patient showed high excreted urine sodium, despite volume depletion and low serum osmolality. Therefore, this patient was diagnosed with salt-losing nephropathy (SLN). SLN should be considered for treatment of VRCZ-associated hyponatremia, together with syndrome of inappropriate secretion of ADH.

[A case of nephrotic syndrome achieving remission with cyclosporine monotherapy].

The case was a female in her early 80's. Due to abdominal bloating and lower limb edema, she visited a nearby doctor, was diagnosed to have nephrotic syndrome, and then was referred to our department. Upon initial consultation, TP of 4.1 g/dl, Alb of 1.7 g/dl, UN of 73 mg/dl, and Cr of 1.43 mg/dl, along with pleural effusion were observed by chest X-ray. A renal biopsy was not performed because permission could not be obtained. Despite the fact that management of the edema was performed using diuretic agents and albumin preparations, a reduced renal function and deterioration of the fluid retention were gradually observed. She originally displayed lower back pain and digestive symptoms and, therefore, cyclosporine monotherapy was initiated in order to address concerns of side effects such as osteoporosis and peptic ulcer due to adrenocortical steroid drugs (hereinafter abbreviated as steroid). Subsequently, hemodialysis was temporarily required but reduced urine protein and an improved renal function were gradually observed and she eventually achieved a complete remission. The possibility of a spontaneous remission of membranous nephropathy, etc. was considered, but a relapse occurred when the amount of cyclosporine was reduced. Thereafter, a complete remission was obtained with an increased dosage. As a result, the effectiveness of cyclosporine was thus confirmed. In treating nephrotic syndrome, steroid therapy is commonly performed and it is common for cyclosporine to be limited to steroid-resistant cases and/or steroid-dependent cases. However, it is believed that monotherapy could also be an option in cases in which the use of steroids is difficult, such as in cases of elderly patients.

Metabolic alkalosis due to short bowel syndrome in a hemodialysis patient.

A 53-year-old man on hemodialysis suffered from short bowel syndrome after subtotal colectomy and partial resection of the small intestine. Laboratory tests showed multiple electrolyte disorders and enlarged sodium and chloride ion (Cl-) gaps despite treatment with large volume of sodium chloride replacement via central venous infusion. Blood gas analysis showed slightly high bicarbonate ion levels and metabolic alkalosis was suspected, which is uncommon in end stage kidney disease. The measurement of electrolytes in feces from ileostomy showed relatively high Cl- excretion. The loss of Cl- to feces may have caused the metabolic alkalosis; thus, additional Cl- replacement may have been necessary.

Anti-mitochondria antibody-related tubulointerstitial nephritis accompanied by severe hypokalemic paralysis.

A 47-year-old man presented with severe hypokalemic paralysis and respiratory failure. A large amount of potassium was administered along with providing intensive care, and his condition improved. Hypokalemia was attributed to increased urinary potassium excretion. A kidney biopsy was performed to make a definitive histological diagnosis. It revealed acute tubulointerstitial nephritis (TIN). After the diagnosis, prednisolone was administered, and the TIN gradually improved. From the clinical course and laboratory findings, the TIN was presumed to be an autoimmune disorder. Further specific autoantibody tests were positive for anti-mitochondrial antibody (AMA), which has been gaining increasing attention in regard to TIN. In addition, all previous cases of TIN associated with AMA have affected females. The detailed pathogenetic mechanisms are as yet unclear and require further investigation.

A case report of proliferative glomerulonephritis with monoclonal immunoglobulin M-kappa deposits without associated lymphoproliferative disorder or detectable paraproteinemia.

A 53-year-old man presented with proteinuria and hematuria. No significant abnormality was detected in his physical examination or laboratory tests, including evidence of paraprotein in serum and urine. Renal biopsy revealed mesangial proliferation, thickened glomerular basement membranes, and spike formation. Immunofluorescence revealed deposition of immunoglobulin (Ig) M heavy chain, kappa (κ) light chain, and complement component C3 along capillary walls in the glomeruli. Light chain staining indicated significant restriction, because only κ chain, not lambda chain, was present in glomeruli. Aggregated electron dense deposits were observed in the subepithelial area and within the lamina densa on electron-microscopic examination. Cryoglobulinemia and amyloidosis were ruled out. Clinically, steroid therapy was not initiated due to patient preference, and the only prescribed medication was an angiotensin II receptor blocker. At the approximately 3-year follow-up, estimated glomerular filtration rate had decreased very mildly. The present case demonstrates that deposition of monoclonal IgM-κ may be associated with membranoproliferative glomerulonephritis-like changes in the glomeruli. Although no underlying hematological abnormality or paraproteinemia was observed in this case within the range of limited clinical examination, the patient's condition is consistent with proliferative glomerulonephritis with monoclonal IgM deposits, similar to the recently established proliferative glomerulonephritis with monoclonal IgG deposits. Further elucidation of the pathophysiology and effective treatments of the disorder should be expected in the future through the accumulation of similar cases.

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients.

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.

Increased double product on Monday morning during work.

It has been reported that cardiovascular events often occur on Monday morning, especially in the young working population. Because hypertension is a major cardiovascular risk, we examined whether blood pressure was elevated on Monday, especially in the morning during work. However, there were no weekly rhythms in blood pressure itself. Instead, we found significant interactions between the double product (systolic blood pressure × heart rate) and weekly (high on Monday) and circadian (high in the morning) rhythms. Further studies are required to determine whether Monday morning preference in cardiovascular events is caused by increased double product.

Tuberculous Fasciitis in Polymyositis: A Rare Case of Extrapulmonary Tuberculosis.

A 71-year-old woman with polymyositis presenting with left thigh pain and an intermittent fever was admitted to Osaka Rosai Hospital. We initially diagnosed that her pain and fever were caused by a soft tissue infection because her polymyositis was controlled. She did not respond to various antibiotic therapies. Chest computed tomography demonstrated miliary tuberculosis (TB). Ziehl-Neelsen staining of liver biopsy specimens revealed epithelioid cell granuloma and acid-fast bacilli. Therefore, we finally diagnosed the lesion as TB fasciitis that improved with anti-TB drug therapy. The atypical presentation of TB fasciitis demonstrates the clinical importance of eliminating TB infections in immunocompromised hosts.

Serum Uric Acid Level Predicts Progression of IgA Nephropathy in Females but Not in Males.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is one of most common forms of glomerulonephritis. At this point, the clinical impact of hyperuricemia on IgAN is not clear. The aim of the present study was to explore the clinical impact of hyperuricemia on the progression of IgAN. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 935 IgAN patients who were diagnosed by kidney biopsy at Osaka University Hospital, Osaka General Hospital, and Osaka Rosai Hospital. were included in this study. PREDICTOR: Uric acid levels at renal biopsy. OUTCOMES: The outcome of interest was the time from the kidney biopsy to the time when a 50% increase in the baseline serum creatinine level was observed, which was defined as "progression". MEASUREMENTS: The baseline characteristics according to the kidney biopsy at the time of diagnosis were collected from the medical records, and included age, gender, body mass index, hypertension, diabetes (use of antidiabetic drugs), serum levels of creatinine, urinary protein, smoking status, RAAS blockers and steroid therapy. RESULTS: An elevated serum uric acid level was an independent risk factor for progression in female patients (per 1.0 mg/dL, multivariate-adjusted incident rate ratio 1.33 [95% confidence interval 1.07, 1.64], P = 0.008) but not in male patients (1.02 [0.81, 1.29], P = 0.855). To control a confounding effect of renal function on an association between serum uric acid level and progression in female patients, age- and serum creatinine-matched and propensity score-matched analyses were performed, and these results also supported the effect by uric acid on kidney disease progression independent of basal kidney function. LIMITATIONS: A cohort analyzed retorospectively. CONCLUSIONS: This study revealed that an elevated uric acid level was an independent risk factor for ESKD in female IgAN patients. Therefore, uric acid might be a treatable target in female IgAN patients.

The Rho-ROCK system as a new therapeutic target for preventing interstitial fibrosis.

The small GTPase Rho is involved in cell-to-substratum adhesion and cell contraction. These actions of Rho mediated by downstream Rho effectors such as Rho-associated coiled-coil forming protein kinase (ROCK) may be partly responsible for the progression of renal interstitial fibrosis. A body of evidence has been accumulated with regard to the involvement of the Rho-ROCK signaling pathway in the development of fibrotic lesions in various organs including the kidney. Tubulointerstitial fibrosis is a final common pathway to the eventual structural desolation of kidneys, and therefore is an important therapeutic target to cure or reverse the progressive functional deterioration. In this review, we will highlight the possible involvement of the Rho-ROCK signaling pathway in the pathogenesis of tubulointerstitial fibrosis and discuss the therapeutic approach toward tubulointerstitial fibrosis by the inhibition of the Rho-ROCK pathway.

Antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis with membranous nephropathy treated using thiamazole.

A 21-year-old woman with nephrotic syndrome was referred to our hospital. She had congenital diaphragmatic hernia, hypoxic ischemic encephalopathy, and mental retardation, and had been treated for hyperthyroidism with thiamazole in another hospital. Serum creatinine was 37.8 µmol/L and antineutrophil cytoplasmic antibody against myeloperoxidase (MPO-ANCA) was 39 EU. Urinalyses were 3+ for proteins and 3+ for occult blood. A renal biopsy was performed. An examination using light microscopy (LM) revealed necrotizing glomerulonephritis with crescent formation. Immunofluorescence microscopy showed granular staining with immunoglobulin G and complement component 3 along the capillary walls. Electron microscopy (EM) disclosed subepithelial dense deposits. A renal biopsy suggested necrotizing glomerulonephritis with membranous nephropathy (MN) in stages I or II. Since many cases of drug-induced ANCA-associated glomerulonephritis (AAG) have been reported, we stopped thiamazole and treated with corticosteroid. The MPO-ANCA titer became negative 49 days after the initiation of treatment. Two years after the first treatment, the MPO-ANCA titer became elevated again and was 82 EU. The patient was administered cyclophosphamide and prednisone. However, the MPO-ANCA titer did not decrease. A renal biopsy was performed again 3 years after the first renal biopsy. LM revealed no crescentic formation but demonstrated spike formations along the glomerular basement membrane. EM also disclosed subepithelial dense deposits, but less than the first biopsy. The renal biopsy suggested MN in stages II or III. AAG was regarded as inactive after corticosteroid treatment. Therefore, ciclosporin administration was started. In conclusion, we experienced a rare case of AAG complicated with MN. The histopathologic results showed that immunosuppressive therapy seemed to be effective in treating crescentic glomerulonephritis; furthermore, it reduced proteinuria but could not reduce the MPO-ANCA titer.