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Siblings with nephronophthisis occasionally show different clinical courses; however, the reasons for this remain unclear. We herein report cases of nephronophthisis in a pair of dizygotic twins with different clinical courses. The brother developed end-stage kidney disease at 17 years old; however, his sister did not show kidney insufficiency. Kidney biopsies revealed severe tubulointerstitial damage at 14 and 22 years old in the brother and sister, respectively. Both had a homozygous NPHP1 deletion with different heterozygous mutations related to hereditary cystic kidney disease. Since the dizygotic twins were exposed to similar environmental factors, genetic factors may have influenced their clinical course more strongly than environmental factors.

A 37-year-old African–British man was referred to our hospital for detailed examination because of persistent fever, swelling and pain in both ankle joints, and blurred vision for two months. Inguinal lymph node biopsy showed a large number of epithelioid granulomas without necrosis. Granulomatous anterior uveitis, nephropathy, high serum angiotensin-converting enzyme activity, and high serum-soluble interleukin-2 receptor were observed, and the diagnosis of systemic sarcoidosis was made. His serum creatinine was 1.4 mg/dL and hematuria, leukocyturia, and urine protein were also seen. The renal biopsy finding was mesangial proliferative glomerulonephritis, with no findings of granuloma formation or tubular interstitial nephritis. Immunofluorescence staining showed deposition of IgG, C3, and C1q in the mesangial region. IgG3 was dominant in subclass staining. There was no monoclonality on kappa and lambda staining. Electron microscopy showed predominant deposition in the mesangial region with some subepithelial and endothelial deposition. His hematuria and leukocyturia disappeared with steroid therapy, suggesting sarcoidosis-related nephropathy. A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region is presented. No cases of such histological findings have been reported so far, and it is necessary to analyze further cases to clarify the pathogenic significance of the renal biopsy findings observed in this case.

Renin-angiotensin-aldosterone system (RAAS) is primarily involved with pathological mechanism of developing hypertensive emergencies. However, none of clinical practice guidelines mention RAAS blockers for the treatment of hypertensive emergencies. A 44 year-old woman presented with severe hypertension, brain stem posterior reversible encephalopathy syndrome and severe acute kidney injury (AKI). We started anti-hypertensive therapy with continuous intravenous nitroglycerin and oral calcium channel blocker (CCB) and spironolactone. Since severe AKI persisted despite this therapy, we administered losartan potassium, which resulted in improvement in her blood pressure and creatinine. Clinical course of our patient suggests that timely initiation of ARB and spironolactone for hypertensive emergencies could be beneficial in terms of blood pressure control and for protection of target organs from this condition.

Introduction Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. Methods We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. Results Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-μm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. Conclusions In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients., Graphical abstract

Background Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. Methods To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. Results In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15−/− mice. Alox15−/− CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15−/− CKD mice. Mediator lipidomics revealed that Alox15−/− CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. Conclusion Increased PGD2 in Alox15−/− CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the LMX1B gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]) in exon 4 of the LMX1B gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between LMX1B and proper GBM morphogenesis.

For continuous renal replacement therapy in small infants, due to the large extracorporeal volume involved, blood priming can be necessary to prevent hypotension and hemodilution. Because packed red blood cells (RBCs) have high levels of potassium and citrate, closed-circuit dialysis is often performed. We assessed the metrics of closed-circuit dialysis and serial citrate concentration changes. We performed dialysis of closed circuits primed with expired human packed RBC solution and 5% albumin. Blood and dialysate flow rates were 70 and 33.3 mL/min, respectively. The extracorporeal volume was 70 mL. We measured pH, electrolytes, and citrate in the closed circuit every 3 min for 15 min. We also assessed the adequacy of closed-circuit dialysis using the formula: [dialysate flow rate (mL/min) × time of dialysis (min)]/extracorporeal volume (mL) and we assessed the correlation between citrate and ionized calcium concentrations. To reach normal concentrations of sodium, potassium, and chloride, 2.4 times as much dialysate fluid as extracorporeal volume was needed. In contrast, for ionized calcium, bicarbonate, and citrate, 3.8 times as much dialysate fluid as extracorporeal volume was required. By simple linear regression analysis, the concentration of citrate was significantly correlated with that of ionized calcium. For closed-circuit dialysis using an RBC solution, the formula [dialysate flow rate (mL/min) × time of dialysis (min)]/extracorporeal volume (mL) would be a better parameter to estimate efficacy, compared with other metrics. Additionally, the citrate concentration can be readily estimated from the ionized calcium concentration during closed-circuit dialysis.

In recent years, bioimpedance analysis has come to be widely used in clinical practice for dialysis patients, but there is not sufficient consensus on its significance. We aimed to examine the merits of performing bioimpedance analysis in addition to conventional evaluation methods for dry weight such as measuring human atrial natriuretic peptide (hANP), blood pressure, and cardiothoracic ratio in patients on chronic hemodialysis.Body composition of 78 hemodialysis patients was performed by using a new and more accurate segmental multifrequency bioimpedance analysis device (SecaMean age of the patients was 66.9 ± 12.6 years and 80.8% were males. Mean value of hANP and the ratio of extracellular water to total body water (ECW/TBW) were 61.4 ± 36.4 pg/mL and 46.1 ± 3.9%, respectively. The calculated ECW/TBW cutoff point for hANP 50 pg/mL was 45.0%, with sensitivity of 74.4% and specificity of 64.7%. Patients with an ECW/TBW of more than 45% and hANP value of 50 pg/mL had a higher blood pressure and cardiothoracic ratio on chest X-ray examination.Our results suggest that the ratio of extracellular water to total body water of more than 45% and hANP value of ≥ 50 pg/mL were overhydrated in chronic hemodialysis patients. Whether monitoring levels of these parameters has a role in the outcome including patients' survival and cardiovascular events requires further study.

Acidemia is one of the risk factors for end-stage kidney disease and increases the mortality rate of patients with chronic kidney disease (CKD). Although urinary ammonium (U-NH4 + ) is the crucial component of renal acid excretion, U-NH4 + concentration is not routinely measured. To estimate U-NH4 + , urine osmolal gap (UOG = urine osmolality - [2(Na+ + K+ ) + urea + glucose]) is calculated and the formula (U-NH4 + = UOG/2) has traditionally been used. However, the usefulness of this formula is controversial in CKD patients. We assessed the relationship between U-NH4 + and UOG in patients with CKD. Blood and spot urine samples were collected in 36 patients who had non-dialysis-dependent CKD. The mean ± SD age of patients was 72.0 ± 14.8 years, and the mean ± SD serum creatinine and U-NH4 + were 2.7 ± 2.3 mg/dl and 9.3 ± 9.2 mmol/L, respectively. A significant relationship was found between UOG/2 and U-NH4 + (r = .925, p < .0001). U-NH4 + estimated using the UOG was on average higher by 4.7 mmol/L than the measured one. Our results suggested that UOG could be a useful tool in clinical settings, especially in patients with moderate to severe CKD.

Background There is no evidence on how to use the information from bioimpedance analysis (BIA) devices in clinical management, including setting of target dry weight (DW), or improving outcomes in hemodialysis (HD) patients. Methods Here, we investigate preferable cut off values of fluid status (extracellular water/total body water ratio; ECW/TBW) detected by a new and more accurate BIA device (Seca®) in 78 HD patients. Results Patients with an ECW/TBW of more than 45% and human atrial natriuretic peptide (HANP) value of > 50 pg/mL had a higher blood pressure and cardio-thoracic ratio on chest x-ray examination.Conclusions Our results suggests that ECW/TBW of more than 45% and HANP value of > 50 pg/mL were overhydrated and had a worse prognosis.

Background Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. Methods To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. Results In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15−/− mice. Alox15−/− CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15−/− CKD mice. Mediator lipidomics revealed that Alox15−/− CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. Conclusion Increased PGD2 in Alox15−/− CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD. Supplementary Information The online version contains supplementary material available at 10.1007/s10157-021-02021-y.

Background Complications of acute kidney injury (AKI) are common in patients with coronavirus disease in 2019 (COVID-19). However, clinical characteristics of COVID-19-associated AKI are poorly described. We present two cases of severe COVID-19 patients with AKI. Case presentation A 77-year-old woman was suspected of having vancomycin-associated AKI, and a 45-year-old man was suspected of having heme pigment-induced AKI caused by rhabdomyolysis. The granular cast, which is known to be a valuable diagnostic tool for confirming the diagnosis of acute tubular necrosis, was detected in both patients at the onset of AKI. Interestingly, both patients also developed microscopic hematuria at the occurrence of AKI, and one patient had elevated d-dimer and low platelet levels simultaneously. Conclusions Some reports suggested that COVID-19-associated microangiopathy contributed to the kidney damage. Therefore, it is possible that our patients might have accompanied renal microangiopathy, and that this pathological background may have caused exaggerated tubular damage by vancomycin or heme pigment. The etiology of AKI in patients with COVID-19 is multifactorial. Superimposition of nephrotoxin(s) and virus-associate intra-renal microangiopathy may be a crucial trigger of kidney injury leading to severe AKI in COVID-19 patients. Therefore, in COVID-19 patients, risk factors for AKI should be taken into consideration to prevent its progression into severe AKI.

Gitelman syndrome (GS), an autosomal recessive kidney disorder, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Generally, diagnosis is made in school-aged children but multiple cases have been diagnosed in adulthood. This study examines the phenotypic differences between genetically confirmed cases and mutation-negative cases in adults. A comprehensive screening of 168 genes, including GS-related genes, was performed for 84 independent individuals who were referred to our institute with a clinical diagnosis of GS. The cases of pseudo-Bartter syndrome (BS)/GS because of diuretic abuse or other causes, which was determined based on patients' medical records, were excluded during registration. Of these 70 eligible cases for analysis, 27 (38.6%) had genetic confirmation of GS, while 37 (52.8%) had no known variants associated with GS and were considered to be unsolved cases. Note that unsolved cases comprised older, mostly female, individuals with decreased kidney function and multiple basic features of GS. The phenotype of unsolved cases is similar to that of pseudo BS/GS cases, although these cases were excluded in advance. However, the genetic and autoimmune profiles of these unsolved cases have not yet been investigated to date. Therefore, these cases may be categorized into new disease groups.

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the LMX1B gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]) in exon 4 of the LMX1B gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between LMX1B and proper GBM morphogenesis.

Background: Tolvaptan is the only therapeutic drug for autosomal dominant polycystic kidney disease (ADPKD). The influence of mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) on the treatment effects of tolvaptan is not well documented in the literature. Methods: We retrospectively evaluated the relationship between genotype and the efficacy of tolvaptan in 18 patients with ADPKD who had been treated at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020. Results: The annual change in estimated glomerular filtration rate (ΔeGFR/y) from before to after tolvaptan was from a median of −5.5 to −2.5 mL/min/1.73 m2 in the PKD1 truncating group, −3.3 to −2.4 mL/min/1.73 m2 in the PKD1 non-truncating group, −3.1 to −1.6 mL/min/1.73 m2 in the PKD2 group, and −1.9 to −2.6 mL/min/1.73 m2 in the group with no PKD1/2 mutation. The median degrees of improvement of ΔeGFR/y were 2.5 (45%), 0.4 (10%), 0.6 (28%), and −0.7 (−37%) mL/min/1.73 m2, respectively. Compared with the group of patients with any PKD1/2 mutation, the group with no PKD1/2 mutation showed significantly less improvement in ΔeGFR/y with tolvaptan (0.6 vs. −0.7 mL/min/1.73 m2, respectively; p = 0.01) and significantly less improvement in the annual rate of increase in total kidney volume (TKV) with tolvaptan (−6.7 vs. −1.1%, respectively; p = 0.02). Conclusion: Patients with ADPKD and no PKD1/2 mutation showed less improvement in ΔeGFR/y and the annual rate of increase in TKV with tolvaptan. Detecting PKD1/2 mutations may be useful for predicting the effectiveness of tolvaptan.

Key Clinical Message We report a patient with adult‐onset nephronophthisis (NPHP) that was identified a homozygous full gene deletion of NPHP1 and a heterozygous PKD1 mutation. We suggest that the PKD1 mutation may have epistatically ameliorated NPHP disease progression and that the screening of larger cohorts for similar possible epistatic effects is needed.

Background: Genetic characteristics of polycystic kidney disease (PKD) patients without apparent family history were reported to be different from those with a positive family history. However, the clinical course of PKD patients with no apparent family history is not well documented in the literature. Methods: We evaluated the relationship between genotype and the clinical course of 62 PKD patients with no apparent family history. Results: The annual decline of renal function was faster in the patients with PKD1/PKD2 mutation (PKD1 truncating [–3.08; 95% CI –5.30 to –0.87, p = 0.007], PKD1 nontruncating [–2.10; –3.82 to –0.38, p = 0.02], and PKD2 [–2.31; –4.40 to –0.23, p = 0.03]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, estimated glomerular filtration rate (eGFR), height-adjusted total kidney volume (TKV), and mean arterial pressure (MAP). There was no significant difference in the annual decline of renal function among the different PKD1/PKD2 groups, but Kaplan-Meier analysis showed that progression to eGFR < 15 mL/min/1.73 m2 was significantly faster in PKD1 truncating group (p = 0.05). The annual rate of TKV increase was larger in the patients with PKD1/PKD2 mutation (PKD1 truncating [4.63; 95% CI 0.62–8.64, p = 0.03], PKD1 nontruncating [3.79; 0.55–7.03, p = 0.02], and PKD2 [2.11; –1.90 to 6.12, p = 0.29]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, eGFR, and MAP. Conclusion: Detection of PKD1/PKD2 mutation, especially PKD1 truncating, is useful for predicting the renal outcome and rate of TKV increase in PKD patients with no apparent family history.

Objective Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys. Methods Urinary sodium excretion and expression of renal sodium transporters were examined in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin. In addition, we examined metformin effects using ex vivo preparations of mice kidney slices. Results In this study, we demonstrated that metformin increased urinary sodium excretion by reducing phosphorylation of the thiazide-sensitive Na-Cl cotransporter (NCC) in acute and chronic metformin administration. We also confirmed reduction of phosphorylated NCC in an ex vivo study. The activity of other renal sodium transporters, such as NKCC2, ENaC, and NHE3 did not show significant changes. WNK-OSR1/SPAK kinase signals were not involved in this inactivation effect of metformin on NCC. Conclusion Metformin increased urinary sodium excretion by reducing phosphorylation of NCC, suggesting its role in improving hypertension.

Distinguishing autosomal-dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture-based next-generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD. Through our analysis, 32 patients had PKD1 or PKD2 mutations. Additionally, 3 patients with disease-causing mutations in NPHP4, PKHD1, and OFD1 were diagnosed with an inherited renal cystic disease other than ADPKD. In patients with PKD1 or PKD2 mutations, the prevalence of polycystic liver disease, defined as more than 20 liver cysts, was significantly higher (71.9% vs 33.3%, P = .006), total kidney volume was significantly increased (median, 1580.7 mL vs 791.0 mL, P = .027) and mean arterial pressure was significantly higher (median, 98 mm Hg vs 91 mm Hg, P = .012). The genetic screening approach and clinical features described here are potentially beneficial for optimal management of adult sporadic polycystic kidney disease patients.

We encountered 2 patients with symptomatic huge simple renal cysts. In case 1, 4,000 mL of cyst fluid was drained via a catheter, but intracystic bleeding occurred immediately afterwards. Transcatheter arterial embolization (TAE) was performed, after which the bleeding stopped, and cyst drainage was repeated successfully. After 2 years, the total cyst volume was reduced from 11,775 mL to 75.4 mL. In case 2, TAE was performed prophylactically before drainage. Subsequently, 9,400 mL of fluid was removed from multiple cysts. After 1 year, the total cyst volume was reduced from 9,215 mL to 633 mL without bleeding. Based on these 2 cases, prophylactic TAE before drainage may be useful in patients with huge renal cysts.

Chronic kidney disease (CKD) is known to be associated with cancer mortality. However, no study has considered the well-known cancer prognostic factors, ECOG Performance Status (PS) and cancer treatment, as confounding factors. We assessed the independent relationship between CKD and cancer death in stage IV cancer patients. In this retrospective observational study, we included stage IV cancer patients diagnosed from 2009 to 2014 in a single center. We collected baseline clinical and laboratory variables, and cancer-specific variables, and assessed the presence of CKD. Our primary outcome was all-cause mortality. The secondary outcome was cancer-specific mortality and site-specific cancer mortality. Among 961 eligible stage IV cancer patients (median age 69 years, 51.8% male), 150 patients had CKD. During follow-up (median 9.8 months), 638 patients died, of whom 526 patients died from cancer. After adjusting for prognostic variables, including ECOG PS and cancer treatment, all-cause mortality and cancer-specific mortality were significantly higher in CKD patients than in non-CKD patients (HR 1.41, 95% CI 1.13–1.77 and HR 1.43, 95% CI 1.12–1.83, respectively). In patients with breast and kidney and urinary tract cancers, CKD was associated with a significantly increased risk of death (HR 7.01, 95% CI 1.47–33.4 and HR 3.33, 95% CI 1.42–7.78, respectively). CKD at the time of stage IV cancer diagnosis was associated with all-cause mortality and cancer-specific mortality. Moreover, the association between CKD and cancer-specific death was site specific for breast cancer and kidney and urinary tract cancer.

Background There have been still few case reports of pseudohypoaldosteronism type II (PHA2), also known as Gordon's syndrome, genetically diagnosed, and this is the first report of familial PHA2 case in Japan with a novel D564N mutation in WNK4. Methods A 29-year-old woman was admitted to our hospital due to hyperkalemia (serum potassium: 6.4 mmol/L). She had mild hypertension (135/91 mm Hg), a bicarbonate level at the lower limit of the normal range (HCO3 : 22 mmol/L) with a normal anion gap, low plasma renin activity (0.2 ng ml-1 hr-1 ), and high urinary calcium excretion (505.4 mg/g Cre). A hereditary condition was suspected because her mother also had the same symptoms. We performed a comprehensive genetic analysis for major inherited kidney diseases with next-generation sequencing including the genes responsible for PHA2 (WNK1, WNK4, KLHL3, and CUL3). Results Genetic analysis revealed that the patient and her mother had a novel missense mutation (D564N) in the acidic motif in WNK4, which leads to the diagnosis of PHA2. Administration of trichlormethiazide (1 mg/day) effectively ameliorated her blood pressure (114/69 mm Hg), plasma bicarbonate (25 mmol/L), serum potassium (4.3 mmol/L), and urinary calcium excretion (27.2 mg/g Cre). Conclusion We report the first Japanese familial case of PHA2 with WNK4 mutation. D564N mutation in WNK4 is a novel genetic cause of PHA2 with a relatively mild phenotype.

The inappropriate over-activation of the with-no-lysine kinase (WNK)–STE20/SPS1–related proline/alanine-rich kinase (SPAK)–sodium chloride cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1–SPAK–NCC phosphorylation cascade in this model, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-α regulates WNK1 protein expression. In fact, TNF-α increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-α inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1–SPAK–NCC phosphorylation cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1– SPAK–NCC phosphorylation cascade by TNF-α, reflecting a link with the immune system.

An eight-year-old girl with myelodysplastic syndrome (refractory cytopenia) received a bone marrow transplant (BMT) from an unrelated donor because of immunosuppressive therapy failure. Following administration of foscarnet for cytomegalovirus reactivation at day40 post-BMT, serum creatinine increased, and proteinuria, hematuria, and hypertension gradually exacerbated and became prolonged. However, neither schistocytosis nor other organ damage was evident. At six months post-BMT, renal biopsy revealed diffuse glomerular damage with glomerular lobulation, a double contour of the glomerular basement membrane, erythrocyte congestion and thrombi in the glomerular endocapillaries, and mesangiolysis, confirming the diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA). We initiated strict controls regarding fluid balance, salt intake, and blood pressure. The patient's renal function improved 10 months post-BMT. TA-TMA often presents as non-specific symptoms, making diagnosis difficult. In cases of post-transplant renal damage, TA-TMA should be differentiated regardless of whether specific symptoms such as hemolytic anemia and other organ failure are evident, and a renal biopsy should, therefore, be considered.

The pathogenesis of coronary artery aneurysm (CAA) formation in Kawasaki disease (KD) remains unknown. However, inflammatory cytokines are thought to play an important role in KD. Patients with intravenous immunoglobulin (IVIG)-resistant KD are more likely to develop CAA. For such refractory patients, steroids and emerging infliximab (IFX) are used; however, further verification is required for their efficacy and safety. Plasma exchange (PE), which removes various inflammatory cytokines, has been used in Japan for over 15 years to prevent CAA in IVIG-resistant KD patients. The sequential change in inflammatory cytokines during the time course of PE has yet to be investigated. In this study, we measured plasma levels of 13 cytokines in nine children with IVIG-resistant KD before the start of PE (day 0: D0), as well as at 1 or 2 days (D1/2), and 4 or 5 days (D4/5) after starting PE. The median age of onset was 8 months (range: 3-53 months). Before PE, patients were treated with IVIG (median dose: 4 g/kg, range: 3-4 g/kg). The median starting period of PE was 8 days after the onset of fever (range: 6-21 days), while its duration was 3 days (range: 2-5 days). Among the 13 cytokines, interleukin-6, tumor necrosis factor-α, tumor necrosis factor receptor I (TNFR1), TNFR2, granulocyte colony-stimulating factor, and IL-17 were significantly lower at D4/5 compared with D0 and/or D1/2, reflecting the potential central efficacy of PE. While three patients developed moderate CAA, their condition regressed within 1 year. The removal of inflammatory cytokines could be the central efficacy of PE against refractory KD.

Rituximab (RTX) has a significant steroid-sparing effect in children with steroid-dependent nephrotic syndrome (SDNS). However, patients are likely to relapse with the recovery of CD20+ cells. We conducted a small prospective cohort study with a historical control to evaluate the effect of RTX infusion followed by mycophenolate mofetil (MMF) as a maintenance therapy. Nine patients with SDNS who stopped their steroid treatment but were treated with MMF after RTX infusion were prospectively observed (group A). Seven patients with SDNS who discontinued steroid and immunosuppressive agents after RTX administration served as a control (group B). During the first year after the administration of RTX, six patients in group A and one patient in group B did not suffer a relapse (p < 0.05). The number of patients who relapsed during the 1 year preceding RTX treatment did not differ between the two groups [4.1 (A) vs. 5.7 (B)], but it was significantly lower in the MMF-treated group 1 year after the RTX treatment [0.4 (A) vs. 2.3 (B), p < 0.005]. The daily amount of prednisolone after the RTX treatment was lower in group A than in group B (0.11 vs. 0.46 mg/kg/day, respectively; p < 0.05). Three patients in group A and five patients in group B relapsed to SDNS and needed additional RTX treatment(s) within 1 year (odds ratio 5.0). Based on these results, we conclude that maintenance therapy with MMF after RTX is a good clinical option.

グルココルチコイド (以下，ステロイド薬) の全身投与が長期にわたるステロイド依存性ネフローゼ症候群，頻回再発型ネフローゼ症候群，ステロイド抵抗性ネフローゼ症候群などのいわゆる難治性ネフローゼ症候群ではステロイド薬の副作用が大きな問題となる。とりわけ骨合併症である成長障害 (低身長)，骨粗鬆症，大腿骨頭壊死は重篤かつ不可逆的なものが多い。今回，私達はステロイド薬の副作用による骨合併症を呈した難治性ネフローゼ症候群4例に対してリツキシマブ療法を行った。リツキシマブの投与後，全例がステロイド薬からの離脱が可能となり，骨密度の改善や新たな骨合併症の予防が可能となった。リツキシマブは小児の難治性ネフローゼ症候群において再発抑制効果があり1)2)，ステロイド薬の減量中止が可能となるが，infusion reactionをはじめとして，重症感染症，間質性肺炎，進行性多巣性白質脳症などの重篤な副作用を呈することもあり，使用にあたっては注意が必要とされる。

乳幼児は，血液透析中に低血圧やショックに陥りやすい．また透析中不機嫌になると安静が保てなくなり，啼泣や体動などにより容易に脱血不良を起こし，さらにバイタルサインの正確な測定も困難になるなど，透析が困難になることが多い．今回われわれは，透析中に不機嫌になることを繰り返していた生後5か月の血液透析施行中の男児に，無酢酸透析液の使用を試みた．症例は，生後1か月時に，腸間膜裂肛ヘルニアによる絞扼性イレウスのために腸管穿孔を起こし，心肺停止・腎不全に陥った．心肺停止からの回復後，小腸の70％を切除する手術を行った後に，短腸症候群に対し高カロリー輸液が開始され，腎不全に対してカテーテルによる血液透析が開始された．腹腔内癒着のために腹膜透析が不可能であったため，皮下埋め込み型のバスキュラーアクセスを左外頸静脈に留置して，血液透析を継続した．透析中に不機嫌になり啼泣することを繰り返していたために，昨今低血圧や不均衡症状の改善効果が注目されている無酢酸透析液を試みることとした．それまでの透析液に含まれている酢酸は0.5mEq/Lと非常に微量であったが，無酢酸透析液に変更してから，不機嫌や啼泣が緩和され，クリットラインの低下も軽減され，安全に除水できるようになったことより，微量の酢酸が症状を引き起こしていたのだと考えられた．無酢酸透析液使用に伴う有害事象もなかった．透析液中に含まれている酢酸は，内皮細胞におけるNO産生亢進によると思われる末梢血管拡張作用や，単核球からの炎症性サイトカインの産生誘導作用などが報告されている．血圧が下がりやすく，安静が保ちにくい乳幼児の血液透析に，無酢酸透析液は有用であると考えられた．

脊椎脊髄手術を施行した97例中36例に術後フェンタニル持続皮下注入法［20μg/h］（フェンタニル群），43例に塩酸モルヒネ持続皮下注入法［1 mg/h］（モルヒネ群），18例に患者の疼痛の訴えに応じてNSAIDsやブプレノルフィン坐薬ないし，ペンタゾシン筋注による鎮痛処置（従来群）を行った．術後の疼痛の程度をWong & Bakerのface scaleで看護師が術後24時間まで記録した．術後6時間毎の疼痛平均点数では術後18時間までフェンタニル群は従来群よりも鎮痛効果が優位に優れていた．合併症ではモルヒネ群に頻度の多い悪心・嘔吐，刺入部皮膚障害，便秘・腹満がフェンタニル群では有意にこれらの合併症頻度が低かった．しかしフェンタニル群では塩酸モルヒネ群・従来群と比較して有意に呼吸障害が多かった．呼吸障害を呈した11例のうち2例はフェンタニル投与を中止した．術後急性期の鎮痛にフェンタニル持続皮下注入法は有効だが，SaO2モニター，呼吸数を慎重に経過観察していく必要がある．

We develop an approach to the classification of nonflat totally geodesic surfaces in Riemannian symmetric spaces of noncompact type. In this paper, we concentrate on the case of symmetric spaces of type AI, and show that such surfaces correspond to certain nilpotent matrices. As applications, we obtain explicit classifications in the cases of rank two and three.

Calcineurin inhibitors (CIs) with/without intravenous methylprednisolone pulse therapy (MPT) constitute the standard treatment for childhood-onset, steroid-resistant nephrotic syndrome (SRNS). However, some patients fail to achieve remission. We treated SRNS patients resistant to CIs and MPT with additional rituximab combined with MPT and immunosuppressive agents.Ten patients (aged 2-14 years) with CI- and MPT-resistant SRNS were enrolled. Patients were administered rituximab (1-4 doses; 375 mg/m(2)) followed by MPT (30 mg/kg/day of methylprednisolone for 3 consecutive days) once every 2-4 weeks until complete remission (CR). We analyzed clinical outcome and safety.Six patients received a single dose of rituximab, 2 received two doses, and 2 received four doses. Seven patients achieved CR, 1 achieved partial remission, and 2 showed no response. Although 2 patients with no response progressed to end-stage renal failure, 7 patients with CR preserved normal renal function without proteinuria at the last observation. There were two serious adverse events.Additional rituximab combined with conventional MPT and immunosuppressive agents is a promising option for overcoming refractory SRNS. Aggressive B cell suppression by rituximab may ameliorate resistance to conventional treatments and a cocktail of other immunosuppressive agents, such as CIs, MMF, mizoribine, may be beneficial. However, as intense immunosuppression may cause serious adverse events, further evaluation is necessary.