Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology.

Introduction: Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood. Methods: This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing. Results: Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5. One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants, nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant. Conclusion: This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases.

Prevalence of mild cognitive impairment and its association with handgrip strength in patients on hemodialysis.

Dementia is associated with a high risk of death and hospitalization among patients on hemodialysis (HD). We retrospectively evaluated the prevalence of mild cognitive impairment (MCI) in 421 patients on maintenance HD across nine facilities and investigated whether decreased handgrip strength was associated with decreased cognitive function. The Montreal Cognitive Assessment-Japan (MoCA-J) score and handgrip strength were measured. The mean age was 69.8 ± 11.2 years, and the median dialysis vintage 74.5 (IQR 30-150) months. The median MoCA-J score was 25 (IQR 21-27), and MCI was confirmed in 245 (58.2%) patients. Both the MoCA-J score and MoCA-J executive score were associated with age, history of cerebrovascular disease (CVA), and handgrip strength after adjustments. We found, among patients on HD aged under 70 years with a history of CVA, a handgrip strength < 90% (25.2 kg in males and 16.2 kg in females) correlated with significantly lower MoCA-J scores. A high prevalence of MCI and decreased handgrip strength were observed in patients on HD. Handgrip strength may be useful for the easy detection of MCI. A decrease in handgrip strength would allow for the early detection of MCI, especially among patients on HD aged under 70 years with a history of CVA.

Combination of low body mass index and serum albumin level is associated with chronic kidney disease progression: the chronic kidney disease-research of outcomes in treatment and epidemiology (CKD-ROUTE) study.

BACKGROUND: The relationship between protein-energy wasting and chronic kidney disease (CKD) progression is unknown. In the present prospective cohort study, we evaluated the hypothesis that a combination of low body mass index (BMI) and serum albumin level is associated with rapid CKD progression. METHODS: The study cohort comprised 728 predialysis Japanese patients with CKD (stages 2-5) enrolled from 2010 to 2011. Patients were categorized into four groups according to their serum albumin levels and BMI: group 1, low serum albumin level (<4 g/dL) and low BMI (<23.5 kg/m2); group 2, high serum albumin level (≥4 g/dL) and low BMI; group 3, low serum albumin level and high BMI (≥23.5 kg/m2); and group 4, high serum albumin level and high BMI. The primary outcome was a 30 % decline in estimated glomerular filtration rate (eGFR) or start of dialysis within 2 years. The secondary outcome was an annual GFR decline (mL/min/1.73 m2/year). RESULTS: Logistic regression analysis adjusted for baseline characteristics (reference, group 4) showed that only group 1 was associated with a significant risk of CKD progression, with adjusted odds ratio of 3.51 [95 % confidence interval (CI) (1.63, 7.56)]. A multivariate linear regression analysis adjusted for baseline characteristics showed a significant difference in annual eGFR decline between groups 1 and 4 [coefficients ß (standard error) -2.62 (0.75), p = 0.001]. CONCLUSION: This study suggests that combined effects of low BMI (<23.5 kg/m2) and serum albumin level (<4 g/dL) are associated with CKD progression.

IgA-dominant postinfectious glomerulonephritis associated with Escherichia coli infection caused by cholangitis.

A 76-year-old man with a history of type 2 diabetes mellitus was admitted with cholangitis caused by cholangiocarcinoma. Cholangitis with Escherichia coli (E. coli) bacteremia recurred due to the unstable bile drainage. At 1 month after recurrence, rapidly progressive glomerulonephritis with nephrotic syndrome was manifested. Renal biopsy findings were consistent with immunoglobulin A (IgA)-dominant postinfectious glomerulonephritis (PIGN). After ensuring that the recurrent cholangitis was controlled by drainage and antibiotic therapy, oral prednisolone was initiated, and the patient's renal function and proteinuria subsequently gradually improved. This is the first case report of IgA-dominant PIGN associated with cholangitis caused by E. coli infection.

Nephrotic-range proteinuria and interstitial nephritis associated with the use of a topical loxoprofen patch.

A 76-year-old woman with a history of lumbar fracture and marked proteinuria, bilateral pitting edema, malaise and pruritus was referred for an evaluation of an impaired renal function. A renal biopsy led to a tentative diagnosis of acute interstitial nephritis (AIN) with minimal change disease caused by nonsteroidal anti-inflammatory drugs (NSAIDs). Following the discontinuation of oral NSAIDs, the patient's symptoms disappeared spontaneously. However, nephrotic-range proteinuria relapsed one month after discharge, following loxoprofen patch use. The withdrawal of the topical loxoprofen patches once again resulted in the disappearance of all symptoms. This is the first case report of nephrotic-range proteinuria and AIN secondary to topical NSAID patch use.

Decreased mobility after starting dialysis is an independent risk factor for short-term mortality after initiation of dialysis.

AIM: Impaired mobility at the onset of dialysis is considered one of the most important risk factors for short-term mortality after initiation of dialysis in elderly patients. However, whether a decline in mobility after starting dialysis also affects mortality is unclear. METHODS: A total of 202 patients (age, >75 years; mean, 80.4 ± 4.3) were enrolled in this retrospective cohort study in Yokosuka, Japan. They were divided into three subgroups by mobility: independent mobility at onset of dialysis and preservation of mobility after starting dialysis (group 1, n = 104); independent mobility at onset of dialysis and decline in mobility after starting dialysis (group 2, n = 48); and impaired mobility at onset of dialysis (group 3, n = 50). They were followed for 6 months after starting dialysis. A Cox proportional hazards model was used to evaluate the association between mobility and mortality. RESULTS: A total of 24.8% of patients had impaired mobility at the start of dialysis, and 68.9% declined in mobility after starting dialysis. In multivariate Cox proportional hazards analysis, the adjusted hazard ratios of groups 2 and 3 compared with group 1 were 3.80 (95% confidence interval, 1.02-14.10) and 4.94 (95% confidence interval, 1.42-17.10), respectively. CONCLUSION: Not only impaired mobility at the start of dialysis but also a decline in mobility after starting dialysis is associated with short-term mortality after initiation of dialysis.

Periodic hypokalemia associated with cyclic Cushing's syndrome.

A 69-year-old woman presented with periodic hypertension, edema, and hypokalemia that occurred within an interval of a few weeks. Her laboratory test values showed autonomously elevated plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. The patient's Cushingoid features were not evident on first admission. Several weeks later, in spite of constant oral potassium supplementation, severe hypokalemia recurred with Cushingoid features and worsening symptoms of leg edema and pigmentation, which spontaneously disappeared within a few days. Her periodic symptoms occurred in parallel with fluctuations of plasma ACTH and cortisol concentrations. A series of endocrinological and pituitary imaging findings led to a tentative diagnosis of cyclic Cushing's syndrome caused by ectopic ACTH secretion. However, chest and abdominal computed tomography did not reveal any candidate lesion. The patient's periodic hypercortisolemia and symptoms were well controlled after treatment with metyrapone plus dexamethasone. This is a very rare case of periodic hypokalemia and hypertension caused by cyclic Cushing's syndrome.

Sarcoidosis in a chronic dialysis patient diagnosed by sarcoidosis-related hypercalcemia with no common systemic clinical manifestations: a case report and review of the literature.

Sarcoidosis is a systemic granulomatous disease of unknown origin. We herein report a case of sarcoidosis in a chronic dialysis patient diagnosed by hypercalcemia without any common clinical manifestations. The onset of sarcoidosis in chronic dialysis patients is rare; to the best of our knowledge, only 23 cases have been reported. Evaluation of the 23 previously published cases revealed that a diagnosis of sarcoidosis was often achieved by the presence of sarcoidosis-related hypercalcemia without any common clinical presentations, as in the present case. This characteristic may arise from a specific immune deficiency and the unique physiology of 1,25-dihydroxyvitamin D3, a main cause of sarcoidosis-related hypercalcemia, in chronic dialysis patients. These clinical features may be useful to understand the pathogenesis of sarcoidosis.

Baseline characteristics and prevalence of cardiovascular disease in newly visiting or referred chronic kidney disease patients to nephrology centers in Japan: a prospective cohort study.

BACKGROUND: About 39,000 patients were newly prescribed renal replacement therapy in Japan in 2011, resulting in a total of more than 300,000 patients being treated with dialysis. This high prevalence of treated end stage kidney disease (ESKD) patients is an emergent problem that requires immediate attention. We launched a prospective cohort study to evaluate population specific characteristics of the progression of chronic kidney disease (CKD). In this report, we describe the baseline characteristics and risk factors for cardiovascular disease (CVD) prevalence among this cohort. METHODS: New patients from 16 nephrology centers who were older than 20 years of age and who visited or were referred for the treatment of CKD stage 2-5, but were not on dialysis therapy, were recruited in this study. At enrollment, medical history, lifestyle behaviors, functional status and current medications were recorded, and blood and urine samples were collected. Estimated glomerular filtration rate (eGFR) was calculated by a modified three-variable equation. RESULTS: We enrolled 1138 patients, 69.6% of whom were male, with a mean age of 68 years. Compared with Western cohorts, patients in this study had a lower body mass index (BMI) and higher proteinuria. The prevalence of CVD was 26.8%, which was lower than that in Western cohorts but higher than that in the general Japanese population. Multivariate analysis demonstrated the following association with CVD prevalence: hypertension (adjusted odds ratio (aOR) 3.57; 95% confidence interval (CI) 1.82-7.02); diabetes (aOR 2.45; 95% CI 1.86-3.23); hemoglobin level less than 11 g/dl (aOR 1.61; 95% CI 1.21-2.15); receiving anti-hypertensive agents (aOR 3.54; 95% CI 2.27-5.53); and statin therapy (aOR 2.73; 95% CI 2.04-3.66). The combination of decreased eGFR and increased proteinuria was also associated with a higher prevalence of CVD. CONCLUSIONS: The participants in this cohort had a lower BMI, higher proteinuria and lower prevalence of CVD compared with Western cohorts. Lower eGFR and high proteinuria were associated with CVD prevalence. Prospective follow up of these study patients will contribute to establishment of individual population-based treatment of CKD.

Post-staphylococcal infection Henoch-Schönlein purpura nephritis: a case report and review of the literature.

A 37-year-old man developed Henoch--Schönlein purpura nephritis (HSPN) with nephrotic syndrome and rapidly progressive glomerulonephritis after otitis media and externa due to methicillin-resistant Staphylococcus aureus infection. Despite resolution of the infection and prednisolone therapy, his kidney disease worsened. However, the addition of cyclosporine A finally resulted in complete remission of the nephrotic syndrome. A review of similar cases with post-Staphylococcal infection HSPN revealed strong similarities between this entity and immunoglobulin A-dominant postinfectious glomerulonephritis (IgA-PIGN), an increasingly recognized form of PIGN typically associated with Staphylococcal infection, in both clinical and morphological features. Post-Staphylococcal infection HSPN may constitute a subgroup of IgA-PIGN.

Biopsy-proven drug-induced tubulointerstitial nephritis in a patient with acute kidney injury and alcoholic severe acute pancreatitis.

We report a 49-year-old man with alcoholic severe acute pancreatitis (SAP) complicated by drug-induced acute tubulointerstitial nephritis (DI-AIN). Oliguria persisted and became anuric again on day 17 despite improvement of pancreatitis. He presented rash, fever and eosinophilia from day 20. Renal biopsy was performed for dialysis-dependent acute kidney injury (AKI), DI-AIN was revealed, and prompt use of corticosteroids fully restored his renal function. This diagnosis might be missed because it is difficult to perform renal biopsy in such a clinical situation. If the patient's general condition allows, renal biopsy should be performed and reversible AKI must be distinguished from many cases of irreversible AKI complicated by SAP. This is the first report of biopsy-proven DI-AIN associated with SAP, suggesting the importance of biopsy for distinguishing DI-AIN in persisting AKI of SAP.

Anti-centromere antibody is an independent risk factor for chronic kidney disease in patients with primary biliary cirrhosis.

BACKGROUND: Anti-centromere antibody (ACA), a typical autoantibody of systemic sclerosis, is also detected in primary biliary cirrhosis (PBC). However, its pathogenic role is not fully understood. The aim of this study was to determine the association between ACA and kidney function in PBC. METHODS: A cohort of 37 patients diagnosed as having PBC from July 2001 to November 2011 at Yokosuka Kyosai Hospital was retrospectively analyzed for a follow-up period of 12 months. The annual rate of estimated glomerular filtration rate (eGFR) decline within 1 year after the diagnosis was evaluated. The factors associated with eGFR decline were evaluated by linear regression analysis and logistic regression analysis. RESULTS: Overall, 37 PBC patients were included, of whom 12 (32%) had ACA. The patients with ACA had a lower eGFR (65.9 ± 19.9 vs. 80.3 ± 12.1 mL/min/1.73 m(2), P = 0.01), a higher likelihood of chronic kidney disease (CKD) (58 vs. 4%, P = 0.0005), and a higher rate of annual eGFR decline (-4.3 ± 5.1 vs. 0.2 ± 4.6 mL/min/year, P = 0.01) than those without ACA. Univariate regression analysis and multivariate regression analysis adjusted for potential cofounders including age, eGFR, sex, diabetes mellitus, and hypertension showed that ACA was associated with eGFR decline (P = 0.011 and 0.017, respectively). Multivariate logistic regression analysis adjusted for these cofounders showed that ACA was associated with eGFR decline less than -4 mL/min/year (odds ratio 7.21, 95% confidence interval 0.93-56.1, P = 0.059). CONCLUSIONS: ACA is an independent risk factor for CKD in PBC. Evaluation of ACA and kidney function is necessary to prevent CKD progression in PBC patients.

Anti-centromere antibody-positive subjects presenting with hypertensive emergency and renal dysfunction in the absence of skin manifestations: a variant of systemic sclerosis or a novel entity?

Two patients with anti-centromere antibody (ACA), hypertensive emergency, and acute renal failure, mimicking scleroderma renal crisis, without Raynaud's phenomenon and typical skin manifestations of systemic sclerosis (SSc), are reported. A review of 26 ACA-positive patients between March 2003 and March 2011 in Yokosuka Kyosai Hospital identified four additional patients with similar manifestations. All patients were Japanese women between 41 and 84 years of age at presentation. Human leukocyte antigen (HLA) genotyping tests revealed the absence of the HLA-DQB1*0501 and DRB1*0101 alleles, which are associated with disease susceptibility to ACA-positive SSc among Japanese. These subjects' manifestations may represent a novel entity.

Sunitinib-induced nephrotic syndrome and irreversible renal dysfunction.

Sunitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFRs), has become essential for treating imatinib-resistant malignant gastrointestinal stromal tumor. Recently, several cases have been reported that showed proteinuria and kidney dysfunction to be associated with anti-VEGF therapy. Although previous reports indicated that this side-effect is reversible, it is not well understood. We present here the case of a 72-year-old man who presented with nephrotic syndrome and renal dysfunction 6 months after administration of sunitinib. Sunitinib was discontinued, and nephrotic syndrome remitted spontaneously, but renal function recovery was limited. Nine months later, a renal biopsy was performed because sunitinib was again required and pathological examination was needed. The renal biopsy showed marked endothelial cell injury with focal segmental glomerulosclerosis and accelerated VEGF expression by podocytes. Sunitinib was then given at a reduced dose. Kidney dysfunction and nephrotic syndrome are rare but serious complications of sunitinib. The present case suggests that long-term treatment with a high dose of sunitinib can cause irreversible renal dysfunction, and that low-dose treatment makes these side-effects manageable.

Recovery of renal function in a dialysis-dependent patient with microscopic polyangiitis and both myeloperoxidase anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane antibodies.

A 40-year-old man with microscopic polyangiitis developed both myeloperoxidase anti-neutrophil cytoplasmic antibodies (90 EU) and anti-glomerular basement membrane antibodies (134 EU)-positive rapidly progressive glomerulonephritis and heparin-induced thrombocytopenia. Although the patient initially showed no signs of improvement, persistent therapy including 1 g/day intravenous methylprednisolone, 50 mg/day oral prednisolone, plasma exchange, and 900 mg/day intravenous cyclophosphamide resulted in the normalization of both titers, recovery of renal function, and discontinuation of dialysis. Though previous studies showed poor outcomes in such "double-positive" patients, aggressive immunosuppression in younger patients may result in the recovery of renal function, even in those with severe renal dysfunction.