A case of primary aldosteronism with excessive secretion of renin that was unmasked by kidney transplantation.

A 42-year-old man showed marked hypokalemia after kidney transplantation. He was diagnosed with hypertension and suffered from acute myocardial infarction at 33 and 38 years of age. At 40 years of age, hemodialysis was introduced. A left adrenal tumor was noted and suspected as a non-functional adrenal adenoma at that time. Therefore, he received a living-donor kidney transplant at 42 years of age. After kidney transplantation, the serum creatinine level dropped. His blood pressure remained high, and the serum potassium level decreased. The PRA and PAC were elevated, and ARR was not elevated. Based on the results of various confirmatory tests and vein sampling, he was diagnosed with excessive secretion of renin from the native kidneys that was complicated by primary aldosteronism (PA), and left nephrectomy and adrenalectomy were performed. The overproduction of aldosterone in the resected adrenal adenoma and over secretion of renin in the kidney with arteriolosclerosis were immunohistologically confirmed. After surgery, the PAC decreased, but the PRA did not decrease. The postoperative serum potassium level improved, and the blood pressure was well controlled with a small dose of medication. This is the first reported case of PA with hyperreninemia after kidney transplantation. It should be noted that PA in dialysis patients and kidney transplant recipients may not fulfill the usual diagnostic criteria of an elevated ARR. In such patients, PA should be suspected based on the absolute value of the PAC and responsiveness to ACTH stimulation, and adrenal and renal vein sampling is required for a definitive diagnosis.

A Patient with Mitochondrial Disease on Dialysis with Long-term Follow-up of Cardiomyopathy: An Autopsy Case Report.

A 59-year-old man developed diabetes at 24 years old and underwent hemodialysis at 42 years old. At 54 years old, cardiac dysfunction with left ventricular hypertrophy was detected, followed by complete atrioventricular block at 57 years old. The patient was diagnosed with mitochondrial disease based on a myocardial biopsy and the presence of a mitochondrial DNA mutation (3243A>G). He died of septic shock at 59 years old, and an autopsy confirmed mitochondrial cardiomyopathy. If progressive cardiac hypertrophy and conduction disturbances are observed in patients with diabetes mellitus on long-term hemodialysis, mitochondrial disease needs to be considered.

Risk of Cerebral Infarction in Japanese Hemodialysis Patients: Miyazaki Dialysis Cohort Study (MID study).

BACKGROUND/AIMS: Predictors including the preventive effects of antiplatelet and anticoagulant drugs on cerebral infarction (CI) events have not yet been clarified in dialysis patients. The aim of the present study was to examine the risk of CI and preventive effects of these drugs in Japanese hemodialysis patients. METHODS: Patients receiving maintenance hemodialysis (n=1,551, median age (interquartile range), 69.0 (59.0-78.0) years; 41.5% female) were enrolled in the Miyazaki Dialysis Cohort Study and prospectively followed-up for 3 years. Kaplan-Meier and Cox's regression analyses were used to clarify the risk of CI. RESULTS: Eighty-four patients developed CI at an incidence of 21.5/1000 patients per year. The presence of a previous history of CI, atrial fibrillation (AF), and diabetes mellitus in addition to age were also identified as predictive factors for new CI, whereas no relationship was observed between antiplatelet and/or anticoagulant usage and CI. Furthermore, no significant difference was noted in the frequency of CI events between patients with AF who received warfarin and those who did not. CONCLUSIONS: The incidence of CI was higher in dialysis patients with a previous history of CI and AF; however, the preventive effects of antiplatelet/anticoagulant drugs on the development of CI were not evident.

New-onset haematoproteinuria in a 63-year-old man with intraperitoneal lymph node enlargement.

A 63-year-old man was referred to our hospital because of renal dysfunction with haematoproteinuria. Intraperitoneal lymph node enlargement was also noted. M protein was not detected by electrophoresis of his serum and urine; however, an increase in the κ/λ ratio was detected by free light-chain assay. Percutaneous kidney biopsy was performed, and the patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Lymph node biopsy showed follicular lymphoma. Urinalysis findings improved after treatment of the lymphoma. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits is rarely considered to be associated with haematological disease. We report a case of lymphoma-associated proliferative glomerulonephritis with monoclonal immunoglobulin deposits with light-chain abnormality detected by free light-chain assay, but not by electrophoresis.

Glycaemic control is a predictor of infection-related hospitalization on haemodialysis patients: Miyazaki Dialysis Cohort study (MID study).

AIM: Although infection is the second leading cause of death in maintenance haemodialysis patients, the effects of glycaemic control on infection in diabetic haemodialysis patients have not yet been examined in detail. We examined the relationship between diabetes or glycemic control and infection-related hospitalization (IRH) in haemodialysis patients. METHODS: Patients receiving maintenance haemodialysis (n = 1551, 493 diabetic patients) were enrolled in this prospective cohort study in December 2009 and followed-up for 3 years. IRH during the follow-up period was abstracted from medical records. Kaplan-Meier and Cox regression analyses were used to investigate the relationship between diabetes or glycaemic control and IRH. RESULTS: The Kaplan-Meier analysis revealed that the risk of IRH was significantly higher in haemodialysis patients with diabetes, particularly in those with poorly controlled HbA1c levels (HbA1c ≥ 7.0%), than in haemodialysis patients without diabetes. When patients with ≥HbA1c 7.0% were divided into two groups using a median value of HbA1c, the risk of IRH was significantly higher in those with the poorest glycaemic control (HbA1c ≥ 7.4%), an older age, or lower albumin levels. The multivariable-adjusted hazard ratio for the risk of IRH was not higher in the second criteria of HbA1c (HbA1c 7.0-7.3%), but was significantly higher in the group with the poorest glycaemic control (HbA1c ≥ 7.4%) than in those in the good control criterion (HbA1c < 7.0%). CONCLUSIONS: Although diabetes is a risk factor for IRH among maintenance haemodialysis patients, the relationship between glycaemic control and the risk of infection is not linear. Therefore, the risk of infection may increase in a manner that is dependent on the glycaemic control threshold.

Candidate gene analysis using genomic quantitative PCR: identification of ADAMTS13 large deletions in two patients with Upshaw-Schulman syndrome.

Direct sequencing is a popular method to discover mutations in candidate genes responsible for hereditary diseases. A certain type of mutation, however, can be missed by the method. Here, we report a comprehensive genomic quantitative polymerase chain reaction (qPCR) to complement the weakness of direct sequencing. Upshaw-Schulman syndrome (USS) is a recessively inherited disease associated with severe deficiency of plasma ADAMTS13 activity. We previously analyzed ADAMTS13 in 47 USS patients using direct sequencing, and 44 of them had either homozygous or compound heterozygous mutations. Then, we sought to reveal more extensive defects of ADAMTS13 in the remaining three patients. We quantified copy numbers of each ADAMTS13 exon in the patients by using genomic qPCR. Each primer pair was designed to contain at least one of the two primers used in direct sequencing, to avoid missing any exonic deletions. The qPCR demonstrated heterozygous loss of exons 7 and 8 in one patient and exon 27 in the other, and further analysis revealed c.746_987+373del1782 and c.3751_3892+587del729, respectively. Genomic qPCR provides an effective method for identifying extensive defects of the target genes.

Validation of a newly proposed histopathological classification in Japanese patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: A new histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis was recently proposed. We evaluated the predictive value of this classification for renal outcome in Japanese patients. METHODS: We enrolled 122 patients with ANCA-associated glomerulonephritis diagnosed at several institutions in Japan between January 2000 and March 2010. Twenty patients were excluded because of observation durations of <1 year, and/or because their biopsy specimens contained <10 glomeruli. Renal biopsy specimens were categorized into four classes according to the proposed classification. We evaluated the predictive value of immunohistochemical staining for α-smooth muscle actin (SMA), Wilm's tumor 1 (WT1), CD68, and cytokeratin for end-stage renal disease (ESRD). RESULTS: The study population included 54 men and 48 women. Age, estimated glomerular filtration rate (eGFR), and proteinuria were 66.3 ± 11.3 years, 21.6 ml/min. and 1.10 g/24 h, respectively. Eighty-six patients were positive for myeloperoxidase-ANCA, five were positive for proteinase 3-ANCA, and 11 were negative for both antibodies. Median follow-up time was 41.0 months. Twenty-three patients (22.5%) developed ESRD during the follow-up period. Twelve patients died during follow up; 7/12 patients developed ESRD before death, and 5/12 patients died without ESRD. The incidence of ESRD increased with sequential categories: focal, 2/46 (4.3%); crescentic, 9/32 (28%); mixed, 8/18 (44%); and sclerotic, 4/6 (67%). The focal class had the best renal survival and the sclerotic class had the worst renal survival (p < 0.001). Kaplan-Meier renal survival analysis was similar to that of the new classification system proposal. In the multivariate analysis, the classification system tended to be a prognostic factor for ESRD (p = 0.0686, crescentic, mixed and sclerotic vs. focal, hazard ratio (HR) [95% confidence interval, CI]; 2.99 [0.61-22.7], 5.04 [1.11-36.4] and 9.93 [1.53-85.7], respectively). α-SMA-positivity also tended to be associated with ESRD (p = 0.1074). CONCLUSION: The new histopathological classification was associated with eGFR at 1 year and tended to be associated with ESRD in our Japanese cohort with ANCA-associated glomerulonephritis. α-SMA positivity might be an additional prognostic factor for ESRD.

Electrocardiographic assessment of incident atrial fibrillation in hemodialysis patients.

The prevalence and incidence of atrial fibrillation in hemodialysis patients have recently increased, but there are few evident predictors of incident atrial fibrillation in hemodialysis patients. The purpose of this study was to determine whether electrocardiographic findings can predict the development of atrial fibrillation in hemodialysis patients. A cohort of 299 patients (age, 63.1 ± 14.0 years; men, 59.2%; duration of hemodialysis, 80.3 ± 77.7 months) on hemodialysis therapy in December 2004 was included. To determine the incidence of atrial fibrillation, electrocardiographic findings were checked regularly every 1-3 months through December 2009. To detect paroxysmal atrial fibrillation, we examined electrocardiograms any time a patient had cardiac symptoms. Cox proportional hazard analysis was used to determine independent variables for the onset of atrial fibrillation. At the time of enrollment, 37 patients had pre-existing atrial fibrillation, for a prevalence rate of 12.4%. On the other hand, newly developed atrial fibrillation during the 5-year follow-up was determined in 45 patients, for an incidence rate of 4.37/100 patient-years. In multivariate analysis, age (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07) and the presence of a P-terminal force >0.04 mm/s as an electrocardiographic finding (hazard ratio, 4.89; 95% confidence interval, 2.54 to 9.90) were independently associated with new-onset atrial fibrillation. The prevalence and incidence rates of atrial fibrillation are high in maintenance hemodialysis patients. Age and the presence of a P-terminal force >0.04 mm/s as an electrocardiographic finding may predict new-onset atrial fibrillation in these patients.

Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Approximately 10% of cases are classified as atypical due to the absence of Shiga toxin-producing bacteria as a trigger. Uncontrolled activation of the complement system plays a role in the pathogenesis of atypical HUS (aHUS). Although many genetic studies on aHUS have been published in recent years, only limited data has been gathered in Asian countries. We analyzed the genetic variants of 6 candidate genes and the gene deletion in complement factor H (CFH) and CFH-related genes, examined the prevalence of CFH autoantibodies and evaluated the genotype-phenotype relationship in 10 Japanese patients with aHUS. We identified 7 causative or potentially causative mutations in CFH (p.R1215Q), C3 (p.R425C, p.S562L, and p.I1157T), membrane cofactor protein (p.Y189D and p.A359V) and thrombomodulin (p.T500M) in 8 out of 10 patients. All 7 of the mutations were heterozygous and four of them were novel. Two patients carried CFH p.R1215Q and 3 other patients carried C3 p.I1157T. One patient had 2 causative mutations in different genes. One patient was a compound heterozygote of the 2 MCP mutations. The patients carrying mutations in CFH or C3 had a high frequency of relapse and a worse prognosis. One patient had CFH autoantibodies. The present study identified the cause of aHUS in 9 out of 10 Japanese patients. Since the phenotype-genotype correlation of aHUS has clinical significance in predicting renal recovery and transplant outcome, a comprehensively accurate assessment of molecular variation would be necessary for the proper management of aHUS patients in Japan.

Elevated osteoprotegerin levels predict cardiovascular events in new hemodialysis patients.

BACKGROUND: Patients on hemodialysis (HD) frequently experience cardiovascular events associated with vascular calcification. We investigated the involvement of osteoprotegerin (OPG), an inhibitor of vascular calcification, in the incidence of cardiovascular events and mortality among new HD patients. METHODS: We conducted a prospective cohort study of the association of serum OPG levels with morbidity and mortality in subjects who became new HD patients between June 2000 and May 2006. RESULTS: A total of 99 patients (age 58.9 +/- 14.6 years, 65 male, 34 female) were prospectively followed up for 41.5 +/- 20.2 months. During this period, 27 patients developed cardiovascular events and 12 died of causes related to cardiovascular disease. When divided into 2 groups according to OPG levels, the high OPG group showed a higher prevalence of cardiovascular morbidity and mortality compared with the low OPG group. Cox's proportional hazards analysis associated the new onset of cardiovascular events with the high OPG group (HR 2.88, 95% CI 1.09-7.62, p = 0.033). Furthermore, the high OPG group at the start of HD was significantly associated with older age, male gender and a high aortic calcification index. CONCLUSIONS: Elevated levels of serum OPG in new HD patients may predict subsequent cardiovascular events.

Outcome of ANCA-associated primary renal vasculitis in Miyazaki Prefecture.

OBJECT: We examined the prognosis of patients with onset of new primary renal vasculitis (PRV) in Miyazaki Prefecture. PATIENTS AND METHODS: We enrolled and followed-up 56 patients (age, 70.4 +/- 10.9 years, mean +/- SD) with onset of new PRV between January 2000 and December 2004, for a median of 24 months. Patients with PRV were defined according to the EUVAS (European Systemic Vasculitis Study Group) criteria. Outcome and factors predicting unfavorable outcome of death were examined. RESULTS: Among the patients, 25% (n=14) required dialysis therapy immediately at the start of immunosuppressive therapy and of these, renal function recovered in only 3 and 6 died during the first admission. On the other hand, 75% (n=42) did not require immediate dialysis, but 8 patients were introduced to dialysis therapy thereafter. At the end of follow-up, 26 (46%) had survived without dialysis, 10 (18%) were dependent on dialysis and 20 (36%) had died. Infection was the major cause of death (n=11) . The Cox proportional hazards model showed that the presence of lung lesions and immediate dialysis therapy conferred poorer survival rates (HR, 3.32, 95% CI, 1.14 to 9.71; HR 2.73, 95% CI, 1.03 to 7.23, respectively). CONCLUSION: A poor survival rate is independently associated with the presence of lung lesions and advanced renal failure at the start of immunosuppressive therapy in patients with PRV. Half of the deaths were due to infection. Thus, PRV should be identified at an early stage and the treatment protocol should prevent infectious complications. These measures should improve the prognosis of patients with PRV.

Risk factors of the progression of abdominal aortic calcification in patients on chronic haemodialysis.

BACKGROUND: Vascular calcification is an independent determinant of cardiovascular events in maintenance haemodialysis (HD) patients. It is not known whether acute changes of the serum calcium concentration before and after HD (DeltaCa) are associated with the development of aortic calcification. METHODS: We enrolled 71 patients dialysed with a dialysate with 3.0 mEq/l calcium and determined their aortic calcification index (ACI) by abdominal computed tomography twice at an interval of 3 years. To identify the factors contributing to the rate of progression of aortic calcification, we analysed the average values for clinical and laboratory data obtained between the first and second evaluations of ACI. RESULTS: The second ACI (mean+/-SD: 80.2+/-63.9) was significantly greater than the first ACI (61.0+/-61.0) after an interval of 35.8+/-4.2 months. The annualized change of ACI (DeltaACI/year) was significantly and directly associated with the DeltaCa and C-reactive protein (CRP) (both P<0.001, P for trend). Stepwise multivariate regression analysis revealed that DeltaACI/year was positively and independently associated with CRP, presence of diabetes mellitus and DeltaCa, but negatively associated with a premenopausal status in women. Similarly, DeltaCa was positively and independently associated with DeltaACI/year and the ultrafiltration rate, but was negatively associated with pre-HD Ca. CONCLUSION: The increase of serum calcium after HD was related to the rate of progression of aortic calcification. Excess calcium is transferred into patients on HD when using a dialysate of 3.0 mEq/l calcium. This may be a risk factor for the development of vascular calcification.

Incidence of ANCA-associated primary renal vasculitis in the Miyazaki Prefecture: the first population-based, retrospective, epidemiologic survey in Japan.

Clinicoepidemiological manifestations of the vasculitides differ geographically. According to a nationwide, hospital-based survey in Japan, the prevalence of microscopic polyangiitis (MPA) and/or renal-limited vasculitis (RLV) is much higher than that of Wegener's granulomatosis (WG). However, little is known about the incidence of antineutrophil cytoplasmic autoantibodies (ANCA)-associated primary renal vasculitis (PRV) in Japan. The incidence of PRV was retrospectively determined by a population-based method in Miyazaki Prefecture in Japan between 2000 and 2004. PRV was defined according to the following criteria from the European Systemic Vasculitis Study Group: (1) new patients with WG, MPA, Churg-Strauss syndrome (CSS), or RLV, (2) renal involvement attributable to active vasculitis, and (3) ANCA considered positive if the disease was not histologically confirmed. The numbers of patients with PRV in the years 2000, 2001, 2002, 2003, and 2004 were 9, 9, 9, 16, and 13, respectively. The male to female ratio was 24:32 and the average age was 70.4 +/- 10.9 (mean +/- SD) yr. The estimated annual incidence of PRV was 14.8 (95% confidence interval [CI] 10.8 to 18.9) and 44.8 (95% CI 33.2 to 56.3) per million adults (>15 yr old) and seniors (>65 yr old), respectively. Ninety-one percent of the patients were myeloperoxidase (MPO)-ANCA positive, but none were positive for proteinase 3 (PR3)-ANCA. There were no WG or CSS patients. The incidence of PRV did not differ between Japan and Europe, but WG was not widespread in Japan. Furthermore, the ratio of serum MPO to PR3-ANCA among Japanese with PRV was much higher than that found among European and US patients.

Nephrotic syndrome caused by membranous nephropathy: response to a short course of cyclophosphamide alternating with prednisolone.

OBJECTIVE: The optimal duration of immunosuppressive therapy and the timing of treatment for treating membranous nephropathy (MN) have yet to be established. We examined outcomes of a short course of cyclophosphamide alternating with prednisolone for MN patients with nephrotic syndrome. METHODS AND PATIENTS: Cyclophosphamide (2 mg/kg/day for 8 weeks) combined with prednisolone (1 mg/kg every 48 hours for 8 weeks, then tapering off for 1 year) was prescribed for 28 MN patients (12 men and 16 women; mean age 52.4+/-2.25 years SEM). We first evaluated the response rates to this combined therapy, then compared the clinical characteristics of those who achieved remission (group A) with those who did not (group B) within 6 months of the start of treatment. RESULTS: The incidences of complete and partial remission increased with the follow-up period; 32 and 21% by 6 months, 54 and 29% by 12 months, and 79 and 11% by 24 months, respectively. Serum IgG (906+/-100.8 versus 562+/-66.1 mg/day; p<0.01) was significantly higher in group A, and the selectivity index (C(IgG)/C(albumin) 0.16+/-0.015 versus 0.30+/-0.040; p<0.01), significantly lower. Nephrotic syndrome persisted in 3 group B patients (23%), who finally had impaired renal function. CONCLUSION: MN patients with nephrotic syndrome responded favorably to a short course of cyclophosphamide combined with prednisolone. The serum IgG level and selectivity index may serve as markers of early response to this treatment.