Unfavorable effects of history of volume overload and late referral to a nephrologist on mortality in patients initiating dialysis: a multicenter prospective cohort study in Japan.

BACKGROUND: Patients with late referral and positive history of volume overload may have a poor prognosis after initiating dialysis due to insufficient and/or inadequate management of complications of renal failure and the lack of better dialysis preparation. Little is known about the influence of the relationship between history of volume overload and late referral on prognosis. METHODS: We analyzed 1475 patients who had initiated dialysis for the first time from October 2011 to September 2013. late referral was defined as referral to a nephrologist < 3 months before dialysis initiation. The major outcomes were all-cause death and deaths due to cardiovascular diseases (CVD). The impact of late referral and history of volume overload on all-cause mortality was assessed by Cox proportional hazards models. RESULTS: Among 1475 patients, the mean patient age was 67.5 years. During the median follow-up of 2.2 years, 260 deaths occurred; 99 were due to CVD. Cox proportional hazards models demonstrated that late referral (adjusted hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.00-1.82) and history of volume overload (adjusted HR, 1.39; 95% CI, 1.06-1.81) were risk factors for all-cause mortality. Furthermore, late referral coexisting was associated with a history of volume overload increased mortality (adjusted HR, 2.10; 95% CI, 1.39-3.16 versus absence of late referral without history of volume overload) after adjusting for age, sex, diabetes, atherosclerotic disease, and laboratory values. CONCLUSIONS: Both late referral and history of volume overload were associated with increased risks of all-cause mortality. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN000007096). Registered 18 January 2012, retrospectively registered. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000008349 .

A case of acute renal failure of multiple myeloma due to monoclonal type I cryoglobulinemia with thrombotic microangiopathy.

The term cryoglobulinemia (CG) is used to refer to vasculitis due to so-called mixed cryoglobulins containing immune complexes. Although most cases of monoclonal CG, called type I CG, are asymptomatic, purpura, skin ulcers, and renal failure develop in some cases. Hematological disorders are the underlying diseases in most cases, on which the therapeutic strategies available and the prognosis of patients depends. We here report a case of a 47-year-old man who had pain in both his ankles, with palpable purpura and epistaxis, and presented with acute renal failure. Monoclonal immunoglobulin (Ig) G-κ protein was detected and cryoglobulin was also positive. Renal biopsy revealed emboli with a fibrillar structure in the glomeruli and renal tubule lumina. The complication of thrombotic microangiopathy (TMA) occurred during the course. Therefore, plasma exchange and hemodialysis were added to methylprednisolone pulse therapy. The treatment was successful, dissipating the purpura. However, the purpura relapsed and renal dysfunction progressed when the administration of oral steroids was tapered. Bone marrow biopsy was performed again, which indicated an increase in abnormal plasma cells. The patient was finally diagnosed as multiple myeloma. Then, bortezomib-dexamethasone therapy was initiated. This is the first case of type I CG with monoclonal IgG complicated by TMA during the course; it provides insight into the pathogenesis of renal dysfunction associated with type I CG.

Predicting the outcome of chronic kidney disease by the estimated nephron number: the rationale and design of PRONEP, a prospective, multicenter, observational cohort study.

BACKGROUND: The nephron number is thought to be associated with the outcome of chronic kidney disease (CKD). If the nephron number can be estimated in the clinical setting, it could become a strong tool to predict renal outcome. This study was designed to estimate the nephron number in CKD patients and to establish a method to predict the outcome by using the estimated nephron number. METHODS/DESIGN: The hypothesis of this study is that the estimated nephron number can predict the outcome of a CKD patient. This will be a multicenter, prospective (minimum 3 and maximum 5 years follow-up) study. The subjects will comprise CKD patients aged over 14 years who have undergone a kidney biopsy. From January 2011 to March 2013, we will recruit 600 CKD patients from 10 hospitals belonging to the National Hospital Organization of Japan. The primary parameter for assessment is the composite of total mortality, renal death, cerebro-cardiovascular events, and a 50% reduction in the eGFR. The secondary parameter is the rate of eGFR decline per year. The nephron number will be estimated by the glomerular density in biopsy specimens and the renal cortex volume. This study includes one sub-cohort study to establish the equation to calculate the renal cortex volume. Enrollment will be performed at the time of the kidney biopsy, and the data will consist of a medical interview, ultrasound for measurement of the kidney size, blood or urine test, and the pathological findings of the kidney biopsy. Patients will continue to have medical consultations and receive examinations and/or treatment as usual. The data from the patients will be collected once a year after the kidney biopsy until March 2016. All data using this study are easily obtained in routine clinical practice. DISCUSSION: This study includes the first trials to estimate the renal cortex volume and nephron number in the general clinical setting. Furthermore, this is the first prospective study to examine whether the nephron number predicts the outcome of CKD patients. The results from this study should provide powerful new tools for nephrologists in routine clinical practice. TRIAL REGISTRATION: UMIN-Clinical Trial Registration, UMIN000004784.

Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury.

AIM: Cot/Tpl2, a serine/threonine (Ser/Thr) protein kinase, has been classified as a member of the mitogen-activated protein kinase (MAPK) family, and is known to have a pleiotropic role. Many studies have reported the involvement of Cot/Tpl2, mainly as a member of the Toll-like receptor (TLR) 4 signalling pathway in lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) production. At the same time, it is also related to the caspase-dependent apoptotic pathway. Thus, the role of Cot/Tpl2 in ischaemia/reperfusion injury (IRI) in which TNF-alpha and apoptosis are the major pathogenetic factors was studied. METHODS: IRI was induced in wild type (Cot/Tpl2(+/+)) mice and in Cot/Tpl2-deficient (Cot/Tpl2(-/-)) mice. The extent of tubular injury and renal function were studied. TNF-alpha production, neutrophil infiltration and apoptosis were also compared between the two groups. RESULTS: Cot/Tpl2(-/-) mice had preserved renal function compared with wild type mice in IRI. Although Cot/Tpl2 was phosphorylated in IRI and in the cultured tubular epithelial cells (TEC) after stimulation with LPS and hydrogen peroxide, there were no significant differences in terms of TNF-alpha production, neutrophil infiltration or MAPK activation between Cot/Tpl2(+/+) and Cot/Tpl2(-/-) mice. In contrast, Cot/Tpl2(-/-) mice showed obviously reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling positive cells and cleaved caspase-3 positive cells. Furthermore, Cot/Tpl2-deficient TECs demonstrated significantly less caspase-3 activation after hydrogen peroxide stimulation with comparable caspase-9 activation to wild type TEC. CONCLUSION: Cot/Tpl2 did not function as a member of MAPK family, but as a promoter of apoptosis in IRI. These results suggest that Cot/Tpl2 could be a possible therapeutic target in IRI.

[Case of thrombotic thrombocytopenic purpura with a positive Coomb test].

We report a case of thrombotic thrombocytopenic purpura (TTP) with a positive Coombs' test. A 59-year-old female was admitted to our hospital in February, 1997 with symptoms of heart failure. Ultrasound cardiography showed moderate pericardiac effusion and she was diagnosed as having pericarditis. After admission she had anorexia and her urine volume was reduced. Laboratory tests showed anemia and thrombocytopenia. Her Coombs' test result was positive. Her renal function gradually worsened and her conscious level was reduced. We diagnosed her as TTP and judged that she needed hemodialysis. We performed plasma exchange and started steroid therapy. The renal biopsy was compatible with TTP. After treatment, her level of consciousness improved, but her renal function did not improve. On the 51st hospital day she fell into acute respiratory distress syndrome (ARDS) and entered ICU. We considered ARDS caused by infection and continued treatment, but she died of shock and lactate acidosis. Activity of von Willebrand factor-cleaving protease in our case was 15% before the first PE, and 25 % just before death. A case of TTP without collagen disease usually shows a negative Coombs' test result. We think that this was a rare case in which autoimmune hemolytic anemia was supervened with TTP.