Skin Perfusion Pressure Outperforms Ankle-Brachial Index in Predicting Mortality and Cardiovascular Outcomes in Hemodialysis Patients.

AIMS: Skin perfusion pressure (SPP) and ankle-brachial index (ABI) are useful in screening for peripheral arterial disease in patients undergoing hemodialysis (HD). We compared the prognostic abilities of the SPP and ABI in predicting the composite outcomes of mortality and atherosclerotic vascular events. METHODS: This single-center prospective cohort study enrolled 258 patients undergoing HD. The patients with SPP and ABI measurements were divided into tertiles. Log-rank tests, Cox regression analyses, and discrimination parameters were used for comparisons. RESULTS: Over a median follow-up period of 3.7 (1.4-5.0) years, 119 composite events were recorded. The incidence rates of composite events were 27.5, 13.3, and 9.1 per 100 person years, respectively, across the SPP tertiles (log-rank: p＜0.001), and 23.2, 13.2, and 11.6 per 100 person years across the ABI tertiles (p=0.003). With the 3rd tertiles as references, the 1st tertiles of the SPP and ABI were significantly associated with the composite outcome (adjusted hazard ratio [aHR]: 2.58, 95% confidence interval [CI]: 1.57-4.23 and aHR: 1.70, 95% CI: 1.06-2.73, respectively). Adding the tertiles of the SPP to a predictive model with established risk factors significantly improved the model performance. This improvement was larger than that of the ABI in terms of net reclassification (0.330 vs. 0.275) and integrated discrimination (0.045 vs. 0.012). Furthermore, in patients with a normal ABI, the 1st SPP tertile (＜71 mmHg) was significantly associated with the outcome (aHR, 1.97; 95% CI, 1.13-3.41) when compared to the 3rd tertile. CONCLUSIONS: Even patients with a normal ABI have a poor prognosis if their SPP levels are low. SPP outperformed ABI in predicting mortality and cardiovascular outcomes in HD patients.

Autopsy Findings of Heterozygous Fabry Disease with the Severe Phenotype: A Case Report.

Fabry disease (FD) is an inherited X-linked lysosomal storage disorder, with hemizygous males being more severely affected than heterozygous females. Herein, we report a rare case of FD in a heterozygous female with a severe phenotype. The patient had obesity and hyperlipidemia and had her first cerebral infarction at the age of 33 years. She underwent renal biopsy and was diagnosed with FD with morphological features of focal segmental glomerulosclerosis nephropathy at the age of 34 years. Her leukocyte alpha-galactosidase A activity was 2.3 Agal/U (normal: >20 Agal/U), and genetic analysis revealed the presence of the classical phenotype. Enzyme replacement therapy (ERT) was initiated at the age of 35 years; however, peritoneal dialysis owing to end-stage renal failure occurred at the age of 37 years. The patient died of a cerebral hemorrhage at the age of 44 years. Her Mainz Severity Score Index at the time of death was 48/76, suggestive of the severe phenotype. Autopsy findings revealed remarkable globotriaosylceramide accumulation on electron microscopy, particularly in the major organs and their vascular smooth muscle cells. Regarding the vertebral arteries which sourced the cerebral hemorrhage, the effects of FD-induced vascular thickening and long-term renal failure-induced atherosclerosis were confirmed. Furthermore, the patient's vascular sclerosis was modified with acquired factors such as lifestyle-related disease associated with obesity. We recommend intensified treatment for metabolic factors simultaneous with ERT to help in delaying the progression of FD.

Low plantar skin perfusion pressure predicts long-term atherosclerotic vascular events and mortality in maintenance haemodialysis patients.

BACKGROUND AND AIMS: End-stage renal disease is associated with an increased risk of atherosclerotic vascular disease (AVD). We investigated whether low plantar skin perfusion pressure (SPP), a useful indicator of peripheral arterial disease (PAD), predicts systemic AVD events and mortality in outpatients undergoing maintenance haemodialysis (HD). METHODS: A total of 206 HD patients were enrolled and followed for 5 years. They were divided into 3 groups according to measured SPP: group 1 (G1), SPP >70 mmHg (n = 123); G2, SPP 50-70 mmHg (n = 61); and G3, SPP <50 mmHg (n = 22). RESULTS: During the follow-up period (median, 4.2 years), 56 AVD events (27.2%) and 68 deaths (33.0%) occurred. In G1, G2, and G3, the event-free survival rates were 74%, 55% and 19%, respectively, for AVD events (p < 0.01) and 73%, 54% and 26%, respectively, for mortality (p < 0.01). A Cox multivariate analysis showed that lower SPP was an independent predictor for AVD events [hazard ratio (HR) 3.12, 95% confidence interval (CI) 1.45-6.77, p < 0.01 for G3 vs. G1] and mortality (HR 3.06, 95% CI 1.57-5.98, p < 0.01 for G3 vs. G1). Furthermore, the addition of the SPP value to a model with established risk factors improved the predictability of increasing the net reclassification improvement (NRI; 0.463, p < 0.01) and integrated discrimination improvement (IDI; 0.039, p < 0.01) for AVD events. Similar results were obtained for mortality. CONCLUSIONS: Low plantar SPP can stratify risk and improve the predictability of both systemic AVD events and mortality in the maintenance HD population.

The effectiveness and safety of computed tomographic peritoneography and video-assisted thoracic surgery for hydrothorax in peritoneal dialysis patients: A retrospective cohort study in Japan.

INTRODUCTION: Albeit uncommon, hydrothorax is an important complication of peritoneal dialysis (PD). Due to paucity of evidence for optimal treatment, this study aimed to evaluate the effectiveness and safety of computed tomographic (CT) peritoneography and surgical intervention involving video-assisted thoracic surgery (VATS) for hydrothorax in a retrospective cohort of patients who underwent PD in Japan. METHODS: Of the 982 patients who underwent PD from six centers in Japan between 2007 and 2019, 25 (2.5%) with diagnosed hydrothorax were enrolled in this study. PD withdrawal rates were compared between patients who underwent VATS for diaphragm repair (surgical group) and those who did not (non-surgical group) using the Kaplan-Meier method and log-rank test. RESULTS: The surgical and non-surgical groups comprised a total of 11 (44%) and 14 (56%) patients, respectively. Following hydrothorax diagnosis by thoracentesis and detection of penetrated sites on the diaphragm using CT peritoneography, VATS was performed at a median time of 31 days (interquartile range [IQR], 20-96 days). During follow-up (median, 26 months; IQR, 10-51 months), 9 (64.3%) and 2 (18.2%) patients in the non-surgical and surgical groups, respectively, withdrew from PD (P = 0.021). There were no surgery-related complications or hydrothorax relapse in the surgical group. CONCLUSIONS: This study demonstrated the effectiveness and safety of CT peritoneography and VATS for hydrothorax. This approach may be useful in hydrothorax cases to avoid early drop out of PD and continue PD in the long term. Further studies are warranted to confirm these results.

Exit Site Infection due to Mycobacterium chelonae in an Elderly Patient on Peritoneal Dialysis.

Nontuberculous mycobacteria (NTM) are rarely isolated from peritoneal dialysis (PD)-associated catheter infections. However, NTM infection is usually difficult to treat and leads to catheter loss. Prompt diagnosis is essential for appropriate treatment. A 70-year-old Japanese man who had been on PD for 2 years and with a medical history of 2 episodes of exit site infections (ESIs) due to methicillin-resistant Staphylococcus aureus was admitted to the hospital due to suspected ESI recurrence. However, Gram staining of the pus revealed no gram-positive cocci. Instead, weakly stained gram-positive rods were observed after 7 days of incubation, which were also positive for acid-fast staining. Rapidly growing NTM Mycobacterium chelonae was isolated on day 14. Despite administering a combination antibiotic therapy, ESI could not be controlled, and catheter removal surgery was performed on day 21. Although PD was discontinued temporarily, the patient did not require hemodialysis, without any uremic symptoms. The catheter was reinserted on day 48, and PD was reinitiated on day 61. The patient was discharged on day 65. Antibiotic therapy was continued for 3 months after discharge, with no indications of recurrent infections observed. It is important to consider the risk of NTM infections in patients on PD. Acid-fast staining could be a key test for prompt diagnosis and provision of an appropriate treatment.

Severe refractory TAFRO syndrome requiring continuous renal replacement therapy complicated with Trichosporon asahii infection in the lungs and myocardial infarction: an autopsy case report and literature review.

BACKGROUND: TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis/renal failure, and organomegaly) syndrome is a systemic inflammatory disorder and unique clinicopathological variant of idiopathic multicentric Castleman disease that was proposed in Japan. Prompt diagnosis is critical because TAFRO syndrome is a progressive and life threating disease. Some cases are refractory to immunosuppressive treatments. Renal impairment is frequently observed in patients with TAFRO syndrome, and some severe cases require hemodialysis. Histological evaluation is important to understand the pathophysiology of TAFRO syndrome. However, systemic histopathological evaluation through autopsy in TAFRO syndrome has been rarely reported previously. CASE PRESENTATION: A 46-year-old Japanese man with chief complaints of fever and abdominal distension was diagnosed with TAFRO syndrome through imaging studies, laboratory findings, and pathological findings on cervical lymph node and bone marrow biopsies. Interleukin (IL)-6 and vascular endothelial growth factor (VEGF) levels were remarkably elevated in both blood and ascites. Methylprednisolone (mPSL) pulse therapy was initiated on day 10, followed by combination therapy with PSL and cyclosporine A. However, the amount of ascites did not respond to the treatment. The patient became anuric, and continuous renal replacement therapy was initiated from day 50. However, the patient suddenly experienced cardiac arrest associated with myocardial infarction (MI) on the same day. Although the emergent percutaneous coronary intervention was successfully performed, the patient died on day 52, despite intensive care. Autopsy was performed to ascertain the cause of MI and to identify the histopathological characteristics of TAFRO syndrome. CONCLUSIONS: Bacterial peritonitis, systemic cytomegalovirus infection, and Trichosporon asahii infection in the lungs were observed on autopsy. In addition, sepsis-related myocardial calcification was suspected. Management of infectious diseases is critical to reduce mortality in patients with TAFRO syndrome. Although the exact cause of MI could not be identified on autopsy, we considered embolization by fungal hyphae as a possible cause. Endothelial injury possibly caused by excessive secretion of IL-6 and VEGF contributed to renal impairment. Fibrotic changes in anterior mediastinal fat tissue could be a characteristic pathological finding in patients with TAFRO syndrome.

Successful Recovery from Spontaneous Spinal Epidural Hematoma in a Patient Undergoing Hemodialysis.

BACKGROUND Spontaneous spinal epidural hematoma (SSEH) occurs in the spinal epidural space in the absence of traumatic or iatrogenic causes, and is considered to be a neurological emergency, as spinal cord compression may lead to neurological deficit. Prompt diagnosis of SSEH can be difficult due to the variety of presenting symptoms, which may resemble those of stroke. Patients who undergo hemodialysis (HD) are at risk of bleeding due to anticoagulation during dialysis and uremia. However, SSEH in HD patients undergoing HD has rarely been reported. CASE REPORT A 70-year-old Japanese man, who has been undergoing maintenance HD for the previous three years, was admitted to Kariya Toyota General Hospital, Aichi, Japan, with acute chest and abdominal pain, and with complete paraplegia. The patient denied any recent trauma or medical procedures. Magnetic resonance imaging showed an extensive hematoma in the thoracic and lumbar epidural space, extending from T8 to L5. The patient's symptoms improved within three hours following hospital admission, and after three days without HD treatment, the SSEH decreased in size, and the patient successfully recovered without residual neurological deficits and without requiring surgery. CONCLUSIONS The management of SSEH in patients undergoing HD can be difficult, due to anticoagulation during dialysis and uremia. Prompt diagnosis and close neurological monitoring are important for appropriate management. In patients whose symptoms improve within a short period, conservative management may be considered.

Acute kidney injury caused by decompression illness successfully treated with hyperbaric oxygen therapy and temporary dialysis.

A 52-year-old Japanese male professional diver was referred to our hospital for decompression illness (DCI). After 1 h of diving operation at 20 m below sea level, he complained of dyspnea, chest pain, and abdominal pain. He dove again, intending to ease the symptoms, but the symptoms were never relieved. He dove for a total of 4 h. No neurological abnormalities were observed. Computed tomography images revealed portal venous gas and mesenteric venous gas, in addition to bubbles in the femoral veins, pelvis, lumbar canal, intracranial sinuses, and joints. Hyperbaric oxygen therapy (HBOT) was immediately administered. His symptoms improved after the first course of HBOT, however, the patient had anuria for almost 36 h after admission and exhibited acute kidney injury (AKI). Serum creatinine and creatine kinase (CK) levels were increased to maximal values of 6.16 mg/dL and 18,963 U/L, respectively. Blood flow signals were not detected on kidney Doppler ultrasound. We considered that AKI was caused by blood flow impairment and capillary leak syndrome due to DCI in addition to rhabdomyolysis secondary to arterial gas embolism in the skeletal muscles. Temporary dialysis was required to correct the acidemia and electrolyte disturbance. Diuretic phase was initiated, and the patient was put off dialysis on day 3. Serum creatinine and CK levels returned to normal on day 11. He was successfully treated without any complications. Although AKI is a rare manifestation, we should consider AKI risk in patients with severe DCI.

Peritoneal dialysis-associated catheter infection caused by Mycobacterium abscessus in an elderly patient who was successfully treated with catheter removal.

An 89-year-old Japanese man on peritoneal dialysis (PD) was suspected of having a PD-associated catheter infection. He visited the hospital because of the discharge of pus from the exit site of his catheter. Gram staining of the pus showed Gram-positive bacilli, but these were acid-fast bacilli. The rapidly growing nontuberculous mycobacteria, Mycobacterium abscessus, was isolated. PD catheter removal and debridement were immediately performed. The patient received combination antibiotic therapy. His clinical course was good, but he required hemodialysis due to the discontinuation of PD. However, the patient and his family chose not to continue hemodialysis even when the symptoms of uremia appeared. Best supportive care was arranged by his primary care physician. M. abscessus is a rare causative organism for PD-associated catheter infections and is difficult to treat. In our case, a rapid and precise diagnosis was made using acid-fast staining and Mycobacterium culture. The risk of nontuberculous mycobacterial infections should be considered in patients on PD.

Skin Perfusion Pressure and the Prevalence of Atherothrombosis in Hemodialysis Patients.

End-stage renal disease is associated with atherothrombosis (ATIS), which, in turn, can promote peripheral arterial occlusive disease (PAOD), coronary artery disease (CAD), and/or cerebrovascular disease (CVD). The aim of this study was to determine whether low plantar skin perfusion pressure (SPP) was related to ATIS among 122 patients receiving maintenance hemodialysis (HD) from March to November 2013 at our outpatient facility. We routinely measured SPP and used the value for analysis. In addition, we retrospectively evaluated the prevalence of ATIS with patients categorized to CAD, CVD, or PAOD groups. Of the 122 outpatients, ATIS was diagnosed in about half (N = 60, 49.2% vs. 62, 50.8%; average SPP, 56.6 vs. 72.9 mm Hg, respectively). These data show that SPP was significantly lower in patients with ATIS (difference, 16.3 mm Hg; P < 0.001) and there was a negative relationship between average SPPs and past history of ATIS complications. When the patients were stratified by the presence of diabetes mellitus, this trend was stronger. Particularly, receiver operating characteristic analysis of HD patients with diabetes revealed a cutoff point of 53.0 mm Hg and an area under the curve value of 0.84, with a sensitivity of 77.0% and specificity of 91.3%. Therefore, we concluded that SPP enables the evaluation of not only local PAOD, but also systemic ATIS. Moreover, we found that a cutoff point of 53.0 mm Hg was useful for detection of ATIS in HD patients.

Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis.

BACKGROUND: Serum asymmetric dimethylarginine (ADMA) levels are increased in maintenance hemodialysis patients, and this abnormality may increase cardiovascular risk. We investigated whether combined administration of oral folate and intravenous methylcobalamin in such patients is more beneficial than oral folate alone at decreasing circulating ADMA levels. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: Patients undergoing hemodialysis. INTERVENTION: 40 patients were randomly assigned to 1 of 2 groups. For 3 weeks, they received supplementation with either folate alone (15 mg/d; n = 20; folate group) or coadministered folate (15 mg/d) and methylcobalamin (500 mug after each hemodialysis treatment 3 times weekly; n = 20; methylcobalamin group). PRIMARY OUTCOMES: normalization of plasma homocysteine levels (<15 mumol/L), decrease in serum ADMA levels. SECONDARY OUTCOMES: change in augmentation index in the carotid artery and ratios of S-adenosylmethionine to S-adenosylhomocysteine (as a transmethylation indicator) and dimethylamine to ADMA (as an indicator of ADMA hydrolysis). MEASUREMENTS: Blood samples were collected under fasting conditions during the prehemodialysis procedure. RESULTS: The proportion showing normalization of plasma homocysteine levels was much greater in the methylcobalamin group (18 of 20 patients; 90%) than in the folate group (6 of 20; 30%; P < 0.001). The percentage of decrease in ADMA levels was greater in the methylcobalamin than folate group (25.4% +/- 10.2% vs 13.2% +/- 11.2%; P < 0.001). The increase in ratio of S-adenosylmethionine to S-adenosylhomocysteine was not different between the 2 groups; however, the ratio of dimethylamine to ADMA was increased in only the methylcobalamin group (P = 0.04). Augmentation index was decreased in only the methylcobalamin group (P = 0.03). LIMITATIONS: This study had an open-label nature and did not examine long-term effects of homocysteine-normalizing therapy (no clinical end points). CONCLUSION: Coadministration of intravenous methylcobalamin and oral folate in hemodialysis patients normalized hyperhomocysteinemia and decreased ADMA levels and arterial stiffness. We suggest that this regimen may have greater potential than folate alone to decrease cardiovascular risk in such patients.

Complement fragment C4d deposition in peritubular capillaries in acute humoral rejection after ABO blood group-incompatible human kidney transplantation.

BACKGROUND: Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR. METHODS: Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive. RESULTS: All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P<0.05). CONCLUSIONS: C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.

Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation.

BACKGROUND: Hyperhomocysteinaemia, which is considered to be induced by impairment of the remethylation pathway in patients with chronic renal failure (CRF), cannot be cured solely by folic acid therapy. In the present study, we investigated the additional benefit of administration of methylcobalamin, which is a co-enzyme in the remethylation pathway, on lowering total homocysteine (tHcy) plasma concentrations in haemodialysis (HD) patients receiving high-dose folic acid supplementation. METHODS: In order to assess the efficacy on lowering plasma tHcy levels (fasting concentration), 21 HD patients, were randomly assigned and provided folic acid supplementation: 15 mg/day orally (group I, n=7); methylcobalamin 500 mg intravenously after each HD, in addition to folic acid (group II, n=7); or vitamin B(6) (B(6)), 60 mg/day orally, in addition to folic acid and methylcobalamin (group III, n=7). All patients were treated for 3 weeks. A methionine-loading test was conducted before and after supplementation. The following measurements were also made before and after supplementation for each group: serum folic acid, B(6), and vitamin B(12) (B(12)) concentrations (including measurement of proportion of methylcobalamin fraction). Twelve HD patients receiving methylcobalamin alone served as the HD control group and seven healthy volunteers served as the normal control group for this study. RESULTS: In our randomized HD patients the proportions of methylcobalamin fraction (48.3+/-7.5%) and plasma vitamin B(6) concentration (2.9+/-1.1 ng/ml) were significantly lower than in the normal controls (methylcobalamin 58.7+/-2.2%, P<0.01; B(6) 20.1+/-10.8 ng/ml, P<0.01), while folic acid and vitamin B(12) were not significantly different from the normal controls. Mean percentage reduction in fasting tHcy was 17.3+/-8.4% in group I, 57.4+/-13.3% in group II, 59.9+/-5.6% in group III, and 18.7+/-7.5% in HD controls. The power of the test to detect a reduction of tHcy level was 99.6% in group II and 99.9% in group III when type I error level was set at 0.05. Groups II and III had normal results for the methionine-loading test after treatment. Treatment resulted in normalization of fasting tHcy levels (<12 ng/ml) in all 14 patients treated by the combined administration of methylcobalamin and supplementation of folic acid regardless of whether there was supplementation of vitamin B(6). CONCLUSION: The benefit of methylcobalamin administration on lowering plasma tHcy levels in HD patients was remarkable. Our study suggested that both supplementations of high-dose folic acid and methylcobalamin are required for the remethylation pathway to regain its normal activity. This method could be a therapeutic strategy to combat the risk associated with atherosclerosis and cardiovascular disease in patients with chronic renal failure.