Comorbidities Can Predict Mortality of Kidney Transplant Recipients: Comparison With the Charlson Comorbidity Index.

BACKGROUND: Comorbid conditions are important in the survival of kidney transplant recipients. The weights assigned to comorbidities to predict survival may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified Charlson comorbidity index (CCI) in renal allograft recipients (mCCI-KT), thereby improving risk stratification for mortality. METHODS: A total of 3765 recipients in a multicenter cohort were included to develop a comorbidity score. The weights of the comorbidities, per the CCI, were recalibrated using a Cox proportional hazards model. RESULTS: Peripheral vascular disease, liver disease, myocardial infarction, and diabetes in the CCI were selected from the Cox proportional hazards model. Thus, the mCCI-KT included 4 comorbidities with recalibrated severity weights. Whereas the CCI did not discriminate for survival, the mCCI-KT provided significant discrimination for survival using the Kaplan-Meier method and Cox regression analysis. The mCCI-KT showed modest increases in c-statistics (0.54 vs 0.52, P = .001) and improved net mortality risk reclassification by 16.3% (95% confidence interval, 3.2-29.4; P = .015) relative to the CCI. CONCLUSION: The mCCI-KT stratifies the risk for mortality in renal allograft recipients better than the CCI, suggesting that it may be a preferred index for use in clinical practice.

Haploinsufficiency of cathepsin D leads to lysosomal dysfunction and promotes cell-to-cell transmission of α-synuclein aggregates.

Lysosomal dysfunction has been implicated both pathologically and genetically in neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease (PD). Lysosomal gene deficiencies cause lysosomal storage disorders, many of which involve neurodegeneration. Heterozygous mutations of some of these genes, such as GBA1, are associated with PD. CTSD is the gene encoding Cathepsin D (CTSD), a lysosomal protein hydrolase, and homozygous CTSD deficiency results in neuronal ceroid-lipofuscinosis, which is characterized by the early onset, progressive neurodegeneration. CTSD deficiency was also associated with deposition of α-synuclein aggregates, the hallmark of PD. However, whether partial deficiency of CTSD has a role in the late onset progressive neurodegenerative disorders, including PD, remains unknown. Here, we generated cell lines harboring heterozygous nonsense mutations in CTSD with genomic editing using the zinc finger nucleases. Heterozygous mutation in CTSD resulted in partial loss of CTSD activity, leading to reduced lysosomal activity. The CTSD mutation also resulted in increased accumulation of intracellular α-synuclein aggregates and the secretion of the aggregates. When α-synuclein was introduced in the media, internalized α-synuclein aggregates accumulated at higher levels in CTSD+/- cells than in the wild-type cells. Consistent with these results, transcellular transmission of α-synuclein aggregates was increased in CTSD+/- cells. The increased transmission of α-synuclein aggregates sustained during the successive passages of CTSD+/- cells. These results suggest that partial loss of CTSD activity is sufficient to cause a reduction in lysosomal function, which in turn leads to α-synuclein aggregation and propagation of the aggregates.

Rhabdomyolysis associated with initiation of febuxostat therapy for hyperuricaemia in a patient with chronic kidney disease.

WHAT IS KNOWN AND OBJECTIVE: Febuxostat is now recommended as the first-line pharmacological urate-lowering therapy for gout in the American College of Rheumatology guidelines. There is no case of rhabdomyolysis associated with febuxostat among reported side effects of the drug. Our objective is to report on a case of rhabdomyolysis associated with initiation of febuxostat in a patient with chronic kidney disease (CKD). CASE SUMMARY: A 73-year-old male patient visited our emergency room due to progressive weakness in both lower extremities starting 3 days earlier. Ten days before presentation, his primary physician had changed his prescription from allopurinol to febuxostat (80 mg) because of poor control of uric acid levels. There was tenderness in both thighs. Initial creatinine kinase (CK) was 7652 U/L (0-170 U/L), and a bone scan using (99m) Tc-HDP revealed strong uptake in soft tissues in both thighs and buttocks. Electromyography (EMG) and nerve conduction velocity (NCV) showed abnormal spontaneous activities (ASA), suggesting myopathy, not nerve damage. On day 7 of admission, after conservative management and febuxostat withdrawal, he could walk on the ward. He is being followed in our clinic as an outpatient with no sequelae. WHAT IS NEW AND CONCLUSION: This report is first case of rhabdomyolysis associated with initiation of febuxostat. Febuxostat should be withdrawn when rhabdomyolysis is confirmed.

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates.

Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, α-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of α-synuclein aggregates in autophagosomes. Neuronal toxicity caused by α-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of α-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

A case of isolated bilateral pulmonary arterial calcification diagnosed in utero.

We report a very rare case of isolated multiple pulmonary arterial calcification with severe bilateral peripheral pulmonary arterial stenosis diagnosed in utero. Despite treatment with bisphosphonate for 6 months, systolic right ventricular pressure increased persistently and surpassed left ventricular pressure. After successful bilateral pulmonary arterioplasty at 13 months of age, the patient showed decreased systolic right ventricular pressure with normal interventricular septal configuration. This is the first case report for an isolated pulmonary artery calcification without other arterial calcification proven by non-contrast computed tomography of a living patient.

Development of pulmonary arteriovenous fistulas after bidirectional cavopulmonary shunt.

BACKGROUND: A high incidence of pulmonary arteriovenous fistulas (PAVF) has been reported after bidirectional cavopulmonary shunt (BCPS) or total cavopulmonary shunt (TCPS; BCPS in patients with interrupted inferior vena cava). However, the definite diagnostic criteria or standard diagnostic modality of PAVF has not yet been defined. The goal of this study was to evaluate the diagnostic modalities and the prevalence of PAVF. METHODS: We selected 10 patients with TCPS and 27 patients with BCPS. Lung perfusion scan, contrast echocardiogram, and pulmonary angiogram were performed. The results were compared among groups of patients and among each diagnostic modality. RESULTS: All 10 patients with TCPS and 16 and 13 patients with BCPS showed positive results on contrast echocardiograms and lung scans, respectively. Six patients with TCPS and 4 patients with BCPS showed positive results on pulmonary angiograms. All patients with TCPS developed subclinical or clinical PAVF and 19 patients with BCPS developed subclinical PAVF and none of them had clinical PAVF during the short-term follow-up. CONCLUSIONS: Most patients with bidirectional cavopulmonary anastomosis have subclinical evidence of right-to-left intrapulmonary shunting. This problem can be demonstrated with various diagnostic modalities.

Natural course of supravalvar aortic stenosis and peripheral pulmonary arterial stenosis in Williams' syndrome.

We investigated the catheterization and angiographic findings of 26 patients with Williams' syndrome to evaluate the natural course of supravalvar aortic stenosis and peripheral pulmonary arterial stenosis. The severity of the stenosis was correlated with age and body surface area in terms of the pulmonary arterial index, right ventricular systolic pressure, sinutubular ratio (ratio of measured to mean normal diameter of sinutubular junction), and systolic pressure gradient across the sinutubular junction. In patients with pulmonary arterial stenosis (n=20), right ventricular systolic pressure tended to decrease, and pulmonary arterial index increased, with increase in age and body surface area. Between the groups with and without pulmonary arterial stenosis, there was significant difference in age (mean 4.70 vs. 9.87, p=0.019), body surface area (0.62 vs. 1.16, p=0.002), pulmonary arterial index (152 vs. 317, p=0.002) and right ventricular systolic pressure (73.9 vs. 33.0, p=0.006). As all patients showed similar diameters at the sinutubular junction regardless of age and body size, sinutubular ratio decreased with increases in age and body surface area. The group with abnormal coronary arteries (n=7) had smaller sinutubular ratio (0.46 vs. 0.61, p=0.021) and higher pressure gradients between the left ventricle and the aorta (67.6 vs. 42.2, p=0.023) than did the group with normal coronary arteries. Stenosis of a coronary artery, or a branch of the aortic arch, was observed only in three patients with diffuse aortic stenosis. Our results suggest that, with time, peripheral pulmonary arterial stenosis tends to improve, and supravalvar aortic stenosis to progress. Failure of growth of the sinutubular junction might be responsible for the progression of the aortic lesion. Progression of the aortic lesion may be associated with involvement of the coronary arteries.

Rare variants of divided right ventricle with sequestered apical trabecular component.

The right ventricle may be divided into two or more compartments by various structures in various ways. Rarely, the apical trabecular component may be sequestered from the rest of the right ventricle. We report 4 cases with different underlying lesions that share a common pathology of apical sequestration of the right ventricle resulting in diverse hemodynamic consequences. Case 1 had pulmonary valve stenosis. The apical sequestration of the right ventricle resulted in no significant hemodynamic consequence. Case 2 had multiple defects in the muscular ventricular septum. The volume of left-to-right shunt seemed to be reduced because of the commitment of some of the defects to the sequestered cavity. Case 3 had a large defect in the trabecular septum. As the defect involved the whole septum that was related to the sequestered right ventricular apex, the left ventricle together with the sequestered right ventricle formed a boot-shaped chamber. Hemodynamically, the muscular shelf was an interventricular septum. Case 4 had a coronary artery fistula to an isolated cavity that occupied the apical region of the right ventricle. The pathology was similar to the case that was reported as a five-chambered heart. The abnormal cavity was, in fact, the sequestered right ventricular apex.

Abnormal morphological patterns of the left ventricular myocardium in the critical stenosis of the aortic valve and the intact ventricular septum.

The evaluation of prognostic factors in infants with critical stenosis of the aortic valve and intact ventricular septum is often misleading due to a complex interaction among lesions in the mitral and aortic valves, and the left ventricular myocardium. The clinical parameters on the left ventricular function, such as ejection fraction and left ventricular end-diastolic volume, are of particular interest as their effects on survival are very controversial. We performed a clinicopathologic analysis of two autopsied cases of this disease. Besides the morphological hallmarks of the aortic and mitral valves, these two cases showed two extreme types of pathology in the left ventricular myocardium, which might have significant impacts on the clinical evaluation of the left ventricular function. Case 1 showed endocardial fibroelastosis associated with abnormal intertrabecular spaces (so-called spongy myocardium), obscuring accurate estimation of the left ventricular end-diastolic volume. Case 2 showed ischemic necrosis of the apical part of the left ventricular myocardium. This infarct was associated with acute and chronic subendocardial ischemia and mild endocardial fibroelastosis. Aggravation of the left ventricular failure could be caused by the recent ischemic insult. The evaluation of the left ventricular function, therefore, should include the evaluation of the morphologic status of the myocardium as regards to whether there is ischemia, endocardial fibroelastosis or hypertrophied trabeculae in addition to stenotic lesions in the aortic and mitral valves.