Faculty Bibliography

Background/UNASSIGNED:Patients on maintenance hemodialysis are particularly vulnerable to infection and hospitalization from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to immunocompromised patients and the clustering that occurs in outpatient dialysis units, the seroprevalence of COVID-19 antibodies in this population is unknown and has significant implications for public health. Also, little is known about their risk factors for hospitalization. Methods/UNASSIGNED:nasopharyngeal, real-time, reverse-transcriptase PCR (RT-PCR); SARS-CoV-2 IgG seropositivity; hospitalization; and mortality. Results/UNASSIGNED:<0.001) compared with those who tested negative. Higher positivity rates were also observed among those who took taxis and ambulettes to and from dialysis, compared with those who used personal transportation. Antibodies were detected in all of the patients with a positive PCR result who underwent serologic testing. Of those that were seropositive, 32% were asymptomatic. The hospitalization rate on the basis of either antibody or PCR positivity was 35%, with a hospital mortality rate of 33%. Aside from COPD, no other variables were more prevalent in patients who were hospitalized. Conclusions/UNASSIGNED:We observed significant differences in rates of COVID-19 infection within three outpatient dialysis units, with universal seroconversion. Among patients with ESKD, rates of asymptomatic infection appear to be high, as do hospitalization and mortality rates.

The most common renal disease associated with human immunodeficiency virus infection (HIV) is HIV-associated nephropathy (HIVAN), especially in the African American patient population. However, various patterns of glomerulonephritis (GN) are not uncommon, collectively accounting for nearly half of the renal biopsies performed in HIV patients. Most GNs that occur in HIV patients are immune complex mediated, often with concurrent infections such as hepatitis B or C. Fibrillary glomerulonephritis (FGN), a rare primary glomerular disease, has only been reported in 2 HIV patients, and both patients had concurrent hepatitis C (HCV) infection. Here we report a unique case of FGN with unusual ultrastructural morphology in an HIV-positive African American patient without concurrent HCV infection. The patient presented with nephrotic range proteinuria and renal insufficiency. A percutaneous kidney biopsy showed mesangial and segmental endocapillary proliferative GN with crescent formation. Immunofluorescence studies revealed IgG-, κ-, and C3-positive deposits in the mesangium and capillary loops. Electron microscopy demonstrated diagnostic features of FGN: randomly-arranged fibrillary deposits with a diameter of 15 - 30 nm. The deposits had an unusual distribution pattern of hump-like large deposits on the subepithelial aspect. Additionally, smaller deposits were also present in the mesangium. To our knowledge, this is the first reported case of FGN in an HIV patient without concurrent HCV infection.
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Albuminuria is a strong, independent predictor of chronic kidney disease progression. We hypothesize that podocyte processing of albumin via the lysosome may be an important determinant of podocyte injury and loss. A human urine derived podocyte-like epithelial cell (HUPEC) line was used for in vitro experiments. Albumin uptake was quantified by Western blot after loading HUPECs with fluorescein-labeled (FITC) albumin. Co-localization of albumin with lysosomes was determined by confocal microscopy. Albumin degradation was measured by quantifying FITC-albumin abundance in HUPEC lysates by Western blot. Degradation experiments were repeated using HUPECs treated with chloroquine, a lysosome inhibitor, or MG-132, a proteasome inhibitor. Lysosome activity was measured by fluorescence recovery after photo bleaching (FRAP). Cytokine production was measured by ELISA. Cell death was determined by trypan blue staining. In vivo, staining with lysosome-associated membrane protein-1 (LAMP-1) was performed on tissue from a Denys-Drash trangenic mouse model of nephrotic syndrome. HUPECs endocytosed albumin, which co-localized with lysosomes. Choloroquine, but not MG-132, inhibited albumin degradation, indicating that degradation occurs in lysosomes. Cathepsin B activity, measured by FRAP, significantly decreased in HUPECs exposed to albumin (12.5% of activity in controls) and chloroquine (12.8%), and declined further with exposure to albumin plus chloroquine (8.2%, p<0.05). Cytokine production and cell death were significantly increased in HUPECs exposed to albumin and chloroquine alone, and these effects were potentiated by exposure to albumin plus chloroquine. Compared to wild-type mice, glomerular staining of LAMP-1 was significantly increased in Denys-Drash mice and appeared to be most prominent in podocytes. These data suggest lysosomes are involved in the processing of endocytosed albumin in podocytes, and lysosomal dysfunction may contribute to podocyte injury and glomerulosclerosis in albuminuric diseases. Modifiers of lysosomal activity may have therapeutic potential in slowing the progression of glomerulosclerosis by enhancing the ability of podocytes to process and degrade albumin.

Calcineurin inhibitors (CNI) have been clearly associated with posttransplant thrombotic microangiopathy (PTTMA). We report a case of de novo PT-TMA involving predominantly small arteries and arterioles of a renal allograft in a patient receiving tacrolimus. Serial biopsies demonstrate the natural history of this lesion through the chronic nonspecific phase. The case is discussed in the context of a literature review of PT-TMA in general and CNI use in particular.

The proliferation signal inhibitors (PSIs)-sirolimus, everolimus, and temsirolimus-have been associated with a noninfectious pneumonitis characterized by lymphocytic alveolitis and bronciolitis obliterans with organizing pneumonia (BOOP). This condition usually occurs within the first year. Herein we presented a case of a deceased donor renal transplant with interstitial pneumonitis developing 6 years after a switch from tacrolimus to sirolimus due to chronic graft dysfunction. After the addition of intravenous pentamidine due to the suspicion of Pneumocystis pneumonia, there was marked clinical deterioration requiring intubation. Open lung biopsy revealed sirolimus-induced pulmonary toxicity (BOOP) with the additional finding of a drug-induced phospholipidosis (DIPL) that we ascribe to pentamidine treatment. After cessation of both drugs and application of corticosteroid therapy, there was only partial improvement. Eight months later the residual interstitial fibrosis demands supplemental home oxygen. We review the literature on PSI-induced pneumonitis and discuss the pathophysiology of a potential interaction with pentamidine. We caution against its use in the setting of PSI-induced pneumonitis. It is currently unknown whether these concerns also apply to prescription of other more commonly used medications associated with DIPL, eg, amiodarone and aminoglycosides.

PURPOSE/OBJECTIVE:This study examined the effects of gender on graded exercise stress test (GXT) response in moderate-altitude (MA)-acclimatized cyclists during sea-level (SL) simulation. It was hypothesized that alterations in arterial saturation would relate to changes in VO2peak. METHODS:Twenty competitive cyclists (12 males, 8 females) who were residents of MA locations underwent two randomized bicycle GXTs: one under local normoxic hypobaria, and the other under simulated SL conditions. RESULTS:Under the SL condition, the cyclists demonstrated a significant increase (2-3%) in absolute and relative VO2peak, improved (4%) economy at lactate threshold (LT), and time-adjusted peak power (7%); the range of improvement between individuals varied from -6% to +25%. Simulated SL also resulted in a greater arterial saturation (S(a)O2) at rest and VO2peak, and significantly less desaturation (4 vs 8%) from rest to VO2peak. The individual variability in the change (Delta) in VO2peak was not significantly correlated to SL S(a)O2 or any other S(a)O2 variable analyzed, regardless of whether we examined each gender individually or combined. Significant correlations were found between Delta-peak power and Delta-economy as well as Delta-VO2peak and Delta-GXT time. These correlations as well as degree of improvement varied by gender. CONCLUSIONS:These data suggest that chronic residence at MA may attenuate the occurrence of exercise-induced arterial hypoxemia and eliminate the relationship between S(a)O2 and Delta-VO2peak that has been reported among SL residents acutely exposed to altitude. Additionally, the improvements that occur in predictors of aerobic performance when MA residents are exposed acutely to SL conditions have a large degree of individual variability, and the mechanism(s) for improvement may vary by gender.

Maximal aerobic capacity (Vo(2max)) decreases progressively with age, primarily because of a reduction in maximal cardiac output (Q(max)). This age-associated decline in Vo(2max) may be partially mediated by the development of oxidative stress that can suppress beta-adrenergic-receptor responsiveness and, consequently, reduce Q(max). To test this hypothesis, Vo(2max) (indirect calorimetry) and Q(max) (open-circuit acetylene breathing) were determined in 12 young (23 +/- 1 yr, mean +/- SE) and 10 older (61 +/- 1 yr) adults following systemic infusion of either saline (control) and/or the powerful antioxidant ascorbic acid (acute: bolus 0.06; drip 0.02 g/kg fat-free mass) and following chronic 30-day oral administration of ascorbic acid (500 mg/day). Plasma ascorbic acid concentration was not different between young and older adults and was increased similarly, independent of age [change (Delta) acute = 1,055 +/- 117%; Delta chronic = 62 +/- 19%]. Oxidized low-density lipoprotein concentration was greater (P < 0.001) in older (57 +/- 5 U/l) compared with young (34 +/- 3 U/l) adults and was reduced in both groups (P < 0.02) following acute (Delta = -6 +/- 2%) but not chronic (P = 0.18) ascorbic acid administration. Control (baseline) Vo(2max) and Q(max) were positively related (r = 0.76, P < 0.001) and were lower (P < 0.05) in older (34 +/- 2 ml.kg(-1).min(-1); 16.1 +/- 1.1 l/min) compared with young (43 +/- 3 ml.kg(-1).min(-1); 20.2 +/- 0.9 l/min) adults. Following ascorbic acid administration, neither Vo(2max) (young acute = 41 +/- 2; young chronic = 42 +/- 2; older acute = 34 +/- 2; older chronic = 34 +/- 2 ml.kg(-1).min(-1)) nor Q(max) (young acute = 20.1 +/- 0.9; young chronic = 19.1 +/- 0.8; older acute = 16.2 +/- 1.1; older chronic = 16.6 +/- 1.4 l/min) was changed. These data suggest that ascorbic acid administration does not affect the age-associated reduction in Q(max) and Vo(2max).