COVID-19 in solid organ transplant recipients: a single-center experience

Solid organ transplant (SOT) recipients may be at risk for severe COVID-19. Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the effective treatment strategy for these patients is unknown. We describe our institutional experience with COVID-19 in SOT. Demographic, clinical, and treatment data were extracted from the electronic patient files. A total of 23 SOT transplant recipients suffering from COVID-19 were identified (n = 3 heart; n = 15 kidney; n = 1 kidney-after-heart; n = 3 lung, and n = 1 liver transplant recipient). The presenting symptoms were similar to nonimmunocompromised patients. Eighty-three percent (19/23) of the patients required hospitalization, but only two of these were transferred to the intensive care unit. Five patients died from COVID-19; all had high Clinical Frailty Scores. In four of these patients, mechanical ventilation was deemed futile. In 57% of patients, the immunosuppressive therapy was not changed and only three patients were treated with chloroquine. Most patients recovered without experimental antiviral therapy. Modification of the immunosuppressive regimen alone could be a therapeutic option for SOT recipients suffering from moderate to severe COVID-19. Pre-existent frailty is associated with death from COVID-19.     

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant – a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO₂/FiO₂ ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.     

Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

cAMP is an important mediator of cystogenesis in polycystic kidney disease (PKD). Several adenylyl cyclase (AC) isoforms could mediate cAMP accumulation in PKD, and identification of a specific pathogenic AC isoform is of therapeutic interest. We investigated the role of AC6 in a mouse model of PKD that is homozygous for the loxP-flanked PKD1 gene and heterozygous for an aquaporin-2-Cre recombinase transgene to achieve collecting duct-specific gene targeting. Collecting duct-specific knockout of polycystin-1 caused massive renal cyst formation, kidney enlargement, and severe kidney failure, with a mean survival time of 2 months. In contrast, coincident collecting duct-specific knockout of polycystin-1 and AC6 (also homozygous for the floxed ADCY6 gene) markedly decreased kidney size and cystogenesis, improved renal function, reduced activation of the B-Raf/ERK/MEK pathway, and greatly increased survival. Absence of collecting duct AC6 did not alter urinary cAMP excretion or kidney cAMP concentration. In conclusion, AC6 is a key mediator of cyst formation and renal injury in a model of PKD.Polycystic kidney disease (PKD) is the fourth leading cause of ESRD in the United States. Renal cyst development and expansion in PKD critically depend on vasopressin (AVP).¹ Crossing Brattleboro rats, which have no AVP, with autosomal recessive PKD rats markedly inhibits cystogenesis, whereas an AVP analog restores the cystic phenotype.² The recent Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes trial found that the AVP V2 receptor antagonist tolvaptan slowed the increase in kidney volume and the decline in kidney function in PKD patients over a 3-year period.³ The cystic effect of AVP is likely caused in large part by stimulation of cAMP.¹ In cells from PKD kidneys, cAMP agonism stimulates cell growth, whereas in normal cells, cAMP inhibits cell growth.¹ The mechanism of cAMP-stimulated cell proliferation has been largely ascribed to protein kinase A activation of the B-Raf/mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway.^1,4 Intracellular Ca²⁺ may be important in determining the effect of cAMP on cell proliferation: under normal conditions, Akt, a serine-threonine protein kinase, inhibits B-Raf (another serine-threonine protein kinase); however, in PKD cells, intracellular Ca²⁺ is reduced, which decreases Akt activity, permitting cAMP activation of B-Raf.¹ In addition, cyst fluid secretion is driven by chloride transport stimulated by cAMP.^1,4 Thus, cAMP is a key factor in cyst formation and enlargement, and AVP is important in driving cAMP formation.The renal collecting duct (CD) is the major source of cysts in humans and animal models of autosomal dominant PKD and autosomal recessive PKD.¹ Given that cAMP plays a central role in the pathogenesis of PKD, it would be important to define which adenylyl cyclase (AC) isoforms are involved in AVP-mediated cyst formation in the CD. The CD contains intercalated and principal cells. Only principal cells give rise to cysts in mouse models of CD PKD1 deficiency, and only AC3, AC4, and AC6 are expressed in mouse principal cells.⁵ It is unknown which of these three AC isoforms is involved in AVP-stimulated cyst formation in the CD; however, AC3 and/or AC6 may be particularly important, because their expression has been localized to primary cilia (albeit in nonprincipal cells^6,7), the cellular organelle found to be critically important in controlling cyst development.⁸To begin to evaluate the role of individual AC isoforms in PKD renal disease, we have now studied mouse models of polycystin-1 deficiency with or without AC6 deficiency. Given that no specific AC isoform inhibitors exist (although this area represents an active area of drug development⁹), a genetic engineering approach was used. We previously reported a mouse model of PKD by selectively deleting the Pkd1 gene in CD principal cells.^10,11 In this model, mice containing loxP sites within introns 1 and 4 of the Pkd1 gene are bred with mice transgenic for the aquaporin-2 promoter driving expression of Cre recombinase (AQP2-Cre); the AQP2 promoter is expressed in the kidney only within principal cells. In the current study, we found that mice with homozygous Pkd1 gene disruption in the CD (PKD knockout [KO]) have multiple large cysts and markedly enlarged kidneys at 33 days of age (Figure 1A). The mean survival was 59±6 days (Figure 1B), and BUN, used as an indicator of renal function, was greatly elevated (135±8 mg/dl) (Figure 1C). Thus, mice with homozygous Pkd1 gene disruption in the CD had rapid cyst progression, marked renal failure, and early mortality.Open in a separate windowFigure 1.AC6 KO improves survival and lessens kidney disease in PKD KO mice. Coincident AC6 KO reduced kidney and cyst size. A shows representative images from 15 different kidneys of each genotype. B shows activated caspase 3 (apoptosis) or proliferating cell nuclear antigen (PCNA; proliferation), both of which are green, and AQP2 (red; to help show cyst walls, although not all cyst walls are red) staining in representative kidney sections from five different kidneys of each genotype. C shows mouse survival probability (all animals are PKD KO; legend shows AC6 genotype; n=26–52 per data point). D shows BUN at 33 days of age (n=15–27). *P<0.05 versus PKD KO alone.To examine the role of AC6 in PKD, mice were generated with targeted homozygous disruption of both the Pkd1 and adenylyl cyclase 6 (ADCY6) genes. Mice with loxP-flanked exons 3–12 of the ADCY6 gene, which encode the first catalytic domain, were used (we previously reported CD-specific KO of AC6; these mice have a mild urinary concentrating defect and normal renal histology at 1 year of age¹²). A key feature of these double KO mice (PKD/AC6 KO) is that the Pkd1 and ADCY6 genes are deleted in the same cells (i.e., whenever Cre is expressed); regardless of whether 100% of principal cells are affected, both target genes have an extremely high likelihood of undergoing recombination. Notably, kidney polycystin-1 mRNA levels were similar between PKD KO and PKD/AC6 KO mice (Figure 1, Figure 1). PKD/AC6 KO mice manifested greatly increased survival compared with PKD KO mice (Figure 1). When PKD/AC6 KO mice died, the average age of death was 209±11 days; however, approximately one third of mice were alive at 1 year. The increased survival was associated with markedly reduced BUN (36±2 mg/dl) compared with PKD KO animals (Figure 1). Mice homozygous for PKD KO but heterozygous for AC6 KO had an intermediate survival time (Figure 1).

Table 1.

Effect of AC6 KO on kidney parameters in PKD KO mice

Role of wastewater irrigation in mosquito breeding in south Punjab,Pakistan

Mosquito breeding within the wastewater irrigation system around the town of Haroonabad in the southern Punjab, Pakistan, was studied from July to September 2000 as part of a wider study of the costs and benefits of wastewater use in agriculture. The objective of this study was to assess the vector-borne human disease risks associated with mosquito species utilizing wastewater for breeding. Mosquito larvae were collected on a fortnightly basis from components of the wastewater disposal system and irrigated sites. In total, 133 samples were collected, about equally divided between agricultural sites and the wastewater disposal system. Overall, 17.3% of the samples were positive for Anopheles, 12.0% for Culex and 15.0% for Aedes. Four anopheline species, viz, Anopheles stephensi (84.3% of total anophelines), An. subpictus (11.8%), An. culicifacies (2.0%) and An. pulcherrimus (0.2%) were present, as were two species of Culex, viz, Cx. quinquefasciatus (66.5% of culicines) and Cx. tritaeniorhynchus (20.1%). Aedes were not identified to species level. The occurrence of different species was linked to particular habitats and habitat characteristics such as physical water condition, chemical water quality and the presence of fauna and flora. Anophelines and Aedes mosquitos were mainly collected during the month of July, while Culex were collected in September. The prevalence of established vectors of human diseases such as An. stephensi (malaria), Cx. tritaeniorhynchus (West Nile fever, Japanese encephalitis) and Cx. quinquefasciatus (Bancroftian filariasis, West Nile fever) in the wastewater system indicated that such habitats could contribute to vector-borne disease risks for human communities that are dependent upon wastewater use for their livelihoods. Wastewater disposal and irrigation systems provide a perennial source of water for vector mosquitos in semi-arid countries like Pakistan. Vector mosquitos exploit these sites if alternative breeding sites with better biological, physical, and chemical conditions are not abundant.     

High prevalence of syphilis and other sexually transmitted diseases among sex workers in China: potential for fast spread of HIV

OBJECTIVES: In China, in the early 1980s, sexually transmitted diseases (STD) started to increase steeply. Sex workers and their clients appeared to play an important role in the spread of STD. Prostitution is illegal in China, and therefore no specific services exist for sex workers unless they are arrested and detained in re-education centres. Staff of a maternal and neonatal hospital in Guangzhou felt the need for an STD care and prevention programme for sex workers outside detention, and started a programme within their hospital, which was unique in the Chinese context. METHODS: From March 1998 to mid-October 1999 sex workers were recruited through various outreach methods, and were interviewed, counselled and examined for the presence of STD/HIV. RESULTS: A total of 966 women, originating from all over China but working in Guangzhou, entered the programme. The median duration of prostitution was one year, and the median number of clients was seven per week. Antibodies to HIV were present in 1.4%. The prevalence of STD was very high: syphilis 14%, Chlamydia trachomatis 32%, gonorrhoea 8% and trichomoniasis 12.5%. Knowledge about STD/HIV transmission and condom use was poor. CONCLUSION: Given the high prevalence of STD, the potential for the further spread of HIV is clearly present. STD care and prevention programmes for these women, outside detention, are urgently needed, and appear also to be feasible in China.     

Risk factors for infection after liver transplantation

Infection is a common cause of morbidity and mortality after liver transplantation. Risk factors relate to transplantation factors, donor and recipient factors. Transplant factors include ischaemia-reperfusion damage, amount of intra-operative blood transfusion, level and type of immunosuppression, rejection, and complications, prolonged intensive care stay with dialysis or ventilation, type of biliary drainage, repeat operations, re-transplantation, antibiotics, antiviral regimen, and environment. Donor risk factors include infection, prolonged intensive care stay, quality of the donor liver (e.g. steatosis), and viral status. For the recipient the most important are MELD score >30, malnutrition, renal failure, acute liver failure, presence of infection or colonisation, and immune status for viruses like cytomegalovirus. In recent years it has become clear that genetic polymorphisms in innate immunity, especially the lectin pathway of complement activation and in Toll-like receptors importantly contribute to the infection risk after liver transplantation. Therefore, the risk for infections after liver transplantation is a multifactorial problem and all factors need attention to reduce this risk.