Hepatocardiorenal syndrome in liver cirrhosis: Recognition of a new entity?

Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome (HRS), outside of conventional understanding that liver cirrhosis is traditionally considered the sole origin of a cascade of pathophysiological mechanisms directly affecting the kidneys in this context. In the absence of established heart disease, cirrhotic cardiomyopathy may occur more frequently in those with liver cirrhosis and kidney disease. It is a specific form of cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli and altered diastolic relaxation with electrophysiological abnormalities. Despite the clinical description of these potential cardiac-related complications of the liver, the role of the heart has traditionally been an overlooked aspect of circulatory dysfunction in HRS. Yet from a physiological sense, temporality (prior onset) of cardiorenal interactions in HRS and positive effects stemming from portosystemic shunting demonstrated an important role of the heart in the development and progression of kidney dysfunction in cirrhotic patients. In this review, we discuss current concepts surrounding how the heart may influence the development and progression of HRS, and the role of systemic inflammation and endothelial dysfunction causing circulatory dysfunction within this setting. The temporality of heart and kidney dysfunction in HRS will be discussed. For a subgroup of patients who receive portosystemic shunting, the dynamics of cardiorenal interactions following treatment is reviewed. Continued research to determine the unknowns in this topic is anticipated, hopefully to further clarify the intricacies surrounding the liver-heart-kidney connection and improve strategies for management.

IgA vasculitis nephritis-outcomes in adult-onset disease.

OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.

COVID-19 Infection and Vaccination and Its Relation to Amyloidosis: What Do We Know Currently?

Amyloidosis is a complex disorder characterized by deposited insoluble fibrillar proteins which misfold into ß-pleated sheets. The pathogenesis of amyloidosis can vary but can be the result of immune dysregulation that occurs from sustained high inflammatory states, often known as AA amyloidosis. Multi-organ involvement including hepatic, gastrointestinal, renal, cardiac and immunological pathological manifestations has been observed amongst individuals presenting with amyloidosis. The recent global pandemic of severe acute respiratory syndrome coronavirus 2, also referred to as coronavirus 2019 (COVID-19), has been shown to be associated with multiple health complications, many of which are similar to those seen in amyloidosis. Though COVID-19 is recognized primarily as a respiratory disease, it has since been found to have a range of extra-pulmonary manifestations, many of which are observed in patients with amyloidosis. These include features of oxidative stress, chronic inflammation and thrombotic risks. It is well known that viral illnesses have been associated with the triggering of autoimmune conditions of which amyloidosis is no different. Over the recent months, reports of new-onset and relapsed disease following COVID-19 infection and vaccination have been published. Despite this, the exact pathophysiological associations of COVID-19 and amyloidosis remain unclear. We present a scoping review based on our systematic search of available evidence relating to amyloidosis, COVID-19 infection and COVID-19 vaccination, evaluating current perspectives and providing insight into knowledge gaps that still needs to be addressed going forward.

Concurrent presentation of IgG4-related tubulointerstitial nephritis and ANCA MPO crescentic glomerulonephritis.

Concurrent IgG4-related tubulointerstitial nephritis and anti-neutrophil cytoplasmic antibodies (ANCA) myeloperoxidase (MPO) crescentic glomerulonephritis is an uncommon scenario, and the link between the two conditions, if any, is incompletely understood. We report the case of a 58-year-old woman who presented with a 2-month history of malaise and joint pain and was found to have acute kidney injury and hemato-proteinuria. Initial immunological tests revealed positive anti-neutrophil cytoplasmic antibodies with a peri-nuclear pattern (pANCA). An enzyme-linked immunoassay (ELISA) for anti-MPO antibodies was also positive, leading to a tentative diagnosis of ANCA-associated small vessel vasculitis with renal involvement. Steroid treatment was commenced, and an urgent kidney biopsy was performed. This showed crescentic glomerulonephritis, but also demonstrated concurrent tubulointerstitial nephritis with a dominance of IgG4-producing plasma cells. Serum IgG4 levels were also elevated. The patient was initially treated with intravenous cyclophosphamide and steroids and then switched to rituximab. When last seen, she was well after 1 dose of rituximab, with kidney function, inflammatory parameters, and serum IgG4 levels returning to normal levels. The concurrent presentation of ANCA-associated vasculitis and IgG4 renal disease is rare with only few cases reported in the literature. More work is needed to understand pathophysiology, outcomes, and management options for this complex scenario.

Remote digital urinalysis with smartphone technology as part of remote management of glomerular disease during the SARS-CoV-2 virus pandemic: single-centre experience in 25 patients.

Background: The COVID-19 pandemic has necessitated the provision of healthcare through remote and increasingly digitalized means. The management of glomerular pathology, for which urinalysis is crucial, has been notably affected. Here we describe our single-centre experience of using remote digital urinalysis in the management of patients with glomerular disease during the COVID-19 pandemic. Method: All patients with native kidney glomerular disease who consented to participate in digital smartphone urinalysis monitoring between March 2020 and July 2021 were included. Electronic health records were contemporaneously reviewed for outcome data. Patient feedback was obtained through the testing portal. Results: Twenty-five patients utilized the digital urinalysis application. A total of 105 digital urinalysis tests were performed for a wide variety of indications. Four patients experienced a relapse (detected remotely) and two patients underwent three successful pregnancies. The majority of patients were managed virtually (60%) or virtually and face to face (F2F) combined (32%). The average number of clinic reviews and urine tests performed during the pandemic either virtually and/or F2F was comparable to levels pre-pandemic and the ratio of reviews to urinalysis (R:U) was stable (pre-pandemic 1:0.9 versus during the pandemic 1:0.8). Patients seen exclusively F2F with supplementary home monitoring had the highest R:U ratio at 1:2.1. A total of 95% of users provided feedback, all positive. Conclusion: Remote urinalysis proved a safe and convenient tool to facilitate decision-making where traditional urinalysis was difficult, impractical or impossible. Our approach allowed us to continue care in this vulnerable group of patients despite a lack of access to traditional urinalysis.

Acute interstitial nephritis following SARS-CoV-2 virus vaccination.

A number of reports have described new onset or relapse of existing glomerular disease after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. More and more of these cases continue to emerge, and the European Medicines Agency (EMA) has recently launched an in-depth investigation to ascertain the true frequency of such renal side effects. In comparison, acute interstitial nephritis after SARS-CoV-2 vaccination has only been described in 1 solitary case. Here, we describe a case of acute kidney injury due to biopsy-proven acute interstitial nephritis soon after SARS-CoV-2 vaccination with the Astra-Zeneca vaccine. The patient responded well to steroids, although he required temporary renal replacement therapy. A thorough medical history failed to elucidate any plausible explanation or trigger other than the preceding vaccination. We acknowledge the possibility that other factors could have triggered acute interstitial nephritis in the case described here. Similar uncertainty exists regarding glomerular disease reported in conjunction with SARS-CoV-2 vaccination. However, we note that acute interstitial nephritis associated with vaccination has been described before the pandemic, and we therefore feel that a link is possible. We suggest that nephrologists should be vigilant when they see cases of unexplained acute interstitial nephritis. A history of preceding SARS-CoV-2 vaccination should be explored, and cases should be reported within national systems of pharmacovigilance.

Native and transplant kidney histopathological manifestations in association with COVID-19 infection: A systematic review.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in clinically significant multi-system disease including involvement in the kidney. The underlying histopathological processes were unknown at the start of the pandemic. As case reports and series have been published describing the underlying renal histopathology from kidney biopsies, we have started to gain an insight into the renal manifestations of this novel disease. AIM: To provide an overview of the current literature on the renal histopathological features and mechanistic insights described in association with coronavirus disease 2019 (COVID-19) infection. METHODS: A systematic review was performed by conducting a literature search in the following websites-'PubMed', 'Web of Science', 'Embase' and 'Medline-ProQuest' with the following search terms-"COVID-19 AND kidney biopsy", "COVID-19 AND renal biopsy", "SARS-CoV-2 AND kidney biopsy" and "SARS-CoV-2 AND renal biopsy". We have included published data up until February 15, 2021, which includes kidney biopsies (native, transplant and postmortem) from patients with COVID-19. Data on clinical presentation, histopathological features, management and outcome was extracted from the reported studies. RESULTS: The total number of biopsies reported on here is 288, of which 189 are postmortem, 84 native and 15 transplants. The results are varied and show underlying pathologies ranging from collapsing glomerulopathy and acute tubular injury (ATI) to anti-nuclear cytoplasmic antibody associated vasculitis and pigment nephropathy. There was variation in the specific treatment used for the various renal conditions, which included steroids, hydroxychloroquine, eculizumab, convalescent plasma, rituximab, anakinra, cyclophosphamide and renal replacement therapy, amongst others. The pathological process which occurs in the kidney following COVID-19 infection and leads to the described biopsy findings has been hypothesized in some conditions but not others (for example, sepsis related hypoperfusion for ATI). It is important to note that this represents a very small minority of the total number of cases of COVID-19 related kidney disease, and as such there may be inherent selection bias in the results described. Further work will be required to determine the pathogenetic link, if any, between COVID-19 and the other renal pathologies. CONCLUSION: This report has clinical relevance as certain renal pathologies have specific management, with the implication that kidney biopsy in the setting of renal disease and COVID-19 should be an early consideration, dependent upon the clinical presentation.

Etanercept-Induced Anti-Glomerular Basement Membrane Disease.

Anti-glomerular basement membrane (anti-GBM) disease is a rare form of small-vessel vasculitis that typically causes rapidly progressive glomerulonephritis with or without alveolar haemorrhage. Previously, there has only been one reported case of tumour necrosis factor-α (TNF-α) antagonist-induced anti-GBM disease. Here, we describe the first reported case of etanercept-induced anti-GBM disease. A 55-year-old Caucasian man was referred to our tertiary specialist renal centre with a history of painless macroscopic haematuria. The patient has been receiving weekly etanercept injections over the past 12 months for psoriatic arthropathy. The serum immunology panel results highlighted a significantly raised anti-GBM titre (370.1 U). Etanercept was stopped, and the patient was empirically commenced on pulsed methylprednisolone, cyclophosphamide, and plasma exchange. A renal biopsy showed crescentic glomerulonephritis. Few days after admission, he tested positive for coronavirus disease 2019 (COVID-19), and a decision was made to withhold cyclophosphamide. There was further decline in renal function with hyperkalaemia for which he received 2 sessions of haemodialysis. He was restarted on cyclophosphamide upon discharge. The patient was switched to rituximab treatment afterwards as he developed leucopenia 2 weeks following the commencement of cyclophosphamide. The serum creatinine level continued to improve and remained dialysis-independent. In conclusion, with the increased use of etanercept and other TNF-α antagonists, the prescribing clinician must be aware of the rare but life-threatening drug-induced vasculitis. We recommend careful monitoring of renal indices with the use of this class of medications.

Thrombotic microangiopathy secondary to recurrent prostate cancer.

An 86-year-old man returned to the UK from Spain with symptoms suggestive of gastrointestinal bleeding. He was found to have an acute kidney injury and thrombocytopenia. Further investigations identified the presence of a microangiopathic hemolytic anemia, supporting the diagnosis of a thrombotic microangiopathy. Differentials included atypical hemolytic uremic syndrome and secondary thrombotic microangiopathy. Thrombotic thrombocytopenic purpura (TTP) and STEC (Shiga toxin-producing E. coli) hemolytic uremic syndrome were excluded by a normal ADAMTS-13 and negative E. coli serology and stool PCR. The patient was treated with blood and platelet transfusions. He received eculizumab and hemodialysis whilst a screen for secondary causes was undertaken. Thrombotic microangiopathy was shown to be secondary to recurrence of prostate cancer, which had been treated 16 years previously. He later recovered his renal function and receives ongoing hormonal treatment for his prostate cancer.

Opportunities in the cloud or pie in the sky? Current status and future perspectives of telemedicine in nephrology.

The use of telehealth to support, enhance or substitute traditional methods of delivering healthcare is becoming increasingly common in many specialties, such as stroke care, radiology and oncology. There is reason to believe that this approach remains underutilized within nephrology, which is somewhat surprising given the fact that nephrologists have always driven technological change in developing dialysis technology. Despite the obvious benefits that telehealth may provide, robust evidence remains lacking and many of the studies are anecdotal, limited to small numbers or without conclusive proof of benefit. More worryingly, quite a few studies report unexpected obstacles, pitfalls or patient dissatisfaction. However, with increasing global threats such as climate change and infectious disease, a change in approach to delivery of healthcare is needed. The current pandemic with coronavirus disease 2019 (COVID-19) has prompted the renal community to embrace telehealth to an unprecedented extent and at speed. In that sense the pandemic has already served as a disruptor, changed clinical practice and shown immense transformative potential. Here, we provide an update on current evidence and use of telehealth within various areas of nephrology globally, including the fields of dialysis, inpatient care, virtual consultation and patient empowerment. We also provide a brief primer on the use of artificial intelligence in this context and speculate about future implications. We also highlight legal aspects and pitfalls and discuss the 'digital divide' as a key concept that healthcare providers need to be mindful of when providing telemedicine-based approaches. Finally, we briefly discuss the immediate use of telenephrology at the onset of the COVID-19 pandemic. We hope to provide clinical nephrologists with an overview of what is currently available, as well as a glimpse into what may be expected in the future.

​False-positive paracetamol levels in a patient with hyperbilirubinaemia: clinical perspectives.

​Serum concentrations of paracetamol are measured to investigate the cause of acute hepatitis, monitor the clearance of paracetamol from the body and to determine if supratherapeutic levels warrant treatment with N-acetylcysteine (NAC). ​A 49-year-old man treated for ischaemic colitis developed worsening renal and liver function tests. As part of the investigation of hepatorenal failure, paracetamol levels were requested, which were elevated at 14 mg/L (normal <4 mg/L) resulting in treatment with NAC. Despite treatment, levels of paracetamol remained elevated and the link between hyperbilirubinemia and false-positive paracetamol levels was identified. ​Bilirubin and its by-products have intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum, causing interference in the enzymatic colorimetric assay most commonly used to measure paracetamol concentration, resulting in false-positive paracetamol levels. Laboratories correct for this interference above a predetermined bilirubin concentration, termed the Icteric Index; however, in our case this interference occurred at a lower level of hyperbilirubinaemia than previously identified as significant. This interaction was found to be more significant at lower bilirubin levels when low or no paracetamol levels were present in the serum, resulting in a change to laboratory practice and development of a 'Sliding Scale' approach to analysis. ​Concurrent bilirubin or Icteric Index measurement is recommended for all laboratories that use the enzymatic colorimetric assay for paracetamol measurement. Lower Icteric Index or bilirubin thresholds are required when low or no paracetamol levels are present in the serum to prevent false-positive paracetamol results. We describe a new 'Sliding Scale' approach to analysis, and highlight an important interaction for clinicians to be aware of.

The outcome of kidney transplant from living donors with pelvi-ureteric junction dysfunction.

PURPOSE: To assess the effect of receiving a kidney with PUJ dysfunction on the recipient renal graft function. METHODOLOGY: 198 patients, who underwent renal transplantation from 1st January 2004 to 31st December 2014 in a single Center in the North West of England, were retrospectively reviewed using a computerized database. Split kidney function and the PUJ dysfunction for the donors were assessed using Tc-99 m MAG3 renogram. Each recipient with PUJ dysfunction was matched with a control recipient by age, gender, and number of days after transplantation. Both groups were followed up for 3.5 years post-transplantation. RESULTS: Of the 198 recipients included in the study, 19 recipients received kidneys from donors with PUJ dysfunction. Prevalence of PUJ dysfunction was 9.5% and it was more common in males than females. There was no difference between the case group and the control group in terms of age, gender, and follow-up time post-transplantation. There was also no difference between the case group and the control group in mean creatinine (130 µmol/l and 138 µmol/l respectively, p = 0.305) or the mean eGFR (48.6 ml/min and 47.5 ml/min respectively, p = 0.054) at 3.5 year post-kidney transplantation. CONCLUSION: This study showed that PUJ dysfunction of renal allograft has a negligible effect on graft function over 3.5 years period post-transplantation. A prospective randomized trial is needed to test these findings. In the presence of widened gap between demand and supply in renal transplantation, PUJ dysfunction in potential donors should not preclude them from donation.

Treatment Outcomes of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis in Patients Over Age 75 Years: A Meta-Analysis.

BACKGROUND: The benefits of treating anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) in advancing age remains unclear with most published studies defining elderly as ≥65 years. This study aims to determine outcomes of induction immunosuppression in patients aged ≥75 years. METHODS: A cohort of patients aged ≥75 years with a diagnosis of AAV between 2006 and 2018 was constructed from 2 centres. Follow-up was to 2 years or death. Analysis included multivariable Cox regression to compare mortality and end-stage renal disease (ESRD) based on receipt of induction immunosuppression therapy with either cyclophosphamide or rituximab. A systematic review of outcome studies was subsequently undertaken amongst this patient group through Pubmed, Cochrane and Embase databases from inception until October 16, 2019. RESULTS: Sixty-seven patients were identified. Mean age was 79 ± 2.9 years and 82% (n = 55) received induction immunosuppression. Following systematic review, 4 studies were eligible for inclusion, yielding a combined total of 290 patients inclusive of our cohort. The aggregated 1-year mortality irrespective of treatment was 31% (95% CI 25-36%). Within our cohort, induction immunosuppression therapy was associated with a significantly lower 2-year mortality risk (hazard ratio [HR] 0.29 [95% CI 0.09-0.93]). The pooled HR by meta-analysis confirmed this with a significant risk reduction for death (HR 0.31 [95% CI 0.16-0.57], I2 = 0%). Treated patients had a lower pooled rate of ESRD, but was not statistically significant (HR 0.71 [95% CI 0.15-3.35]). CONCLUSION: This meta-analysis suggests that patients ≥75 years with AAV do benefit from induction immunosuppression with a significant survival benefit. Age alone should not be a limiting factor when considering treatment.