INTRODUCTION
Since the first cases of the coronavirus disease 2019 (COVID-19) pandemic were identified in Wuhan, China, in December 2019, the global landscape has shifted immeasurably. The disease has spread worldwide, leading to more than 4.4 million cases and over 320,000 deaths (as of 20 May 2020). The kidneys, patients with underlying kidney disease and the nephrologist have not been spared. Patients with chronic kidney disease (CKD) are considered particularly vulnerable and acute kidney injury (AKI) is a serious complication in patients hospitalised with COVID-19. Higher than expected mortality rates have been reported in renal transplant recipients. This report will offer some insights into the effects of the disease and offer a local perspective. Importantly, this is a rapidly evolving situation with the number of patients affected steadily increasing; new knowledge and insights into management options are being gained almost daily.
ACUTE KIDNEY INJURY
Early reports suggested an incidence of AKI of 5%–10% in hospitalised COVID-19 patients in China.(1,2) Patients present with proteinuria, some haematuria and raised creatinine levels, all of which impact negatively on the survival. The pathogenesis of the AKI remains uncertain but may include injury due to hypotension and hypoperfusion; post-mortem studies also demonstrated direct virus-induced tubular toxicity.(3) Hypercoagulation and microthrombi seen in other organs could also contribute significantly towards both tubular and cortical injury leading to irreversible kidney failure in some patients.(4) Indications for initiating dialysis are the same as for other causes of AKI. There is no benefit to early versus late dialysis initiation in AKI due to other causes,(5) and in the absence of proof to the contrary we can assume the same in patients with COVID-19. The most appropriate mode of dialysis remains controversial with many nephrologists advocating continuous renal replacement therapy (CRRT) or sustained low-efficiency dialysis.(6) The major benefit of CRRT is that it requires less intensive staffing; this limits patient contact and allows more patients to receive treatment where staffing is limited. CRRT is significantly more costly (an important consideration in our economic setting), and there are risks of supply chain management being unable to keep up with fluid and disposable requirements. CRRT also restricted to one machine per patient (or two if shortened) so may be less viable if equipment is limited.
As per the last Kidney Disease Improving Global Outcomes conference, there is no benefit of higher versus standard dose of dialysis, provided dialysis targets are met.(7) Thrombosis of the vascular access and filter are significant problems using conventional heparin doses; various heparin protocols have been tried to mitigate this problem. Citrate anticoagulation remains an option but should be employed only if the staff are familiar with the technique.(8) Ronco et al. favour the use of extracorporeal therapies for the added benefit of removing of pro-inflammatory cytokines.(9) However, Dellinger et al. in the EUPHRATES trial reported no benefit for this in patients with sepsis and multi-organ failure.(10)
The emerging entity of collapsing glomerulopathy, a distinct variant of focal segmental glomerulosclerosis recently described in patients with COVID-19, has stimulated some interest but remains to be confirmed as a distinct entity associated with the disease.(11)
Consensus among colleagues in the South African Renal Society is that individual renal units should use techniques that are available and that they have experience with. Peritoneal dialysis (often neglected) remains an option, especially in rural hospitals with no haemodialysis facilities; it may prove difficult to perform especially with intubated patients requiring proning, but there are several reports of this being used successfully and should remain an option.(12) There is an increased exposure of staff to the patient in this labour-intensive treatment, so where available automated PD should be considered.(13)
CKD AND −PATIENTS ON RENAL REPLACEMENT THERAPY
Patients with CKD and those on chronic renal replacement therapy are particularly vulnerable to severe COVID-19. These patients are older and have significant co-morbidities such as diabetes, hypertension and ischaemic heart disease. In addition they have alterations to their immune response, uraemia, hypoalbuminemia and malnutrition that compound the risk. Patients receiving in-centre thrice-weekly haemodialysis are especially at risk because of commuting and exposure to other vulnerable patients and staff. With this in mind, the International Society of Nephrology, Center for Disease Control and American Society of Nephrology have all developed guidelines that recommend the optimal management of the patients, staff and dialysis units to minimise the risk of infection. These guidelines are available online and are regularly updated.(14–16)
In South Africa, the National Department of Health has provided a basic guideline for the care of haemodialysis patients and the management of dialysis units under COVID-19.(17) The three major dialysis providers were prompt to respond in drawing up their own guidelines, in addition to local Dialysis Association of South Africa (DASA) guidelines.(18) The various guidelines are all comparable in that they cover the basic process of early identification of patients with symptoms or fever, triage mechanisms, the use of personal protection equipment (PPE) in various situations, the appropriate use of infection prevention and control measures, the placement and management of suspected and confirmed COVID-19 cases and converting infected patients to home haemodialysis or peritoneal dialysis. Importantly, guidelines for staff protection are also included. In Cape Town, one of the major dialysis providers has opened a unit dedicated to outpatient dialysis of patients who have confirmed COVID-19. Different approaches to isolating suspected and confirmed cases have been recommended.
RENAL TRANSPLANT RECIPIENTS
Renal transplant recipients are at significantly higher risk of developing critical COVID-19 disease than the general population and seem to have a significantly higher risk of dying.(19,20) The main reasons for this are the chronic state of immunosuppression and co-existing co-morbidities, with age and deteriorating kidney function also contributing. Sound advice to any recipient would be to practise self-isolation as far as is possible, avoid face-to-face contact and pursue medical follow-up via tele- or video-consultation as far as possible.(21)
Transplant programmes have also been profoundly affected. In most high-income countries, living donation transplants has been suspended; in the United States as many as 70% of transplant centres have ceased all activity. Concerns were raised about the potential impact of false-negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA tests on either the donor or the recipient, with scarce resources (intensive care beds, theatres, nursing staff, doctors) being diverted as an additional challenge for transplant services. Unlike other solid organ transplants (heart, lung, liver), patients with end-stage kidney failure can be kept alive with dialysis, and the consensus is that renal transplantation should only continue in situations where it is considered life-saving.(22)
Initial case reports suggest that most renal transplant patients with COVID-19 present with the typical features of fever, cough and bilateral lung infiltrates on chest X-ray and some delayed symptoms and atypical presentations have also been described. Mortality rates of 8%–30% are reported in these patients.(20,23) The principles of management for COVID-19 are the same as in the general population. Specific measures are the adjustment of immunosuppressive medication and the possible institution of specific anti- viral drugs. Recommendations are based partially on the previous experiences of viral infections in renal transplant recipients.(24) As an underlying principle, the first recommended step is cessation of the anti-metabolite (mycophenolate mofetil or azathioprine) in all recipients.(25) In moderate to severe cases, recommendations are to reduce calcineurin inhibitor (CNI) doses as well, with cessation of the drug in severe infection. These recommendations are opinion based on the caveat to balance treatment choices with the individual patient's risk of acute rejection. In cases where the risks are high, the anti-metabolite could be reintroduced at half- or even full dose, from 14 days after the patient has recovered. There is no consensus on the use of increased doses of oral corticosteroids.(25) Of interest are previous reports that cyclosporine (but not tacrolimus) has an inhibitory effect on the proliferation of corona- and hepatitis viruses in vitro (26) but a switch from tacrolimus to cyclosporine is not recommended.(25)
The use of any specific antiviral medication is considered investigational. It is imperative that the use of any of these medications should be as part of a clinical trial. Hydroxychloroquine, touted initially as beneficial in the general population, has failed to live up to this promise.(27) Both hydroxychloroquine and azithromycin have potentially worse side effects in transplant recipients using calcineurin inhibitors because they potentially induce prolonged QT times and can lead to fatal arrhythmias.(25) Macrolides also impair the breakdown and metabolism of CNIs and can lead to CNI toxicity with acute renal impairment. The same concerns exist for lopinavir/ritonavir, with suggested modifications in CNI dosage.(24) Remdesivir, permitted by the American Food and Drug Administration in extreme circumstances, is not available locally.
LOCAL EXPERIENCE AND IMPACT
It is still too early in the pandemic experience to describe with any degree of certainty the effects of COVID-19 on kidney patients and renal staff in South Africa. An informal poll amongst members of the South African Renal Society at the end of April 2020 revealed a total of 23 COVID-19 cases being treated by nephrologists, of which 14 were in patients receiving chronic dialysis, and two patients who were initially thought to have AKI but were subsequently found to have underlying CKD. The first case of COVID-19 in a renal transplant recipient was reported in the first week of May 2020. A Cape Town-based nephrologist contracted the disease in April from an unknown source and has made a full recovery; three staff members of a state dialysis unit in Cape Town were also reported to have community-acquired disease and recovered.
In an attempt to document events, the South African Renal Society has initiated two projects. The first will track dialysis and transplant patients who develop COVID-19 disease. A second study will document all cases of AKI in patients with COVID-19 disease. Both projects are to report accurate case numbers, clinical details and outcomes with various treatment strategies, thereby adding to the body of knowledge and insight into managing the disease that could be of significant benefit as the pandemic progresses. South African Renal Society members are contributing at international levels in the development of guidelines.(14) They are also actively collaborating with other African countries to share experience and protocols in managing renal transplant recipients with COVID-19, for publication in the African Journal of Nephrology. The South African Renal Society has officially cancelled its planned conference for 2020. Nephrologists who are members of the South African Renal Society established a very active WhatsApp discussion group in 2019, and a weekly webinar since April 2020 to share their experiences.
The first-reported COVID-19 outbreak in a South African dialysis unit was at NRC Berea, attached to St. Augustine's hospital in Durban. Nine patients tested positive for COVID-19 following initial contact with an asymptomatic index case dialysed in the unit. NRC and Netcare instituted prompt but detailed and well-designed actions. Of the positive cases, five were offered home haemodialysis and four patients were admitted to the hospital. Two hospitalised cases recovered and two died (both elderly patients with multiple co-morbidities). Seven staff members also contracted the disease, all fortunately recovered. All haemodialysis patients and staff at the unit were screened, and patients were classified as high or low risk. The unit was urgently redesigned with a dedicated low- and high-risk areas, and clear spaces for donning and doffing of PPE. The two groups were dialysed in shifts on separate days with full cleaning protocol instituted following each shift. In addition, low-risk patients were transferred to other NRC units in the vicinity if capacity for the high-risk patients were exceeded; high-risk patients from other units were referred to NRC Berea if indicated.(28) No staff were infected. These kinds of outbreaks are to be expected as the pandemic spreads in the community. Certain units have reduced dialysis to twice-weekly sessions for their patients to mitigate the risk. This does require patient cooperation and careful vigilance and monitoring of patients’ fluid intake and dietary adherence. That more dialysis units and CKD patients will become infected is almost inevitable as is the reality that more renal caregivers, will become ill.
Asymptomatic patients pose a serious challenge. A Cape Town unit based in private practice reported seven positive cases amongst patients (and one staff member) following mass testing when a patient developed overt COVID-19 symptoms. The cases were thought to be asymptomatic, but on careful re-examination, several patients reported minimal symptoms. Some patients fear the stigma of the disease and the possibility of having to dialyse in a group with known COVID-19 disease and therefore conceal or under-report symptoms.(29) The paediatric community has also not gone unscathed: there was a scramble to test all doctors possibly exposed after a completely asymptomatic paediatric CKD patient tested positive on a routine pre-operative test prior to surgery at a public hospital.(30)
CONCLUSION
The COVID-19 road ahead is bound to be a long and rocky one, for renal patients and their caregivers as well as the society in general. COVID-19 has had an unprecedented impact on all aspects of human life – from health to the economy and in the way we socialise. It has also impacted on our scientific milieu, testing our ingenuity in discovering the nature of this novel virus and the desperate search for a cure and vaccine. The urge ‘to do something’ for very ill patients must be tempered by the reality that in a crisis like the one we are currently facing, the need to follow scientific principles is especially essential in order to protect our vulnerable population of patients. We are overwhelmed by an avalanche of COVID-19 information, much of which fails to pass scientific muster and does requires critical insights to ensure that we use the correct information appropriately.(31)