Guidelines for the prevention, detection and management of the renal complications of COVID-19 in Africa

Africa trails the rest of the world in COVID-19 cases and deaths. However, as the pandemic spreads through the continent, we expect increases in community infection in the months ahead. Patients with kidney disease, especially those with end-stage kidney disease and those with kidney transplants, are at high risk for acquiring the disease and dying from it. While there is limited evidence for the benefit of interventions, we have the advantage of learning from the experiences of those in China, Europe and the Americas. This document sets forth guidance for dealing with our patients who have acute and chronic kidney disease, including those on renal replacement therapy and the staff involved in their care. Emphasis is placed on preparedness and prevention strategies. As evidence and experience accumulate, it is likely that updated guidance will be needed. Bien que les preuves d’interventions soient limitées, nous avons l’avantage de tirer des enseignements des expériences de ceux qui se trouvent en Chine, en Europe et dans les Amériques. Ce document présente des conseils pour traiter nos patients atteints d’insuffisance rénale aiguë et chronique, y compris ceux sous thérapie de suppléance rénale et le personnel impliqué dans leurs soins. L’accent est mis sur les stratégies de préparation et de prévention. Au fur et à mesure que les preuves et l’expérience s’accumulent, il est probable que des directives actualisées seront nécessaires.

cardiac disease, chronic kidney disease (CKD) and patients on immunosuppression [9]. c. Genetic susceptibility or protection is not proven. d. Mortality seems lower in Africa, although there is no proven reason. This may be a false impression as numbers of infections are still relatively low. e. Infection and viral shedding may persist for several weeks. The implications for infection control remain unclear. Recent data suggest that it is unlikely that live virus is shed beyond the second week of infection [10].

CKD-related issues
a. Mortality is higher in patients with CKD [11].
b. Chronic haemodialysis (HD) patients are vulnerable due to their frequent travel for dialysis, regular contact with dialysis staff and other patients and multiple comorbidities. They also have a higher mortality [12,13].

Case definitions
a. Confirmed case: a person who has tested positive for the SARS-CoV-2 pathogen in accordance with testing standards, irrespective of clinical signs and symptoms. b. Suspected case: a person who develops a fever ≥ 37.5°C or respiratory symptoms such as coughing or difficulty breathing within 14 days of coming into contact with a confirmed case while that patient was symptomatic. c. Contacts: contacts are identified after epidemiological investigation and include patients who received HD on the same shift as a confirmed case, patients who received HD without proper prior disinfection of equipment after HD of a confirmed case, and patients or healthcare workers who were exposed (within 2 metres) to a confirmed case without adequate personal protective equipment (PPE).
These guidelines draw from international and local experience with this disease. As expected in a rapidly developing pandemic, there is a paucity of high-quality evidence. Individual centres will have to adapt guidance provided based on the unique circumstances in their countries as well as available resources.
The International Society of Nephrology (ISN) [12] and the European Dialysis and Transplant Association (EDTA) [13] have dedicated web pages with collected resources and recommendations.

CHrONIC KIDNEY DIsEAsE [14,15]
Patients with CKD stages 3-5 have been identified as a high-risk group for COVID-19 complications. Many have hypertension, diabetes and coronary artery disease, which are additional risk factors. Many patients are on immunosuppression for glomerular or multisystem diseases.

INtrODUCtION
COVID-19 is a condition caused by the SARS-CoV-2 coronavirus. This novel virus has spread around the world and has caused significant fatalities in many countries. The virus's impact on health systems and economies has caused widespread distress.
On the African continent, the virus has been documented in all 47 countries, with almost 85,000 cases and 2,760 deaths as at 16 May 2020 [1,2]. Public health guidelines prepared by various international organizations and countries are widely available and give advice to prevent infection in the general population. This document gives guidance on the specific issues relating to the prevention of COVID-19 infection and the care of affected patients with kidney disease.

Virus-related issues
a. It is a highly infectious virus with an R0 factor (the number of new infections estimated to arise from a single case) of approximately 3 (compared to influenza with an R0 of approximately 1) [3]. Efforts to reduce the spread may lower the R0 to < 1 in some areas. b. It is spread by droplets from the respiratory tract laden with virus -this may contaminate fomites and surfaces. Direct airborne spread may occur if a carrier is in close proximity (< 2 metres) when droplets are expelled. Aerosolised virus may persist for a period in the air but the significance is not yet clear [4]. c. Asymptomatic individuals may spread the virus although the frequency of this is not known [5]. d. Masks worn by infected persons may reduce environmental contamination by viral particles [6]. e. Virulence in an immune naïve population may result in significant fatalities (0.5-5%). The mortality estimates are affected by the testing strategy. Mortality rates may be lower if undiagnosed, asymptomatic cases are accounted for [7]. f. Infection is currently diagnosed by nucleic acid detection methods using a reverse transcriptase polymerase chain reaction (RT-PCR) technique. Nasopharyngeal swabs are currently preferred but sputum, tracheal aspirates or broncho-alveolar lavage fluid (if available) are more sensitive. Saliva may be an option in future. Negative tests do not rule out infection completely and may need to be repeated if the index of suspicion remains high [8].

Patient-related issues
a. Asymptomatic infection is common [5]. b. Mortality is higher in the elderly and patients with comorbidities including hypertension, diabetes, asthma, a. Many patients in this group are on angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). It has been speculated that these increase the risk of complications, but this is unproven and has not been observed in clinical settings thus far. Patients should not stop their prescribed medicines, including ACE inhibitors or ARBs, unless indicated for other reasons [16,17]

Guidance for government authorities
Governments should include haemodialysis units in their integrated plans for dealing with the COVID-19 pandemic. These should include: a. Acknowledging the high risk of patients with kidney disease as noted above. b. Accommodation and concessions in lockdown regulations to allow travel to and from treatment centres for patients and staff. c. National, local and regional plans for different scenarios including dealing with isolated or high-volume outbreaks.  [20][21][22][23][24][25][26][27][28]. See further guidance below. e. National guidelines on staff policies including nonpunitive, sick-leave policies and return to work policies should be formulated [25]. f. National authorities should plan for an increase in demand for renal replacement therapy (RRT) related to AKI. This may require the acquisition of additional equipment and the training of staff. International and regional cooperation with assistance from the African e. Donning and doffing of PPE -see guidance from the CDC and WHO [24,26,27]. f. Disinfection of surfaces and the environment as per protocols (see below). g. Unit protocols for suspected and confirmed cases (see below). h. "What do you do if you suspect you have been exposed?" Procedures if a staff member is ill Staff policy on sick leave should be non-punitive, to encourage staff to report their symptoms timeously. In severely staff-constrained settings, personnel who have been exposed may need to continue working while wearing masks and with adequate hand sanitization unless proven positive or symptomatic. Staff should not move between units.

staff facilities
Staff eating and common areas should not be filled to the point where physical distancing is not possible. This will require staggered mealtimes and the suspension of group activities or staggered group activities such as prayer and training.
All staff and patients should be screened daily for fever > 37.8°C.

Provision of PPE
Adequate supplies of PPE and cleaning equipment should be made available. See WHO and CDC guidance and recent advice from the Kenyan Renal Association [24,26,28]. Dialysis staff should employ standard contact and droplet precautions, including isolation gowns, gloves, masks, and eye protection (shields or goggles), as appropriate ( Figure 1). Because PPE will need to be deployed for many weeks or months in this current pandemic, care must be taken to establish policies that will not exhaust the available supplies of these precious resources.

DIALYsIs PrEPArEDNEss CHECKLIsts
Checklists can be used to assess preparedness of dialysis units for the triage and management of COVID-19 cases. Examples are available through the George Institute for Global Health [21,] and the CDC [33]. Alternatively, local authorities may create area-specific checklists using the guidance contained in this document.

CONtACt trACING [34]
8.1. There is a paucity of high-quality evidence on this topic. Figure 3 shows examples of different scenarios. Renal guidelines for COVID-19 in Africa   Figure 3.

strAtEGIEs rEGArDING COVID-19 IN PD PAtIENts [39]
This is the summary of guidelines issued by the International Society of Peritoneal Dialysis, which can be accessed at https://ispd.org/strategies-covid19/.
People on PD should stay at home. Hospital visits should be undertaken only for urgent indications (for example, suspected peritonitis). Consultations should otherwise be conducted using telehealth. If needed, consultations should be timed to avoid long periods in a waiting area. All patients should wear a mask when outside their homes.
1. Normal universal precautions and handwashing must be applied everywhere at all times. Surface disinfection should be regularly carried out.

Continued education and training of staff about
COVID-19 is recommended for every PD unit. Selfmonitoring for COVID-19 for individual healthcare staff members and screening tests for suspected cases is recommended.
3. At home, patients should have at least 2 weeks of PD supplies and sufficient medications in case they must self-isolate, or if there is a break in the supply chain.
4. In the PD unit, non-essential procedures, for example PET or clearance measurements, should be avoided to minimize unnecessary patient contact. 11. Severely or critically ill COVID-19-positive patients requiring life support due to multiple organ dysfunction syndrome can be temporarily transferred to automated peritoneal dialysis or to haemodialysis.
12. Precautionary measures for PD staff performing inhospital dialysis is essential.
13. Personal protective equipment should be available for all members of the PD team.
14. Universal hygiene measures must be strictly observed by healthcare staff. 15. In hospitals, effluent from PD bags should be discarded as medical waste. At home, patients may discard the fluid in the toilet (preferably after adding bleach to the fluid or the toilet). Aerosols can be generated by toilet flushes, so the toilet lid should be shut before flushing. Uninfected persons should not do this without wearing PPE. Bags can be double-bagged and kept for three days before discarding [40].

Definition of AKI [42]
Kidney Disease Improving Global Outcomes (KDIGO) defines AKI as any of the following: • Increase in serum creatinine by 0.3 mg/dL (26.5 μmol/L) or more within 48 hours or • Increase in serum creatinine to 1.5 times baseline or more within the last 7 days or • Urine output less than 0.5 mL/kg/h for 6 hours.
KDIGO has also recommended a staging system for the severity of the AKI (Table 1).

Pathophysiology and burden of AKI associated with COVID-19
AKI is more common among patients with more severe disease, particularly in ICU settings, and is considered a negative prognostic factor with respect to survival [11,43,44]. It is thought that a maladaptive systemic inflammatory Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; RRT, renal replacement therapy; CRRT, continuous renal replacement therapy; HDF, haemodiafiltration; slED, sustained low-efficiency dialysis; PD, peritoneal dialysis; sCr, serum creatinine; us, ultrasound.

AKI
Increase in sCr by ≥ 0.3 mg/dl within 48 hrs Increase in sCr to ≥ 1.5 times baseline within 7 days Decrease in urine volume to < 0. 5  immune response, in the face of a cytokine storm, contributes to hypoperfusion-related injury of the renal tubules [35,37].
Some evidence suggests the possibility of a direct cytopathic effect of SARS-CoV-2. ACE 2 and members of the serine protease family, essential for viral uptake by host cells, are highly expressed on podocytes and tubular epithelial cells.
Reports of albuminuria and haematuria in the setting of COVID-19, along with isolation of viral RNA from the urine, further supports potential viral tropism for the kidney [45].
AKI is common in the ICU setting, affecting up to 40% of patients, with a frequent need for dialysis [46][47][48]. Approximately 5% of hospital admissions require dialysis [48].
Inevitably, the question arises whether RRT should be approached differently in the acute care setting. If a cytokine storm is contributing to disease severity in COVID-19, then in theory convective-based clearance may be superior for removal of large-sized cytokines compared to diffusionbased modalities. While this argument has been made repeatedly in the management of sepsis, clinical evidence has been, at best, inconclusive [36].

Management of AKI in COVID-19 patients
Risk factors and comorbidities must be assessed. These include advanced age, smoking, diabetes mellitus, chronic obstructive airways disease, chronic liver or kidney disease, congestive heart failure and history of radiocontrast administration or other medicines that affect kidney function.

Fluid resuscitation
The need for prompt fluid resuscitation to restore euvolaemia and systemic haemodynamics in septic patients is well established. Growing evidence suggests that the cardiac output does not always increase in many critically ill patients when challenged with a fluid bolus.
a. The exact amount and precise timing of tapering such resuscitation is not established. With regard to AKI, fluid resuscitation is based on the theory that restoration of circulating volume will improve renal perfusion [49].
b. The improvement of haemodynamic macrovascular parameters may result in the restoration of cortical renal perfusion but this does not occur in all cases of septic shock [50]. c. Fluids are not different from drugs and carry side effects such as the activation of cytokines, shedding of the capillary glycocalyx and adversely affecting the capacity of the kidney to adequately filter excess fluid and nitrogenous waste. d. The recently released "hour-1 bundle" recommends that fluid resuscitation should be performed in septic patients with hypotension or lactate ≥ 4 mmol/L with 30 mL/kg of crystalloids [51]. e. In adult patients admitted to the ICU with sepsis, a positive fluid balance after the first day was associated with an increased risk of AKI. Fluid overload increases mortality. Excess fluid has been shown to be a negative predictor for recovery of renal function [52,53]. f. Current international guidelines from the Surviving Sepsis Campaign recommend crystalloids for initial resuscitation and subsequent volume replacement, with albumin "when patients require substantial amounts of crystalloids". However, the debate on which type of fluid to use in the resuscitation phase is still open. A recent meta-analysis reported that crystalloids were less effective than colloids in stabilizing resuscitation endpoints such as mean arterial pressure, cardiac index and central venous pressure [54]. g. Finally, evidence supporting albumin use in patients with septic shock comes from the ALBIOS study in which albumin administration was used to replenish albumin instead of using it for treating hypovolaemia [55].

Dialysis modalities
Depending of the availability of the modality and/or trained personnel, the available modalities for RRT are: a. Continuous renal replacement therapy (CRRT) b. Prolonged intermittent renal replacement therapy (PIRRT) or slow low-efficiency dialysis (SLED) with high flux filters c. Intermittent haemodialysis (IHD) with high flux filters d. Peritoneal dialysis (PD) either as continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or intermittent peritoneal dialysis (IPD). The use of acute peritoneal dialysis can be lifesaving and should be considered in settings where haemodialysis is not available [56,57]. . e. Loop diuretics may be used in the management of volume overload, according to the treating physician's discretion. f. If there is a lack of dialysis or ICU nurses, non-dialysis or non-ICU nurses may be recruited to monitor patients undergoing RRT, under the supervision of an ICU or dialysis nurse [57]. g. For patients on chronic PD, the dialysis can be continued as APD in hospital, to reduce the exposure of nursing staff. If volume control cannot be maintained with PD, the patient may need temporary haemodialysis [56,57,59]. h. It is essential that contact precautions and guidelines in the use of PPE are adhered to at all times.

Vascular access
If a patient develops indications to start dialysis -or if a patient on chronic HD needs vascular access -a doublelumen internal jugular catheter (preferably) should be inserted. If this is not possible, a subclavian or femoral catheter may be used. This should be placed by the physician with the most expertise in placement of central venous catheters, e.g. a vascular surgeon, ICU physician or radiologist [32]. Ultrasound-guided placement is recommended, where available. Jugular catheters are more convenient when a patient needs to be in the prone position to facilitate ventilation.

Care and disinfection of dialysis equipment
a. CRRT filter changes can be performed every 72 hours. If the need exceeds the number of machines available, shorter periods (e.g. 12 hours) may be attempted using higher flow rates (40-50 mL/kg/h). b. After treatments, dialysis equipment should be disinfected according to national guidelines. The equipment should be disinfected before being removed from the room. Additional cleaning may be needed before the machine can be used for another patient [57].

Crrt and sLED in the ICU
The preferred modalities for RRT in critically ill patients are continuous renal replacement therapies (CRRT) or sustained low-efficiency dialysis (SLED) and other hybrid treatments (PIRRT) [37,57]. CRRT is a commonly initiated treatment in the ICU. Indications include AKI with metabolic acidosis, hyperkalaemia, excessive uraemia or refractory fluid overload.

suggested prescription
a. Modalities used will depend on the availability of staff and equipment and the clinical complexity of the case. b. CVVH pre-and/or post-dilution with a prescribed dose 25-30 mL/kg/h (to obtain an administered dose 20-25 mL/kg/h). In the presence of a cytokine storm higher doses may be required. The dose should be regularly reassessed to determine if treatment goals are being met [47]. c. CRRT is beneficial for maintenance of volume balance, haemodynamic stability, and to allow adequate nutritional support. It will improve the clearance efficiency of medium-sized and small molecular toxins and can maintain body temperature. CRRT is particularly indicated in patients with AKI who are suspected to have high levels of cytokines and with haemodynamic instability. d. If a patient surge overwhelms the CRRT capacity at an institution, consideration should be given to using CRRT machines for prolonged intermittent treatments -for example 10 hours instead of continuouswith higher flow rates -such as 40-50 mL/kg/h -and then using the machine for another patient, after cleaning as per institutional policies. e. Prolonged intermittent or SLED techniques are not inferior to continuous therapies. High-flux membranes are essential, if available, in this context. f. Advantages of SLED include its use in haemodynamically unstable patients, the ability to use equipment for multiple patients, reduced requirements for anticoagulation, lower cost and wider availability. g. Intermittent (standard duration) haemodialysis can be used in stable patients. h. High-quality water generated by reverse osmosis should be used for all therapies.

Anticoagulation
Patients with COVID-19 have a high risk of thromboembolic events and many centres use higher dosages of thrombosis prophylaxis than usual (often double-dose) [60,61]. The choice of anticoagulation is based on the patient's need for systemic anticoagulants, the risk or presence of bleeding, and the available drugs and expertise. Choices include: a. Regional citrate anticoagulation, where available. b. Systemic heparinization with unfractionated heparin. c. Treatment without using anticoagulants.
Many COVID-19-infected patients requiring intensive care management show altered liver function values. This may be secondary to drug-induced hepatotoxicity as well as due to possible liver involvement. This is associated with an increased risk for citrate accumulation.

Drug modification in COVID-19 patients undergoing dialysis [62]
Dose adjustments should be discussed between the primary physician, the nephrologist and the clinical pharmacist. Note that these are not treatment recommendations.
a. Anti-viral therapy: no adjustment of dose requiredfor example, lopinavir/ritonavir, darunavir/ritonavir, darunavir/cobicistat. b. Hydroxychloroquine (note that there is no clear evidence of efficacy and some safety concerns have been raised): for CRRT no dose adjustment is required; for haemodialysis or peritoneal dialysis, administer 50% of the dose and monitor ECG for detection of QT prolongation. c. Ribavirin: use not recommended in severe renal dysfunction.

GUIDELINEs FOr KIDNEY trANsPLANt rECIPIENts [63]
Kidney transplant patients taking immunosuppression are at higher risk of complications from COVID-19 [64]. Information about this disease and its impact on transplantation is evolving rapidly, so the guidance may change over time. Many of the recommendations are based on experience with the CMV and BK viruses.

Epidemiology
Data on transplant patients are limited but increasing [64][65][66][67][68]. The lymphocyte count is lower in those who require ICU care. It is not possible to tell if lymphopaenia is a manifestation of a more severe form of disease, or if it is a predisposing factor for severe disease.

When to resume immunosuppressive therapy
A proposed approach in severely ill patients is to resume the CNI at half of the previous dosage, starting at least 3 days after clinical resolution and after two negative swabs (one at discharge and one 3 days later), with the aim of gradually reaching a trough level of 3-5 ng/mL of tacrolimus or 200-300 ng/mL of cyclosporine at the second hour (C2). Resumption of full-dose CNI dosage and maintenance of the prednisolone can be considered after 15 days free of symptoms and an additional negative swab. Caseby-case evaluation for re-initiation of MPA, AZA and mTORi is needed [72].

Drug interactions
a. There is a possible increase in the exposure of cyclosporine, tacrolimus and mTOR inhibitors with chloroquine/hydroxychloroquine. It is advised to monitor the trough levels of cyclosporine, tacrolimus and mTORi in this setting [62]. b. Patients starting anti-retroviral drugs that contain ritonavir or cobicistat must stop mTORi and CNIs. If the aim is to continue tacrolimus, it should be administered only when blood levels are < 5 ng/mL and the dose should not exceed 0.5 mg (overall dose reduction to one-fifth or lower). Cyclosporine should be given only when levels are below 50 ng/mL (overall dose reduction to one-fifth or lower, administered once a day) [62]. c. Administration of azithromycin should be accompanied with monitoring of cyclosporine levels. Azithromycin may cause increased cyclosporine concentrations through glycoprotein inhibition and/or competition for biliary excretion [62].

CONCLUDING rEMArKs
These guidelines on COVID-19 and the kidney were commissioned by the executive committee of the African Association of Nephrology and represent a major collaborative effort by African nephrologists. They should be of practical value across the African continent and beyond.
Renal guidelines for COVID-19 in Africa