Sandbox: GDS
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here

# Overview
Renal transplant patients are under immunosuppression to modulate the immune response to graft. Moreover these patients have various underlying chronic kidney diseases and other co-morbidities such as diabetes and hypertension, which can impact the results in COVID-19 infection. Hence these patients are at a higher risk of developing COVID-19 associated complications. The clinical manifestations, treatment, and prognosis of COVID-19 infection may be different from the general population. It is believed that any transplant recipient presented to the infection would result in a high level of cases; however, the risk of the donor to recipient transmission is unknown.

# Historical Perspectives
The etiological agent involved is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), first detected in Wuhan, China. On March 12, 2020 the World Health Organization declared the COVID-19 outbreak a pandemic. The earlier SARS epidemic of Hong Kong  is known to affect both pediatric and adult renal transplant patients where the severity of disease in adult patients was more than that in pediatric patients The first reported case of COVID-19 infection in renal transplant patient, was a 52yearold man who received livingrelated kidney transplantation 12 years for chronic glomerulonephritis, in Wuhan, China. He made a successful recovery and was discharged on day 13.

# Classification
Classification of COVID-19 infection in renal transplant patients depends on the severity of COVID-19 manifestations. COVID-19 infection classification according to WHO is following:

# Pathophysiology

## Genetics
Angiotensin-converting enzyme 2 and Dipeptidyl peptidase have been implicated in the uptake of SARS-Cov and MERS-CoV Several studies have indicated that viral S-protein RBD interacts with host ACE2 receptor. S protein changes thus make the human cells permissive to SARS-CoV and SARS-CoV-2 infection    ACE2: ACE ratio is higher in the kidneys compared to the respiratory system. (1:1 in the kidneys VS 1:20 in the respiratory system).These receptors are found in the proximal tubules of kidneySARS-CoV2 spike(S) protein is cleaved and activated by transmembrane serine protease family (TMPRSS) after attaching to angiotensin-converting enzyme 2 (ACE2) receptors. This allows the virus to release fusion peptide that aides in membrane fusion..
There is a possibility of association between MHC class I(HLA A, B & C) with incidence of COVID-19 infection as well as severity of complications
. HLA-B*46:01 gene product is believed to show lowest binding to SARS-CoV-2 indicating decreased viral presentation to immune system. Whereas HLA-B*15:03 shows increased affinity to SARS-CoV-2leading to higher likelihood in developing immunity.

## Associated Conditions

### Acute Kidney Injury
- Acute Kidney Injury has been reported in patients with COVID-19 infection along with presence of proteinuria, hematuria. In a case observation, 4 out of 7 patients had AKI which may indicate that renal transplant patients are at higher risk AKI on being infected with COVID-19 whereas only 29% AKI was seen in critically ill patients of general population.
- Acute Kidney Injury seen in COVID-19 infection can be from the cytotropic effect (Uptake of SARS-Cov-2 virus into proximal tubule cells is possible explanation for the AKI seen in COVID patients) of the viral particles as well as systemic inflammatory response induced by the cytokines. Patients admitted with severe disease, acute respiratory distress syndrome (ARDS) or in patients admitted to ICU have a higher incidence of AKI . .  Other possible reasons that can play a role in AKI development, are multi-organ failure resulting in acute tubular necrosis (ATN), volume reduction causing prerenal ATN, high fever, drug toxicity, hypotension, and contrast exposure.
- Pro-inflammatory cytokine levels are elevated in the COVID-19 infection and there is activation of T-cell response.   There is higher cytokine levels and  there is occurrence of cytokine storm in severe cases. In cytokine storm the, the immune system damages the healthy tissue rather than virus. According to an autopsy report of six patients, the light microscopy indicated CD68+ macrophage infiltration of the tubulointerstitium and severe ATN. The tubules showed complement 5b-9 deposition in all six cases, but deposition in glomeruli and capillaries were seldom seen. Some CD8+ T lymphocyte cells and CD56+ (natural killer) cells were seen in kidney tissue

### General COVID-19 Pathophysiology in Renal Transplant Patients
The overall presentation of COVID-19 in renal transplant patients is similar to that in general population.However, the renal transplant recipients are at remain at higher risk to catch COVID-19
and develop severe complications due to chronic immunosuppressed state which is implicated in various viral infections such as cytomegalovirus, herpes zoster, norovirus infectionsetc.
COVID-19 Pathophysiology

# Causes

## Life Threatening Causes
- Even though the CT findings in COVID-19 pneumonia were similar in renal transplant recipients and general population, due to chronic immunosuppression, the clinical features of COVID-19 in renal transplant patients may be atypical.
- In one of the study, nine of the 10 patients had fever, cough, shortness of breath, and fatigue; three had diarrhea; eight had lymphopenia; six had renal injury; and six had liver function damage.
- It needs to be verified whether the severity of COVID-19 pneumonia differs in immunocompromised transplant patients than non-immunocompromised population. According to a report from Chinas Infectious Disease Information system, out of 72,314 COVID-19 cases in general population, 81% were reported as mild, whereas 19% were either severe or critical. And, in report from study in renal transplant patients, the number of severe cases were 80% compared to only 10% in their infected family members and 19% in general population. Moreover, average duration of illness was nearly twice i.e. 35 days compared to 18 days in control group and 17-20 days reported in general population.

# Differentiating from other Diseases
- As the general presentation of COVID-19 is similar in general population and renal transplant patients, it should be differentiated from other diseases presenting with cough, fever, shortness of breath, and tachypnea.
To review the differential diagnosis, click here
- To review the differential diagnosis, click here
- COVID-19 associated AKI in renal transplant patients must be differentiated from other causes of AKI , such as congestive heart failure, hemorrhage, dehydration, liver failure, urinary tract obstruction, Interstitial nephritis, glomerulonephritis and nephrotoxic medications.
For the differential diagnosis of AKI, click here.
- For the differential diagnosis of AKI, click here.

# Epidemiology and Demographics

## Incidence
- Due to the lack of broad screening that includes the general population (including asymptomatic patients) and the lack of PCR and antibody tests with acceptable sensitivity and specificity, an accurate estimate of the incidence rate of coronavirus disease 2019 (COVID-19) cannot be accurately estimated.
- Data indicates that the rate of severe complications of COVID-19 is almost 25%, and kidney is also one of the main organs affected in severe illness.. The risk is further increased in patients having chronic kidney disease(CKD), patients on chronic replacement therapies, and patients with kidney transplants.
- AKI is seen in 5-15% of the SARS-CoV and MERS-CoV infection

## Prevalence
- For details on the real-time prevalence and spread of COVID-19, click here.
- As it is prevalent in all the continents of the world, World Health Organization (WHO) has declared COVID-19 outbreak a pandemic.
- Among patients with influenza-like-illness and without risk factors for COVID-19, 5% were positive for COVID-19.
- In an analysis of 14 articles
- Median interval of transplantation - 4 years. (range .25-30.1)
- Median interval of transplantation - 4 years. (range .25-30.1)

## Case-fatality rate
- Due to limited testing of asymptomatic individuals, the potential inaccuracies of early PCR tests and antibody tests, the inconsistent reporting and lack of organized data, an accurate case-fatality rate of COVID-19 has yet to be established.
- According to analysis of recent studies
, a fatality rate of 17.4% (4/23) in renal transplant patients was reported

## Age
- Renal transplant patients of all ages are at a higher risk of COVID-19 due to immunosuppression.
- The youngest renal transplant patient who died of COVID-19 according to recent studies was 71 years old.
- In general population, COVID-19 associated AKI has higher incidence in elderly.

## Gender
- Men are more likely to be affected by COVID-19 than women.
- Women dying from COVID-19 are generally elder than men(median age: 82 vs. 79 years for women vs. men, respectively).

## Race
*According to study done in New York, 14 recipients (39%) were black, and 15 recipients (42%) were Hispanic.

# Risk Factors
There are various factors that can predispose renal transplant patients to COVID-19.
- Immunosuppression
- Chronic Renal Failure
- Co-Morbidities
Diabetes
Hypertension
Hyperlipidemia
H/o Heart Disease
- Diabetes
- Hypertension
- Hyperlipidemia
- H/o Heart Disease
- Male Sex
- Old Age
- Current or h/o smoking tobacco
- Possible a/w donor COVID-19 infection

# Screening
According to one of the COVID-19 Rapid Guidelines for renal transplant patients:
Screening for AKI
Serial monitoring of kidney function tests should be considered in renal transplant patients'
- BUN
- Creatinine
- Urine analysis
Gut Ischemia, coagulopathies, and disseminated intravascular coagulopation have been seen later in the course of illness
- The following should be measured in all patients with severe COVID-19 infection on admission to prevent and screen for coagulopathies.
D-dimer
Ferritin
Troponin
- D-dimer
- Ferritin
- Troponin

# Natural History, Complications and Prognosis
Even though the course of infection of COVID-19 in the general population and the renal transplant recipients has been the same, the mortality in COVID-19 affected renal transplant recipients have been reported to be higher than the general population. It has been widely feared that the scope of complications in the transplant recipients would be more severe than what is generally seen in the population due to a suppressed state of immunityThe incidence of AKI has also been reported to be higher in COVID-19 infection

# Diagnosis

## Diagnosis of Choice
- Renal transplant patients present with similar CT an Chest X-Ray finding which are seen in the general population, although the features of COVID-19 infection may be atypical in such patients.
- Renal Transplant patients who develop AKI can be diagnosed using KDIGO criteria:
Increase in S. Creatinine:  0.3 mg/dl (26.5 mol/l) within 48 hours
Increase in S. Creatinine:  1.5 times baseline within the previous 7 days
Urine volume 6 hours
- Increase in S. Creatinine:  0.3 mg/dl (26.5 mol/l) within 48 hours
- Increase in S. Creatinine:  1.5 times baseline within the previous 7 days
- Urine volume 6 hours

## Symptoms
Presenting symptoms in renal transplant patients are similar to those of non-renal transplant patients. Further symptomology depends on the clinical complications that develop due to COVID-19.
- Respiratory symptoms
Cough
Chest Pain
Shortness of breath
- Cough
- Chest Pain
- Shortness of breath
- Fever
- Hypoxia: SpO2 depends on the severity of COVID-19 infection. In moderate infection the SpO2 > or = 90%
- Diarrhea
- Fatigue
- Features of Uremia and Azotemia may be present in severe renal compromise
Further classification of patients into the severity index can be done using the WHO guidelines.

## Physical Examinationin
Physical examination of COVID-19 in renal transplant patients are similar to ones seen in general population.: COVID Physical Exam
If the patient develops Acute Kidney physical examination is remarkable for:
- Signs of dehydration, such as tachycardia, tachypnea, hypotension, and dry mucosa
- Fluid retention, leading to edema and swelling of periorbital and extremities
- Confusion due to severe dehydration and electrolyte imbalances
- Decrease in urine output:Oliguria or Anuria
- cardiac arrhythmia due to electrolyte imbalances such as high level of Potassium

## Past Medical History
- Renal transplant patients usually have chronic co-morbidities
Diabetes
Hypertension
Hyperlipidemia
Chronic renal failure
H/o Heart Disease
H/o Liver Disease
- Diabetes
- Hypertension
- Hyperlipidemia
- Chronic renal failure
- H/o Heart Disease
- H/o Liver Disease

## Laboratory Findings
- Lymphocyte count
Lower baseline values of lymphocyte count and lymphocytes percentages have been reported in patients. Furthermore the lymphocyte count continued to decrease during the course of illness.
Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
- Lower baseline values of lymphocyte count and lymphocytes percentages have been reported in patients. Furthermore the lymphocyte count continued to decrease during the course of illness.
- Renal transplant patients generally have a low lymphocyte count due to immunosuppression, hence finding a further drop in the lymphocyte count can be of prognostic value.
- D-dimer
- Ferritin
- Troponin
Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia ) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly.  D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.
- Microvascular thrombosis and disseminated intravascular coagulation( with gut ischemia ) can occur later in the course of illness. They are characterized by marked increase in the levels of D-dimer particularly.  D dimer, ferritin, and troponin should be measured in all patients with severe COVID-19 infection on admission and in those who fail to show any clinical improvement.
- High C-Reactive Protein - Creactive protein (CRP) was significantly elevated in patients at the time of admission. The levels of CRP remained elevated during the admission
If the renal transplant patients reports AKI then following laboratory findings can be done:
- Elevated serum creatinine
- Elevated BUN level
Plasma BUN-creatinine ratio> 20 in prerenal AKI
Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Plasma BUN-creatinine ratio> 20 in prerenal AKI
- Plasma BUN-creatinine ratio< 15 in intrinsic AKI or acute tubular necrosis
- Fractional excretion of sodium (FENa)
(FENa)< 1% in prerenal AKI
(FENa)> 2% in intrinsic AKI or acute tubular necrosis
- (FENa)< 1% in prerenal AKI
- (FENa)> 2% in intrinsic AKI or acute tubular necrosis
- Urinary sediment
Hyaline casts in prerenal AKI
Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Hyaline casts in prerenal AKI
- Granular or Muddy brown casts in intrinsic AKI or acute tubular necrosis
- Several biomarkers have been found to diagnose and predict AKI that include:
neutrophil gelatinase-associated lipocalin (NGAL)
kidney injury molecule 1 (KIM-1)
liver-type fatty acid-binding protein
interleukin 18 (lL-18)
insulin-like growth factor-binding protein 7
tissue inhibitor of metalloproteinase 2 (TIMP-2)
calprotectin
urine angiotensinogen (AGT)
urine microRNA
- neutrophil gelatinase-associated lipocalin (NGAL)
- kidney injury molecule 1 (KIM-1)
- liver-type fatty acid-binding protein
- interleukin 18 (lL-18)
- insulin-like growth factor-binding protein 7
- tissue inhibitor of metalloproteinase 2 (TIMP-2)
- calprotectin
- urine angiotensinogen (AGT)
- urine microRNA

### Electrocardiogram
- There are no associated ECG findings due to COVID-19 complications in renal transplant patients. However hypokalemia due to AKI can cause ECG changes.
- To view the electrocardiogram findings on COVID-19, click here.

### X Ray
- X-ray findings in the renal transplant patients were similar to the findings seen in the general population.
- To view the x-ray finidings on COVID-19, click here.

## Echocardiography or Ultrasound
- If the renal transplant patient develops AKI, USG can help diagnose hydronephrosis and reduced renal blood flow.
- To view the echocardiographic findings on COVID-19, click here.

### CT
- CT scan finding in renal transplant patients infected with COVID-19 were similar to those in the general population.
- To view the CT scan findings on COVID-19, click here.

### MRI
- There are no MRI findings associated with COVID-19 in renal transplant patients.
- To view the MRI findings on COVID-19, click here.

## Other Imaging Findings
- To view other imaging findings on COVID-19, click here.

## Other Diagnostic Studies
- To view other diagnostic studies for COVID-19, click here.

# Treatment

## Medical Therapy

### Acute Pharmacotherapy
Currently, there are a variable number of protocols that have been described for the management of COVID-19 in renal transplant patients:-
According to the British Transplantation Society Guideline:-
According to a protocol described in Iranian Medical Journal

### Chronic Pharmacotherapy
In renal transplant patients, the immune responses are altered, especially the T cell response, due to generalized immunosuppression. Due to recent timeframe of outbreak of COVID-19 and insufficient scientific evidence, there is limited evidence on decreasing or changing the pattern of immunosuppression in renal transplant patients who have been infected with COVID-19.
- Clinical presentation of COVID-19 infection in renal transplant patients are like the clinical presentations of infection in general population. .Moreover, renal transplant patients are generally immunocompromised, and this predisposes them to severe infection with COVID-19. Rejection of the graft can occur if immunosuppression is reduced in these patients.  Hence given the high rate of mortality in COVID-19 infections, it is suggested that a careful risk vs benefits assessment of whether to continue immunosuppression should be done.
- Managing the immunosuppression in renal transplant patients is difficult and should be based on
Age
Severity of COVID-19 infection
Presence of Co-Morbidities
Time since the transplant
- Age
- Severity of COVID-19 infection
- Presence of Co-Morbidities
- Time since the transplant
- In patients with mild to moderate infection, it has been a practice to continue or decrease the doses of immunosuppressive drugs, however this approach can cause high mortality in patients having COVID-19 infection.
Commonly followed protocols for the used immuno-suppressant drugs is as follows:-
- Antiproliferative agents such as MMF and azathioprine 
Should be stopped at the time of admission to hospital
- Should be stopped at the time of admission to hospital
- Prednisolone
The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
Corticosteroids have beneficial effects such as
Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
Vascular protective effects
Maintenance of integrity and permeability of endothelium.   
- The dosage can be either increased or left unchanged. These can provide immunological protection to the renal graft.
- Corticosteroids have beneficial effects such as
Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
Vascular protective effects
Maintenance of integrity and permeability of endothelium.   
- Immunomodulation and anti-inflammatory properties
Inhibition of proinflammatory cytokines
Reduction of white blood cell traffic
- Inhibition of proinflammatory cytokines
- Reduction of white blood cell traffic
- Vascular protective effects
Maintenance of integrity and permeability of endothelium.   
- Maintenance of integrity and permeability of endothelium.   
- Tacrolimus
- Low doses of tacrolimus can be given but more evidence is required.
- Low doses of tacrolimus can be given but more evidence is required.
- The dose should be reduced to 50%. Target levels for tacrolimus should be 3-5 ng/ml.
- The dose should be reduced to 50%. Target levels for tacrolimus should be 3-5 ng/ml.
- Tocilizumab.
- COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trials of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered.
- COVID-19 infection has been found to cause cytokine storm and inflammation due to antiviral immune response, hence trials of anti-interleukin 6 monoclonal antibody Tocilizumab and continuing steroids in infected patients has been considered.
- Cyclosporine
Cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.
Cyclosporine levels should be targeted at 25-50 ng/ml.
- Cyclosporin A has been shown to have an inhibitory effect on proliferation of corona viruses and hepatitis C virus in vitro, not seen in tacrolimus. Cyclosporin A is thought to inhibit the replication of a diverse array of coronaviruses through its impact on cyclophilin A and B.
- Cyclosporine levels should be targeted at 25-50 ng/ml.

## Surgery and Device Based Therapy
Currently there are no suurgical intervention required for COVID-19 infection in renal transplant patients.

### Transplantation
- The risk of the donor to recipient transmission is unknown.
- The chances of a donor to recipient infection might be affected by exposure of the donor, the infectivity of the donor during the incubation period, and the degree of viremia as well as the viability of virus in the specific organ system. An avid knowledge of local epidemiology is required to identify donors and recipients who may recently be exposed. One method is to have both donor and recipient practice strict social distancingi.e. 2-week home segregation prior to transplant and PCR testing for both individuals, before transplant. The reason for swabbing at the end of the segregation period is to screen asymptomatic shedders.
- In spite of the conceivable negative outcomes, temporary interruption of kidney transplantation might be needed in regions where the rate of infection is high.. 
- If a life-saving procedure needs to be performed, then appropriate assessment of infection in donor and recipient must be done along with appropriate informed consent.
- If a transplant candidate is found to be infected with COVID-19, the transplant should be delayed until the patient shows clinical improvement as well as no viral detection. Viral shedding  for an increased duration of time has been reported.
Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
Patients should have 2 negative PCRs at least 24hrs apart
- Patients should be tested 10-14 days after symptom onset and only once all the symptoms have resolved.
- Patients should have 2 negative PCRs at least 24hrs apart

## Primary Prevention
- The kidney transplant population must comply with the recommended measures of protection in the general population. Physicians can recommend the use of a mask on an individual basis, especially when the patient goes to health center or other place with agglomeration. People who show symptoms of being infected with SARS-CoV-2 should wear masks to prevent the spread of the disease to others..
- It is prudent to approve a sick leave in patients whose profession involves a high hazard for disease.
- It is recommended to screen kidney transplant patients through teleconsultation so as to decrease the time spent in healthcare centers and decrease the risk of infection 
- Maintenance of general hygiene. Washing your hands as often as possible with cleanser and water, or with a alcohol based hand sanitizer (60% alc), particularly: after utilizing the restroom, before eating, in the wake of blowing, coughing or sneezing and after direct contact with patient or their surroundings. Abstain from touching your eyes, nose and mouth before washing your hands.
- Regular cleaning of home with disinfection of objects and surfaces.
- Keep a distance of at least two metres from people with general symptoms such as fever, cough, malaise, sore throat or dyspnea). Abstain from sharing personal belongings.
- During the lockdown circumstance you should stay at home aside from the specified exemptions, as indicated by the standards built up by the political and wellbeing specialists. Telephone the kidney transplant facility at your referral community or the telephone numbers approved by the wellbeing specialists.
- Attempt to follow a right eating routine. Abstain from smoking and liquor. These substances weaken the immune system, and increase the risk of infectious diseases.

## Secondary Prevention
All kidney transplant patients with suspected symptoms of COVID-19 are advised to contact their healthcare provider (ideally by phone), to discuss the full course of their treatment and other chronic conditions that they are having. Depending upon the symptoms :-
- Mild symptoms ie
without Dyspnea or Tachypnea
Temperature <38C
Kidney receptor with adequate functional reserves
The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 2448h.
- without Dyspnea or Tachypnea
- Temperature <38C
- Kidney receptor with adequate functional reserves
The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 2448h.
- The patient can be asked to remain in contact via teleconsultation to have the diagnostic tests performed, monitor the symptoms and communicate alarming to the transplant team every 2448h.
- Moderate/Severe symptoms
Temperature >38C
Presence of Dyspnea
Presence of Tachypnea
Fragile Kidney receptor
Patient can be asked to report to Emergency Department for clinical evaluation..
- Temperature >38C
- Presence of Dyspnea
- Presence of Tachypnea
- Fragile Kidney receptor
Patient can be asked to report to Emergency Department for clinical evaluation..
- Patient can be asked to report to Emergency Department for clinical evaluation..

## Cost Effectiveness of Therapy
Currently various investigational and experimental  pharmacological therapies are being tested for COVID-19 treatment. The cost of treatment generally depends on the multitude of COVID-19 complications that an individual develops.

## Future or Investigational Therapies
Various pharmacological therapies are currently under investigation as potentials to treat COVID-19
For detailed information click here