IV. Utilization of HCV viremic donors in kidney transplantation: a chance or a threat?
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- Please summarise this article in your own words
- What is the level of evidence provided by this article?
- Please reflect on the guidelines provided above and on your practice.
- Will you accept living or deceased donation from HCV positive donors?
Dear All
I enjoyed reading your comments.
Will you consider HBC-positive donors based on this article (LEVEL 5)? Why and HOW?
•In this open-label, single-group, a pilot trial at the University of Pennsylvania ClinicalTrials.gov number, NCT02743897)THINKER PILOT STUDY.
•aimed to determine the safety and efficacy of transplanting kidneys from HCV genotype 1–viremic donors into HCV- negative patients, followed by elbasvir–grazoprevir (Zepatier) treatment early post-transplant
•Background: 2/3 of HCV+kidneys with acceptable KDPI are discarded, 7-8% of patients per year are delisted before transplant.
•Patient profiles: short wait times –High Risk of not being transplanted.
•Per protocol, 10 patients received HCV-infected kidneys. The median age of the recipients was 59 years (interquartile range, 51 to 63); half the recipients were men and 2 were black. The median time from eligibility on the waiting list for hepatitis C–infected kidneys to transplantation was 58 days
•On day 3 after transplantation, all recipients had detectable HCV RNA; viral loads ranged from less than 15 IU per millilitre (detectable but unquantifiable) to 193,000 IU per millilitre (Fig. 1). Elbasvir–grazoprevir was initiated in all recipients. Nine recipients had HCV genotype 1a infection; none had identifiable NS5A resistance. All recipients were cured of HCV; a cure was defined as a sustained virologic response 12 weeks after the end of treatment.4,5 The median 6-month serum creatinine level was 1.1 mg per deciliter
•This pilot trial showed that transplantation of HCV genotype 1–infected kidneys into HCV-negative recipients, followed by the use of direct-acting antiviral
agents can provide potentially excellent allograft function with a cure of HCV infection(Likelihood of cure>95%).
This is the conclusion of the KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease.
1:We recommend all kidney donors be screened for HCV infection with both immunoassay and NAT (if NAT is available). (1A)
2:We recommend that the transplantation of kidneys from HCV RNA-positive donors be directed to recipients with positive NAT. (1A)
3: After the assessment of liver fibrosis, potential HCV- positive living kidney donors who do not have cirrhosis should undergo HCV treatment before donation; they can be accepted for donation if they achieve SVR and remain otherwise eligible to be a donor. (Not Graded)
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–There has been a consensus that kidneys from HCV NAT–positive donors should not be transplanted into anti HCV–negative recipients. Kidneys from donors with anti-HCV who are HCV NAT–negative can generally be used safely in negative anti-HCV patients.
So there is no strong evidence to accept HCV +VE kidney donors to HCV -VE recipients until now.
could be used in some situation of donor unavailability and staying long time on dialysis
M Veroux , C Puliatti, M Gagliano, D Cappello, M Macarone, D Vizcarra, M Spataro, M Di Mare, N Ginevra, P Veroux. Use of hepatitis B core antibody-positive donor kidneys in hepatitis B surface antibody-positive and -negative recipients. Transplant Proc. 2005 Jul-Aug;37(6):2574-5.
Only in certain situations … because the evidence provided by this article is week as it is level 5
From living donor, I will not accept because of the possible risk to the donor since HCV is associated with the possibility of glomerulonephritis which can have bad impact on the kidney and according to British guidelines any patient with active HCV infection should be excluded form donation
And I will only accept the donor after treatment with SVR for 1 year
From deceased donor I may accept if the following are met
And I will initiate prophylactic treatment with Elbasvir/grazoprevir once daily for 2-3 months starting from day -1 before transplantation except if the recipient is HCV positive I will initiate treatment before transplantation
No, but if we face a patient with only one HCV NAT+ potential donor, them will discuss this issue.
Reese PP, Abt PL, Blumberg EA, Goldberg DS. Transplanting Hepatitis C-Positive Kidneys. N Engl J Med. 2015;373(4):303-305.
NO, until further long-term studies are done with larger sample sizes are conduction. Also as started in the article by the expert opinion that “The patient needs to be informed that the data regarding the utilization of HCV NAT + organs in HCV negative recipients is still limited, and that current data are based on studies conducted on small populations”
i would accept as second option, , if there is no suitable HCV NAT negative kidney donor, to reduce the waiting time on dialysis and overcome the shortage of kidney donors. As the prevention of viremia post transplantation was successful by 100% especially the genotype 1 and 4 with DAA including Sofosbuvir,Grazoprevir,elbasvir in combination.
In kidney transplant,there are a lot of limitations in performing large size studies and RTC.In the presence of increased number of a waiting patient, clinicians should consider all options in their decision making and be alert to new published evidence that clarifies the balance of benefit versus harm; patient preference should have a substantial influencing role.
The evidence is weak, I will not accept such donors.
The issue of transplantation is associated generally with expected risk during perioperative period,and coming future, so its aprocess associated with multiple questions from recipient and his/her family , especially in living donoation, so added risk as acquiring HCV infection in the future life which is due to immunosuppressant medication which is vital in maintaining graft survival, its a complex issue, need to be fully clarified scientifically, evident based with many trials with large sample studies, and issuing of transplantation center that has tools of investigation , monitoering and applied protocol treatment.
Solving other issues of legislation, consents and insurance is a challengeable issue
We can’t consider HBC-positive donors based on article level 5, however this review is really benefit.
According to the big gab between the number of recipients and donors
We need new sources for donation
HBC positive donor isn’t the first choice but in some cases it would be the only solution, for example recipients on waiting list for long time.
In this case, we should compare the mortality and morbidity if we deny HCV POS donor
25% of patients on waiting list die or get worse
Although not all recipient become actively infected and new treatments are available with accepted results
We need large studies (RCT) with long follow up duration to get over results belonging to graft survival and function- recipient response to DAAs- liver cirrhosis……
For the moment, we should at least well select the donor by performing a precise investigations such as pangenotyping and NAT test, and avoid as we can donors with relapsing HCV infection or donors with some genotypes (NS5A PROTEASES INHIBITOR( 1a- 3))
In addition medication should be available when we plan for accepting HCV pos donor
With this evidence I am not ready to practice in my setting.
Yes sir, based on this article which is a descriptive article of various small case series,
we would perform HCV NAT D+/R- kidney transplantation.
Why?
How ?
Yes. But it should be done after detailed counselling of the patient/ donor.
Why: Because HCV infection is prevalent and DAAs are now available with excellent results in treating HCV infection.
For living donation: HCV positive donor for HCV positive recipient, but only after treatment of both the donor and recipient with DAAs and documented SVR.
For deceased donation: In exceptional circumstances, like requirement of urgent transplant (no vascular access, persistent uremia etc). The recipient should not be high-risk and devoid of any liver disease.
Prophylactic DAA initiation prior to transplant would be my strategy for combating the viremia.
Close follow-up especially with respect to LFT, HCV NAT and proteinuria assessment would be needed.
Apart from the level of evidence of the article itself, the studies explained here show that viremia invetible in HCV ab-/+ with (NAT 4). Although treatable, I would prefer treating ve donor before transplantation. In Turkey, till nearly HCV treatment was approved by insurance. even dialysis patients were treated, and viral clearance was maintained in a huge number of patients. In the era of COVID, this became a problem due to a lack of resources. accepting HCV-positive donors is not a routine here. Instead, the paired donation is preferred solution. cadaveric HCV-positive patients are not accepted. The main problem is financial. For same reason, ABO incompatible transplantation is not accepted (it was performed many years ago, as far as I remember).
My opinion will be with the utilization of viremic organs with a guarantee of anti-viral therapy.
could be used in some situation of donor unavailability and staying long time on dialysis
My answer is yes. We can accept kidney allografts from Hepatitis C positive donors with the following considerations:
– Both donor and recipients are HCV positive (I will not proceed with transplantation from a HVC positive donor to a HCV negative recipient).
– Appropriate plan to start proper antiviral treatment of HCV with no anticipated contraindications.
Yes. because there are a lot of approved benefits, with a small risk according to recent studies
the evidence is level 5 is can not based on it so more studies needed to support the out come of transplant such group of pateint
The transplantation of HCV NAT þ kidneys to naïve recipients may constitute a solution to organ shortage. However, such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection. Every effort should be made to ensure DAA therapy and reduce the mortality of patients awaiting kidney transplantation. The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation. It is rational to prioritize the utilization of HCV NAT þ organs in recipients already infected with HCV. The latest analyses show that transplanting HCV NAT þ kidneys to HCV-negative recipients can be cost effective because it could shorten the waiting time by 2 years. The optimal immunosuppression scheme for transplants from an HCV NAT þ donor to a naïve recipient remains to be determined. Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D+/R- kidney transplantation among candidates.
In my country HCV viraemic donor is excluded in transplant program.
Ø In the past, HCV-positive organs were discarded nearly three times more often than HCV-negative ones were. Between 2005 and 2014, although 6456 kidneys from HCV-seropositive donors were available for transplantation, only 37% of them were actually transplanted. However, only approximately 16% of them would have been HCV viremic.
Ø The attitude toward an HCV-positive donor has completely changed with the introduction of obligatory testing for HCV RNA (NAT) as part of HCV infection diagnostics, in addition to the serological tests mandated by the United Network for Organ Sharing (UNOS) for potential organ donors in US. This allowed the identification of donors with active viremia (HCV Ab+/ NAT + or HCV Ab-/NAT+) and those without it (HCV/NAT-). Such differentiation of donors is key because not every HCV positive donor poses a risk of virus transmission through transplantation.
Ø Kidney transplantation from an HCV donor (Ab+/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
Ø In contrast, HCV NAT + donors, regardless of their serological status, are patients with active viremia and account for 4.2% of donors in the US. HCV viremia in the donor is associated with a high risk of virus transmission.
Ø The efficacy of HCV NAT D+/R- kidney transplantation has been reported in several clinical trials:
1. THINKER study and its continuation, 20 HCV-naïve kidney transplant recipients (KTRs) received HCV-viremic organs. Viral transmission was observed in 100% of patients. Elbasvir/grazoprevir (EBR/GZR) was initiated as soon as viremia was detected (i.e. on average 3 days after transplantation) and continued for 12 weeks. This enabled a sustained virologic response (SVR) in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts.
2. EXPANDER study, in turn, utilized prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and the treatment was continued for 12 weeks. For those with genotypes other than 1, sofosbuvir (SOF) was added to EBR/GZR. SVR was achieved in 100% of cases, and severe complications such as AR, graft loss, or liver damage were not observed
3. A study by Potluri et al. showed that over the period from 2015 to 2019, the willingness to accept a seropositive organ increased six fold
Ø The optimal immunosuppression scheme for transplants from an HCV NAT + donor to a naïve recipient remains to be determined. An analysis by Bae et al. showed that KTRs infected with HCV have a 20% lower probability of receiving a less effective inductive treatment with interleukin 2 receptor antagonists rather than with anti-thymocyte globulin. Non-pangenotypic DAAs impact calcineurin inhibitors trough level; hence pose a risk of underimmunosuppression. Pangonotypic DAAs significantly mitigate this risk. When GLE/PIB is used, for instance, no tacrolimus dose adjustment is required prior to therapy administration; however, the tacrolimus level needs to be monitored.
Ø The utilization of organs with active HCV viremia is associated with high costs. However, keeping patients on the waiting list is also costly in terms of the need for dialysis or the use of devices aiding cardiac function
What is the level of evidence provided by this article?
Ø Level 5
HCV testing and risk of transmission :
Identification of donors with and with active viremia (HCV Ab+/ NAT+ or HCV Ab-/NAT+). Because not all HCV-positive donors have a risk of the virus being transmitted during transplantation, such donor distinction is essential
HCV Ab+/NAT- donors are those in whom the virus has been eradicated spontaneously or through antiviral treatment.
In contrast, HCV NAT + donors have active viremia independent of their serological status. Virus transmission is quite likely if the donor has HCV viremia.
Viremia always develops in recipients after HCV Dþ/R- NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients :
The transmission of viruses was seen in all cases. Elbasvir/grazoprevir (EBR/GZR) was started as soon as viremia was found, which was typically three days following transplantation. It was maintained for 12 weeks
The EXPANDER research, in turn, employed DAA treatment as a preventative measure. Before transplantation, one dosage of EBR/GZR was given, and the medication was maintained for a further 12 weeks.),. In all patients, SVR was obtained, and serious side effects such AR, graft loss, or liver damage were not noticed.
Acceptance of HCV-viremic organs:
According to a research by Potluri et al., from 2015 to 2019, there was a six-fold rise in the readiness to receive a seropositive organ. Other research, however, indicates that HCV +ve infected recipients are reluctant to accept an infected transplant. Because of this, kidneys with HCV NAT positive are transplanted into patients with HCV negative recepients.
Selection criteria:
KTRs who get organs from HCV NAT + donors and have untreated liver problems, diabetes, or obesity have a higher risk of developing metabolic issues.
Donor HCV viremia is not regularly reported despite this. Knowing the viral load might help identify those who are more likely to develop HCV-related problems and determine the best time to start DAA treatment.
, It appears appropriate to exclude donors who have previously received NS5 inhibitor treatment with no effect or who have relapsed In order to prevent problems with viral clearance following transplant and a situation where the patient won’t have access to anti viral medication .
Conclusions:
Prioritizing the use of HCV NAT+ organs in recipients who have already acquired the virus makes sense.
This results in fewer expenses, reduces the possibility of difficulties, and looks more ethically appropriate
level of evidence V
according to our local policy Deceased kidney donation is not allowed till now
and living kidney donation with +ve serology or positive NAT are not allowed for kidney donation
HCV donors with active viremia can increase the donor pool of kidneys available to overcome the shortage of renal grafts and decrease the waiting time for cases in need for transplantation thereby decreasing mortality rate for patients on long waiting lists .
KDIGO(1990) allowed KT from HCV antibody-positive donors to HCV positive recipients.
Underutilization
Kidney transplantation from HCV-viraemic
Donors to HCV-viraemic recipients
Accepting HCV-viremic organs
Donor/recipient selection criteria
DAAs
Optimal timing of DAA initiation
Immunosuppression
Informed consent
Must be taken from HCV negative recipient whom accepted a graft from HCV positive donor after explaining the benefits and risks to him.
HCV-viremic organ refusal
HCV NAT D+/R- transplants can be lifesaving in spite of the risks associated with this procedure due to shortage of organs and the long duration of waiting-on-waiting lists which can be more hazardous than receiving a graft of HCV infected donor.
Insurance coverage
HCVNAT +organs should be prioritised to recipients already infected with HCV and only proposed to negative recipients as second option meanwhile it solves the problem of organ shortage and when balancing the risk to hazards ratio it can be more beneficial .
LEVEL OF EVIDENCE IS 5
I will consider to Transplant patient with HCV positive donor to HCV positive recipient.
HCV negative recipient, it is debatable, yet I will discuss the risk and benefit to the patient and the excellent treatment of HCV currently which get be SVR 90% and above in 12 weeks.
HCV infected kidneys were either discarded or transplanted to HCV positive patients .In order to overcome the kidney donor pool shortage , kidneys from HCV infected patients are increasingly transplanted to HCV negative recipients . previously HCV positive donors were discarded from donation due to
1- poor experience with utilizing HCV infected kidneys
2- Fear of HCV transmission to the recipient and active viremia , specially that the few cases of solid organ donation from HCV positive donor to HCV negative recipients reveleade development of viremia in almost all cases after liver, pancreases and kidney donation.
3- fear of being sued.
Challenges facing utilizing HCV positive kidneys include
1- risk of viral transmission : viremia commonly detected with HCV NAT positive donors and less common with HCV Ab + /NAT -ve donors (32-300 per 10000 donors).
2- risk of drug – drug interactions between tacrolimus and DAA , this can be overcomed via using pangenotypic DAA
HCV viral status is classified according to serological tests into
1- HCV Ab +/NAT -ve :
indicate previous infection either cleared spontiniously or after treatment.
2- HCV NAT +ve : indicate active viremia
La Hoz et al compared the outcome of HCV Ab +/NAT -ve and HCV NAT +ve with HCV negative donors and found comparable results regarding e GFR , rate of AR at 6 and 12 months.
· Currently, after introduction of highly effective DAA treatment for HCV , those donors could be used under certain circumstances.
AASLD recommendations for organ donation from HCV infected donor (other than the liver)
1- Use combination therapy of 2 or 3 drugs together.Start with GLE/PIB for 8 weeks or SOF/VEL for 12 weeks for treatment of HCV naïve recipent
2- Use pangenotypic drugs as first line as have wider therapeutic rang of action and less drug-drug interaction with IS drugs .
3- Time for initiating prophylactic or preemptive treatment is not well established but AASLD recommend starting prophylaxix at day 7 post transplantation
4- Screening for NAFLD is not routenly recommended.
5- Quantifing the level of donor viremia is recommended as there is a relation between HCV RNA level and recipient risk of viremia.
6- Determing the donor genotype and presence of RAS is very important as donors who were previously treated with NS5 inhibitors and treatment relapsers should be excluded from donation.
7- Patients who require desensitization or non standard IS are not recommende to receive HCV infected graft even if DAA will be given as the drug-drug interaction will lead to state of under immunesuppression or lower efficacy of DAA drugs.
8- Non compliance : patients who are expected not to be compliant with prophylactic treatment and regular monitoring should not be offered HCV infected graft.
9- Drug – drug interaction must be carefully scheduled and proper selection of DAA and monitoring of the recipient liver function is amust
Currently used treatment protocols for HCV +D/-R
1- In THINKER trial : viremia was detected early post operative (day 3) and DAA were administrated for 12 weeks using Elbasver/grazoprevir for genotype 2and 4 and adding ribavirin for genotype 1
2- Prophylactic approach: in EXPANDER trail used prophylactic one dose of EBR/GZR
before transplantation, and the treatment continued for 12 weeks . For genotypes other than 1, sofosbuvir was added to EBR/GZR.
3- Short course of DAA for 8 weeks consisting of glecaprevir/pibrentasvir was also effective in acheiving SVR.
Determining the best IS protocol to balance between adequate immunesupresive status (HCV is a risk factor for AR) and minimizing the risk of fulminant hepatitis is still under investigations.
level of evidence : 5
reflect on the guidelines provided above and on your practice:
In our hospitalwe start evaluating the potential donor with HCV Ab if positive we proceed to HCV RNA quantitative PCR .If there is active viremia at any level we do not accept this donor and the donor is referred to hepatology outpatient clinic to recieve treatment. If the potential donor was prevoiusly treated HCV , we would accept him only if has SVR for at least 12 months.
The only case that we would accept donor with active HCV infection (positive PCR and normal LFT) is if no other avialble donor for a patient who is running out of vascular access.
Renal transplantation is the best modality of renal replacement therapy but unfortunately due to non-availability of donors-not every kidney patient has the access to renal transplant. In order to overcome shortage of donors and increase the donor pool,HCV positive donors can be considered for donation. Previously HCV positive donors were allowed to donate to HCV positive recipients. But now with the new innovations in Hepatitis treatment –HCV positive patients can be considered for donation to Negative patients according to recent guidelines.
DONOR SELECTION:
Anti-HCV antibodies and PCR for HCV RNA should be done in all donors. Chances of viremia are less if anti-HCV antibodies are positive but PCR is negative as this indicate spontaneous clearance. Risk of firearm is higher if both are positive, or if only PCR is positive but anti-HCV antibodies are negative. Therefore, donor selection is very important for HCV positive donors in order to reduce chances of hepatic and extra-hepatic complications in recipients. Ideally the donor should be treated and SVR should be achieved before donation .Relapse cases and those patients who are treated with NS5 inhibitors should not be considered for donation.
RECIPIENT SELECTION:
Regarding recipient, he should be counseled in detail about the risk and benefit ,should have normal liver function tests and fibro scan also to be normal before transplant. Other factors which need to be considered before donation are that patients who are obese , diabetic ,co-infection with hepatitis B and HIV or plan to receive intense immunosuppression i.e., desensitization should be excluded.
TREATMENT
Pangenotyping DAAs are highly effective and have little side effects and drug drug interaction. .Combination of GLE/PIB for 8 weeks or SOF/UEL for 12 weeks should be prescribed to naïve recipients of HCV viremic kidneys. Different protocols for commencing antiviral therapy is such patients have been mentioned in various studies .Few centers started before transplant, others when HCV viremia was detected, some centers delay treatment for weeks after transplant and also few centers reduce the duration of treatment. In all cases, SVR achieved however, percentages varies. If treatment is delayed for many months after transplantation, then poor patient and graft survival due to chances of fulminant hepatitis or fibrosing cholestatic hepatitis and risk of TMA .
.Recipients should be closely monitored for hepatic and extra-hepatic involvement by doing liver function tests, PCR for HCV and renal profile and quantification of proteinuria.
What is the level of evidence provided by this article?
Narrative review level 5 of evidence
Please reflect on the guidelines provided above and on your practice.
In our practice, we do not take HCV positive donors but those who have been treated and their PCR is negative considered for donation as shortage of donors and also as we do not have deceased donor program in our country.
Will you accept living or deceased donation from HCV positive donors?
Not in the living donation case but in deceased donors can be in special circumstances like recipients with difficult vascular access and no other option available for dialysis and patients does not have any liver disease and patient will be started on prophylactic antiviral therapy immediately after transplant
Kidney allografts from Hepatitis C positive donors can be accepted with the following precautions:
. Donor and recipient are HCV positive (transplantation from a HVC positive donor to a HCV negative recipient not to proceeded ).
. Proper antiviral treatment of HCV without contraindications.
Introduction
Historically, donors with HCV ab positive were excluded from donation, due to the concomitant risk amplification of HCV related complication subjected by long standing recipient immunosuppression. Unless cases with both donor and recipient HCV positivity, transplantation was feasible then.
Trials to expand donor pool were limited by the early 90s, as detection of active viremia or effective HCV therapy were not available at all.
This study is concerned mainly by the possibility of allowing donation or not in HCV positive donors based on the recent new therapies and updated necessary investigation.
The study of La Hoz et al. led to changing the whole world perspective of reconsidering HCV donors in order to expand organ pool donation. They compared the results of renal transplantation from HCV donors based on nucleic acid testing rather than antibody testing solely. They assessed the outcomes of NAT + and HCV Ab +/NAT – donors versus HCV-negative donors.
Improved renal functions were reported in terms of eGFR within both 6 months and a year post transplantation with better graft survival rate, and lower exposure to acute rejection (AR) episodes. After the evolution of direct antiviral agents (DAAs), renal transplantation was attempted with careful donor selection to HCV negative recipients in the context of clinical trials. Waiting lists became of shorter duration with good results as well.
The utilization of other probable virally infected organs with higher incidence of disease transmission and even rejection or death either as CMV when compared to HCV seems contradictory. The introduction of obligatory testing for HCV RNA (NAT) as part of HCV infection aided the accurate assessment of viral load as well as detection of active viraemic status of candidate donors. However, screening for HCV viremia is recommended from the early posttransplant period.
Despite a negative serological result, still the residual risk for viral transmission encountered about 0.26 to 300.6 for every 10000 donors and 0.027 to 32.4 for every 10000 donors in cases of using NAT. This was confirmed by a study conducted by Suryaprasad et al. that observed three cases of nonintentional HCV transmission despite a negative NAT result for the donor. It was attributed to then to the probability of existence of other factors rather than being transmitted by the transplanted organ itself.
This led to further recommendation to perform testing of all donors for other viruses based on NAT as human immunodeficiency virus, and HBV infections.
In 2017, the THINKER study was started including 20 HCV-naïve kidney transplant recipients (KTRs) who received HCV-viraemic organs. Viral transmission occurred by 100% of patients. The administration of Elbasvir/grazoprevir (EBR/GZR) was initiated once viremia was detected; average 3 days post transplantation till a period of 12 weeks.
The results were hopeful as sustained virologic response (SVR) in all the patients as well as allograft function were similar to HCV negative grafts after assessment by 6 and 12 months.
Prior to transplantation, two genomes only were accepted after being tested for the resistance associated substitutions (RAS); that why only genotypes 1 and 4 were included. DAAs for 16 weeks were the chief line of therapy of genotype one.
This opened the gate for other studies as the EXPANDER study to consider the use of as prophylactic DAA therapy prior to transplantation. One dose of EBR/GZR was administered pretransplantation, along with maintenance for 12 weeks. Genotypes other than 1, it was recommended to use sofosbuvir (SOF) besides EBR/GZR. Results were highly satisfactory regarding 100 % achievement of SVR as well as fatal complications as AR, graft loss, or liver damage were not encountered.
Sise et al. performed an interesting study based on the use of glecaprevir/pibrentasvir (GLE/PIB) for 8 weeks to be used from the second to fifth day post transplantation. This study was concerned to shorten the duration of DAA therapy while maintaining the same outcome as other studies in terms of SVR and graft survival. Durand et al. conducted another study which confirmed the same satisfactory results.
Gupta et al. performed the DAPPeR study, relying on comparing different doses for DAAs therapy along with no therapy which confirmed the important role of DAA as a breakthrough in renal transplantation.
Other real life studies followed the previous steps on larger scale they revealed the different motives of the recipients either to accept or refuse HCV known grafts were affected by the expected effectiveness of treatment, quality of the organ, and the duration of being on the organ waiting list.
Donor/recipient selection criteria
Patients having long waiting list times and NAFLD benefit the most among others. Lentine et al. survey advised not to offer HCV grafts to patients with HCV-naïve with cirrhosis or history of liver disease association. Other considerations as donor viral load, the need for recipient desensitization therapy, history of previous antiviral treatment failure and viral genotype have impact on selection.
The recent implementation of FibroScan as a standard recipient assessment evaluation before HCV graft transplantation improved selection of the recipient.
As regards to DAAs, pangenotypic DAAs are preferred. The AASLD and Infectious Diseases Society of America (IDSA) guidelines recommend the use of GLE/PIB for 8 weeks or SOF/VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viraemic organs. Attention should be paid for cases with hepatic dysfunction, concomitant medications as antiepileptic drugs, besides the protocol of immunosuppression. Premature withdrawal of DAA therapy can be hazardous by allowing the chance of development of drug resistance.
There has been debate regarding the optimal timing for initiation of DAAs administration. The AASLD/IDSA guidelines advised the initiation of prophylactic or preemptive therapy by one week postoperatively.
Delayed introduction of DAAs posed the patients to fatal complications as fibrosing cholestatic hepatitis and acute rejection. The KDIGO recommendations were clear to avoid the development of HCV GN related complications to monitoring proteinuria every 6 months, as well as performing renal biopsy in case of HCV infection post transplantation. Situations where the occurrence of relapse is confirmed associated with the development of denovo GN is an urgent indicator of immediate DAA therapy.
Studies based on adopting prophylactic regimen rather than therapeutic treatment proved the less association of encountering acute rejection episodes.
The best outcome was the standard 12- to 16-week treatment interval that achieved SVR in 100% of patients under both prophylactic and reactive approaches.
Goldberg et al. and Durand et al. showed that the quality of HCV donated organs reached KDPI values of 42–45% which was of excellent quality.
Important issues must be considered prior to acceptance of HCV graft as informed consent, insurance, in addition to cost effectiveness of the treatment.
The final conclusion is that the transplantation of HCV NAT + grafts to naïve recipients offers a good solution for the shortage of organs. The role of DAA therapy early pre and post transplantation is crucial. The need for proper donor and recipient selection.
Level of evidence is V.
In our center practice, donors known to have HCV are accepted after being treated or having a low viral load, no hepatic dysfunction and assessment by routine FibroScan. Gastroenterology approval is also included in our protocol. Prophylactic antiviral therapy can be used on need. Follow up for detection of probable viral load is also routine along with liver functions and proteinuria.
Our centre accepts only living donor up till now. HCV donors are not contraindicated after proper donor and recipient selection.
Utilization of HCV viremic donors in kidney transplantation: a chance or a threat?
Q1- Please summarise this article in your own words.
Introduction of highly effective oral direct-acting antivirals (DAAs) to the treatment of chronic
hepatitis C virus infection (HCV) enabled transplantation of HCV viremic organs to naive recipient.
The currently there is a fact that a kidney transplant from an HCV nucleic acid testing positive (
NAT +) donor to naive recipients is an effective and safe solution to the problem of the insufficient number of organs available for transplantation.
Introduction:
Transplantation is best treatment for ESRD it improves quality of life , patient survival and it is cost effective . but the problem is the shortage of donor pool. Dialysis patient had higher cardiovascular mortality than the general population.
The use of organs from HCV donors with active viremia could alsoincrease the donor pool. In the past, HCV infection in a donor was considered a contraindication for kidney transplantation .
(KDIGO) guidelines, since the 1990s, kidneys from HCV antibody-positive donors have been used as transplants under the condition that the recipe ent is also HCV Ab+.
The current guidelines of the American Society of Transplantation do not forbid the transplantation of infected organs to recipients not infected with HCV.
In the past ,only 37% of them were actually trans planted.
The transplantation outcome was poor in the era of purely interferon-based treatment. .
HCV testing and risk of transmission:
Donors identified as active viremia (HCV Ab+/ NAT+or HCV Ab- /NAT+) and those without it (HCV NAT- )
HCV Ab+/NAT- donors occur if eradicated spontaneously or through antiviral treatment. Spontaneous eradication of the virus is possible in up to 45% of cases.
Kidney transplantation from an HCV donor ( Ab+/ NAT-) to an HCV-negative recipient can result in sero conversion, but the risk of viremia is minimal.
Although the risk of viral transmission is low, screening for HCV viremia is advisable in an early post -transplant period.
HCV viremia in the donor is associated with a high risk of virus transmission.
Viremia almost always develops in recipients after HCV D+ /R- NAT kidney transplants.
The introduction of routine HCV NAT testing helped
reduce the diagnostic window which is , 2–6 months for serological assays to 5–7days for NAT, which limiting the risk of unintentional virus transmission from an organ donor.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients:
THINKER study involoves 20 HCV-naïve kidney transplant recipients (KTRs) received HCV-viremic organs Viral transmission occurred in 100% of patients. Elbasvir/grazoprevir used for 12 weeks. sustained virologic response (SVR) is achieved in all patients.
Sise et al. used glecaprevir/pibrentasvir (GLE/PIB) for only 8 weeks duration . All patients achieved SVR and acute cellular rejection (ACR) and BK viremia were observed in three out of thirty patients.
Gupta et al. used to reduce the time of DAA therapy after HCVNATD+/ R- transplantation .
In the DAPPeR study, use of a single dose of DAAs, followed by one or three doses after transplantation. Associated with infection transmission of approximately 30%, while a 4-day treatment limit it to 7.5%. Only six required treatment, while the rest had low, self-limiting viremia. 83% of the treated patients achieved SVR.
Several other real-life and clinical studies have pro vided satisfactory results in treating HCV from a donor organ.
Willingness to accept HCV-viremic organs:
over the period from 2015 to 2019, the willingness to accept a seropositive organ increased six fold.
patients with long anticipated waiting times should be considered for HCV NAT D+/ R- transplants if this may reduce the waiting time.
A survey by Lentine et al. showed that HCV-naïve patients with cirrhosis or a history of liver disease are not offered HCV-viremic organs
the implementation of FibroScan in standard recipient evaluation prior to HCVNAT D+/R- transplantation could facilitate proper recipient selection.
Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NATD+/ R- protocols. Drug–drug interaction between immunosuppressive agents and DAAs may lead to Under immunosuppression or decreased efficacy of DAA therapy. thiscan be reduced by early initiation of pangenotypic treatment.
the donor genotype and the presence of RAS might be of great importance in patients who are known to be treatment-experienced.
the American Society of Transplant Surgeons, , stated that a lack of knowledge of the genotype or the presence of RAS should not be a contraindication for HCV NATD+/R- kidney transplantation, provided that treatment can be initiated without delay.
Patients who are predicted not to comply with procedures, DAA treatment , and surveillance requirements after transplant should also not be offered HCV-viremic organs.
DAAs:
HCV therapy involves a combination of two or three DAAs with little adverse effect and high efficacy.
Pan genotypic DAAs are preferred. The draw backs are accessibility to DAAs and the high cost of DAA therapy.
Infectious Diseases Society ofAmerica (IDSA) recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs.
multiple factors should be considered before initiating DAA therapy include any evidence of liver dysfunction, concomitant medications.
As drug- drug interaction – 45% of patients may require an adjustment of the dosage of the calcineurin inhibitor during DAA therapy, antiepileptic drugs and high doses of proton pump inhibitors (PPIs; taken twice daily), are not recommended to be taken together with any DAA.
Optimal timing of DAA initiation:
The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation.
Durand et al. began treatment before transplantation. THINKER study, DAAs were introduced after HCV viremia was detected , Some centers postpone treatment for a couple of weeks .
Postponing treatment for a few months may be associated with serious complications.
Immunosuppression:
The optimal immunosuppression protocol for trans plants from an HCV NAT+ donor to a naïve recipient remains to be determined. Bae et al. showed that KTRs infected with HCV have a 20% lower probability of receiving a less effective inductive treatment with interleukin 2 receptor antagonists rather than with ATG.
New study shows that patients infected with HCV should receive standard immunosuppression and that depletive induction should not be avoided .
In one study the type of calcineurin inhibitor (cyclosporine vs. tacrolimus) used in maintenance immunosuppression does not influence the mortality rate in patients with HCV Ab+.
the use of mycophenolate mofetil in the one analysis was related to a lower mortality rate.
Non-pangenotypic DAAs impact calcineurin inhibitors trough level; hence pose a risk of under immunosuppression. Pangonotypic DAAs significantly reduce this risk. When GLE/PIB is used, no tacrolimus dose adjustment is required prior to therapy administration; however, the tacrolimus level needs to be monitored.
Q2- What is the level of evidence provided by this article?
Level 5
Q3- Please reflect on the guidelines provided above and on your practice.
I have very limited experience about this subject as HCV NAT +VE is declined.
Q4- Will you accept living or deceased donation from HCV positive donors?
Yes it is not contraindicated and because of presence of effective DDA therapy. and good outcome from the studies.
Introductions:
Transplantation us standard care for patient with ESRD ,buts its faced with reduce
donors available for transplantation.
review analyzes the possibilities and limitations of the usage of HCV NAT +donor organs
Many steps are being taken to increase the organ donor pool including living donors and
donors after cardiac death.
Another step taken in order to resolve the organ shortage issue is also the use of organs
from donors infected with the hepatitis C virus (HCV). The advent of new, highly effective
interferon free therapies with an efficacy exceeding 95% allowed to utilize HCV-viremic
organs.
Underutilization:
Before HCV Nat positive where discarded cause of fear of transmit of infection.
La Hoz et al. compared the results of kidney transplantation from HCV NAT þ and HCV
Abþ/NAT” donors in relation to those from HCV-negative donors [15]. They reported
better kidney function as manifested by estimated glomerular filtration rate (eGFR) within
6 months after transplantation.
Significant shortening of the time spent on a waiting list and encouraging outcomes of
HCV NAT D+/R- transplantations translated to the utilization of this practice as a
standard of care by 14% of transplant centers .
CV testing and risk of transmissions:
HCV Abþ+/NAT- donors are those in whom the virus has been eradicated spontaneously
or through antiviral treatment. Spontaneous eradication of the virus is possible in up
to45% of cases, but non-immunocompetent patients have a smaller chance for
spontaneous eradication .
Kidney transplantation from an HCV donor (Abþ+/NAT-) to an HCV-negative recipient
can result in seroconversion, but the risk of viremia is minimal.
contrast, HCV NAT + donors, regardless of their serological status, are patients with
active viremia and account for 4.2% of donors in the US .
HCV viremia in the donor is associated with a high risk of virus transmission. Despite a
negative serological result, the residual risk ranges from 0.26 to 300.6 for every 10000
donors and ranges from 0.027 to 32.4 for every 10000 donors when NAT is utilized .
Kidney transplantation from HCV-viremia donors to HCV-a viremia recipients
The efficacy of HCV NAT D+/R- kidney transplantation has been reported in several
clinical trials .
In the THINKER study and its continuation, 20 HCV-naïvKTRs) received HCV-viremic
organs.
Viral transmission was observed in 100% of patients.
Elbasvir/grazoprevir (EBR/GZR) was initiated as soon as viremia was detected
,continued for 12 weeks. This enabled a sustained virologic response (SVR) in all the
patients,
and allograft function after 6 and 12 months did not vary from that of matched recipients
of HCV-negative grafts.
and only genotypes 1 and 4 were acceptable. Those with genotype 1 were treated using
DAAs for 16 weeks, and ribavirin was added as need.
The EXPANDER study, in turn, utilized prophylactic DAA therapy. One dose of EBR/GZR
was administered before transplantation, and the treatment was continued for 12 weeks .
For those with genotypes other than 1, sofosbuvir (SOF) was added to EBR/GZR. SVR
was achieved in 100% of cases, and severe complications such as AR, graft dysfunction
,liver impairment was not reported.
shortening the treatment duration to below the standard of 12 weeks has also attracted
much interest. Size et al. conducted a study in which glecaprevir/pibrentasvir is utilized
for 8week.
Kapila et al. presented the largest such study, which included 64 KTRs. Treatment with
GLE/PIB or sofosbuvir/ledipasvir lasted 12 weeks and was initiated 72 days after
transplantation.
Willingness to accept HCV-viremic organ:
80% of patients are willing to accept ,transplantation from HCV D +,under certain
condtion,18%wont accept under any condition most a accepting recipients are HCV
naïve.
Selection of patient for HCV D+/R-:
patients with long anticipated waiting times should be considered for HCV NAT D+/R-
transplants if this may reduce the waiting time.
Patients requiring nonstandard immunosuppression or desensitization therapy are
frequently excluded from HCV NAT D+/R- protocol.
Pangenotypic DAA regimens have limited drug–drug interactions with tacrolimus and
may limit the need to adjust the dose of calcineurin inhibitors, even though tacrolimus
levels have to be monitored.
excluding donors who were previously treated with NS5 inhibitors or those who have
relapsed seems a reasonable mean to avoid difficulties in viral clearance after
transplantation and a situation when no antiviral treatment will be available for the
patient.
DAAs :
HCV therapy involves a combination of two or three DAAs that target nonstructural
proteins of the HCV and may be delivered with little adverse effect and high efficacy.
Pangenotypic DAAs are preferred.
The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for
8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-
viremic organs other than the liver.
Many factors must be considered:
Presence of liver disease.
Drug-drug interaction. that up to 45% of patients may require an adjustment of the
dosage of the calcineurin inhibitor during DAA .
Availability and cost.
Compliance of patient.
High dose PPI.
Antiepileptic.
Optimal timing of DAA initiation:
The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or
preemptive treatment latest by 7 days after transplantation .
Durand et al. in their study began treatment before transplantation, while in the
THINKER study, DAAs were introduced after HCV viremia was detected.
Some centers postpone treatment for a couple of weeks until the patient and
immunosuppressive treatment are stable enough to avoid the need for early DAA therapy
withdrawal.
recent survey conducted by Lentine et al. showed that the majority of transplant centers
initiated DAA therapy after HCV viremia was detected and after hospital discharge.
Postponing treatment for a few months may be associated with serious complications:
Fulminant hepatitis or fibrosing cholestatic hepatitis .
Thrombotic microangiopathy .
AR or glomerulonephritis.
Studies have reported the development of GN on the 18th day after liver transplantation
from a donor with an active HCV infection as well as renal failure requiring dialysis owing
to delayed DAA therapy.
Immunosuppression:
Recent studies have shown that patients infected with HCV should receive standard
immunosuppression and that depletive induction should not be avoided if there are
reasons to introduce it.
Non-pangenotypic DAAs impact calcineurin inhibitors trough level; hence pose a risk of
underimmunosuppression.
Pangonotypic DAAs significantly mitigate this risk.
When GLE/PIB is used, for instance, no tacrolimus dose adjustment is required prior to
therapy administration; however, the tacrolimus level needs to be monitored.
KDPI:
HCV Abþ-/NAT- donors do not constitute a risk of HCV transmission, their KDPI should
not be calculated on the basis of the serological status of HCV, and this has been proven
by studies that showed a comparable eGFR 6 months after transplantation, which is
considered an indicator of the long-term survival of a transplant.
Informed consent :
The regulations introduced by the OPTN/UNOS require informed consent from the
recipient deciding to accept HCV D+. education and risk and benefits explained.
CV-viremic organ refusal:
Utilization of HCV-viremic kidneys increases the total number of transplantations and
results in a shorter waiting time for individuals remaining on the waiting list.
INSURANCE Coverage:
Which is important cause of high cost of DAA.
some authors think that in the absence of an assurance that medical treatment costs will
be covered and given the possibility that patients may not be able to personally cover
the treatment costs, such solutions should not be considered.
Cost-effectiveness:
Utilization of HCVD+ may reduce cost.
The latest analyses show that transplanting HCV NAT + kidneys to HCV-negative
recipients can be cost effective because it could shorten the waiting time by 2 years.
Conclusions :
It is rational to prioritize the utilization of HCV NAT + organs in recipients already
infected with HCV.
Such organs should be offered to HCV negative recipients only as a secondary choice.
Currently, it seems premature to utilize HCV NAT D+/R – kidney transplantation as a
standard of care. Further studies are required to draw solid conclusions regarding the
long-term consequences of adopting such a treatment approach.
HCV-positive organs were rejected from donation nearly 3 times more often than HCV-negative ones. Recently there is an approach to give these organs to HCV- ve as the risk of transmitting the disease is less than the risk of transmitting other viral diseases but this approach is still practiced in few cases.
Not all patients, with positive HCV serology, can transmit the infection. Nucleic acid testing (NAT) can define the possibility of transmission more accurately than serology and was adopted by most of the guidelines.
Several studies adopted different protocols for recipients who accepted kidneys from JCV positive donors with promising results. The acceptance of infected graft was less in the HCV positive recipients which occur due to lack of treatment information from their side
The selection of recipient for these organs depends on their duration in the waiting list and the status of their liver. Donor selection depend on the genotype, relapse and previous treatment with NS5 inhibitors
Use of DAA is faced with many issues: Drug-drug interactions, path of drug elimination and kidney function. Early introduction of treatment can limit the exposure to viremia and the development of complications. The standard duration for treatment is 12 to 16 weeks.
So, kidney transplant from an HCV NAT positive donor to naive recipients can be an effective and safe solution to the problem of the insufficient number of organs available for transplantation
the level of evidence is V
in Sudan donors who are HCV positive are not accepted. I think I can accept those donors only for patients who have been in the waiting list for long time and they are in health center provided with the necessary facilities.
Summary of utilization of HCV viremic donors in kidney transplantation: a chance or a threat? Introduction:
As many steps are being taken to increase the organ donor pool.
Using donors from the hepatitis C virus is another way to overcome the organ shortage.
Kidigo guideline HCV antibody-positive can donate for HCV positive
Current guideline of the American society of transplantation HCV positive donors can donate to HCV-negative recipient
This study high light the usage of HCV-viraemic donor organs and the limit of such donor organs
Recently HCV-viraemic organs were offered to HCV-negative recipients only within the clinical trials for a carefully selected group of patients.
HC Testing and risk of transmission:
NAT testing HCV RNA add more advantage to detect viremia and those without it to assess the risk of virus transmission
Kidney transplantation from an HCV donor (Ab+/NAT-) to an HCV-negative recipient can result in seroconversion but the risk of viremia is minimal.
Kidney transplantation from HCV-viraemic donors to HCV-viraemic recipients:
The efficacy of HCV NAT D+/R- kidney transplantation has been reported in several clinical trials.
Several real-life and clinical studies have provided satisfactory results in treating HCV from a donor organ.
Need education program and access to help KTRs make an informed decision regarding HCV NAT D+/R- transplant.
HCV NAT D+/R- Transplant requires careful donor and recipient selection
Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT D+/R- protocols
As per the American society of transplant surgeons, a lack of knowledge of the genotype or the presence of RAS should not be contraindicated for HCV NAT D+/R- kidney transplantation provided that treatment can be initiated without delay.
HCV involves a combination of two or three DAAs that target non-structural proteins of the HCV and may be delivered with little adverse effects.
The optimal time for introducing treatment in such cases of virus transmission from the donor is not yet established early introduction of treatment can also limit exposure to viremia and the development of a complication.
KTRs have HCV receiving fewer effects with interleukin.
KDPI:
The regulations introduced by the OPTN/UNOS require informed consent from the recipient deciding to accept a kidney from a PHS criteria donor.
The utilization of organs with active HCV viremia is associated with high costs.
HCV NAT+ kidney to HCV-negative recipient can be continued as shortened waiting time by 2 years.
Conclusion:
HCV positive is superior to giving kidneys with HCV positive.
Hepatitis C positive donor offer to hepatitis C negative recipient as the second option.
Efforts should be made to ensure DAA therapy and reduce the matching of patients waiting for kidney transplantation.
Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D+/R-
level 5
in our centre we are not accept donor with hepatitis C postive
Please summarise this article in your own words
This narrative review was published in a renal failure journal with a current impact factor of 2.60, in 2022
Summary
Kidney transplantation is still the best option to improve patient quality of life and improved survival however organ shortage is increasing and according to the data from OPTN more than 90,000 patients are on the waiting list for organ transplantation with an average waiting time on dialysis accede 3-5 years in the US. in order to increase the pool of donors in addition to the living donation and DCD donation, one step is to accept the donation from those with HCV viremia, especially in the era of the new therapies which includes interferon-free regimens with sustained viral response
Previous guidelines prohibit donations from active HCV (HCV +D to negative recipients, and only limited the donation to D+ / R+ve and even such practice is also limited due to the difficulty to differentiate the donors with active viremia in addition to the limited treatment options. This study emphasizes not only the possibilities of the usage of HCV-viremic donor organs built on recent limited data but also on extra features that limit the practice of such donor organs.
What is the level of evidence provided by this article?
Narrative review level 5 of evidence
Please reflect on the guidelines provided above and on your practice.
All living donors should be screened for HCV, and HBV infections including HBs Ag, HB c AB, and HBV AB with HBV PCR in case of HBc positive as there is a concern of low risk of seroconversion after transplantation and might need antiviral screening and antiviral prophylaxis while if HBc AB only positive with negative HBV PCR and negative HBsAg so can go for donation and recipient should be vaccinated with monitoring of the Hb AB titer.HCV Ab+ve /NAT-negative donors are those in whom the virus has been eradicated spontaneously or through antiviral
treatment. Spontaneous eradication of the virus is possible in up to 45% of cases, but non-immunocompetent
patients have a smaller chance of spontaneous eradication [23,24]. Kidney transplantation from an HCV
donor (Ab +ve /NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal. Although the risk of viral transmission is low, screening for HCV viremia is advisable in an early post-transplant period
Active HBV infection in the donor should preclude donation
Active HCV can still be considered for Living donation after comprehensive discussion with the donor and the recipients and the donor should receive AVV with good SVR as it’s not only associated with the risk of transmission to the recipient but also still the risk to the donor with complications like HCV related glomerulonephritis
Will you accept living or deceased donations from HCV-positive donors?
In special circumstances yes and should be discussed with the recipient and the donor in case of living donation about the risk of transmission and also the need for treatment with new AVV that can have a cure rate and if HCV RNA is negative, they still can go for donation. Until recently, HCV-viremic organs were accessible to HCV-negative recipients only within clinical trials, for a wisely selected group of patients with definite access to direct antiviral agents (DAAs).
The transmission of HCV to recipient is minimal but there is risk of transmission, so this should be confirmed by HCV-NAT testing to avoid (detect in window period one week) transmission.
According to KDIGO there is no contraindication to proceed if viral load is low, no fibrosis(contraindication donors, non responder/ relapsed, also according to this article too.
DAAs has good result according to AASLD/IDSA also there is no need to dose modification in patients with eGFR<15. If started prophylactically it has a good result. but can be given with precaution if there is risk of other infection, risk of TE. The recommended treatment duration is 12 weeks if achieved SVR.
there is no need to modify the immunosuppression with good precaution as there is possibilities of flare-up and viremia. there is minimal risk of drug interaction. but with all these donation should to encouraged to overcome the need of shortage of donation.
level V
We don’t take HCV positive donation yet.
I believe in future there will be more data for intra/ peri operative complication (TE, MAHA, viremia, infections) as we would be able to accept.
This study is a narrative review (level V of evidence) discussing new strategies in an attempt to include donors with Hepatitis C to be considered expanded criteria donors depending on the criteria discussed. Young patients with opioid abuse have grown significantly as potential deceased donors, with high serology for Hepatitis C in this population group.
This retrospective study from 2005 to 2014 evaluated 6456 kidney transplants where only 37% of HCV-positive donors performed the transplant. In the United Kingdom, 76% were discarded because the serology was positive and only 8.9% because of the quality of the organ. In an American study, 14% of the negatives were the fear of being sued by the patient.
There is a possibility of positive serology (anti HCV positive) with negative viral load (NAT -), which means a spontaneous cure and has a low risk of transmission to the recipient. The presence of viremia increases the risk of transmission, and prophylaxis regimens may be necessary for the recipient in an attempt to avoid transmission. It is not yet well-defined which regimen or even for how long to proceed with the treatment. Apparently, Sofosbuvir with ledispavir for 12 weeks is the most used regimen, and it should be done as early as possible, even before virulence positivity or clinical manifestations. The cost of treatment is an obstacle, but removing the patient from the transplant queue tends to be more cost-effective in the medium to long term.
Desensitization schemes should be excluded. Priority would be to transplant D+/R+., but you can transplant D+/R- considering the possibility of prophylaxis. If viral load is negative, the risk drops considerably. Drug interactions with calcineurin inhibitors should be closely monitored, with serum measurement of the drug, as with antiepileptics. The receiver must be aware of the risks involved and the cost-effectiveness of leaving the queue. This waiting time reduces hemodialysis time by 11 to 24 months.
Patients with a long waiting time, high cPRA, living donors compatible with controlled disease and low viremia, a deceased donor with low viremia, patients aware of the risk and availability of an antiviral regimen with Sofosbuvir and ledispavir for two weeks would make me accept a kidney in these conditions.
Kidney transplantation is the preferred treatment for ESRD.But, the problem is the shortage of available organs . Efforts done to increase the organ donor pool as using organs from donors infected with HCV especially after introduction of highly effective oral direct acting antivirals to the treatment of chronic hepatitis C virus infection.
Underutilization
In the past , HCV organs were discarded, the serological status of the donor was the only cause for discarding these organs due to the fear of transmitting HCV infection.
Some studies showed comparable results in transplantation from HCV NAT+ donors when compared to those from HCV negative donors in GFR and 12 months graft survival rate.
Until recently, HCV viremic organs were offered to HCV negative recipients only in clinical trials, for carefully selected recipients with available direct acting antivirals.
In the latest survey, 14 % of transplant centers utilize HCV NAT D + organ in transplantation of negative recipients.
HCV testing and risk of transmission
HCV nucleic acid tests RNA ( NAT) and serological tests are used for diagnosis of HCV infection.
This allowed the identification of donors with active viremia (HCV Ab+/NAT+ or HCV Ab-/NAT+) and those without it ( HCV NAT- )
Kidney transplantation from HCV Ab+/NAT- donors to HCV negative recipients can result in seroconversion, but the risk of viral transmission is low.
In contrast in HCV NAT + donors , regardless of their serological status, they have active viremia , and carry high risk of virus transmission
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
This is clinical trial
The studies done on kidney transplantation from HCV viremic donors with genotype 1 or 4 to HCV naive recipients showed the viral transmission occurred in 100% of patients and direct acting antivirals were initiated as soon as viremia was detected and continued for 12 weeks and this caused a sustained virologic response in all patients and allograft function after 6 and 12 months did not vary from that matched recipients of HCV negative grafts .
Donor/ recipient selection criteria
Patients with long waiting times should be considered for HCV NAT D+/R- to decrease waiting time especially if they are more likely to deteriorate or die if they waited the organ
HCV naive patients with cirrhosis or history of liver disease are not offered HCV viremic organs
Application of FibroScan in recipient evaluation prior to HCV NATD+/R+ transplantation facilities proper recipient selection
knowledge of viral load enables identification of individual at high risk for development of HCV related complications and determination the optimal time for initiation of DAAs
patients requiring nonstandard immunosuppression or desensitization are excluded
Donors who were previously treated with NS5 inhibitors or those who have relapsed are excluded
Donor’s genotype especially type 1a and 3 which need prolonged treatment
Patients who are predicted to be non compliant should be excluded
DAAs
Therapy involves two or three DAAs
Guidelines recommend GLE/PIB for 8 weeks or SOF/VEL for 12 weeks
Optimal time for initiation
Guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days post transplant
Level 5
No , I don’t accept HCV positive donors
To increase the living donor pool , some centers start to using extending criteria in donor selection , such as accepting donor with HCV
all potential donors should be screened using anti-HCV antibodies and PCR and according to results we divide the donors into 4 groups :
What is the level of evidence provided by this article? 5
Will you accept living or deceased donation from HCV positive donors?
in our transplantation center we didn’t have the facilities and experience in dealing with this type of transplantation , so we will decline any donor with positive HCV
thanks
Summary:
Utilization of HCV viremic donors in kidney transplantation: a chance or a threat?
Kidney transplant is the best available treatment for ESRD. Organ shortage is the main barrier to transplantation. Many steps are being taken to increase the organ donor pool including living donors and donors after cardiac death. The use of organs from donors infected with hepatitis C virus (HCV) is another step to overcome organ shortage. The use of highly effective interferon-free therapies with an efficacy exceeding 95% allowed utilization of HCV-viremic organs especially where the mortality due to drug overuse is increased as in US. Donors with HCV are usually young and had few comorbidities and better organ quality measured by KDPI. HCV (+) donor was contraindication for kidney transplantation. According to KDIGO guidelines, since 1990, kidneys from HCV AB (+) donors have been used as transplants under the condition that the recipient is also HCV Ab (+).
The current guidelines of the American Society of Transplantation do not forbid the transplantation of infected organs to recipients not infected with HCV, but they indicate the necessity for further research on the consequence of such a practice
Underutilization:
Available kidneys from HCV-seropositive donors, only 37% of them were actually transplanted, however, only 16% of them would have been HCV viremia. In UK 76% was discarded due to serological status of the donor, and only 8.9% were discarded due to unsatisfactory organ status. Most available data was in the period of interferon based treatment. Many studies show comparable graft survival of HCV (+) to HCV (-). The latest survey on US transplant programs revealed that 58% of transplant centers offered transplantation from an HCV-viremic donor to an HCV-negative recipient (HCV Dþ/R-).
Until recently, organs from HCV-viremic donors were given to HCVnegative recipients only in clinical trial, with careful selection of the patients and free access to direct antiviral agents (DAAs). Which show encouraging outcomes of HCV NAT D+/R- transplantations, leading to acceptance of this practice as standard of care by 14% of transplant centers according to latest national survey.
Recommendations regarding HCV NAT testing are not unified and vary on other continents.
HCV testing and risk of transmission:
Obligatory NAT for HCV RNA as part of HCV infection diagnosis in addition to serological tests had change the attitude toward an HCV-positive donor as these allow identification of donors with active viremia (HCV Ab+/NAT+OR HCV AB-/NAT+) and those without it (HCV NAT-). This differentiation is of key important, as not every HCV-positive donor has a risk of virus transmission through transplantation.
HCV Ab+/NAT- donors mean they eradicate the virus spontaneously or through antiviral treatment. Kidney transplant from an HCV donor (Ab+/NAT-) to an HCV negative recipient can result in seroconversion, but the risk of viremia is minimal. Screening for HCV viremia is advisable in early post-transplant period.
Donors with active viremia as indicated by HCV NAT+ test is associated with a high risk of virus transmission.
HCV NAT test helped reducing the diagnostic window from 2—6 months for serological assays to 5 – 7 days for NAT, and thereby reduce the risk of the nonintentional viral transmission.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
This possible with use of DAA even before transplantation, the protocol differ widely in the studies.
Incidence of ACR and development of de novo donorspecific antibodies (DSA) did not exceed those observed in HCV-aviremic donors and accounted for 4% and 6% respectively.
Several other real-life and clinical studies have provided satisfactory results in treating HCV from a donor
organ.
Willingness to accept HCV-viremic organs
the willingness to accept a seropositive organ increased sixfold in study that conducted over the period from 2015 to 2019.
McCauley et al. showed that as many as 80% of patients are willing to accept an organ from an HCV NAT (+) donor under certain conditions, while 18% would not accept it under any circumstance.
This
The decision is affected by the expected effectiveness of treatment, quality of the organ, and the duration of being on the organ waiting list and this rise the need for comprehensive education program for the patients.
Donor/recipient selection criteria
Currently there are no universal standards regarding which recipients could benefit from an organ from HCV NAT + donor, which donors can be considered as potential candidates, and the quality of organs obtained from HCV NAT + donor. Patients on the waiting time for long period should be considered for HCV NAT D+/R- transplants. As this carry survival benefit.
HCV-naïve patients with cirrhosis or a history of liver disease should not offered HCV-viremic organs as this may progress their already diagnosed liver disease. Also, patients with metabolic syndrome (DM or obesity) who are at risk of NAFLD even with normal liver enzymes, therefore offering HCV-viremic organs to them poses a threat of progression of liver disease even to hepatocellular carcinoma. In addition, NAFL patients are at a great risk of metabolic complications that increase risk of mortality.
The screening FOR NAFLD is not recommended in the general population and in high risk patients the approach to screening vary across guidelines. The application of fibroscan in standard recipient evaluation prior to HCV NAT D+/R- transplantation could facilitate proper recipient selection.
Viral load (RNA levels) could enable identification of individuals at higher risk of HCV-related complications and determine the optimal time for DAA therapy initiation.
Recipients need aggressive induction or desensitization therapy are contraindication to HCV NAT D+/R- protocol.
Immunosuppressive and DAA agents interaction may cause under immunosuppression or low efficacy of DAA therapy. Pangenotypic DAA regimens have less drug-drug interactions. Tacrolimus level need to be monitoried closely as underimmunosuppression can lead to de novo DSA and AR.
To avoid difficulties in viral clearance after transplantation and situation when no antiviral treatment will be available for the patients, donors who were treated with NS5 inhibitors or those who have relapsed seems reasonable option. Genotype identification is important especially if pangenotype antiviral agents are not available. the American Society of Transplant Surgeons, in its consensus, stated that a lack of knowledge of the genotype or the presence of RAS should not be a contraindication for HCV NAT D+/R- kidney transplantation, provided that treatment can be initiated without delay.
DAA
HCV therapy involves a combination of two and three DAAs that has high efficacy. The availability and high cost of DAA therapy are the only drawback of them. Before starting DAA several factors should be considered; include evidence of liver dysfunction, concomitant medication, and immunosuppression that will be used after transplantation.
Drug-drug interaction must be considered. Calcineurin inhibitor need to be adjusted during DAA therapy to avoid premature withdrawal of DAA thereby avoid risk of DAA resistance. Anti-epileptic medications, also proton pump inhibitors. The dosage need not be adjusted in the case of patients with chronic kidney disease (CKD) or those receiving dialysis. The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver.
Optimal timing of DAA initiation
The optimal time for introducing treatment in such cases of virus transmission from the donor has not yet been established. We need to consider kidney function e GFR.
Optimal timing of DAA initiation
The optimal time for introducing treatment in such cases of virus transmission from the donor has not yet been established. The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation.
higher than expected incidence rate of CMV viremia and BK viremia were observed. Also, increase risk of fibrosing cholestatic hepatitis AR, thrombotic microangiopathy and a series of immunological complications, such as AR or glomerulonephritis (GN). Monitoring proteinuria every 6 months in patients infected with HCV after transplantation.
Immunosuppression drugs
Recent studies have shown that patients infected with HCV should receive standard immunosuppression and that depletive induction should not be avoided if there are reasons to introduce it.
KDPI calculation
In the US, the KDPI is used to estimate the expected organ survival rate after transplantation.
Many factors are taken into account, presence of antiHCV antibodies, which leads to increase in the KDPI and altimetry affect organ allocation.
Informed consent
Informed consent from the recipient deciding to accept a kidney from a PHS criteria donor is required. HCV negative recipient who offered HCV NAT + needs comprehensive counselling regarding the risk and benefit of such transplantation in addition to DAA cost, and give them enough time to formulation questions.
HCV-viremic organ refusal
Utilization of HCV-viremic kidneys increases the total number of transplantations and results in a shorter waiting time for individuals remaining on the waiting list. Given the ever-growing demand for organs that is hard to satisfy, HCV NAT Dþ/R- transplants may be lifesaving in certain circumstances, despite the inherent risk associated with this practice. This is because despite the imbalance between the demand and supply of kidneys available for transplantation, hundreds of HCV-viremic kidneys are discarded annually.
Insurance
Coverage of cost of DAA therapy remains a significant concern for both patients and health care providers and prevents HCV-viremic organs from being fully utilized.
Cost-effectiveness
The latest analyses show that transplanting HCV NAT + kidneys to HCV-negative recipients can be cost effective because it could shorten the waiting time by II months to 2 years.
Conclusion:
In light of the current knowledge, the transplantation of HCV NAT þ kidneys to naïve recipients may
constitute a solution to organ shortage.
Level 5, Narrative article
In my centre; no acceptance to HCV donors yet
yes; with good counselling of the patients and free access to DAA, close monitoring to the recipient post-transplantation.
· After the introduction of the new effective antiviral drugs, it is possible to treat donors with HCV, and to increase the donor pool.
· This study highlighted the possibilities and limitations of accepting HCV + donor
· The introduction of HCV RNA (NAT) as part of HCV infection diagnostics, allowed for diagnosis of donors with active viremia (HCV Ab+/ NAT + or HCV Ab-/NAT+) and those without it (HCV NAT-)
· HCV viremia in the donor is associated with a high risk of virus transmission.
· Viremia always develops in recipients after HCV D+/R- NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants
· HCV NAT testing reduced the diagnostic window, from to 2–6 months for serological assays to 5–7days for NAT
· A study by Potluri et al. showed that over the period from 2015 to 2019, the willingness to accept a seropositive organ increased sixfold
Donor/recipient selection criteria
· Patients with long standing waiting times should be considered for HCV NAT D+/R- transplants
· Recipients with diabetes and obesity, or NAFELD, who receive organs from HCV NAT + donors may have more risk of metabolic complications which increases mortality
· Fibro Scan in standard recipient evaluation prior to HCV NAT D+/R- transplantation could facilitate proper recipient selection
· Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT D+/R- protocols
· Pan genotypic DAA regimens have limited drug–drug interactions with tacrolimus and may limit the need to adjust the dose of calcineurin inhibitors
DAAs
· GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver, is recommended.
· SOF, which is effective in treating genotype 3, is mainly renally excreted. Therefore, it was not recommended for patients with eGFR < 30 mL/min/ 1.73 m2, but it was approved in November 2019 by the US FDA for use in patients with an eGFR below 30 mL/min/1.73 m2 and those who were dialysis-dependent
· The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation
· Complications of delaying treatment for few months:
-Acute infection may lead to fulminant hepatitis or fibrosing cholestatic hepatitis
-Thrombotic microangiopathy and acute rejection or glomerulonephritis can occur
· The standard 12- to 16-week treatment duration allowed the achievement of SVR in 100% of patients under both prophylactic and reactive approaches (after HCV viremia is documented)
· Informed consent from the recipient is required deciding to accept a kidney from a PHS criteria donor, after education process, and giving information on the benefits and risks of such a solution
· Recent analyses showed that transplanting HCV NAT + kidneys to HCV-negative recipients can be cost effective because it could shorten the waiting time by 2 years
Conclusions
· Giving HCV NAT organs for HCV infected recipients have lower costs, less complications, and more ethical
· The transplantation of HCV NAT + kidneys to naïve recipients may reduce organ shortage, but DAA therapy should be used early post transplantation
What is the level of evidence provided by this article?
Please reflect on the guidelines provided above and on your practice.
We usually not accept HCV donors. But according to my knowledge, all HCV dialysis patient who were treated with DAA, have cured from hepatitis C
Will you accept living or deceased donation from HCV positive donors?
Yes. As the DAA drugs available and we strictly follow our patients. But I am with the use prophylactic drugs pre-transplantation
-Due to shortage of organs and long waiting list
use of organs from HCV donors with active viremia could increase the donor pool of kidneys available for transplantation by as many as 500 organs per year.
-According to the KDIGO guidelines, since the 1990s, kidneys from HCV antibody-positive donors have been used as transplants under the condition that the recipient is also HCV Ab.
-× American Society of Transplantation guidelines
allowed the transplantation of infected organs to recipients not infected with HCV, but they indicate the necessity for further research on the consequence of such a practice .
▪︎Underutilization
In the past, HCV-positive organs were discarded nearly three times more often than HCV-negative ones.
In 76% of cases, kidneys were discarded due to serological status of the donor.
With improvement of HCV treatment
The tendency to discard HCV-positive organs started to decrease Within the first 3 months of 2019, 200 kidneys were transplanted into HCV-negative recipients from HCV NAT+ donors.
– number of factors resulted in Underutilization of these kidneys such as difficulties in insurance coverage,risk of virus transmission (59%) , the fear of possible complications; however, in 14% of cases, the main factor was the risk of being sued and in 3% of cases, it was a previous negative experience.
-Until recently, HCV-viremic organs were offered to HCV-negative recipients only within clinical trials, for a carefully selected group of patients with guaranteed access to direct antiviral agents (DAAs).
There is no clear guidelines for transplantation from HCVab +ve donors.
The underutilization of HCV NAT+ organs compared to CMV and HBV may be due to higher risk of de novo hepatitis and a higher risk of death after transplantation, an increased risk of rejection, or opportunistic infections by HBV and CMV.
▪︎HCV testing and risk of transmission
-transplantation from an HCV donor (Ab+/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
Although the risk of viral transmission is low, screening for HCV viremia is advisable in an early post-transplant period.
HCV viremia in the donor is associated with a high risk of virus transmission.
▪︎Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
The efficacy of HCV NAT D+/R-kidney transplantation has been reported in several clinical trials
-the THINKER study 20 HCV-naïve KTRs.received HCV-viremic organs all of them developed Viral transmission . Elbasvir/grazoprevir (EBR/GZR) was initiated 3 days after transplantation for 12 weeks. This enabled a sustained virologic response with good allograft function after 6 and 12months.
-EXPANDER study, used prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, then for 12 weeks ,sofosbuvir was added to EBR/GZR to genotypes other than 1 .
SVR was achieved in 100% of cases,with no severe graft complications.
other real-life and clinical studies have provided satisfactory results in treating HCV from a donor organ,encouraging increased utilization of oragans from HCV positive donors especially in endemic areas.
-An analysis by McCauley et al. showed that as many as 80% of patients
are willing to accept an organ from an HCV NAT+ donor under certain conditions, while 18% would not accept it under any circumstance .
– unfortunately there is no standards governing which patients could benefit from receiving an organ from an HCV NAT + donor and which donors should be considered as potential candidates .
-and no unified regulations exist regarding the quality of organs obtained from HCV NAT + donors.
-patients on waiting list for long time can have more survival benefit instead of
remaining on the wwaitlist which constitute a greater risk than being infected with HCV that may be successfully treated .
-implementation of FibroScan in standard recipient evaluation prior to HCV NAT D+/R-transplantation could facilitate proper recipient selection to avoid metabolic complications and deterioration of asymptomatic liver disease.
-Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT D+/R-protocols.
– Drug–drug interactions between immunosuppressive agents and DAAs may also translate to underimmunosuppression or decreased efficacy of DAA therapy.
▪︎DAAs
-IDSA recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver.
-drug-drug interaction between DAAS and immunosuppression must be considered
As 45% of patients may require an adjustment of the dosage of the calcineurin inhibitor during DAA therapy.
-SOF, which is effective in treating genotype 3, is mainly renally excreted was approved in November 2019 by the US Food and Drug Administration for use in patients with an eGFR below 30 mL/min/1.73 m2 and those who were dialysis-dependent.
▪︎Optimal timing of DAA initiationSome studies started treatment befor transplantation while other started around 3 days after transplantation when viremia appeared
recent survey conducted by Lentine et al. showed that the majority of transplant centers initiated DAA therapy after HCV viremia was detected and after hospital discharge.
Postponing treatment for a few months may be associated with serious complications. An acute infection with HCV , fulminant hepatitis or fibrosing cholestatic hepatitis , higher risk of development of thrombotic microangiopathy and a series of immunological complications, such as AR or glomerulonephritis .
▪︎Immunosuppression
The optimal immunosuppression scheme for transplants from an HCV NAT +donor to a naïve recipient remains to be determined.
Recent studies have shown that patients infected with HCV should receive standard immunosuppression and that depletive induction should not be avoided if indicated
-The acceptance of an HCV NAT+ organ by an HCV-negative recipient should be preceded by a comprehensive education process, including information on the benefits and risks of such a solution and informed consent.
– more studies are needed to evaluate long term effect on patient and graft survival, liver disease and HCC occurrence .
▪︎Level of evidence 5
▪︎Please reflect on the guidelines provided above and on your practice.
We dont accept HCVAB + donors
Will you accept living or deceased donation from HCV positive donors?
ithink under certain conditions with urgent need for transplantation i will accept after clear information to recipient .
Summary:
· HCV positive donors were declined previously, or restricted to HCV positive recipients.
· Use of HCV positive PCR donors to donate negative recipients can help to expand the donor pool, especially with available oral antiviral drugs/ direct acting antiviral (DAA). However, the long-term consequences need further follow up.
Level of evidence: V.
Reflect on your work: we use HCV positive donors only in HCV positive recipient if only available donor (as we don’t have deceased donor program yet).
Acceptance of HCV viremic donor:
– It depends on available expert hepatologist interested in the field of kidney transplantation and availability of DAA.
– I think allocation of HCV positive deceased and living donors for HCV positive recipient is better than their use in HCV negative ones.
– If it is the only available option, can be used in negative recipients with close follow up, use of prophylactic antiviral. Sure, after counseling of both the donor and the recipient for the possible risk.
– Certain perquisites to accept this donor are;
o Standard immunological risk (not needed desensitization protocol for ABO and HLA incompatibility.
o Not used ATG induction to limit post-transplant flare of HCV and fulminant infection.
o Treatment of donor by DAA prior to Tx.
Kidney transplantation is the best renal replacement therapy but shortage of available organs prolong the waiting time on dialysis and is associated with higher mortality rate.
Using organs from donors with HCV is an approach to increase donor pool
Previously, HCV infection was a contraindication for donation for fear of long immunosuppression in recipients.
KDIGO accepted kidney donation from donor with HCV Ab+ to recipients also HCV Ab+ but was limited due to difficulty in determining active viremia.
Recent guidelines allow donors with HCV to donate to recipients without HCV infection.
Underutilization:
HCV positive organs is mostly discarded to avoid HCV transmission to recipients and for fear of complications.
Recently studies showed that HCV NAT+ and HCV Ab+/NAT- donors had similar graft survival as those from HCV negative donors.
Recently, rate of discarding HCV viremic kidneys decreased but still more than that of HCV negative kidneys.
The approach to HCV NAT D+/R- is variable, HCV NAT testing is not unified, in some countries, HCV NAT D+/R- is forbidden.
Underutilization of HCV NAT+ organs is more than that with organs with risk of transmission of HBV or CMV which are accepted due to associated survival benefits.
HCV testing and risk of transmission:
HCV NAT allowed differentiation between donors with active viremia, HCV Ab+/NAT- donors have virus eradicated spontaneously or through antiviral therap.
Kidney transplantation from HCV donor Ab+/NAT- to HCV negative recipient may lead to seroconversion with minimal risk of viremia.
HCV NAT+ donors have active viremia and associated with high risk of transmission.
Current guidelines recommend testing all donors for HIV, HBV and HCV using NAT.
Kidney transplant from HCV viremic donors to HCV-aviremic recipients:
Several clinical trials showed satisfactory results in treating HCV from a donor organ.
The THINKER study, viral transmission was observed in 100%but all received EBR/GZR and SVR was achieved in all patients.
EXPABDER study used prophylactic DAA therapy and achieved SVR in all cases with comparable graft function.
Willingness to accept HCV-viremic organs:
It is increasing recently, however it is mostly accepted under certain conditions and is influenced by quality of organ, duration on the waiting list and expected efficacy of treatment.
Comprehensive education programs are needed to make informed decision.
Donor/recipient selection criteria:
Standards of donor and recipient selection are not well defined.
Patients with log waiting times may receive HCV NATD+/R- to decrease waiting time, achieve survival benefit and avoid remaining on dialysis which constitute a risk of HCV infection.
HCV naïve patients with cirrhosis or liver disease are not offered HCV viremic organs.
Patients with DM and obesity are at risk of undiagnosed liver disease, receiving HCV NAT+ organs increase risk of metabolic complications and mortality.
Fibroscan for recipients of HCV NAT D+/R- may facilitate recipient selection.
There is positive correlation between RNA levels in donors and recipients, Viral load identify those at high risk for HCV related complications.
Patients receiving intense immunosuppression or desensitization are excluded.
Patients at high risk of acute rejection as highly sensitized or re-transplant should be carefully evaluated.
Donors treated with NS5 inhibitors or have relapsed are excluded to avoid difficulties in viral clearance post transplant.
Donor genotype is crucial if pangenotyping antiviral agents are unavailable, however, it is recommended that unidentified genotype or presence of RAS don’t contraindicate HCV NAT D+/R- kidney transplants provided the treatment is available without delay.
Non-compliant patients should not receive HCV viremic organs.
DAAs
Target nonstructural proteins of HCV with little side effects and high efficacy, preferably pangenotyping DAAs but high cost limit its use.
HCV naïve recipients of HCV viremic kidneys should receive GLE/PIB for 8 weeks or SOF/UEL for 12 weeks after considering liver function, concomitant medications and immunosuppression.
SOF is renally excreted but can be used in CKD with GFR <30 or dialysis dependent according to FDA.
Optimal timing of DAA initiation:
The optimal time is not well determined, guidelines suggest prophylactic treatment 7 days before transplant.
Some studies started treatment before transplant, others when HCV viremia was detected, some centers postponed treatments for weeks after stabilization of immunosuppression while others after 76 days post transplant due to financial issues.
In THINKER and EXPANDER studies, no complications were seen with starting treatment early post transplant.
Most centers start DAA after detection of HCV viremia and after hospital discharge.
Postponing treatment for few months may lead to acute infection with HCV leading to fulminant hepatitis or fibrosing cholestatic hepatitis and risk of TMA.
DAA initiation peri-transplant is recommended to limit exposure to viremia, decrease complications and decrease duration of therapy and costs.
Duration of treatment is controversial.
Immunosuppression:
Is not well determined, patients with HCV should receive standard immunosuppression and depletive induction should be used if indicated.
KDPI calculation:
Used to estimate the expected organ survival rate post transplant, presence of anti-HCV antibodies artificially increases KDPI more than the actual quality of organ leading to improper allocation of organs.
Several studies showed excellent quality of organs from donors infected with HCV and KDPI should be calculated according to serological state.
Informed consent:
Should be preceded by comprehensive education process on benefits and risks, limited available data and long term outcomes are unclear.
HCV viremc organ refusal:
leads to longer waiting time on dialysis with increased risk of death
Insurance:
Should cover cost of DAA therapy, refusal of requests cause delay in starting treatment.
Usage of DAA are registered for chronic hepatitis C.
Cost-effectiveness:
Studies showed that HCV NAT D+/R- is cos-teffective and decrease the waiting time.
Level of evidence: 5 (Narrative review article)
In our practice we preferer exclusion of donors with HCV infection but if no other donor is available for the patient, donor with HCV Ab+ but HCV PCR negative can be accepted for donation.
I will not accept potential donors with HCV infection for donation because of the high cost of DAA, the risk of complications due to transmission and the long term outcomes are not well determined
Summary – Utilization of HCV viremic donors in kidney transplantation : chance or threat?
This study is about accepting HCV positive donors for kidney transplant recipients and its outcomes.
Accepting HCV positive donors has been a secondary choice so far, however, with the continued organ shortage, we need to make new ways to accept available donors and make the situation as workable as possible. With this in mind, even with risk of complications, it is time to accept such donors. DAA therapy can reduce patient mortality while waiting for kidney transplant.
Educational programs to increased awareness of HCV infection and HCV NAT positive kidney transplantation. This encourages acceptance of HCV positive donors and ensures that the necessary steps are taken to minimize complications post transplant. However, further studies are needed to confirm long term consequences of utilizing such donors.
Conclusions
It is rational to prioritize the utilization of HCV NAT+organs in recipients already infected with HCV. This will decrease the cost and offering it to HCV naïve patient should be secondary choice only.
2. What is the level of evidence provided by this article?
Level 5
3. Please reflect on the guidelines provided above and on your practice.
In our practice still we don’t have active deceased donor team.
4. Will you accept living or deceased donation from HCV positive donors?
With the availability of DAA, we will accept HCV + to HCV naïve recipient as second choice, provided that DAA are available, and patient consented for that.
1. Please summarise this article in your own words
Introduction
Kidney transplantation is the best available modality for patient with ESRD, it improves patient survival and quality of life. However, there is shortage of organs worldwide. This led to the introduction of expanding criteria donor, including donors with HCV infection. The introduction of highly effective interferon free therapies with an efficacy exceeding 95% allowed to utilize HCV-viremic organs especially in the setting of significant increase in mortality resulting from drug overuse. These donors are usually young, hence have better organs. It is estimated that using organs with HCV viremia could increase the organs transplanted by around 500 kidneys.
Underutilization
In the past, HCV-positive organs were discarded nearly three times more often than HCV-negative ones were.
HCV testing and risk of transmission
Differentiation of donors with active viremia (HCV Ab/ NATor HCV Ab-/NAT) and those without it (HCV
NAT is key because not every HCV-positive donor poses a risk of virus transmission through transplantation.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
Effectiveness and safety of HCV NAT D+/R- kidney transplantation has been reported in several clinical trials like THINKER and EXPANDER studies after 2017. In both studies despite 100% viral transmission, sustained virologic response SVR was achieved in 100% of cases.
Willingness to accept HCV-viremic organs
Despite increasing acceptance of HCV infected kidneys by 6 folds in some studies, still many HCV+ve recipients do not accept infected grafts which led to may infected kidneys transplanted to HCV naïve recipient.
Donor/recipient selection criteria
HCV NAT D+/R- transplants require careful donor and recipient selection. Standards governing
which patients could benefit from receiving an organ from an HCV NAT+ donor and which donors should be
considered as potential candidates are currently lacking.
DAAs
HCV therapy involves a combination of two or three DAAs that target non structural proteins of the HCV and
may be delivered with little adverse effect and high efficacy. Pangenotypic DAAs are preferred. The only drawbacks are accessibility to DAAs and the high cost of DAA therapy.
Conclusions
It is rational to prioritize the utilization of HCV NAT+organs in recipients already infected with HCV. This will decrease the cost and offering it to HCV naïve patient should be secondary choice only.
2. What is the level of evidence provided by this article?
Level 5
3. Please reflect on the guidelines provided above and on your practice.
In our practice still we don’t have active deceased donor team. In my previous program before 2016 we accept HCV+ve donors only for HCV+ recipient. But now, with the availability of DAA I think if we have the chance, we will accept HCV + to HCV naïve recipient as second choice, provided that DAA are available, and patient consented for that.
4. Will you accept living or deceased donation from HCV positive donors?
With the availability of DAA, we will accept HCV + to HCV naïve recipient as second choice, provided that DAA are available, and patient consented for that.
This is a review article with level of evidence 5
Active Hepatitis C infection in the donor is considered an absolute contraindication to donation, because of high risk of viral transmission to the recipient. Historically, kidney donation from Hep C donor was accepted only if the recipient is HCV positive. Because of the shortage in kidney donor pool accepting HCV positive donors will expand the donor pool and chance of getting a kidney offer.
• All potential donors should be screened for Hepatitis C as a routine screening. Patient with positive anti-HCV antibodies should be evaluated further with PCR
• Screening results
– Following initial screening, positive anti-HCV Abs, indicates active infection, whereas positive anti-HCV Abs and negative Hepatitis C PCR indicates either spontaneous resolution of HCV or complete response to treatment. Donor with this type of seroconversion is associated with minimal viremia.
– Positive anti-HCV Abs and PCR indicates active viremia and this type of donation should be discarded as it is associated with high risk of transmission.
– Negative anti-HCV Abs and positive PCR indicates replication of virus early in the window period, since seroconversion need 2-6 months to occur, whereas PCR can be positive as early as 5 to 7 days after infection. This type of donation is also associated with high risk of transmission and viremia
– Positive Hep C donor to negative Hep C recipient donation carries the highest risk of viremia
• Challenges with Hep C donation
Transmission of HCV from kidney donor to the recipient is possible, with subsequent liver extrahepatic complications including GN of the allograft.
In order to avoid complications after transplantation, donor and recipient immune status should be carefully identified. Infected donors should be appropriately treated before transplantation. Genotype of the donor is helpful in determining response to antiviral treatment, since genotypes 1a and 3 are associated with treatment failure. Moreover, donors with a history of treatment with NS5 inhibitors or history of relapse should be excluded.
From recipient’s perspective, recipient has the right to discard kidney from infected donor, however, in real life it was found that around 80% of recipients accept infected kidney donation. Recipients who accept kidneys from infected donor should be compliant with post-transplantation antiviral drugs prophylaxis with frequent monitoring of virus tests and liver function tests and regular follow-up. Recipient should have normal liver function tests at baseline and no history of chronic liver disease.
Recipients requiring aggressive induction therapy or desensitization therapy are usually excluded. Standard immunological risk status is required. Triple maintenance CNI-based immunosuppression and induction (basiliximab or ATG) are accepted for recipient.
DDAs
HCV therapy involves a combination of two or three DAAs that target nonstructural proteins of the HCV and may be delivered with little adverse effect and high efficacy. The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver. Drug-drug interactions must also be accounted for in the DAA therapy selection process to avoid complications, because premature withdrawal of DAA therapy increases the development of drug resistance.
The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation.
Some centers postpone treatment for a couple of weeks until the patient and immunosuppressive treatment are stable enough to avoid the need for early DAA therapy withdrawal.
Postponing treatment for a few months may be associated with serious complications.
KDIGO recommends, among other things, monitoring proteinuria every 6 months in patients infected with HCV after transplantation, and performing a biopsy if HCV infection occurs.
In conclusion, It is rational to prioritize the utilization of HCV NAT þ organs in recipients already infected with HCV. This entails lower costs, limits the risk of possible complications, and seems more reasonable from an ethical standpoint. Such organs should be offered to HCV negative recipients only as a secondary choice. However, this is not always possible in everyday practice.
In my practice we don not accept donors with hepatitis c and we do not transplant kidneys to patients with hepatitis c , only after treatment and complete response.
One of the way to increase donor pool for kidney transplant is by accepting donors infected with hepatitis C virus (HCV). The rate of discarding such organs is very high. All donors should be screened for HCV status using Anti-HCV antibody and viremia using HCV RNA (NAT) testing.
A patient with HCV antibody positive and NAT negative status implies resolution of viremia either spontaneously, or by treatment. Such patients have low risk of viremia post-transplant. A PCR (NAT) positive with positive or negative anti-HCV antibody result implies active viremia and has high risk of viral transmission (always in liver transplant and almost always in kidney transplant).
Transplanting kidney from HCV positive donor to HCV negative recipient expands the donor pool. The recipient should be counselled prior to transplant with respect to the risks and benefits involved. Such a transplant requires selecting appropriate donor and recipient, taking decision regarding use of prophylaxis – its timing and duration, immunosuppression use, and close follow-up.
Appropriate donor/recipient selection: A donor with HCV NAT positive result who has no history of treatment with NS5 inhibitors or relapse after treatment can be taken up. Donor’s genotype, if known, is helpful. Such kidneys can be transplanted in patients with long anticipated waiting times, but patients requiring desensitization or re-transplants, having history of cirrhosis/ liver disease, having non-affordability for DAAS, having poor compliance and poor follow-up should be excluded.
Use of prophylactic DAAs: Pangenotypic DAAs, if available, are preferred in such a scenario. Glecaprevir/ ibrentasvir (GLE/PIB) or sofosbuvir/ Velpatasvir (SOF/VEL) have recommended for treating HCV-naïve recipients of HCV-viremic organs other than the liver. Drug interactions with CNIs, antiepileptics and proton pump inhibitors should be watched for.
Timing of DAA initiation: It is recommended to start treatment prophylactically or pre-emptively within 7 days post-transplant. Timing of initiating DAAs has been evaluated in various trials and it has been shown that postponing treatment can lead to severe complications like fulminant hepatitis, fibrosing cholestatic hepatitis, thrombotic microangiopathy, acute rejection, glomerulonephritis, increased risk of BK viremia etc. Early initiation decreases viremia exposure, decreases duration of treatment, and decreases acute rejection rates. The optimum duration would be 12 to 16 weeks of treatment.
Immunosuppression: Standard immunosuppression should be used. Lymphocyte depleting agents should be used, if indicated.
Post-transplant follow-up: It would include liver function tests, HCV PCR, proteinuria (at least once in 6 months), CNI levels. A kidney biopsy would be required in presence of proteinuria.
So, it is logical to use HCV positive donors for HCV positive recipients. Offering such donors to HCV negative recipients requires detailed discussion with the prospective recipient and evaluation beforehand.
Level of evidence is Level 5: Narrative review
Ours is a living donor transplant unit. We do not accept HCV positive renal donors. Theoretically, if we get an HCV positive donor for an HCV positive recipient, we would go ahead if no other contraindications, but only after treating both the donor and the recipient. DAAs are available in India, and at an affordable cost. Some states in India provide the DAAs free of cost to patients.
Yes. But it should be done after detailed counselling of the patient/ donor.
For living donation: HCV positive donor for HCV positive recipient, but only after treatment both the donor and recipient with DAAs and documented SVR.
For decease donation: In exceptional circumstances, like requirement of urgent transplant (no vascular access, persistent uremia etc). The recipient should not be high-risk and devoid of any liver disease. Prophylactic DAA initiation prior to transplant would be my strategy for combating the viremia.
Summary – Utilization of HCV viremic donors in kidney transplantation : chance or threat?
This study is about accepting HCV positive donors for kidney transplant recipients and its outcomes.
Accepting HCV positive donors has been a secondary choice so far, however, with the continued organ shortage, we need to make new ways to accept available donors and make the situation as workable as possible. With this in mind, even with risk of complications, it is time to accept such donors. DAA therapy can reduce patient mortality while waiting for kidney transplant.
Educational programs to increased awareness of HCV infection and HCV NAT positive kidney transplantation. This encourages acceptance of HCV positive donors and ensures that the necessary steps are taken to minimize complications post transplant. However, further studies are needed to confirm long term consequences of utilizing such donors.
Level of evidence
Level of evidence 5
Practice
We accept live donors with HCV ab if the recipient consents.
Kidney disease is a global condition and the demand for a kidney transplant is in an increase with a low pool of donors. With this fact, there are other methods that are in the venture to try to add to the pool to facilitate kidney transplants. This is why the article is introducing or investigating the possibility of HCV donors to help to reduce the graft demand and the waiting time for transplantation. It was found that HCV-positive donors were younger than those with negative HCV. This was an advantage as it relates to lower comorbidities and improved quality of the organ. With the advance in medicine like the availability of interferons with an efficacy of 95%, there has been an increase in the use of HCV organs.
Due to the limitations of the reduced number of donors, KDIGO has to allow the use of donors with HCV-positive antibodies to a recipient HCV-positive. There are other institutions that have allowed the use of and advice for further investigations to help to understand and evaluate the complexity of the situation.
During the study, it was found that numerous HCV-positive kidneys were discarded but with the new data and investigations, this has slightly changed.
The studies available like the HCV NAT allow in differentiating donors with risk of the virus transmission in comparison with those at low risk by allowing to detect viral activity like HCV Ab+/NAT+ or HCVAb-/NAT+ and those without like HCV NAT-.
For donors with Ab+/NAT-, virus eradication is possible either with the treatment or spontaneously. This is why HCV- recipients are likely can receive from a donor and the viral load is likely to be minimal. Post-transplantation follow-up is important to ensure that early viral detection can be noted even though it is minimal.
Post transplantation or even before transplantation the use of KDPI calculator has been used to estimate the expected organ survival rate after a transplant.
Now with the new therapy, early treatment can be used to help to limit exposure to the virus and as such reduce possible complications. Treatment can be started during the procedure.
So one can conclude once the guidelines are followed and the care is taken then HCV-positive donors can provide to HCV-negative recipients. The practice may not be able to perform in all settings due to the availability of medications and investigations. However, all efforts must be made to ensure medications or treatments can be given to the patients and as such reduce complications and mortality.
The level of evidence in this article is level 5
Once there are proper studies and follow-ups and the recipient is HCV positive then there is a possibility of one accepting the risk.
4. Please reflect on the guidelines provided above and on your practice.
I think that HCV-positive donors can be used for HCV-positive recipients but for a positive donor to donate to a negative recipient, I think that it should be reviewed and re-discussed and investigated
1. Please summarise this article in your own words
Another step taken in order to resolve the organ shortage issue is also the use of organs from donors infected with the hepatitis C virus (HCV). The advent of new, highly effective interferonfree therapies with an efficacy exceeding 95% allowed to utilize HCV-viremic organs
Donors infected with HCV are usually younger than HCV-negative donors, and this can result in fewer comorbidities and improved quality of the organ, as manifested by the Kidney Donor Profile Index (KDPI)
Underutilization
In the past, HCV-positive organs were discarded nearly three times more often than HCV-negative ones were
Despite this, both CMV D/Rand anti-HBcD/Rorgans are accepted for transplantation because of the larger survival benefits for the patient than the risks resulting from the transmission of the virus. This underscores a need for raising awareness of the HCV- viremic organs utilization and efficacy of DAAs.
HCV testing and risk of transmission
testing for HCV RNA (NAT) as part of HCV infection diagnostics, in addition to the serological tests mandated by the United Network for Organ Sharing (UNOS) for potential organ donors in US
This allowed the identification of donors with active viremia (HCV Ab+/ NAT+or HCV Ab-/NAT+) and those without it (HCV NAT-).
HCV Ab/NAT- donors are those in whom the virus has been eradicated spontaneously or through antiviral treatment. Spontaneous eradication of the virus is possible in up to 45% of cases, but non-immunocompetent patients have a smaller chance for spontaneous eradication
Kidney transplantation from an HCV donor (Ab+/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
HCV NAT+donors, regardless of their serological status, are patients with active viremia associated with a high risk of virus transmission.
Viremia always develops in recipients after HCV D+/R- NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
In the THINKER study and its continuation, 20 HCV-naïve kidney transplant recipients (KTRs) received HCV-viremic organs
Viral transmission was observed in 100% of patients. Elbasvir/grazoprevir (EBR/GZR) was initiated as soon as viremia was detected (i.e. on average 3 days after transplantation) and continued for 12 weeks. This enabled a sustained virologic response (SVR) in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts. Notably, KTRs were tested for their genotype and resistanceassociated substitutions (RAS) prior to randomization, and only genotypes 1 and 4 were acceptable. Those with genotype 1 were treated using DAAs for 16 weeks, and ribavirin was added as needed
The EXPANDER study, in turn, utilized prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and the treatment was continued for 12weeks
For those with genotypes other than 1, sofosbuvir (SOF) was added to EBR/GZR. SVR was achieved in 100% of cases, and severe complications such as AR, graft loss, or liver damage were not observed
Virus transmission was observed in 50% of KTRs, and 100% SVR was observed after 12weeks. The authors reported 100%patient survival and one graft loss attributed to vein thrombosis. However, they reported no episodes of AR
Willingness to accept HCV-viremic organs
A study by Potluri et al. showed that over the period from 2015 to 2019, the willingness to accept a seropositive organ increased sixfold However, other studies point to the fact that recipients infected with HCV are unwilling to accept an infected graft. This results in a great majority of HCV NATkidneys being transplanted to HCV-naïve recipients
An analysis by McCauley et al. showed that as many as 80% of patients are willing to accept an organ from an HCV NATdonor under certain conditions, while 18% would not accept it under any circumstance [51]. This decision is mainly influenced by the expected effectiveness of treatment, quality of the organ, and the duration of being on the organ waiting list.
Donor/recipient selection criteria
patients with long anticipated waiting times should be considered for HCV NAT D+/R- transplants if this may reduce the waiting time. Their condition is likely to deteriorate, or they may die, until an organ becomes available; hence, HCV NAT D+/ R- transplantation confers a survival benefit to these patients. Moreover, for these patients, remaining on the waitlist may constitute a greater risk than being infected with HCV that may be successfully treated in great majority of cases.
Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT D+/R- protocols. Drug–drug interactions between immunosuppressive agents and DAAs may also translate to underimmunosuppression or decreased efficacy of DAA therapy. Recent experience shows that this may be mitigated by early initiation of pangenotypic treatment. Pangenotypic DAA regimens have limited drug–drug interactions with tacrolimus and may limit the need to adjust the dose of calcineurin inhibitors, even though tacrolimus levels have to be monitored.
The donor’s genotype is crucial if there is no access to pangenotypic antiviral agents. However, in the case of pangenotypic drugs, there is still the issue of RAS in relation to NS5A protease inhibitors, especially in genotypes 1a and 3, which can result in prolonged treatment and a worse treatment result
DAAs
HCV therapy involves a combination of two or three DAAs that target nonstructural proteins of the HCV and may be delivered with little adverse effect and high efficacy. Pangenotypic DAAs are preferred. The only drawbacks are accessibility to DAAs and the high cost of DAA therapy. The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for 8weeks or SOF/ VEL for 12weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver. However, multiple factors should be considered before initiating DAA therapy, especially if pangenotypic agents are unavailable; these factors include any evidence of liver dysfunction, concomitant medications, and to a lesser extent immunosuppression that will be used after transplantation. Drug-drug interactions must also be accounted for in the DAA therapy selection process to avoid complications, because premature withdrawal of DAA therapy increases the development of drug resistance. Studies have estimated that up to 45% of patients may require an adjustment of the dosage of the calcineurin inhibitor during DAA therapy
patients who require antiepileptic treatment in the period near transplantation, as antiepileptic drugs are not recommended to be taken together with any DAA. A similar situation occurs in the case of high doses of proton pump inhibitors (PPIs; taken twice daily), such as ledipasvir, and this can negatively influence the effectiveness of DAA therapy. However, standard doses of PPIs (corresponding to 20mg of omeprazole) can be used without adverse events.
Optimal timing of DAA initiation
Currently, there is little doubt that antiviral treatment in HCV NATpatients can be postponed until after transplantation, in order to allow them to receive a kidney from a donor infected with HCV. However, the optimal time for introducing treatment in such cases of virus transmission from the donor has not yet been established. The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7days after transplantation
Some centers postpone treatment for a couple of weeks until the patient and immunosuppressive treatment are stable enough to avoid the need for early DAA therapy withdrawal.
The KDIGO recommends, among other things, monitoring proteinuria every 6months in patients infected with HCV after transplantation, and performing a biopsy if HCV infection occurs. Confirmation of a relapse in the development of de novo GN is an indicator of immediate DAA therapy
Despite this, in HCV NAT D/R- transplantations antiviral treatment initiation in the peri-transplant period deems advisable.
Early introduction of treatment can also limit the exposure to viremia and the development of complications. Patients who start receiving treatment on call to operating room develop viremia less frequently
Immunosuppression
An analysis by Bae et al. showed that KTRs infected with HCV have a 20% lower probability of receiving a less effective inductive treatment with interleukin 2 receptor antagonists rather than with anti-thymocyte globulin despite HCV infection being a well-recognized factor that increases the risk of AR. This can be partly related to the clinicians’ fear of overimmunosuppression in patients with HCV infection. Immunosuppressive drugs are known to have a permissive effect on HCV replication. Recent studies have shown that patients infected with HCV should receive standard immunosuppression and that depletive induction should not be avoided if there are reasons to introduce it.
the OPTN/Scientific Registry of Transplant Recipients showed that the type of calcineurin inhibitor (cyclosporine vs. tacrolimus) used in maintenance immunosuppression does not influence the mortality rate in patients with HCV Ab
and the use of mycophenolate mofetil in the same analysis was related to a lower mortality rate
Conclusions
In light of the current knowledge, the transplantation of HCV NATkidneys to naïve recipients may constitute a solution to organ shortage. However, such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection. Every effort should be made to ensure DAA therapy and reduce the mortality of patients awaiting kidney transplantation.
2. What is the level of evidence provided by this article?
Level V
3. Please reflect on the guidelines provided above and on your practice.
In our Center we deal with donor with negative hepatitis B and C
4. Will you accept living or deceased donation from HCV positive donors?
No, I will not accept this donor
such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection
To overcome organ shortage accepting HCV viremia donors for naive recipients is an option.
Is it really safe is the real question?
This article has tried to answer these questions and what strategies should be adopted to utilize these kidneys.
Data from the UK indicate that in as many as 76% of cases, the only cause for discarding the organ was the serological status of the donor, and only 8.9% were dis- carded because of the unsatisfactory condition of the organ itself.
This could have resulted from the fear of transmitting HCV infection as well as the findings of studies showing worse results for transplants from HCV- positive donors to HCV-negative recipients. However, such data are from a period when the treatment of HCV was purely interferon-based.
The first prospective studies assessing the efficacy and safety of utilizing organs from HCV-infected donors appeared in 2017. In the THINKER study and its continu- ation, 20 HCV-naïve kidney transplant recipients (KTRs) received HCV-viremic organs. Viral transmission was observed in 100% of patients. Elbasvir/grazoprevir (EBR/GZR) was initiated as soon as viremia was detected (i.e. on average 3 days after transplantation) and contin- ued for 12weeks. This enabled a sustained virologic response (SVR) in all the patients, and allograft function after 6 and 12months did not vary from that of matched recipients of HCV-negative grafts.
The EXPANDER study, in turn, utilized prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and the treatment was contin- ued for 12 weeks. For those with genotypes other than 1, sofosbuvir (SOF) was added to EBR/GZR. SVR was achieved in 100% of cases, and severe complica- tions such as AR, graft loss, or liver damage were not observed
It is rational to prioritize the utilization of HCV NAT!organs in recipients already infected with HCV.
In light of the current knowledge, the transplant- ation of HCV NAT!kidneys to naïve recipients may constitute a solution to organ shortage. However, such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection.
Such organs should be offered to HCV- negative recipients only as a secondary choice. However, this is not always possible in every- day practice.
The current state of knowledge points to the fact that a kidney transplant from an HCV nucleic acid testing positive (NAT!) donor to naive recipients is an effective and safe solution to the problem of the insufficient number of organs available for transplantation.
We are running a living related renal transplant program where we Ensure that our HVR viremia donors are effectively treated before transplant
● As the demand for organs is still far greater than available , it is urgent to consider increasing the donor pool
● Kidneys from active HCV donors is considerd acontraindication
● positive HCV donors can donate to positive HCV recipiants
● Donors should screened for HCV by NAT and HCV Abs
** D NAT- /Ab + that mean reolution of infection spontenously or by treating
Seroconversion but with minimal viremia
** D NAT +/ Ab + means viremia with high trasmission and viremia
** D NAT + /Ab – it means recent infection
And high risk for viremia and transmission
● The risk of transmission from D+ to R- is 100 %
● Positive Donors should be excluded :
▪︎Recent infection untile he receive treatment
▪︎Donors with genotype 1a , 3 as they associated with failure treatment
▪︎Donors who were previously treated with NS5 inhibitors or those who have relapsed
● Negative Recipiant who considered to receive positive HCV kidney :
• Long waiting list
• Urgent patients ( with no vascular access )
• Compliance to antiviral drugs and procedures
• Unlikely to have undiagnosed liver diseases with normal liver functions and fibroscan
• Willing patients
• Patients don’t requiring standard immunosuppression or desensitization therapy
● Optimal timing of DAA
** The initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation
** DAA can be used after detection viremia or hospital discharge
** DAA can be delayed until IS is stable
** Short course treatment is not recommeneded and treatment for 12 – 16 weeks induces SVR 100 %
** Early treatment associated with low viremia and delay in treatment for months
exposes recipient to serious sequelae and CMV infection
● KTRs undergoing HCV NAT D+/R- transplant may be at increased risk of developing high-level BK viremia
● level : mini review 5
● In our practice we do HCV Ab only if it is positive we exclude the donor
We need more studies to consider these donors
Upon this article I will not proceed transplantation from positive HCV donors
# Introduction:
*Kidney transplantation is the treatment of choice for patients with end-stage renal disease.
*Since the demand for organs still exceeds the supply and with the advent of new, highly effective interferonfree therapies with an efficacy exceeding 95% allowed to utilize HCV-viremic organs,
* HCV positive donors are usually younger than HCV-negative donors, and this can result in fewer comorbidities and improved quality of the organ, as manifested by (KDPI).
*In the past, HCV infection in a donor was considered a contraindication for KT, and according to the (KDIGO) guidelines, since the 1990s, kidneys from HCV antibody-positive (Ab) donors have been used as transplants under the condition that the recipient is also HCV Ab.
# HCV testing and risk of transmission:
*Use of HCV RNA (NAT) as part of HCV infection for HCV-positive donor in diagnosis within the serological tests mandated by the (UNOS) for potential organ donors in US was allowed the identification of donors with active viremia (HCV Ab/ NATor HCV Ab-/NAT) and those without it (HCV
NAT-). Such differentiation of donors is key because not every HCV-positive donor poses a risk of virus transmission through transplantation.
*HCV Ab/NAT- donors are those in whom the virus has been eradicated spontaneously or through antiviral treatment.
*KT from an HCV donor (Ab/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
*Although the risk of viral transmission is low, screening for HCV viremia is advisable in an early posttransplant period.
* Donor with HCV viremia have a high risk of virus transmission.
*Viremia always develops in recipients after HCV D/R- NAT liver, heart, lung, or kidney transplants.
*The introduction of routine HCV NAT testing helped reduce the diagnostic window, in which HCV infection is present but cannot yet be identified, from to 2–6 months for serological assays to 5–7days for NAT, thereby limiting the risk of unintentional virus transmission from an organ donor.
* Suryaprasad et al. described three cases of nonintentional HCV transmission despite a negative
NAT result for the donor.
*The current guidelines of the US PHS have further recommendations to minimize the risk related
to the utilization of organs from PHS criteria donors by test all donors for HIV, HCV, and HBV infections using NAT.
# Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients:
*THINKER study: 20 HCV-naïve (KTRs) received HCV-viremic organs, viral transmission was observed in 100% of patients. (EBR/GZR) was initiated as soon as viremia was detected and continued for 12 weeks, this showed a (SVR) in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts.
* EXPANDER study: utilized prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and the treatment was continued for 12 weeks. For those with genotypes other
than 1, (SOF) was added to EBR/GZR. SVR was achieved in 100% of cases, with no complications.
# Willingness to accept HCV-viremic organs:
*A study by Potluri et al. showed that over the period from 2015 to 2019, the willingness to accept a seropositive organ increased sixfold. However, McCauley et al. showed that as many as 80% of patients
are willing to accept an organ from an HCV NATdonor under certain conditions, while 18% would not accept it under any circumstance.
* This decision is mainly influenced by the expected effectiveness of treatment, quality of the organ, and the duration of being on the organ waiting list
# Donor/recipient selection criteria:
*HCV NAT D/R- transplants require careful donor and recipient selection. Unquestionably, patients with long anticipated waiting times should be considered for HCV NAT D/R- transplants if this may reduce the waiting time.
*For these patients, remaining on the waitlist may constitute a greater risk than being infected with HCV that may be successfully treated in great majority of cases.
*A survey by Lentine et al. showed that HCV-naïve patients with cirrhosis or a history of liver disease are not offered HCV-viremic organs.
*Both diabetes mellitus and obesity, which are components of metabolic syndrome, may affect liver function, so the implementation of FibroScan in standard recipient evaluation prior to HCV NAT D/R- transplantation could facilitate proper recipient selection.
* Knowledge of viral load could enable identification of individuals at higher risk of HCV-related complications and determination of optimal timing of DAA therapy initiation.
*Patients requiring nonstandard immunosuppressionor desensitization therapy are frequently excluded from HCV NAT D/R- protocols.
* Drug–drug interactions between immunosuppressive agents and DAAs may also translate to under immunosuppression or decreased efficacy of DAA therapy, that may be mitigated by early initiation of pangenotypic treatment.
*The American Society of Transplant Surgeons, in its consensus, stated that a lack of knowledge of the genotype or the presence of RAS
should not be a contraindication for HCV NAT D/Rkidney transplantation, provided that treatment can be
initiated without delay.
*Education of patients potentially willing to accept HCV-viremic organs could promote compliance
with posttransplant DAA therapy.
* A unified policy regarding donor and recipient selection for HCV NAT D/R- transplantation could encourage broader utilization of HCV NATorgans.
.# DAAs
*HCV therapy involves a combination of two or three DAAs that target nonstructural proteins of the HCV and may be delivered with little adverse effect and high efficacy.
*Pangenotypic DAAs are preferred. The only drawbacks are accessibility to DAAs and the high cost of DAA therapy.
*The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver.
*Multiple factors should be considered before initiating DAA therapy, especially if pangenotypic agents are unavailable; these factors include any evidence of liver dysfunction, concomitant medications, and immunosuppression that will be used after transplantation.
*Drug-drug interactions must also be accounted for in the DAA therapy selection process to avoid complications.
*Treatment should also consider the path of drugelimination and kidney function, but this has been subject to change recently.
* The AASLD/IDSA guidelines have been drafted such that when applying the recommended schemas of treatment for individual patient groups, the dosage need not be adjusted in the case of patients with (CKD) or those receiving dialysis.
# Optimal timing of DAA initiation
*Currently, there is little doubt that antiviral treatment in HCV NATpatients can be postponed until after transplantation, However, the optimal time for introducing treatment in such cases of virus transmission from the donor has not yet been established.
#Level 5
#Yes, I will accept according to the guide line in case there is no suitable donor.
Summary:
Renal transplantation is the best form of renal replacement therapy. To increase donor pool donation from HCV positive viremia could be an option. Furthermore, the introduction of direct antiviral agent (DAAs) for treatment of HCV positive patient has made the transplantation between HCVNAT +/ R – is a reality.
The availability of testing like HCV RNA (NAT) has helped in categorization of donor into those with active viremia, HCV Ab +/NAT + or HCV Ab -/NAT + and those without, HCV NAT negative. The introduction of this test has helped to reduce the diagnostic window from 2-6 months 5-7 days for NAT.
The THINKER and EXPANDER study both showed that the use of DAA can reduce the risk of transmission of HCV infection from donor to recipient, although there are debates on the number of weeks to be used for the prophylaxis
Potential recipient with possibility of long waiting time for donor should be considered for HCV NAT +/R- so as to reduce the waiting time, cost of been on maintenance dialysis and possible avoidance of contracting HCV infection while still on dialysis waiting for organ.
Appropriate counseling and consent must be obtained from the recipient with full knowledge and possible outcome of receiving kidney form HCV NAT + donor and must be told of limited information on long term complication.
The acceptability of transplant from HCV NAT +, will reduce the waiting list and bridge the gap shortage between demand and supply of organ.
Level of evidence: 5
Reflection on my practice: With this evidence I am not ready to practice in my setting.
In order to overcome overcom shortage of donated kidneys, an expanded criteria donor to include HCV positive deceased donors was suggested .This proposition was gaining an increasing momentum after the introduction of DAA to treat HCV with a successful rate of recovery and achieving SVR rate exceeding 95% .
Nevertheless, an anecdotal reports showed increasing Acute rejection rate in HC viremic allografts vs non HCV viremic kidneys , mainly related to the HCV viremia.
In several kidney transplant programs, HCV positive donors kidneys were transplanted to HCV positive recipients,after adjusting for HCV genotype.
Determining HCV infection status:
HCV antibodies are an indicator of exposure to the virus, but NAT for HCV DNA is confirmatory test for the presence of viral load and its infectivity.
Several studies with promising results:
More than one study showed safer and successful transplantation of HCV Ab+/NAT+ donor kidney to HCV naive recipients. As majority of recipients seroconvert to HCV within few days post transplantation ,subsequently treated with DAA Grazoprevir/
Elbasvir combination with addition of Sofosobir in some situations particularly when HCV genotype 1 was the culprit for 12 to 16 weeks. The success rate of SVR is 100%. With comparable 6 and 12 months allograft function.
Few studies tried even lesser duration of therapy with equivalent efficacy.however, a consensus on optimal duration of therapy is yet to conclude .
Main Criteria to select suitable recipients are;
1-No chronic liver disease.
2- Non diabetic ,obese or have a metabolic syndrome.
3-No other viral infection..
4-No suitable negative donor.
5-life saving kidney transplant.
Drawbacks of the policy are
Resistance to therapy.
It’s a review article with level of evidence 5..
I accept this approach in special circumstances that would be scrutinized for every patient.
Please summarise this article in your own words
INTRODUCTION
Donor pool of kidneys can be increased by utilizing the HCV donors to reduce the shortage of graft kidneys and decrease the waiting time for transplantation.
HCV positive donors are usually than HCV-negative donors, hence have fewer comorbidities and improved quality of the organ. With availability of highly effective interferon free therapies with an efficacy of around 95% has increased utilization of HCV-viremic organs.
KDIGO has permitted kidney transplantation from HCV antibody-positive donors to HCV positive recipients.
The recent guidelines of the American Society of Transplantation also do not exclude HCV positive donors from donation but advocate need of further studies to evaluate this situation.
UNDERUTILISATION
Previously lot of kidneys were discarded due to HCV positivity but now data is improving.
HCV NAT + organs are surprisingly underutilized as compared to HBV + ,CMV+ organs inspite of the fact that high efficacy treatment for HCV is available and complication risk is more in HBV and CMV.
HCV TESTING AND RISK OF TRANSMISSION
Availability of HCV NAT helped in differentiating donors with risk of virus transmission vs those at low risk by detecting active viremia (HCV Ab+/NAT+ or HCV Ab-/NAT+) and those without it (HCV NAT-) .
In HCV donor (Ab+/NAT-) virus eradication is possible either spontaneously or through treatment. Hence, Kidney transplantation from a to a HCV-negative recipient is possible with viremia risk being minimal. Even with minimal risk of viral transmission, screening for HCV viremia is needed in an early posttransplant period.
Recipients of liver, heart and lung transplants from HCV D+ /R- NAT donors always develop viremia.
DONOR/RECIPIENT SELECTION CRITERIA
No standard criteria for selection but recipients having long waiting period can be considered for HCV NAT D+/R- transplants. but many criteria have been proposed for the same.
FibroScan before transplantation could help in selection of suitable recipient.
Pan genotypic DAAs are preferred but the main limitation to it’s use is it’s availability and high cost .
KDPI CALCULATION
It is used to estimate the expected organ survival rate after transplantation. Many factors are taken into account as HCV Ab presence. It was published in 2014 in order to match the quality of the organ to the predicted survival of the recipient.
CONCLUSION
HCV NAT + organs should be primarily reserved forrecipients already infected with HCV and should only be considered for negative recipients as second option if the local transplant protocol / policies permit.
The level of evidence is 5
The utilization of organs with active HCV viremia is associated with high costs. However, keeping patients on the waiting list is also costly in terms of the need for dialysis or the use of devices aiding cardiac function. The latest analyses show that transplanting HCV NAT þ kidneys to HCV-negative recipients can be costeffective because it could shorten the waiting time by 2 years; however, other analyses show that this period is 11 months .
It seems that the cost of DAAs will decrease and shortening the duration of DAA therapy will allow an additional reduction in the cost and availability of such treatments.
Conclusions
It is rational to prioritize the utilization of HCV NAT þ organs in recipients already infected with HCV. This entails lower costs, limits the risk of possible complications, and seems more reasonable from an ethical standpoint. Such organs should be offered to HCVnegative recipients only as a secondary choice. However, this is not always possible in everyday practice.
In light of the current knowledge, the transplantation of HCV NAT þ kidneys to naïve recipients may constitute a solution to organ shortage. However, such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection. Every effort should be made to ensure DAA therapy and reduce the mortality of patients awaiting kidney transplantation.
Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D þ /R- kidney transplantation among candidates. This may encourage the acceptance of HCV-viremic organs and simultaneously maximize compliance and mitigate the risks associated with this procedure. Currently, it seems premature to utilize HCV NAT D þ /Rkidney transplantation as a standard of care. Further studies are required to draw solid conclusions regarding the long-term consequences of adopting such a treatment approach.
The utilization of organs with active HCV viremia is associated with high costs. However, keeping patients on the waiting list is also costly in terms of the need for dialysis or the use of devices aiding cardiac function. The latest analyses show that transplanting HCV NAT þ kidneys to HCV-negative recipients can be costeffective because it could shorten the waiting time by 2 years; however, other analyses show that this period is 11 months .
It seems that the cost of DAAs will decrease and shortening the duration of DAA therapy will allow an additional reduction in the cost and availability of such treatments.
Conclusions
It is rational to prioritize the utilization of HCV NAT þ organs in recipients already infected with HCV. This entails lower costs, limits the risk of possible complications, and seems more reasonable from an ethical standpoint. Such organs should be offered to HCVnegative recipients only as a secondary choice. However, this is not always possible in everyday practice.
In light of the current knowledge, the transplantation of HCV NAT þ kidneys to naïve recipients may constitute a solution to organ shortage. However, such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection. Every effort should be made to ensure DAA therapy and reduce the mortality of patients awaiting kidney transplantation.
Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D þ /R- kidney transplantation among candidates. This may encourage the acceptance of HCV-viremic organs and simultaneously maximize compliance and mitigate the risks associated with this procedure. Currently, it seems premature to utilize HCV NAT D þ /Rkidney transplantation as a standard of care. Further studies are required to draw solid conclusions regarding the long-term consequences of adopting such a treatment approach.
—————
level V
—————
I will not accepting such donors we needs more and detailed studies
Only in certain situations … because the evidence provided by this article is week as it is level 5
From living donor, I will not accept because of the possible risk to the donor since HCV is associated with the possibility of glomerulonephritis which can have bad impact on the kidney and according to British guidelines any patient with active HCV infection should be excluded form donation
And I will only accept the donor after treatment with SVR for 1 year
From deceased donor I may accept if the following are met
And I will initiate prophylactic treatment with Elbasvir/grazoprevir once daily for 2-3 months starting from day -1 before transplantation except if the recipient is HCV positive I will initiate treatment before transplantation
Due to shortage of donors pool, donors with HBV infection can be the best option for potential recipients especially with recipients with history of HBV infection( better quality of life compared to patient still on dialysis. But larger studies needed to support the result of this article
– Kidney transplantation is the treatment of choice for patients with end-stage renal disease.
– Many steps are being taken to increase the organ donor pool including living donors and donors after cardiac death. One of these steps is the use of organs from donors infected with the hepatitis C virus (HCV) especially with The advent of new, highly effective interferon free therapies with an efficacy exceeding 95% .
– In the past, HCV infection in a donor was considered a contraindication for kidney transplantation owing to the risk of long-term immunosuppression in the recipient.
– The current guidelines of the American Society of Transplantation do not forbid the transplantation of infected organs to recipients not infected with HCV, but they indicate the necessity for further research on the consequence of such a practice.
– The tendency to discard HCV-positive organs is visibly changing. Within the first 3 months of 2019, 200 kidneys were transplanted into HCV-negative recipients from HCV NAT +ve donors .
– Until recently, HCV-viremic organs were offered to HCV-negative recipients only within clinical trials, for a carefully selected group of patients with guaranteed access to direct antiviral agents (DAAs).
– HCV Ab+ve /NAT- ve donors are those in whom the virus has been eradicated spontaneously or through antiviral treatment.
– Kidney transplantation from an HCV donor (Ab+ve/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal. Although the risk of viral transmission is low, screening for HCV viremia is advisable in an early posttransplant period. In contrast, HCV NAT + donors, regardless of their serological status, are patients with active viremia and account for 4.2% of donors in the US .
– HCV viremia in the donor is associated with a high risk of virus transmission. Viremia always develops in recipients after HCV D+ve/R- NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants
– the current guidelines of the US PHS have further recommendations on how to minimize the risk related to the utilization of organs from PHS criteria donors. The recommendation is to test all donors for human immunodeficiency virus, HCV, and HBV infections using NAT
– In the THINKER study and its continuation, 20 HCV-naïve kidney transplant recipients (KTRs) received HCV-viremic organs . Viral transmission was observed in 100% of patients. Elbasvir/grazoprevir (EBR/GZR) was initiated as soon as viremia was detected (i.e. on average 3 days after transplantation) and continued for 12 weeks. This enabled a sustained virologic response (SVR) in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts.
– The EXPANDER study, in turn, utilized prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and the treatment was continued for 12 weeks . For those with genotypes other than 1, sofosbuvir (SOF) was added to EBR/GZR. SVR was achieved in 100% of cases, and severe complications such as AR, graft loss, or liver damage were not observed.
– Sise et al. conducted a study in which glecaprevir/pibrentasvir (GLE/PIB) was administered for 8 weeks starting from the second to fifth day after transplantation. Thirty HCV-naïve patients underwent kidney transplantation from HCV-viremic donors and were followed up for a median duration of 9 months. All patients achieved SVR and acute cellular rejection (ACR) and BK viremia were observed in three patients.
– Durand et al. enrolled 10 patients who received GLE/PIB for 4 weeks, with the first dose being administered before transplantation. Virus transmission was observed in 50% of KTRs, and 100% SVR was observed after 12 weeks. The authors reported 100 patient survival and one graft loss attributed to vein thrombosis. However, they reported no episodes of Acute Rejection .
– The breakthrough in transplantation that occurred after the publication of the THINKER and EXPANDER study results encouraged other researchers to attempt replicating these results in ‘real-life’ studies.
– Kapila et al. presented the largest such study, which included 64 KTRs. Treatment with GLE/PIB or sofosbuvir/ledipasvir lasted 12 weeks and was initiated 72 days after transplantation. Three recipients did not develop viremia, even though the donors had low, but detectable viremia lower than 142 IU/mL. All but one patient achieved SVR. One patient did not respond to treatment because of resistance to NS5A inhibitors and was retreated with sofosbuvir/velpatasvir/voxilaprevir . Fibrosing cholestatic hepatitis was observed in two patients; eleven and fourteen weeks after transplant. Both were successfully treated with DAAs.
Donor/recipient selection criteria:
– patients with long anticipated waiting times should be considered for HCV NAT D+/R- transplants if this may reduce the waiting time. Their condition is likely to deteriorate, or they may die, until an organ becomes available; hence, HCV NAT D+/ R- transplantation confers a survival benefit to these patients. Moreover, for these patients, remaining on the waitlist may constitute a greater risk than being infected with HCV that may be successfully treated in great majority of cases
– Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT D+/R- protocols
– it is still essential to identify patients at a high risk of AR, such as highly sensitized patients or those requiring retransplantation, and to carefully weigh the risks and benefits of selecting HCV NAT D+/ R- organs
– excluding donors who were previously treated with NS5 inhibitors or those who have relapsed seems a reasonable mean to avoid difficulties in viral clearance after transplantation and a situation when no antiviral treatment will be available for the patient .
– Patients who are predicted not to comply with procedures, DAA schedule, and surveillance requirements after transplant should also not be offered HCV-viremic organs
DAAs:
– The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver
– multiple factors should be considered before initiating DAA therapy, especially if pangenotypic agents are unavailable; these factors include any evidence of liver dysfunction, concomitant medications, and to a lesser extent immunosuppression that will be used after transplantation.
– epileptics have adrug drug interaction should be considered .
– SOF, which is effective in treating genotype 3, is mainly renally excreted. Therefore, it was not recommended for patients with CKD and an estimated glomerular filtration rate (eGFR) < 30 mL/min/ 1.73 m2 , but it was approved in November 2019 by the US Food and Drug Administration for use in patients with an eGFR below 30 mL/min/1.73 m2 and those who were dialysis-dependent
Optimal timing of DAA initiation:
– antiviral treatment in HCV NAT + patients can be postponed until after transplantation, in order to allow them to receive a kidney from a donor infected with HCV.
– the optimal time for introducing treatment in such cases of virus transmission from the donor has not yet been established.
– The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation .
– Recent studies have adopted various approaches for the introduction of antiviral treatments like in the THINKER study, DAAs were introduced after HCV viremia was detected , Some centers postpone treatment for a couple of weeks until the patient and immunosuppressive treatment are stable enough to avoid the need for early DAA therapy withdrawal & In the study by Molnar et al., DAA therapy was introduced on average 76 days after transplantation .
– Postponing treatment for a few months may be associated with serious complications. An acute infection with HCV has been associated with the development of fulminant hepatitis or fibrosing cholestatic hepatitis , also, there is the rsik of the development of thrombotic microangiopathy and a series of immunological complications, such as AR or glomerulonephritis (GN) .
– The KDIGO recommends, among other things, monitoring proteinuria every 6 months in patients infected with HCV after transplantation, and performing a biopsy if HCV infection occurs. Confirmation of a relapse in the development of de novo GN is an indicator of immediate DAA therapy .
– Despite this, in HCV NAT D+/R- transplantations antiviral treatment initiation in the peri-transplant period deems advisable.
– Early introduction of treatment can also limit the exposure to viremia and the development of complications. Patients who start receiving treatment on call to operating room develop viremia less frequently , also associated with less AR episodes .
the optimum treatment duration after transplantation is also a subject of debate :
– Many different strategies , The standard 12- to 16-week treatment duration allowed the achievement of SVR in 100% of patients under both prophylactic and reactive approaches (after HCV viremia is documented)
Immunosuppressive drugs are known to have a permissive effect on HCV replication. Recent studies have shown that patients infected with HCV should receive standard immunosuppression and that depletive induction should not be avoided if there are reasons to introduce it.
KDPI calculation :
– In the US, the KDPI is used to estimate the expected organ survival rate after transplantation.
– Many factors are taken into account, including the presence of anti HCV antibodies, which in turn often leads to an artificial increase in the KDPI by 0.25 on average in comparison to the actual quality of the organ & this is why the issue of removing anti-HCV antibodies from the KDPI assessment has been advocated in some studies.
– The Kidney Allocation System (KAS) introduced in 2014, which is based on the KDPI, is supposed to better match the quality of the organ to the predicted survival of the recipient. It assumes that an organ with a KDPI of 20% should be transplanted to a recipient with an estimated posttransplant survival score of 20%
Informed consent :
the newest PHS guidelines suggest that the consent to an organ from an HCV NAT þ donor should not be on a separate form, as it currently is, but it should rather be included in the standard form of consent for an organ transplantation .
Conclusions:
– It is rational to prioritize the utilization of HCV NAT + organs in recipients already infected with HCV.
– This entails lower costs, limits the risk of possible complications, and seems more reasonable from an ethical standpoint.
– Such organs should be offered to HCV negative recipients only as a secondary choice. However, this is not always possible in everyday practice.
– In light of the current knowledge, the transplantation of HCV NAT + kidneys to naïve recipients may constitute a solution to organ shortage.
– However, such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection.
– Every effort should be made to ensure DAA therapy and reduce the mortality of patients awaiting kidney transplantation. Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D+/R- kidney transplantation among candidates. This may encourage the acceptance of HCV-viremic organs and simultaneously maximize compliance and mitigate the risks associated with this procedure.
– Currently, it seems premature to utilize HCV NAT D+/R – kidney transplantation as a standard of care. Further studies are required to draw solid conclusions regarding the long-term consequences of adopting such a treatment approach
What is the level of evidence?
– level 5
Will you accept living or deceased donation from HCV positive donors?
– still we need stronger evidence & guidelines for accepting D+/R- , but generally I will have the attitude for accepting such donors with the precauations mentioned above & in as a second option only to be individualized & counselled case by case .
Utilization of HCV viremic donors in kidney transplantation: a chance or a threat?
▪︎This review analyzes the possibilities and limitations of the usage of HCV NAT+ donor organs
¤Introduction
▪︎The advent of new, highly effective interferon free therapies allowed to utilize HCV-viremic organs. ▪︎Donors infected with HCV are usually younger than HCV-negative donors, and this can result in fewer comorbidities & improved quality of the organ.
▪︎In the past, HCV in a donor was considered a contraindication for kidney transplantation. According to KDIGO guidelines, since the 1990s, kidneys from HCV antibody-positive (Ab+) donors have been
used as transplants under the condition that the recipient is also HCV Ab+.
¤ HCV testing and risk of transmission
▪︎To identify donors with active viremia (HCV Ab +/ NAT + or HCV Ab-/NAT+) and those without it (HCV NAT-). Such differentiation of donors is key because not every HCV-positive donor poses a risk of virus transmission through transplantation.
▪︎HCV Ab+/NAT- donors are those in whom the virus has been eradicated spontaneously or through antiviral treatment.
▪︎Kidney transplantation from an HCV donor (Ab+/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
▪︎Although the risk of viral transmission is low, screening for HCV viremia is advisable in an early posttransplant period.
▪︎HCV viremia in the donor is associated with a high risk of virus transmission. Viremia always develops in recipients after HCV D+/R- NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants.
▪︎The introduction of routine HCV NAT testing helped reduce the diagnostic window from to 2–6 months for serological assays to 5–7days for NAT
¤ Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
▪︎The efficacy of HCV NAT D+/R- KT has been reported in several clinical trials and promising results can also be seen in case of other organs, such as the heart or lungs.
¤ Willingness to accept HCV-viremic organs
▪︎This decision is mainly influenced by the expected effectiveness of treatment, quality of the organ, and the duration of being on the organ waiting list. ▪︎There is a need for comprehensive education programs and access to reliable data to help KTRs make an informed decision regarding HCV NAT D+/R- transplants.
¤ Donor/recipient selection criteria
▪︎HCV NAT D+/R- transplants require careful donor and recipient selection. Unquestionably, patients with long anticipated waiting times should be considered for HCV NAT D+/R- transplants if this may reduce the waiting time.
DAAs
▪︎HCV therapy involves a combination of two or three DAAs.
▪︎ Multiple factors should be considered before initiating DAA therapy, especially if pangenotypic agents are unavailable; these factors include any evidence of liver dysfunction, concomitant medications, and to a lesser extent immunosuppression that will be used after transplantation.
▪︎Drug-drug interactions must also be accounted for
in the DAA therapy selection process to avoid complications, because premature withdrawal of DAA therapy increases the development of drug resistance.
Immunosuppression
▪︎ The optimal immunosuppression scheme for transplants from an HCV NAT + donor to a naïve recipient remains to be determined.
☆Conclusion
▪︎Organs from HCV positive should be offered to HCV negative recipients only as a secondary choice. However, this is not always possible in everyday practice. Such practice entails a risk of complications, especially when combined with the difficulty in providing DAA therapy in the direct posttransplant period and the need for careful donor and recipient selection.
▪︎Every effort should be made to ensure DAA therapy and reduce the
mortality of patients awaiting kidney transplantation.
▪︎Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D+/R- kidney transplantation among candidates. This may encourage the acceptance of HCV-viremic organs and simultaneously maximize compliance and mitigate the risks associated with this procedure.
☆Level of evidence: 5
☆Will you accept living or deceased donation from HCV positive donors? Yes, If the recipient is also HCV positive
Summary :
Introduction
Ø Kidney transplantation is the treatment of choice for patients with end-stage renal disease. It reduces mortality in this group of patients and improves their quality of life. However, the demand for transplant organs far exceeds their availability
Ø To resolve the organ shortage issue is using organs from donors infected with the hepatitis C virus (HCV).
Ø The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, since the 1990s, kidneys from HCV antibody-positive (Abþ) donors have been used as transplants under the condition that the recipient is also HCV +ve
Ø The current guidelines of the American Society of Transplantation do not forbid the transplantation of infected organs to recipients not infected with HCV, but they indicate the necessity for further research on the consequence of such a Practice
Underutilization:
Ø In the past, HCV-positive organs were discarded nearly three times more often than HCV-negative ones were
Ø La Hoz et al. compared the results of kidney transplantation from HCV NATþand HCV Ab+ve /NAT” donors to those from HCV-negative donors. They reported better kidney function as manifested by estimated glomerular filtration rate (eGFR) within six months after transplantation, comparable 12-month graft survival rate, and lower frequency of acute rejection (AR) events.
Ø The underutilization of HCV NAT+ organs can seem surprising when compared to the utilization of organs with the risk of transmission of viruses such as hepatitis B virus (HBV) or cytomegalovirus (CMV), which, despite the introduction of appropriate treatment, can result in de novo hepatitis and a higher risk of death after transplantation, an increased risk of rejection, or opportunistic infections by HBV and CMV both CMV D+/R” and anti-HBcþD+ /R” organs are accepted for transplantation because of the more considerable survival benefits for the patient than the risks resulting from the transmission of the virus.
HCV testing and risk of transmission:
HCV-positive donor testing for HCV RNA (NAT) as part of HCV infection diagnostics
allowed the identification of donors with active viremia (HCV A+ve / NATþor HCV Ab-/NATþ) and those without it (HCV NAT-). Such differentiation of donors is critical because not every HCV-positive donor poses a risk of virus transmission through transplantation.
HCV Ab+ve /NAT- donors, are those in whom the virus has been eradicated spontaneously or through antiviral treatment
Kidney transplantation from an HCV donor (Abþ/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
The recommendation is to test all donors for human immunodeficiency virus, HCV, and HBV infections using NAT.
Kidney transplantation from HCV-viremic donors to HCV-viremic recipients:
The efficacy of HCV NAT Dþ/R- kidney transplantation has been reported in several clinical trials
1-The first prospective studies assessing the efficacy and safety of utilizing organs from HCV-infected donors appeared in 2017. In the THINKER study and its continuation, 20 HCV-naïve kidney transplant recipients (KTRs)
received HCV-viremic organs. The viral transmission was observed in 100% of patients.
2-Elbasvir/grazoprevir (EBR/GZR) was initiated as soon as viremia was detected (i.e., on average, three days after transplantation) and continued for 12 weeks. Enabled a sustained virologic response (SVR) in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts.
3-The EXPANDER study, in turn, utilized prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and continued the antiviral treatment for 12 weeks.
accept HCV-viremic organs:
McCauley et al. showed that as many as 80% of patients are willing to accept an organ from an HCV NATþdonor under certain conditions, while 18% would not take it under any circumstance. This decision is mainly influenced by the treatment’s expected effects, the organ’s quality, and the time on the organ waiting list.
Donor/recipient selection criteria:
Ø HCV NAT D +ve /R- transplants require careful donor and recipient selection.
Ø A survey by Lentine et al. showed that HCV-naïve patients with cirrhosis or a history of liver disease are not offered HCV-viremic organs.
Ø Implementing FibroScan in standard recipient evaluation before HCV NAT D+ve /R- transplantation could facilitate proper recipient selection.
Ø Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT Dþ/R- protocols.
Ø Drug-drug interactions between immunosuppressive agents and DAAs may also translate to under-immune suppression or decreased efficacy of DAA therapy. However, recent experience shows that this may be mitigated by early initiation of pan-genotypic treatment.
Ø Pangenotypic DAA regimens have limited drug-drug interactions with tacrolimus
and may limit the need to adjust the dose of calcineurin inhibitors, even though tacrolimus levels have to be monitored.
Ø the American Society of Transplant Surgeons, in its consensus, stated that a lack of knowledge of the genotype or the presence of RAS should not be a contraindication for HCV NAT Dþ/Rkidney transplantation, provided that treatment can be initiated without delay
DAAs
HCV therapy involves a combination of two or three DAAs that target nonstructural proteins of the HCV and may be delivered with little adverse effect and high efficacy. Pangenotypic DAAs are preferred. The only drawbacks are accessibility to DAAs and the high cost of DAA therapy.
Drug-drug interactions must also be accounted for in the DAA therapy selection process to avoid complications because premature withdrawal of DAA therapy increases the development of drug resistance.
The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for eight weeks or SOF/ VEL for 12 weeks to treat HCV-naïve recipients
of HCV-viremic organs other than the liver. However, multiple factors should be considered before initiating DAA therapy, especially if pan-genotypic agents are unavailable; these factors include any evidence of liver dysfunction, concomitant medications, and to a lesser extent, immunosuppression that will be used after transplantation.
Optimal timing of DAA initiation:
Ø The new AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by seven days after transplantation
Ø The KDIGO recommends, among other things, monitoring proteinuria every six months in patients infected with HCV after transplantation and performing a biopsy if HCV infection occurs. Confirmation of relapse in the development of de novo GN is an indicator of immediate DAA therapy. Despite this, in HCV NAT Dþ/R- transplantations, antiviral treatment initiation in the peri-transplant period deems advisable. Early introduction of treatment can also limit exposure to viremia and the development of complications.
Ø The standard 12- to 16-week treatment duration allowed the achievement of SVR in 100% of patients under both prophylactic and reactive approaches (after HCV viremia is documented)
Immunosuppression:
Ø An analysis by Bae et al. showed that KTRs infected with HCV have a 20% lower probability of receiving a less effective inductive treatment with interleukin two receptor antagonists rather than with anti-thymocyte globulin , despite HCV infection being a well-recognized factor that increases the risk of AR. It can be partly related to the clinicians’ fear of overimmunosuppression in patients with HCV infection.
Ø A retrospective analysis by Luan et al. based on data from the OPTN/Scientific Registry of Transplant Recipients showed that the type of calcineurin inhibitor (cyclosporine vs. tacrolimus) used in maintenance immunosuppression does not influence the mortality rate in patients with HCV Ab+ve.
KDPI calculation:
Ø In the US, the KDPI is used to estimate the expected organ survival rate after transplantation
Ø The Kidney Allocation System (KAS), introduced in 2014, based on the KDPI, is supposed to match better the organ’s quality to the predicted survival of the recipient. It assumes that an organ with a KDPI of 20% should be transplanted to a recipient with an estimated posttransplant survival score of 20%.
Ø The excellent quality of organs from donors infected with HCV has been proven by Goldberg et al. and Durand et al., who reported KDPI values of 42–45%
Informed consent:
Ø The acceptance of an HCV NAT + organ by an HCV-negative recipient should be preceded by a comprehensive education process, including information on the benefits and risks of such a solution.
HCV-viremic organ refusal:
Ø HCV NAT Dþ/R- transplants may be lifesaving in certain circumstances, despite the inherent risk associated with this practice
Cost-effectiveness:
Ø The utilization of organs with active HCV viremia is associated with high costs
Conclusions:
Ø It is rational to prioritize the utilization of HCV NAT+ organs in recipients already infected with HCV, entails lower costs, limits the risk of possible complications, and seems more reasonable from an ethical standpoint
Level 5 retrospective study
Please reflect on the guidelines provided above and on your practice
HCV positive donor for HCV positive recipient, but positive donor to negative recipient needs discussion.
Will you accept living or deceased donations from HCV-positive donors:
It is based on the recipient state, according to guidelines
Q1:
Because of organ shortage and effective antivirals for the treatment of HCV infection, transplantation of a kidney from HCV-NAT positive donor would be a solution. Before 1990 positivity of HCV Ab in donor test was considered contraindication for TX. After 1990, according to KDIGO guideline recipients with positive HCV Ab could receive kidney from positive deceased donors because of good KDPIs for this donors. HCV+/NAT- donors create minimal risk of active viremia in HCV negative recipients. But, HCV NAT+ donors have a high risk of transmission. So, all donors should do HIV, HBV and HCV test by NAT. In clinical trials using HCV NAT D+/R- TX, patients had viremia but were treated with EBR/GZR or prophylactic DAA therapy. Sustained virology response was seen in 100% of patients with good TX outcome. Patients with long waiting time could be considered for HCV NAT D+/R- TX. This TX is not suitable for recipients with liver disease, diabetes or obesity with NAFLD. DAA regimens have interactions with CNIs, antiepileptic drugs or PPIs. There are different approaches for DAA therapy. In a few studies, there were increased risk of BK or CMV viremia. Prophylactic and early initiation of DAAs therapy had better results.
HCV positive patients should receive standard immunosuppression or even depletive induction if needed. HCV Ab+/NAT- donors have good outcome and their KDPI should not be calculated based on their HCV Ab+. Informed consent is necessary for recipients who accept HCV NAT+ kidneys. Insurance coverage of DAA therapy is another problem.
Q2: The level of evidence of this article is 5.
Q3: All donors should be screened for HCV Ab and if positive, HCV NAT should be checked. HCV Ab+/NAT- donors have no problem. But, if NAT is positive, there is 100% risk for HCV transmission and is a relative contraindication. In our center, HCV NAT+ is absolute contraindication for kidney TX.
Q4: In normal situation, no.
Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Many steps are being taken to increase the organ donor pool, and the use of organs from donors infected with the hepatitis C virus is one of these steps.
In the past, HCV infection in a donor was considered a contraindication for kidney transplantation owing to the risk of long-term immunosuppression in the recipient. The advent of new, highly effective interferon-free therapies with efficacy exceeding 95% allowed the utilisation of HCV-viremic organs.
HCV testing and risk of transmission:
Attitude toward an HCV-positive donor has changed with the introduction of obligatory testing for HCV RNA (NAT); this allowed the identification of donors with active viremia (HCV Ab+/ NAT + or HCV Ab-/NAT+) and those without it (HCV NAT-). Such differentiation of donors is key because not every HCV-positive donor poses a risk of virus transmission through transplantation.
HCV Ab+/NAT- donors are those in whom the virus has been eradicated spontaneously or through antiviral treatment, Kidney transplantation from an HCV donor (Ab+/NAT-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
HCV NAT + donors, regardless of their serological status, are patients with active viremia. Viremia always develops in recipients after HCV Dþ/R- NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients:
In the THINKER study and its continuation, 20 HCV-naïve kidney transplant recipients received HCV-viremic organs. Viral transmission was observed in 100% of patients. Elbasvir/grazoprevir was initiated as soon as viremia was detected (i.e. on average 3 days after transplantation) and continued for 12 weeks. This enabled a sustained virologic response in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts.
KTRs were tested for their genotype and resistance-associated substitutions prior to randomization, and only genotypes 1 and 4 were acceptable. Those with genotype 1 were treated using DAAs for 16 weeks, and ribavirin was added as needed.
The EXPANDER study, utilized prophylactic DAA therapy. One dose of Elbasvir/grazoprevir was administered before transplantation, and the treatment was continued for 12 weeks. For those with genotypes other than 1, sofosbuvir was added to Elbasvir/grazoprevir. SVR was achieved in 100% of cases, and severe complications such as AR, graft loss, or liver damage were not observed.
Several other real-life and clinical studies have provided satisfactory results in treating HCV from a donor organ. Promising results of HCV NAT D+/R- transplants can also be seen in the case of other organs, such as the heart or lungs.
Willingness to accept HCV-viremic organs;
From 2015 to 2019, the willingness to accept a seropositive organ increased sixfold.
An analysis by McCauley et al. showed that as many as 80% of patients are willing to accept an organ from an HCV NAT + donor under certain conditions. In comparison, 18% would not accept it under any circumstance. This decision is mainly influenced by the expected effects of treatment, the quality of the organ, and the duration of being on the organ waiting list.
Donor/recipient selection criteria:
DAAs:
Optimal timing of DAA initiation:
Immunosuppression:
KDPI calculation:
the presence of anti-HCV antibodies often leads to an artificial increase in the KDPI by 0.25 on average in comparison to the actual quality of the organ, this can lead to improper allocation of organs.
As HCV Ab+/NAT- donors do not constitute a risk of HCV transmission, their KDPI should not be calculated on the basis of the serological status of HCV, and this has been proven by studies that showed a comparable eGFR 6 months after transplantation, which is considered an indicator of the long-term survival of a transplant.
Informed consent:
The regulations introduced by the OPTN/UNOS require informed consent from the recipient deciding to accept a kidney from a PHS criteria donor. The acceptance of an HCV NAT + organ by an HCV-negative recipient should be preceded by a comprehensive education process, including information on the benefits and risks of such a solution.
Insurance:
Coverage of the cost of DAA therapy remains a significant concern for both patients and health care providers and prevents HCV-viremic organs from being fully utilize.
Insurance companies explain their reason for rejection as the intentional transmission of the virus or the off-label usage of DAAs, as DAAs are registered only for treating chronic hepatitis C; hence, in this case, the patients have to deal with an acute infection for the first 6 months.
some authors think that in the absence of an assurance that medical treatment costs will be covered and given the possibility that patients may not be able to cover the treatment costs personally, such solutions should not be considered.
Cost-effectiveness:
The utilization of organs with active HCV viremia is associated with high costs.
Keeping patients on the waiting list is also costly in terms of the need for dialysis or the use of devices aiding cardiac function.
The latest analyses show that transplanting HCV NAT + kidneys to HCV-negative recipients can be cost-effective because it could shorten the waiting time by 2 years.
It seems that the cost of DAAs will decrease and shortening the duration of DAA therapy will allow an additional reduction in the cost and availability of such treatments.
Level 5 (review article).
In my center, our program is only for hepatitis C & B negative donors and recipients.
The evidence to accept such donors is not strong. I will not accept such donors, especially if DAAs are not widely available and are not covered by insurance or provided free of charge at the hospital, further large studies are required to address the risk of transmission and the long-term effect on the graft.
It is not easy question because the answer not depends on doctor decision only but recipient has many fears that may keep him refused.
Community awareness, educational process about this type of transplantation with discussing the risk- benefits has a great role to keep decision clear.
For us , we need more studies to clarify many points about the protocol of transplantation such as (duration of DAA treatment, screening F/U, time of starting our DAA, etc.).
But under special circumstances I will accept to transplant this type of donor such as :
1-Urgent condition included patients with exhausted vascular access for hemodialysis, patients with ongoing uremia despite adequate dialysis prescription, and patients who cannot remain in the dialysis treatment.
2-Avilablity of insurance coverage of DDA.
3-Recipients who active waiting list who have waiting time longer than the median time to receive a kidney in each national society.
4- Consent should be taken after comprehensive explanation
Utilization of HCV viremic donors in kidney transplantation: a chance or a threat?
Trying to increase donor pool , the use of organs from HCV donors with active viremia is one of solution but some points should be signified specially with new highly effective oral direct-acting antivirals (DAAs) which will be discussed in this study.
Still using HCV + ab donor for HCV – recipient in many countries is still contraindicated and most of recipient refusing and the accepted couples who are HCV + ab.
HCV testing and risk of transmission.
Not every HCV-positive donor poses a risk of virus transmission through transplantation but this depends on NAT, which classify our donors to two group.
1-HCV Ab+/NAT- donors which might be treated or spontaneously recovered, kidney transplantation from those to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal so regular screening is important.
2-HCV NAT + donors, regardless of their serological status, are patients with active viremia and HCV viremia in the donor is associated with a high risk of virus transmission.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients.
–THINKER study:100 % viral transmission, DAAs used for 12 weeks and This enabled a sustained virologic response (SVR) in all the patients, and allograft function after 6 and 12 months did not vary from that of matched recipients of HCV-negative grafts.
Many studies shortening the treatment duration to below the standard of 12 weeks and has good result from patient and graft survival.
Willingness to accept HCV-viremic organs/recipient selection.
Still variable and depends on special circumstances as expected effectiveness of treatment, quality of the organ, and the duration of being on the organ waiting list which confers a survival benefit to these patients.
Selection of the recipient is so important such as case with DM and obesity may be liable to metabolic complication if the receive kidney from HVC NAT + donors.
Patients requiring nonstandard immunosuppression or desensitization therapy are frequently excluded from HCV NAT D+/R- protocols and drug- drug interaction should kept in mind.
Donor selection depends on many factors such as donor genotype, treated with NS5 inhibitors or those with history of relapse.
Direct-acting antivirals / Optimal timing of DAA initiation.
HCV therapy involves a combination of two or three DAAs that target nonstructural proteins of the HCV and may be delivered with little adverse effect and high efficacy but we should take care about drug- drug interaction and dose adjustment with GFR.
Optimal time of treatment is still doubtful but AASLD/IDSA guidelines suggest the initiation of prophylactic treatment or preemptive treatment latest by 7 days after transplantation.
Some center start DAA after viremia and other post pone till stabilizing the patient and immunosuppressive medications.
Selecting the appropriate time to introduce treatment, the optimum treatment duration after transplantation is also a subject of debate and new more studies to be clear.
Informed consent.
After comprehensive explanation about risks and benefits from HCV NAT + organ to an HCV-negative recipient, informed consent should be signed.
Conclusions.
Using HCV NAT+ donor for naïve recipient is one of solution to decrease waiting list and time saving for recipients, but need special protocol, DAA is considered the cornerstone of this protocol, more education about risks and benefits is so important and we should keep in mind cost-effectiveness, Finally, more studies needed to clarify all points regarding this special transplantation protocol.
=Level of evidence :V
=Please reflect on the guidelines provided above and on your practice.
Its difficult in our center as its still legally forbidden to transplant HCV donor to naïve recipient , the only option is to transplant from HCV to HCV .
Will you accept living or deceased donation from HCV positive donors?
It is not easy question because the answer not depends on doctor decision only but recipient has many fears that may keep him refused.
Community awareness, educational process about this type of transplantation with discussing the risk- benefits has a great role to keep decision clear.
For us , we need more studies to clarify many points about the protocol of transplantation such as (duration of DAA treatment, screening F/U, time of starting our DAA, etc.).
But under special circumstances I will accept to transplant this type of donor such as :
1-Urgent condition included patients with exhausted vascular access for hemodialysis, patients with ongoing uremia despite adequate dialysis prescription, and patients who cannot remain in the dialysis treatment.
2-Avilablity of insurance coverage of DDA.
3-Recipients who active waiting list who have waiting time longer than the median time to receive a kidney in each national society.
4- Consent should be taken after comprehensive explanation.
Introduction:
Kidney transplantation is the best option for treating kidney failure, as it reduce mortality and enhance quality of life .
in order to make an effort to increase the organ pool to face increasing demand , the new highly effective interferon-free therapy , with high efficacy 95% , allow to utilize HCV-viremic organ, this supply donor pool by about 500 organs/yeasr.
Infected donors with HCV are usually younger , with lower comorbidity and good organ quality.
In the past HCV infection was excluded from donation , fear of recipient get infected on account of low immunity.
According to kdigo since 1990s, the HCV Ab+ve donors can be accepted for donation to HCV Ab+ve recipients.
Underutilization:
Although a pool of 6456 HC-seropositive were available for donation , only 37% was donate .however only 16% of them was HCV viremic .
Data from Uk indicate that discarding organ is based on serological status rather than the quality of organ it self , so overcoming of this challenge will enhance donor pool, and make transplantation the best treatment for kidney failure as a reality by number , and that time this fear was a rise from worse outcome of transplant from HCV +ve donors, but this data was collected at the time where the HCV treatment was interferon based regiment.
Untill recently, HCV+ve donors was offered to HCV-ve recipients in clinical trial only, but significant encouraging of this practice are develop , because of the promising outcome of HCV NAT D+/R- transplantation, and shortening of the waiting list as well .
HCV testing and risk of transmission:
Categorization of donors with active viremia HCV Ab+/NAT+ or HCV Ab-/NAT+ and those without it, is become easy with the introduction of HCV RNA as well as serological tests.
Kidney transplantation from HCV Ab +\NAT- to a recipient of HCV -, can result in seroconversion , but the risk of viral transmission is minmal, but early test for HCV post transplantation is advisable.
Routine HCV NAT testing is norrowing the window and avoid unintentional transmission from organ donor.
Suryaprasad et al.; describe 3 cases of nonintentional HCV transmission, despite -ve donor NAT , they found that transmission is gained from donor organ, except for 3 recipient who isn’t get infected, this open an window of other factor may cause such infection, which is not yet identified.
Current guideline of the US PHS further recommend NAT testing for HCV, HBV, HIV in all donors, to minimize the related to utilization.
Kidney transplantation from HCV-viremic donors to HCV-a viremic recipients:
Several clinical trials show the efficacy in practicing donation from HCV infected donors to HCV-ve recipients;
Donor/recipients selection criteria;
lentine et al.; advice not offered HCV-viremic organ to HCV-naive patient with liver cirrhosis or a history of liver disease, and this risk are aggrevated as some recipients are either diabetic, prediabetic, or have NAFLD, which may lead to a higher risk of mortality.
DAAs:
AASLD and IDSA recommend GLE/PIB for 8 weeks, or SOF/VEL for 12 weeks for the treatment of HCV-naive recipients of HCV-viremc organs, with consideration of factors such as; prescence of liver disease, concamitant medication, and immunosuppressant.
Anti-epileptic drugs should not be taken with DAAs, and avoid high dose of PPIs.
Immunosupressant:
Bae et l.; KTRs infected with HCV have a 20% lower probability of receiving a less effective inductive therapy with IL2 receptor antagonist, rather than ATG.
AR may arise from over fear from immunosuppressant .
Some study show that HCV should receive standard immunosuppressant medication, and induction therapy should not be avoided.
A retrospective study Luan et al.; show that there was no different of using whatever type of CNI (TAC vs CYC) in mortality rate in HCV Ab +, while Mycophenolate show lower mortality rate.
level of evidence: ((V)).
The reflection of this guidelines in our local practice:
It will be a challengeable based on a trial of risk with no guarantee to follow a scientifc evidence and availability of assessing the condition and intervene accordingly to controll the infection , considering balanced DAAs/Immunosuepressants.
Decision maker and to sign informed consent, involving awareness of risks.
The acceptance of donation from HCV+, will be guaranted with the above measures and guidelines mentioned in this articles, which by the end of the day show no differences between HCV+D/R-, with -ve matched group especially if risky recipients are avoided ; DM, prediabetes, obese, NAFLD, with application of proper DAAs therapy according to guidelines.
SUMMARY
Introduction
The kidney transplantation remains the best form of renal replacement therapy, but the gap between the need and supply of organ keeps increasing daily and hence necessary efforts must be adopted to reduce discarding of potentially useful kidney organs. The use of organ from HVC positive viremia that use to be a contraindication to donation could bridge this gap as KDIGO advocated for use of HCV antibody positive to a naive recipient. Furthermore, the introduction of direct antiviral agent (DAAs) for treatment of HCV positive patient has made the transplantation between HCVNAT +/ R – a reality.
HCV Testing and Risk of Transmission
The availability of testing like HCV RNA (NAT) has helped in categorization of donor into those with active viremia, HCV Ab +/NAT + or HCV Ab -/NAT + and those without, HCV NAT negative. The introduction of this test has helped to reduce the diagnostic window from 2-6 months 5-7 days for NAT.
The THINKER and EXPANDER study both showed that the use of DAA can reduce the risk of transmission of HCV infection from a donor to a naive recipient, although there still debates on the number of weeks to be used for the prophylaxis
Donor/ Recipient Selection Criteria
Patient with possibility of long waiting time for donor should be considered for HCV NAT +/R- so as to reduce the waiting time, cost of been on maintenance dialysis and possible avoidance of contracting HCV infection while still on dialysis waiting for organ. Nevertheless, recipient with possible underlying liver condition may require for detail test like fibroscan as part of evaluation with knowledge into the genotype of the HCV infection in the donor as this could influence the type of DAA combination to be used. It is of note that drug-drug interaction is high among recipient on different DAA combination and with the immunosuppressives therapy and all this must be taken into consideration to prevent resistance or acute rejection of the graft
Inform consent/ Insurance
A special kind of consent must be obtained from the recipient with full knowledge and possible outcome of receiving kidney form HCV NAT + donor and must be told of limited information on long term complication and there is paucity of data on this kind of organ donation. Also, consent must be obtained that the recipient will be adherent to the use of the DAA while ensuring there will be availability of the DAA from the health insurance because of the high cost of the drug
Conclusion
Although, the acceptability of transplant from HCV NAT +, will reduce the waiting list and bridge the gap shortage between demand and supply of organ, it is not without it own challenges of risk of transmission of the infection to HCV NAT – recipient. Also, the availability of DAA due to the cost must be assured before going ahead with transplantation.
Level of evidence id 5
Reflection on my practice. Presently in my center we don’t accept donors with HCV positivity either to HCV -/+ recipient because of fear of transmission and litigation. However, in my center we only do screening and ELIZA test for HCV and am looking inward now that we might have missed window period in some few donors. Probably with the availability of DAA though expensive we might start to push for HCV NAT +/ R- transmission with adequate counselling and obtaining consent.
Please summarise this article in your own words
– Kidney transplantation is the treatment of choice for patients with end-stage renal disease.
-It not only reduces mortality in this group of patients but also
improves their quality of life.
-The main issue does not allow to utilize it fully is the number of organs available for transplant.
-Introduction of highly effective oral direct-acting antivirals (DAAs) to the treatment of chronic hepatitis C virus infection (HCV) enabled transplantation of HCV viremia organs to naive recipients and increasing number of reports on the satisfying effects of using HCV viremia organs, including kidneys, they are more often rejected than those from HCV negative donors.
-The current state of knowledge points to the fact that a kidney transplant from an HCV nucleic acid testing positive (NATþ) donor to naive recipients is an effective and safe solution to the problem of the insufficient number of organs available for transplantation.
-This review analyzes the possibilities and limitations of the usage of HCV NAT þ donor organs.
– It not only reduces mortality in this group of patients but also improves their quality of life. However, the demand for transplant organs far exceeds their availability.
– According to data published by the Organ Procurement and Transplantation Network (OPTN), more than 90,000 people are awaiting a kidney transplant and have a higher mortality rate compared to general population which is
mostly attributable to cardiovascular disease and can be result of a long waiting time for an organ, which in the US can extend to 3–5 years .
– Many steps taken in order to resolve the organ shortage issue is also the use of
organs from donors infected with the hepatitis C virus (HCV).
– HCV testing and risk of transmission
– Donors with active viremia are those with HCV Ab(+)/ NAT (+) or HCV Ab(-)/NAT(+).
– HCV Ab(+)/NAT(-) donors: the virus has been eradicated spontaneously or through antiviral treatment.
– HCV NAT testing helped reduce the diagnostic window, in which HCV infection is present but cannot yet be identified, from to 2–6months for serological assays to 5–7days for NAT.
– Despite a negative serological result, the residual risk ranges from 0.26 to 300.6 for every 10000 donors and ranges from 0.027 to 32.4 for every 10000 donors when NAT is utilized.
– PHS criteria donors: the recommendation is to test all donors for HIV, HCV, and HBV infections using NAT.
– Viremia always develops in recipients after HCV D(+)/R(-) NAT liver transplants, and almost always in the case of heart, lung, or kidney transplants.
– Screening for HCV viremia is advisable in an early post- transplant period.
– HCV NAT(+) donors, are patients with active viremia and account for 4.2% of donors in the US.
-Spontaneous eradication of the virus is possible in up to 45% of cases, but non-immunocompetent patients have a smaller chance for spontaneous eradi- cation.
– KT from an HCV donor (Ab(+)/NAT(-) to an HCV-negative recipient can result in seroconversion, but the risk of viremia is minimal.
Kidney transplantation from HCV-viremia donors to HCV-viremia recipients
-In the THINKER study HCV-naïve kidney transplant recipients received HCV-viremia organs and viral transmission occurred in 100% of patients.
-Elbasvir / grazoprevir (EBR/GZR) was initiated as soon as viremia was detected and taken for 12 weeks ,allograft function was similar to that of matched recipients of HCV-negative grafts after 6 and 12 months .
– Only genotypes 1 and 4 were the acceptable ones.
– The EXPANDER study, applied prophylactic DAA therapy and the treatment was continued for 12 week , SVR was attained for all cases without complications.
– Other trials studied decreasing the duration of DAA therapy but results were variable.
-The incidence of ACR and development of de novo donor specific antibodies (DSA) did not exceed those observed in HCV-viremia donors and accounted for 4% and 6% respectively.
Willingness to accept HCV-viremia organs
-From 2015 to 2019, the willingness to accept a seropositive organ increased six fold.
– Recipients infected with HCV are unwilling to accept an infected graft.
-80% of patients are willing to accept an organ from an HCV NAT(+) donor under certain conditions, while 18% would not accept it under any circumstance.
-There is a lack of knowledge among patients about HCV infection
Donor/recipient selection criteria
– There are no standardized criteria but recipients having long duration of waiting need to be considered for HCV NAT D+/R- transplants offering them a better quality of life decreasing their mortality risk .
– Recipients with undiagnosed liver disease receiving HCV-viremia organs increases the risk of progression of liver disease, including hepatocellular carcinoma even in patients with NAFLD without evidence of cirrhosis.
– Fibro Scan before HCV NAT D+ /R- transplantation could facilitate suitable recipient selection.
– Knowing the viral load in a case helps identifying cases prone to HCV related complications to start DAAs at the proper time.
– Pan genotypic DAA regimens have limited drug–drug interactions with CNI but their levels need monitoring .
– Previously treated donors with NS5 inhibitors or those who have relapsed better to be excluded in order not to be exposed to viral clearance resistance after transplantation .
– If pan genotypic antiviral agents are not available it is mandatory to know the donor’s genotype .
– NS5 protease inhibitors resistance can remain for a year and can affect the results of recurrent treatment opposite to NS3-4A protease inhibitors resistance.
– Genotypes 1a and 3 a are associated with high risk donors.
– The American Society of Transplant Surgeons recommended that not knowing the genotype or the presence of RAS must not be an obstacle for HCV NAT D+/R-kidney transplantation, in the presence of appropriate therapy .
DAAs
– Pan genotypic DAAs are preferred the limitation to its use is it’s availability and high cost .
– AASLD and IDSA advised for GLE/PIB for 8 weeks or SOF/VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremia organs other than the liver along with multiple considerations as concomitant drugs taken.
– Drug drug interaction, all anti-epileptic are contraindicated in these patients.
Optimal timing of DAA initiation
It is not defined yet , the new AASLD/IDSA guidelines advice for the initiation of prophylactic treatment maximally 7 days after transplantation.
– Different studies applied variable approaches ,in fact most centers started antiviral therapy after HCV viremia detection or after hospital discharge, meanwhile delaying therapy is associated with hazardous complications as fulminant hepatitis.
– Yuzawa et al. mentioned that there is no association between donor-derived HCV viremia and CMV viremia, while Molnar et al. found that KTRs undergoing HCV NAT D+/R – transplant can have an increased risk of BK viremia.
– The KDIGO recommends, monitoring proteinuria every 6 months in HCV infected candidates post transplantation, and doing a biopsy if HCV infection occurs.
– De novo GN necessitates immediate DAA therapy .
– Studies revealed that prophylactic antiviral treatment provides better outcomes and less risk of AR but this was controversial.
The duration of therapy is also debatable where the studies showed that the standard 12-16-week therapy achieved SVR in 100% of patients either for prophylactic or reactive purposes.
Immunosuppression
– Bae et al. mentioned that KTRs infected with HCV have a 20% lower chance of receiving a less effective inductive treatment with interleukin 2 receptor antagonists rather than with anti-thymocyte globulin.
– Recent studies revealed that patients infected with HCV should receive standard immunosuppression and that depletive induction mustn’t be avoided if needed.
KDPI calculation
-It is used to estimate the expected organ survival rate after transplantation.
– Many factors are taken into account as HCV Ab presence.
– Kidney Allocation System (KAS) based on the KDPI was published in 2014 in order to match the quality of the organ to the predicted survival of the recipient, supposing that an organ with a KDPI of 20% should be transplanted to a recipient with an estimated posttransplant survival score of 20%.
– HCV infected donors had organs with excellent quality as demonstrated by studies.
Informed consent and HCV- viremia organ refusal
– Must be taken from HCV negative recipient whom accepted a graft from HCV positive donor after explaining the benefits and risks to him.
– HCV NAT D+/R- transplants can be lifesaving in spite of the risks associated with this procedure due to shortage of organs and the long duration on waiting lists which can be more hazardous than receiving a graft of HCV infected donor.
Insurance and Cost-effectiveness
-For the DAAs expensive cost can be an obstacle to proceed with the transplantation from HCV infected donor because delay of therapy in non-immunocompetent cases can be fatal.
– The cost is even more while being on dialysis and its complications, aiding cardiac function.
Conclusion
– HCVNAT +organs should be prioritized to recipients already infected with HCV and only proposed to negative recipients as second option meanwhile it solves the problem of organ shortage and when balancing the risk to hazards ratio it can be more beneficial
What is the level of evidence provided by this article?
Level 5
Please reflect on the guidelines provided above and on your practice.
In our hospital we only do living related kidney donor transplant, and we have 2 pateints (R – HBsAg – D- negative ),(R- negative — Donor- HCV )and the DAAs sometime difficulty and usually not avavible in our country.
Will you accept living or deceased donation from HCV positive donors?
-Yes , if the patient with only one HCV NAT+ potential donor.
-Giving advice and risks that may occur after the transplant and the use of expensive medicines
Please summarise this article in your own words
In the endless need for organs there may be options to increase donors pool, one of them to utilize the organs from hepatitis C Ab+/NAT+ donors to either hepatitis C positive patients and even healthy controls(no hepatitisC).
Due to high mortality rate among patients on dialysis, and the long waiting time for getting an organ, this option is highlighted hear, it decreases the longevity on aiiting list and, gives a better survival benefit, taking in consideration the risk of transmission of disease and the increased cost.
HCV testing and risk of transmission
After the introduction of NAT a serology test for HCV,HIV,HBV..etc, that can detect the disease earlier after inoculation of virus(in 5-7 days), the older teast needs months to detect the virus(2-6 months),thus reduce the faulty transmission of virus by 10 times, HCV Ab+/NAT- means the virus eradicated either spontaneously or by new medications (DAAs), patients with NAT+ are with active HC viremia these around 4% of the US donors population and might be higher in some regions., this viremia increase the risk of viral transmission to the donor.
Kidney transplantation from HCV-viremic donors to HCV-aviremic recipients
there are many small sample studies conducted in concern to HCV Ab+/NAT- or NAT+
to hepatitis C infected recipients (THINKER) showed 100% transmission rate but it was controlled by Elbasvir/grazoprevir (EBR/GZR) initiated soon(few days) after viral detection in recipients, and continued for 12 weeks, sustained viral response achieved in
all patients, and graft loss was comparable to those received HCV negative donors.
Other ( EXPANDER) study, prophylactic DAA therapy. One dose of EBR/GZR was administered before transplantation, and the treatment was continued for 12 weeks, SVR was achieved in 100% of cases, and severe complications such as AR, graft loss, or liver damage were not observed.
Many studies discuss the shortening treatment time with conflicting results.
(DAPPeR) study, patients received a single dose of DAAs, followed by one or three doses after transplantation. Administering two doses of DAAs resulted in an infection transmission of approximately 30%, while a 4-day protocol helped limit it to 7.5%. Only six patients required treatment, while the rest had low, self-limiting viremia. Ultimately, 83% of the treated patients achieved SVR. One patient, in whom the infection relapsed,did not achieve SVR with the first or second course of treatment, and the Incidence of ACR and development of de novo donorspecific antibodies (DSA) did not exceed those observed in HCV-aviremic donors and accounted for 4% and 6% respectively.
Willingness to accept HCV-viremic organs
It is shown in one study that the willingness to have HCV positive donor organs increased by 6 folds, by non infected population but not the same the infected poteitial recipients.
Donor/recipient selection criteria
FibroScan in standard recipient evaluation prior to HCV NAT Dþ/R- transplantation could facilitate proper recipient selection, figuring out any liver disease that could be increased the risk of hepatocellular Ca, or worsening liver (example NAFLD) disease.
A strong positive correlation has been reported between RNA levels in organ donors and recipients, but donor HCV viremia is not routinely reported. Knowledge of viral load could identify those with higher risk of HCV-related complications and determine the optimal timing for DAAs initiation.
Special concern about the induction therapy to those recipients of NAT+ HCV donors, the immunosuppressive medication use and doses, drug drug interactions, and the risk of rejection.
Donor genotype and the presence of RAS might be of importance in patients, excluding donors who were previously treated with NS5 inhibitors or those who have relapsed after transplantation.
Situation when no antiviral treatment will be available for the patient, either by insurance and financial issues.
DAAs
HCV therapy involves a combination of two or three DAAs that target nonstructural proteins of the HCV and may be delivered with little adverse effect and high efficacy.
Drug drug interaction, all anti-epileptic are contraindicated in these patients., and these agents should be started as soon as possible.
Immunosuppression
Immunosupressive medication dose should be not decreased.
KDPI calculation
Leads to an artificial increase in the KDPI by 0.25 on average in comparison to the actual quality of the organ, thus should not decrease the access.
Informed consent&HCV-viremic organ refusal
Should be taken form the recipients about the risk by receiving organ from NAT+ HCV, possible complications, and what is the benefit achieved by this practice in patient survival and lesser time on waiting list.
Insurance& Cost-effectiveness
IN nonimmunocompetent patient, the cost issues and prolonged time before starting treatment can have catastrophic results, liver failure , fulminant hepatitis …etc, thus better education and conversation with insurance companies and patient him self might decline this risk.
and the cost is even more while being on dialysis and its complications, aiding cardiac function.
Conclusion
The transplantation of HCV NAT þ kidneys to naïve recipients may constitute a solution to organ shortage.
Every effort should be made to ensure DAA therapy and reduce the mortality of patients awaiting kidney transplantation.
Extended education programs should also be implemented to increase awareness of HCV infection and HCV NAT D+/R- kidney transplantation among candidates, increasing donor pool.
Early to utilize HCV NAT D+/R -kidney transplantation as a standard of care, needing larger number studies to figure out the pros and cons of this practice.
What is the level of evidence provided by this article?
Level of evidence V -erratic review.
Please reflect on the guidelines provided above and on your practice.
I think this will not change our practice because we only do living related kidney donor transplant, and the price of DAAs and difficulty in providing them to our patients is the other issue.
Will you accept living or deceased donation from HCV positive donors?
No, but if we face a patient with only one HCV NAT+ potential donor, them will discuss this issue.
Please summarise this article in your own words
There is a long waiting list of patients awaiting renal transplant. Measures are being taken to decrease the waiting list. One such step is accepting kidney from those donors are who are hepatitis C positive. The new interferon free therapies have allowed HCV viremic organs especially in the setting of significant mortality.
All donors should be screened for HCV. If there is active HCV infection then kidney donation is contraindicated due to high risk of transmission. This can be accepted if recipient is also HCV positive.
Following are possible scenarios :
If the donor is positive and recipient is negative then there almost 100% risk.
Hepatitis C antibody + PCR –
It shows spontaneous resolution . This may not be the case in immune compromised . Donation can lead to seroconversion and small viremia
Hepatitis C antibody + PCR +
High risk of transmission and viremia
Hepatitis C antibody – PCR +
Shows early window period. High risk of transmission and viremia
Selection Process:
This should be careful assessment and there is no fixed or standard guidelines when donor is HCV NAT positive and recipient is negative. The indication of such transplantation is shortage of other suitable donors.
Contraindications-
HCV – naive with history of liver disease, obesity diabetes
Those requiring desensitisation
Those requiring non standard immune suppression
Donors with history of relapse
Those treated with NS5i
The patient should be counselled in detail about the risks and benefits and long term outcomes though there are not much studies .
HCV therapy targets non structural proteins of hepatitis C virus. It is combination of 2-3 DAA.
Para genomic DAA are preferred but is costly treatment. The AASLD and Infectious Diseases Society of America (IDSA) recommend GLE/PIB for 8 weeks or SOF/ VEL for 12 weeks for the treatment of HCV-naïve recipients of HCV-viremic organs other than the liver. However, multiple factors should be considered before initiating DAA therapy, like evidence of liver dysfunction, concomitant medications, and to a lesser extent immunosuppression that will be used after transplantation
Induction
Avoid ATG
IL 2 receptor blockers may be suitable.
if treatment is delayed then there can be risk of TMA, acute rejection , acute GN, and liver failure
Monitoring.
Watch for proteinuria on six monthly basis
Consider biopsy if HCV infection develops
Benefits of such transplantation include short waiting list , less mortality, less dialysis and improved survival
However complication can be there like viral infection and its complications, higher cost.
In conclusion
The HCV Ab positive donation may only be best suitable for HCV NAT positive recipients.
Those who are HCV negative may receive donation from HVC Ab positive in there is severe shortage of donors but such decision should be made after careful assessment