Treatment of HCV with the new DAAs: Before or After Kidney Transplant?

In the pre-DAA era, the dogma was to treat HCV pre-transplant for two reasons: active HCV increases post-transplant hepatic complications, NODAT, and decreases patient and graft survival and that IFN cannot be used post-transplant because of higher risk of graft rejection. The highly effective and safe newer DAA options have literally eliminated both of these problems making the hitherto unfeasible strategy of treating HCV post-transplant feasible.

Needless to say, pre-transplant treatment can improve the risk of HCV-related morbidity, incidence of diabetes and possibly cardiovascular disease in waitlist candidates but they do have to wait longer (3-5 years) for an HCV negative kidney post treatment. Instead, if they choose to receive a HCV+ kidney and get treatment post-transplant they just have to wait only for 6 months to 1 year. The downsides of waiting longer (after successful HCV treatment) are worsening of their general condition during the wait time and even never getting transplanted at all. Receiving an HCV+ kidney and treating HCV post-transplant is safe, shortens waiting time and is cost effective. 

Purely on a utilitarian basis, it does make sense to treat HCV post-transplant, unless the wait time is expected to be short i.e. AB blood group, live donor transplant, centers with short waiting time or if liver disease is severe enough to warrant early treatment. For live donor transplants planned within 24 weeks, HCV treatment should not unnecessarily delay the transplant itself as the cure can be obtained with DAAs post- transplant. If the transplant is expected to be delayed (>24 weeks), it is wise to treat GT1/4 pre transplant with renal safe non-sofosbuvir regimens but for non GT1/4, depending on the expected time of transplant, sensitization and risk of rejection, liver status, general condition  and patient preference, the treatment can be performed either pre-transplant with IFN/ribavirin or post- transplant with sofosbuvir based DAA regimen.

Transplanting HCV+ve kidneys into HCV-ve Recipients: solves problems raises questions 

The recent THINKER trial reported successful treatment of HCV in 10 NAT negative recipients transplanted with GT1 positive kidneys, under ATG induction and triple drug (CNI, MMF, steroid) immunosuppression. Although all recipients had viremia on day 3, sustained viral response (SVR) at 4 weeks was 100% with Elbasvir/Grazoprevir. At 6 months none had virological relapse and graft function was excellent (median eGFR at 6 months was 62.8ml/min/1.73m2). The only major adverse event observed was sub-nephrotic proteinuria/FSGS in one patient that occurred after SVR at 12 weeks and so is less likely to be HCV related. Another patient had a transient increase in the class I DSA without any rejection. This D+/R- study provided the recipients with high quality donor kidneys (median KDPI 42%) and significantly reduced the wait time (range between 11 days to maximum of 130 days). Although very successful, this small pilot study raises many questions:

• Liver outcomes, patient/graft survival in case a SVR does not occur (rare)
• Cost-benefit ratio if second line DAA is required
• Potentially increased risk of DSA and rejection
• Treatment options if donor has non GT1/4 HCV infection

Current challenges in HCV treatment and Future of DAA

Growing RAV (resistance associated variants) and DAA resistance is a threat to HCV treatment. Further DAA treatment for non GT1/4 in renal failure and allograft dysfunction is still a challenge. Pan-genotypic DAAs which are effective and safe in renal failure will hopefully soon be a reality. Glecaprevir/Pibrentasvir is one such DAA now awaiting FDA approval. It has been found to result high SVR irrespective of genotypes, liver status, previous IFN exposure and CKD stage (98% SVR in stage 4/5). The effectiveness in DAA exposed patients is being currently studied by MEGALLAN part 2 study.

Post by Prabhu Kanchi

Treatment of HCV with the new DAAs: Part 1

The Burden of Hepatitis C

The estimated global Hepatitis C viral infection (HCV) burden was slashed down to 71 million by the WHO in 2015, from the earlier estimate of 130-150 million, after Rao et all showed that only 51% of patients with positive serology actually carried the virus (detectable RNA by NAT, nucleic acid amplification test). The remaining HCV seropositive have either cleared the virus [spontaneously or after treatment] or have a false positive serology. These NAT negative seropositive patients are considered non-infectious. NAT positive but seronegative individual are always infectious, except for the rare patients with false positive NAT (< 0.2%). NAT is the only reliable way to diagnose HCV in transplant candidates since these patients can be seronegative (due to immunosuppressive state) despite viremia and can have normal liver enzymes despite having liver disease.

Overall, genotypes GT1 followed by GT3 are the most common strains and have a global prevalence compared to GT 2,4 and 6. GT5 is the least common of all having prevalence of <1% and limited to southern Africa. In the United States, approximately 70% of chronic HCV infections are caused by GT1 (55% of 1a, 45% of 1b) followed by GT2 (15 to 20%) and GT3 (10 to 12%). GT 1 is the more aggressive of all and also more resistant to interferon therapy but GT2 has greater risk of CKD progression than GT1.

Serology, NAT and HCV Transmission in the Transplant Setting

Transmission of a virus in eclipse phase (see below) is a well-known phenomenon with HIV and HBV. The eclipse phase is the time lag for the NAT to detect viremia after an acute infection. Even with the new generation HCV PCR tests, there is an eclipse phase of about 5-7 days. 
The first ever report of transmission of HCV from a NAT negative donor was reported in 2015. Notably in all the reported cases, the deceased donors had high risk behavior. The HCV infection being missed in a potential transplant recipient or a live donor in the eclipse phase has not been reported yet but is theoretically possible, especially in centers/countries with high HCV prevalence. 

Direct Anti-Viral Agents (DAAs) and renal disease

DAA in Chronic Kidney Disease

The introduction of DAAs was met with excitement by nephrologists, see previous RFN coverage. The treatment of GT1/4 in CKD is quite straight forward as non-Sofosbuvir regimens are available i.e.  Elbasvir/Grazoprevir (EG) and PrOD (Paritaprevir, ritonovir, Ombitasvir, Dasabuvir +R(ribavirin in GT1a). See here for coverage of the C-SURFER on the blog. These combinations can be used even in CKD4/5D as they are metabolized by the liver.

In contrast Sofosbuvir has renal excretion, accumulates in renal failure (eGFR < 30ml/min/1.73m2) and unfortunately further worsens the renal failure and hence contraindicated in CKD 4/5D. Since a Sofosbuvir-based DAA regimen (Sofosbuvir plus Velpasvir or Ledipasvir or Daclastasvir or Simeprevir) is the only approved treatment for non GT1/4 ,patients with eGFR< 30ml/min/1.73m²  should be treated with pegIFN/ribavirin and those with less severe CKD can be still treated with Sofosbuvir without any dose reduction. This might change after the results of the study looking at effectiveness of low dose Sofosbuvir/Velpatasvir in non GT1/4 HCV patients with CKD5D, are available.

DAA in renal transplantation

Paritaprevir (effect of which is enhanced by ritonavir) inhibits the CYP3A4 enzyme causing 4-6 fold elevation in cyclosporine levels and nearly 60-80 fold elevation in tacrolimus levels, making use of the PrOD regimen less desirable in transplant setting. Even though PrOD was effective in liver transplant studies and no rejection reported with CNI dose changes, it has been never used in renal transplant studies. Since there is little direct data in allograft dysfunction, the data from CKD may be extrapolated to the transplant setting.

HCV Positive Donors

D+ donor kidneys are non-inferior

Outcomes of HCV D+/R+ was considered inferior to D-/R+ since the early viral replication with immunosuppression was thought to increase the risk of the liver disease, graft failure and patient mortality. It was even considered that transplantation outcomes with HCV+ donors not different from HCV+ patients remaining on dialysis. In reality, the risk was later found to be very small from 13 year UNOS data published in 2012. The risk of receiving a HCV+ kidney translated to only <1% lower survival at 1 year and a 2% lower survival at 3 years. Also, recently Morales showed that 10 year patient and survival graft survival was not different between D+ and D- to R+ patients.

HCV+ Donor Kidneys are underutilized

Increasing IV drug abuse in the past two decades has increased the prevalence of HCV in the young. Many of these newly infected population are unaware of the infection and so unlikely to get treatment but more likely to die due to drug over-dosage and hence are potential donors of  high quality kidneys. About 300-500 unrealized opportunities exist each year in US and nearly 4100 HCV positive good quality kidneys (with average KDPI 70%) were discarded between 2005- 2014.

In the following post I will deal with treatment issues including whether to treat with DAAs pre or post transplant.

Post by Prabhu Kanchi, Nephrology Fellow, Ottawa

Jaundice and Renal Failure

In patients with combined renal and liver dysfunction it is important to differentiate between renal impairment that is secondary to liver disease i.e. hepatorenal syndrome, and conditions where an insult directly affects both the liver and kidney.  

I recently saw a 20-something year old student who was a regular kayaker in local rivers.  He had a 5 day history of myalgia, fever and headache with no vomiting or diarrhoea.  He took paracetamol (acetaminophen) and ibuprofen within recommended limits for his symptoms.  In the 24 hours prior to his admission he developed jaundice and noticed decreased urinary output. On arrival to hospital he was jaundiced but examination was otherwise unremarkable.  There were no signs of chronic liver disease and the liver was not palpable.  He was hemodynamically stable.  Blood tests showed a raised (conjugated) bilirubin at 453umol/L (25 mg/dL), ALT within normal limits and mildly elevated ALP at 162U/L.  He had an acute kidney injury with creatinine 427umol/L (4.83 mg/dL), potassium 3.4mmol/L.  He was anemic and thrombocytopenic with a neutrophilia, and blood film showed toxic granulation, with no red cell fragments.  An ultrasound of his liver was unremarkable and his kidneys were at the upper limit of normal size with no hydronephrosis. For 36 hours he was anuric despite fluid resuscitation, and required a short period of CRRT.  After this time he began passing urine and his creatinine spontaneously fell, although bilirubin remained elevated.  He was treated empirically with ceftriaxone and doxycycline for leptospirosis, and six days later urine PCR and serum IgM came back positive for leptospirosis.  

Photo from ACG Case Reports Journal

Leptosporosis is a zoonosis usually transmitted to humans through rodent urine in water.  The majority of cases cause a self-limiting febrile illness, but in its severe form - Weil’s syndrome – patients can develop jaundice, renal failure, pulmonary haemorrhage and aseptic meningitis.  Renal impairment in leptospirosis can be secondary to a number of different mechanisms including sepsis/critical illness, a direct nephrotoxic effect to the renal tubule by the leptospira toxin, tubulointerstitial nephritis, rhabdomyolysis and hyperbilirubinemia.  Patients often maintain good urine output despite renal injury, and tubular dysfunction means most patients are hypo- or normokalemic even if oliguric.  Another characteristic finding is enlarged kidneys with normal parenchymal echogenicity on ultrasound.  

Included in our initial differential was that his renal impairment was secondary to hyperbilirubinemia.  Bilirubin causes renal impairment again through a range of mechanisms including direct toxicity to the nephron, bile acid casts causing tubular obstruction, and hypoperfusion from vasodilation.  Renal biopsy can show pigmented bile casts within the tubules and tubular hypertrophy (see image).  Electron microscopy can show bile acid accumulation within lysosomes and dilated mitochondrial cristae.  In those with normal baseline renal function and short-lived hyperbilirubinemia changes are often mild and reversible, but irreversible damage can occur in those with underlying renal impairment.  

Early clues for leptospirosis in this case include hypokalemia despite being oligoanuric, enlarged kidneys on ultrasound and of course his social history.  


Post by Ailish Nimmo

Clinical Pearl - Bleeding and Liver Disease

Bleeding is a common complication of liver disease and given that we as nephrologists are sometimes asked to place lines or perform renal biopsies on patients with cirrhosis, it is important to know the physiology behind the reason for excessive bleeding in these individuals. Here is a nice clinical pearl from our Hematology colleagues at MGH:

Endogenous tPA is cleared by the liver and therefore circulating levels of tPA are elevated in patients with cirrhosis. This is the main reason that these patients bleed. Phrased another way, the main hemostatic defect in liver disease is not thrombin generation (defective production of procoagulant clotting factors) but rather accelerated clot lysis. Therefore, an antifibrinolytic treatment (like amiocaproic acid) that inhibits the binding of fibrinolytic molecules (plasmin, plasminogen) to fibrin and thus helps prevent breakdown of existing clots is an elegant and effective way to treat bleeding in cirrhosis. A reduced dose should be given in patients with renal dysfunction and it should be noted that this drug has been associated with AKI in some patients due to urinary tract obstruction and ATN.

Posted by Rebecca Karp Leaf MD and Walter Dzik MD.

Update from Hepatology: AKI and HRS in patients with cirrhosis

In the recent edition of Hepatology, the International Club of Ascites (ICA) have published their revised recommendations on the diagnosis and management of AKI in patients with cirrhosis. They first proposed diagnostic criteria for Hepatorenal syndrome (HRS) in 1996 and last updated them in 2007 (covered by RFN). Since their first publication, there has been much work done in defining AKI with RIFLE, AKIN and KDIGO and this is reflected in the ICA’s latest guidance. This time, they have gone beyond defining HRS to include staging of AKI in patients with cirrhosis and proposed how this could be used to inform management.
Here are the definitions they propose (the ICA-AKI classification):

The first thing to note is that they’ve removed the fixed threshold of sCr of ≥ 1.5 mg/dl (133 mmol/l) from the old criteria and brought in an absolute increase in sCr.  Indeed, the eagle eyed amongst you will have noticed that their definitions and staging of AKI are based on the KDIGO criteria but with the use of urine output removed. The rationale for this being that patients with cirrhosis can often be oliguric with avid sodium retention but still have preserved renal function. Conversely, they can have an increased urine output as a result of diuretic therapy.
Whilst a sCr less than 7 days before admission would be the ideal result to use as baseline, they have pragmatically suggested that the most recent value available in the last 3 months can be used. When this is not available, the admission sCr should be used as baseline. They do not recommend using the reverse application of the MDRD formula to calculate an estimate of baseline sCr as MDRD is known to be inaccurate in patients in cirrhosis (covered in a previous RFN post ). If no previous sCr is available and the admission value is ≥ 1.5 mg/dl (133 mmol/l), decisions should be based on clinical judgement.
Moving onto management, the ICA has suggested the following algorithm:

Treatment for those with AKI stage 1 is outlined in the table. Note that the plasma volume expansion can be with crystalloid or albumin (or blood in the case of GI bleeding) at this stage. Those who present with AKI stage 1 who progress are then treated in the same way as patients who present with AKI stage 2 and 3 i.e. stopping the diuretics and 48 hours of albumin 1g/kg (max dose 100g per day). Further management then varies on the aetiology and whether or not this is HRS, which the algorithm helpfully informs. The new criteria for HRS:

Again, they have removed the cut off value in sCr from the diagnosis in favour of a dynamic change in sCr as per the ICA-AKI criteria. Importantly, they have suggested revising the diagnostic criteria for type 1 HRS and with it the indications for treatment with vasoconstrictors. Type 1 HRS is currently defined as a doubling of the initial sCr to level ≥ 2.5mg/dl (226 mmol/l) in < 2 weeks. Evidence however suggests that a higher sCr at the beginning of treatment leads to a lower chance of response to vasoconstrictors and albumin. With the new algorithm, patients at AKI stage 2 or 3 or who have progression from stage 1 that meet all the other criteria for HRS, should receive treatment with vasopressors irrespective of the final value of sCr. This will allow treatment earlier and hopefully lead to better outcomes though at present there is no data to confirm this.

No consensus was reached on the optimal management of those patients who present with AKI stage 1 but then have stable renal function (i.e. do not regress or progress). Whilst all agreed that if the patient has a final sCr ≥ 1.5 mg/dl (133 mmol/l), they should be treated according to the right side of the algorithm, most of them had concerns about the use of vasoconstrictors for those with HRS if the sCr was < 1.5 mg/dl (133 mmol/l). Hence, they advise to treat these patients on a case-by-case basis.




Authored by David Baird,
Royal Infirmary of Edinburgh

Hepatitis C cure on the Horizon: Implications for Nephrology

You have probably noticed the flurry of articles published this week in the NEJM, coinciding with the International Liver Congress meeting in London, reporting incredible results with new direct-acting antiviral agents in Hepatitis C. This is undoubtedly one of the biggest medical stories of the year and a triumph for science, coming just 25 years after the discovery of the RNA virus. The studies were in patients with genotype 1 HCV although apparently the response is equally as good in other genotypes. The new agents interrupt viral replication which is vital for HCV to exist. Briefly, 2 different regimes have demonstrated sustained viral responses of 94-99% within 12-24 weeks in chronic Hepatitis C patients with and without cirrhosis and with and without previous treatment failures with standard therapy. The agents were administered as once daily in pill form and were well tolerated overall. Ledipasvir and sofosbuvir were the agents in one group of studies and ABT-450, ritonavir, dasabuvir and ombitasvir in the other studies (latter group all had ribavirin; no additional benefit with ribavirin in ledipasvir and sofosbuvir studies).

These new agents have shown spectacular success in achieving a sustained viral response in patients with Hepatitis C and will soon replace standard interferon-based therapy. There is a high burden of renal disease in patients with Hepatitis C, largely glomerular disease (mixed cryoglobulinemia, MPGN and less commonly membranous nephropathy). Treatment of these diseases is primarily directed against the underlying HCV infection. There are many issues with this:

·         Ribavirin is contraindicated at GFR <50mls/min.

·         Pegylated interferon is contraindicated at GFR<15mls/min (with the added issue of assessing renal function in liver patients).

·         Renal transplant recipients who are anti-HCV positive pre-transplant have increased proliferation of HCV, a significantly increased risk of post-transplant chronic active hepatitis, de-novo glomerular disease and may have an increased risk of death.

·         Interferon-alfa is associated with aggressive renal allograft rejection that frequently leads to graft loss, necessitating treatment pre-transplant if at all. Likely mechanisms of this include upregulation of NK cells/cytotoxic T-cells, induction of cytokine gene expression and cell surface expression of HLA antigens.

For nephrologists, we want to know what role these agents will have in our patients. The first issue to note is that all these studies excluded patients with a creatinine clearance <60mls/min (as per Cockcroft-Gault in ABT-450 based studies; unknown method in the ledipasvir/sofosbuvir studies).
As per the manufacturer, sofosbuvir has never been studied in patients with a creatinine clearance <30mls/min. However, a trial is underway examining its use in this population. I could not find any data on the other agents regarding renal function.

The incredible results of these studies should have beneficial knock-on effects for nephrology, including a lower incidence of HCV-related nephropathies, the ability to treat patients post-transplant and maybe even less demand for combined liver-kidney transplant. However, some uncertainty remains particularly regarding how to use these agents in CKD/ESRD and predictably, economics. Estimated treatment costs of $90,000 will preclude many in the developing world, in particular, from accessing these curative agents. We await with interest how the story progresses from here.

Perils of Estimating GFR in Patients with Cirrhosis

In my attempt to highlight nephrology content in non-renal journals, I will this month focus on a series of articles in Hepatology concerning eGFR in cirrhotic patients. We are all aware of the concerns using creatinine-based tools for estimating GFR in this patient cohort given their malnourished, low muscle-mass state. The use of Cystatin-C based equations may theoretically be more informative as this protein is not influenced to the same degree by non-renal factors. However, Cystatin-C is far from perfect and is influenced by sepsis, inflammation and steroid use. Other concerns include the use of the MDRD-6 equation due to the inaccurate determination of albumin (may receive IV infusions) and urea (increased by GI bleed/steroids) in these equations.

As liver patients with renal dysfunction have such a poor prognosis, they are prioritized for liver transplant by way of inclusion in the MELD score, the prognostic tool used to allocate liver allografts. Since adopting MELD, the number of combined liver-kidney transplants (cLKT) has continued to grow, with cLKT considered when GFR<30mls/min and sometimes at higher eGFR. As the demand for kidneys continues to outstrip supply, nephrologists in particular have legitimate concerns regarding the potential for inappropriate use of precious renal allografts in cLKT. This may occur if eGFR underestimates true GFR as may occur with creatinine-based equations. Also concerning is overestimation of true GFR resulting in denial of cLKT where it may actually be indicated, leading to inferior patient outcomes. (See the post by Andrew regarding combined liver-kidney transplant allocation).

Francoz et al studied 300 patients with cirrhosis being evaluated for transplant that had iohexol clearance measured. This was compared to MDRD-4, MDRD-6 and CKD-EPI equations (all using creatinine only) and found that MDRD-6 was the most accurate although it did underestimate true GFR and all 3 equations had poor correlation (R2 0.37-0.4). MDRD-4 and CKD-EPI overestimated GFR especially in those with GFR<60mls/m.

DeSouza et al also looked at patients being evaluated for transplant (n=202) and measured GFR using inulin clearance. Throughout all severities of cirrhosis, Cystatin-C equations were superior with CKD-EPI (Cys-C) the best, compared to creatinine-based MDRD & CKD-EPI methods (which significantly over-estimated true GFR). Of note it outperformed CKD-EPI (creatinine-cystatin-C combined).

Mindikoglu et al examined 72 outpatients with stable cirrhosis comparing CKD-EPI (creatinine-cystatin-C combined) to 24-hour creatinine clearance, Cockcroft-Gault equation and multiple other creatinine-based methods including MDRD & CKD-EPI. Their gold standard was iothalamate clearance. CKD-EPI (creatinine-cystatin-C) performed better than all others including CKD-EPI (Cys-C), unlike DeSouza et al.

Confusing right? What we can take away from these useful studies is that Cystatin-C based equations may be better than creatinine alone equations (remember Francoz et al did NOT use Cystatin-C). However, it should be noted that the diagnostic performance of the best equations in the studies was still markedly lower than reported in validated normal populations. 
My feeling is that in borderline cases when a cLKT is being considered, we need additional data. I would consider a borderline case stable renal dysfunction in the eGFR 20-50mls/min range (arbitrary I know!), not including co-existent ESLD/ESRD or obvious acute hepatorenal cases which will recover with a functioning liver allograft. As renal biopsy is usually not desirable in patient with chronic liver disease, it seems sensible to actually measure GFR in these cases. This appears to be the prudent approach to take to strike a balance between providing a kidney to those who need it and not inadvertently denying an organ to a wait-listed ESRD patient.

When should a Liver Transplant Recipient get a Combined Liver Kidney Transplant?

Currently there is huge variation in the number patients receiving a kidney transplant at the time of their liver transplant across the US; Combined Liver Kidney Transplant (CLK). The rate of good quality (standard criteria) kidneys being transplanted at the time of liver transplant varies from about 20% in the Midwest to about 6% in centers on the east coast, for example. The reasons for this disparity are varied and there is a real worry that many Liver transplant patients are receiving a kidney when one is not really needed. This reduces the number of good kidneys in the kidney alone pool. In 2012 liver-kidney transplants were the highest of all combined liver transplantations in the US.

Liver wait list patients are frequently very sick and renal dysfunction is common in this population of patients. Elevated creatinine can significantly raise the MELD score placing candidates towards the top of the liver wait list. There is a survival advantage of CLK vs Liver Transplant alone (LTA). This puts pressure on physicians and surgeons to consider transplanting a kidney with the liver. There may also be financial and statistical reasons for a center to transplant a kidney with a liver. The outcome data favoring CLK over LTA in renal failure patients is all retrospective, non-randomized and does not take into account the cause of peri-transplant renal failure and whether the patient truly had established ESRD or CKD4 at the time of transplant.  Another factor putting pressure on medical professionals to perform CLK transplants is the fear of ‘getting it wrong’. Survival is very poor in patients who do not recover renal function after LTA vs those who do. Currently a patient put onto the kidney alone list after LTA will have to wait the average 5 years for their kidney (average kidney alone wait list time in SE USA). Given the poor outcomes described by Northrup, these patients are likely to die with a functioning liver waiting for a kidney.

So can we predict who who will develop ESRD after LTA? A number of studies have looked at this using various prediction parameters.

In summary:

- RRT for less than 30days pre-LTA are likely to recover renal function

- RRT for greater than 90days preLTA are unlikely to recover

- Patients with eGFR consistently less than 30ml/min/1.73m2 (MDRD) for 90days prior to LTA had an increased risk of ESRD.

- ATN vs HRS as a cause of renal failure at time of LTA increases the risk of post LTA CKD 4/5.

So how can we improve the allocation of kidneys in CLK patients?

Dr Carl Berg is the Chairman of the OPTN/UNOS policy oversight committee, incoming UNOS Vice President and a Liver Transplant Physician at Duke University Medical Center. He recently presented a talk that highlighted the issues described above. He and others (Richard Formica and Bertram Kasiske) are working on proposals that will:

- Avoid giving kidneys to liver transplant patients with a high likelihood of renal recovery

- Provide fail-safe mechanism to provide less penalty for “guessing wrong” and not putting in a kidney with a liver

- Create a system that is not easily manipulated.

Some of the proposed ideas are as follows (these are not official UNOS/OPTN proposals but are proposals based on the expert opinions of the three mentioned authors CB, RF, BK):

Fail safe:

1) The patient receives a time credit of the 25th percentile of waiting time for the center they are listed in.

2) In addition, the patient receives credit for the time spent from transplant of the primary organ (time of arterial anastomosis to time of listing).

This time credit should encourage doctors to allow time for the kidney to recover but not discourage living donation.

Proposed criteria for offering a kidney at the time of Liver transplant

•ESRD (as defined by the Form 2728)

•Metabolic disease requiring CLK

•Acute renal failure with ≥8 weeks of dialysis

•CKD with eGFR or CrCl ≤30 mL/min

The duration and time of CKD first documentation needs to be assessed.

This is an interesting and difficult area for the transplant physician. I certainly agree that clearer guidelines are needed to ensure our limited pool of good kidneys is used wisely and no ‘game playing’ occurs. With regard to Dr Berg’s proposals; the AKI and CKD criteria are most troublesome. We all know kidneys can recover function weeks after an AKI event. Clinical diagnosis of AKI or even diagnosing CKD in these patients in difficult and requires great clinical skill from the nephrologist. Performing a kidney biopsy to gauge likelihood of recovery and cause of AKI sounds attractive but is risky and costly in this patient group.

Posted by Andrew Malone

Blast from the past: the hepatorenal reflex revisited

How does sodium retention occur in liver cirrhosis? Most of us accept Schrier’s peripheral arterial vasodilation hypothesis. This hypothesis postulates that overproduction of vasodilatory substances in the splanchnic circulation in cirrhosis leads to splanchnic pooling and decreased “effective” arterial blood volume which will trigger the activation of sodium and water retaining mechanisms (i.e. renin-angiotensin-aldosterone)


However, this hypothesis has come under scrutiny recently. In elegant studies done in dogs with experimental liver cirrhosis, Levy et al. observed that sodium retention and plasma volume expansion precede the development of systemic vasodilation, suggesting that systemic vasodilation in cirrhosis is likely a homeostatic response to ECF volume expansion.


Experimental evidence collected over several decades point towards the existence of an intrahepatic vascular sensor involved in ECF volume regulation: the hepatorenal reflex. Under normal conditions, hepatic sensors would respond directly or indirectly to a decrease in ECF volume in the intrahepatic circulation and will activate renal sympathetic nerves to produce sodium retention and maintain sodium balance. Along this line of thinking, hepatic denervation abolishes this reflex.


The hepatorenal reflex has been implicated in the pathophysiology of sodium and water retention in liver cirrhosis. Apparently, the distorted liver architecture and abnormal intrahepatic circulation in cirrhosis will produce changes in portal venous flow that will pathologically activate this reflex with the subsequent development of sodium retention. Adenosine plays a central role in this reflex. Adenosine receptor blockers were shown to exert a natriuretic effect, prevent the decline in creatinine clearance and to decrease mortality in an animal model of liver cirrhosis. More studies are needed to clarify whether adenosine antagonists could be clinically beneficial in these patients.


Helbert Rondon, MD, FACP, FASN

Hyperkalemia in patients with cirrhosis; good or bad?

Hypokalemia and metabolic alkalosis are considered precipitating factors for hepatic encephalopathy, as hypokalemia stimulates ammoniagenesis in the proximal tubule.

Although, the mechanism is not entirely clear, the likely hypothesis is as follows:

*Hypokalemia causes the movement of potassium out of the cells.
*To maintain electric neutrality, H+ ions move into the cells leading to intracellular acidosis (cellular ph decreases).
*This triggers the conversion of glutamine in the proximal tubule, to NH4+ and bicarbonate.
*Ammonia (NH3+ and NH4+) is selectively, either excreted in the urine or returned to the renal venous circulation (~25-45%).
*Ammonia, that subsequently enters portal circulation, is not metabolized by the cirrhotic liver, therefore likely to precipitate encephalopathy.

Potassium sparing diuretics such as spironolactone and epleronone are used to prevent hypokalemia and metabolic alkalosis for this reason. See Conall's post about diuretic choice in decompensated liver disease. Yet, frequently, hyperkalemia, and not hypokalemia, is a cause of concern among physicians, and frequently leads to discontinuation of spironolactone, administration of loop diuretics, dietary potassium restrictions, all of which further add to the risk of encephalopathy.

Conversely, high potassium levels may be protective by reducing the risk of hepatic encephalopathy. Although, somewhat speculative, this may happen in two ways

1. Hyperkalemia may decrease total ammonia production in the proximal tubule by increasing intracellular ph and thereby impairing ammoniagenesis.
2. Potassium competes with NH4+ for absorption by the NKCC2 transporter at the thick ascending limb of loop of henle, thereby reducing ammonia accumulation (read ammonia trapping) in the medullary interstitium and hence less ammonia available for absorption in the systemic circulation.
   

In an interesting study done by Zavagli et al, patients with higher potassium levels (5.4-5.5 meq/l) had a much better survival and less hepatic encephalopathy episodes as compared to patients with lower potassium levels (3.4-3.5meq/l).

While I certainly do not recommend ignoring severe or symptomatic hyperkalemia in liver cirrhosis patients, educating physicians about aggressive correction of hypokalemia, rather than mild hyperkalemia, may serve these patients best.

Viresh Mohanlal, MD

Hepatorenal syndrome: some help from the renal service

Hepatorenal syndrome (HRS) is a frequent consult encountered on the nephrology service. The criteria have recently been revised. Conall reviewed the revised criteria on a prior post last year. To review the pathophysiology of HRS click here.

In a cirrhotic patient with AKI, HRS commonly appears in the top 3 of a differential diagnosis. However, when a large database was reviewed (single center), the major causes of AKI in a cirrhotic patients in descending order of frequency were:

*32% infection-induced renal failure
*24% parenchymal renal disease
*22% prerenal
*11% ATN
*8% HRS
*3% nephrotoxic renal failure

Potential therapies- Albumin, octreotide and midodrine have shown some benefit and a retrospective study of 53 pts showed some survival benefit with octreotide and midodrine combination in these patients. Prostaglandin analogues, ACEi, NAC and endothelin receptor antagonist have all been looked at, but these data are inconclusive. A randomized study of 46 patients in Spain and a randomized double blinded study of 112 pts in the US compared the use of terlipressin (a vasopressin analogue) and albumin together versus albumin (+ placebo) alone. The results showed improvement in renal function but the overall survival was not different in the two groups. There was, however, some increase in the risk of cardiovascular side effects. At this time terlipressin is not approved by the FDA in the US.

Dialysis typically only offered when liver recovery is expected or possible (acute liver injury) or when liver transplant is a valid option. Conventional dialysis in often proves challenging as hypotension is common in patients with liver failure. However, some simple changes can minimize hypotension. These include: use of less negatively charged dialyzer membrane, circuit priming with isotonic NaHCO3 (instead of normal saline), cooling, increasing Na in dialysate, low UF, citrate anticoagulation and midodrine/terlipressin before HD.

Extracorporeal albumin dialysis (ECAD) using molecular adsorbents recirculating system (MARS) is something new on the horizon. Basically, this is hemodialysis with an albumin-containing dialysate. Charcoal and anion exchange columns are connected to a hemodialysis or hemoperfusion apparatus. This system effectively removes albumin-bound substances, including bilirubin, bile acids, aromatic amino acids, medium chain fatty, NO and cytokines. So, it functions more like a liver substitute (in removing albumin bound substances) in addition to providing dialysis.

In small and mostly uncontrolled studies ECAD has been shown to decrease mortality and improved renal function. In a prospective randomized controlled study it was shown to improve hepatic encephalopathy. The major downsides are hypotension, increased bleeding, cost hypoglycemia and non cardiogenic pulmonary edema. Results of ongoing clinical trials will shed more light on this form of therapy.

A liver or a simultaneous liver and a kidney (SLK) transplant is the best options for these patients. About 50% of the times, HRS resolves following the liver transplant but some patients remain dialysis dependant. This raises the question of SLK transplant. Although no strict guidelines apply, according to the Consensus Conference held in 2008 (ASTS, AST, UNOS, ASN), AKI or hepatorenal syndrome with SCr ≥ 2.0 mg/dL and dialysis ≥ 8 weeks, qualify for a SLK. Even with these advances HRS continues to be a diagnosis associated with considerable morbidity and mortality associated with it.

Tarun Kaur, MD