Cholesterol Management.

Cholesterol management, what to do?

New guidelines on managing cholesterol were published in Circulation this month by the ACC/AHA task force. As we spend much of our time in CKD clinic managing cardiovascular risk factors such as blood pressure, diabetes, lifestyle factors and cholesterol I think it is important we are up to date on the latest guidelines.

The task force based their recommendations based on randomized controlled trials based on fixed doses of statins in those at risk for atherosclerotic cardiovascular disease. The authors also emphasize the continuing importance of lifestyle modification for the reduction of ASCVD.

Those who benefit from statins are (Task Force Summary):

1. Individuals with clinical ASCVD

2. Individuals with primary elevations of LDL–C ≥190 mg/dL

3. Individuals 40 to 75 years of age with diabetes and LDL–C 70 to189 mg/dL without clinical ASCVD

4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher.

Risk calculator

The Caveats; no evidence for statin therapy in these groups:

Primary prevention in over 75s unless clinically evident ASCVD present

Those with NYHA HF class II – IV

Those on hemodialysis

Significant changes to note:

No specific LDL-C and non-HDL-C targets recommended once on statin therapy

The de-emphasis of surrogate markers such as CRP and calcium scores.

Cautious use and clinical judgment in those over 75 years without clinical ASCVD

What about renal patients?

The Task Force Authors looked at the TNT trial and the subgroup analysis from Shepard et al. The guidelines do not explicitly recommend the use of statins in CKD patients but they do highlight the beneficial findings of high dose (80mg) atorvastatin.

Shepard et al did a subgroup analysis of the TNT trial looking at secondary prevention of major cardiovascular events in patients with an MDRD eGFR less than 60. In the original TNT study patients were age 35 to 75 and patients on long-term immunosuppression or with nephrotic syndrome were excluded. At baseline patients already had an LDL-C of less than 130mg/dl. Shepard showed that 80mg of atorvastatin reduced the RR of a major CV by 32% compared with 10mg of atorvastatin.

My impression is that we should use statins in our CKD patients but remain cautious with respect to drug interactions and side effects.

Cholesterol RCTs in renal patients (a refresher on the evidence ).

4D - Die Deutsche Diabetes Dialyse Studie.

N Engl J Med, 353 (2005), pp. 238–248

This German trial looked at 18 to 80 year olds with type 2 DM on hemodialysis for less than 2 years. Patients with LDL-C outside the 80 to 190 range were excluded as were failed kidney transplant patients. After a 4 week lipid-med free wash out patients were assigned to atorvastatin 20mg or placebo. The primary outcome was a composite of cardiovascular death. About 1200 patients were enrolled for a mean of nearly 4 years. In this trial statin did reduce LDL-C levels but there was no significant difference in the primary or secondary outcomes.

AURORA.

N Engl J Med. 2009 Apr 2;360(14):1395-407

Were the 4D study focused on the high risk diabetic population on HD this trial investigated the efficacy of statin therapy in the general dialysis population. Patients were 50 to 80 years and on regular hemodialysis or filtration for 3 months. Expected transplantation within the next year or statin therapy within the last 6 months excluded patients. Randomization was to rosuvastatin 10mg or placebo and the primary endpoint was cardiovascular death or non-fatal stroke or MI. Again, statin therapy reduced cholesterol levels significantly but there was no difference in primary or secondary outcomes. Further more, there was no correlation between primary outcome and baseline LDL-C or 3 month LDL-C.

SHARP.

Lancet. 2011 Jun 25;377(9784):2181-92.

This trial attempted to look at the effects of simvastatin 20mg + ezetimibe 10mg versus placebo on major atherosclerotic events in patients with CKD with no previous MI or revascularization3. About 3000 of the 9000 patients were on dialysis. The authors concluded that combination therapy produced a relative risk reduction of 17% for major ASCVD outcomes. This trial came in for a lot of criticism mainly because the authors appeared to extrapolate their results by assuming all patients actually took their assigned meds. 2700 patients were enrolled for a mean trial length of over 3 years.

ALERT (Assessment of LEscol in Renal Transplantation)

Lancet, 361 (2003), pp. 2024–2031

This study assessed the use of statin therapy on transplant patients. Enrolled patients were between 30 and 75 and had a kidney or KP transplant for more than 6 months with stable renal function. All patients were on ciclosporin and had total cholesterol levels between 4 and 8 mmol/l. Patients were excluded if they had rejection in the last 3 months or were already on statin therapy. 2100 patients were enrolled and followed for a mean of 5 years. Randomization was to fluvastatin 40mg or placebo. The primary end point was cardiac death, non-fatal MI or coronary revascularization. Fluvastatin lowered LDL-C by 32% but there was no significant difference in the primary endpoints. Interestingly in this study only about 13% in each group had diabetic nephropathy and about 5% had ‘hypertensive nephrosclerosis’ as a cause of their primary renal failure. This study was conducted in Canada and Europe.

Stenting for atherosclerotic renal artery stenosis: Another nail in the coffin

Despite a lack of strong evidence, angioplasty and stenting of atherosclerotic renal artery stenosis (RAS) became a common intervention in the last decade. It was often performed on incidental lesions discovered  during “drive-by” angiography in cardiac procedures. In the last few years, enthusiasm has cooled as two randomized trials; the ASTRAL and STAR trials have failed to show any benefit of the procedure.The ASTRAL trial received significant criticism in some corners of the medical press –as headlines like this show! 

The CORAL trial recently reported in the NEJM has added to the weight of evidence against the procedure. It included 947 patients with either systolic hypertension >155mmHg on two agents or an eGFR <60ml/min and RAS of >80% or >60% with a pressure gradient > 20mmHg. All patients received, amlodipine, atorvastatin, and candesartan +/- hydroclorothiazide.

In short there was no difference in the primary and composite endpoints of Death, MI, Stroke, heart failure, progression of CKD and need for RRT. The only exception was for that of BP in which a significant but minor (2mmHg) drop in the intervention arm.

This is another large, RCT demonstrating a lack of benefit or renal artery stenting, therefore for the vast majority of patients with RAS and either hypertension or CKD, management of RAS should be limited to medical therapy.

There remains uncertainty around patient groups in which their may still be benefit such as those with severe stenosis to a single functioning kidney, severe stenosis and AKI and patients flash pulmonary oedema. It is hard to imagine recruitment of these groups in numbers sufficient to adequately power a clinical trial.

Posted by Jonathan Dick

Does JC Virus Nephropathy Exist?

The JC virus is a member of the Polyomavirus family, which includes the BK virus.  It infects about 80% of healthy adults and establishes latency in renal tissue. It was first isolated in 1971 from the brain of a patient (initials JC), with Hodgkin’s lymphoma who died of progressive multifocal leukoencephalopathy. While working on a transplant service some years ago and reviewing screening results for polyoma virus, I noticed a high rate of JC viruria which didn’t always correlate with BK replication. Allograft function always seemed to remain excellent and I was unsure of the relevance of the results. Thankfully we soon stopped checking polyoma viral loads in the urine so I stopped worrying about a test I didn’t know how to interpret. I have wondered since does JC Nephropathy even exist so decided look at the evidence.

A few points to note regarding JC Virus and renal transplant patients:

·         The relationship between JC virus replication and immunosuppression is less well defined than with BK virus. A study of renal transplant recipients and matched non-immunosuppressed controls had similar rates of JC viruria (but more high levels in the transplant patients). Also, JC viruria appears to respond less well to immunosuppression reduction.

·         Dan Brennan’s group recently prospectively reviewed the interaction between BK and JC virus in 200 renal transplant patients in the first year. They detected BK and JC viruses in the urine of 35 and 16% of transplant recipients respectively with BK viral load being 400 times higher than JC. Interestingly, the presence of BK viruria made concurrent JC viruria significantly less likely and no episodes of JC viremia or JC nephropathy were observed. Moreover, a lower acute rejection rate and improved graft survival was observed among those who had JC viruria which was independent of the lower BK levels.

·         Regarding JCV viremia in the renal transplant recipients, it seems to be uncommon (maybe 10-15%), transient and low level. Rates may not be different to immunocompetent individuals and it does not appear to correlate with renal dysfunction.  Viremia appears to be even less common in other solid organ recipients.

·         In the few reported cases of apparent JC Nephropathy, there has been poor correlation with JC viremia in contrast to the relationship with BK viremia and BK nephropathy.  A prospective cohort of 980 renal transplant patients reported >40% JC viruria, 14.5% JC viremia with 0.9% developing JC Nephropathy. The patients who were biopsied with JC shedding mostly had stable renal function and were biopsied due to decoy cell shedding. The few who had a bump in creatinine which prompted biopsy had other reasons to explain the allograft dysfunction (e.g. ATN). Reduction of immunosuppression did not clear viral replication but no graft loss occurred.

·         Many people in the 1950s-60s were exposed to contaminated vaccines containing the SV-40 (Simian Virus 40) virus, another Polyoma virus. The immunohistochemical stain used to diagnose Polyoma Virus nephropathy on biopsy uses antibodies mostly specific to SV-40 and cannot distinguish between BK, JC and SV-40 viruses. There is speculation that SV-40 may also potentially cause nephropathy.

Ok enough already, does JC Virus Nephropathy exist?

…..Probably! Certainly it appears to be rare and not correlated with BK Nephropathy. It has a different relationship with immunosuppression from BK Nephropathy and appears to have a favorable outcome.

So what is the significance of JC Virus replication post renal transplant?

Very little, at least for viruria. In fact, patients seem to have less BK replication when JC viruria is present and there is even a suggestion of a better outcome in patients shedding JC, which is independent of the lower incidence of BK replication.

Should we screen for JC Virus replication post kidney transplant?

I don’t see a compelling reason based on our current knowlegde.

Transplantation of HIV+ organs: from ban to HOPE

Organ donation from HIV positive patients has been prohibited in the USA since 1988. Pre-transplant screening for HIV is mandatory using nuclear amplification test (NAT), though false negative results during “window period” are a potential concern in donor selection.

Elmi Muller spoke at our Transplant Grand Rounds yesterday and told us about the challenge she faces in South Africa, where HIV infection affects more than 15% of the population, HIV patients frequently develop HIV-associated nephropathy (HIVAN) and progress to ESRD. Moreover, the availability of renal replacement therapy (hemodialysis) is limited.

In the early 90's, there were a number of uncertainties related to transplanting HIV positive patients including the worrisome concern about introducing a donor-derived virus that could lead to out of control HIV infection (resistant strain?); the effect on the immune system of HIV infection in combination with immunosuppression (worse immunodeficiency?); and the financial burden of expanding the services of transplantation to HIV+ patients in a country with limited health budget.

Against all the odds, Elmi performed four cases of HIV positive kidney donors to HIV positive recipients in South Africa in 2008. No IRB approval... Elmi reported having some intuition that it would work and she was in touch with other physicians around the world who shared her view. In her side, HIV resistance rate is very low in South Africa.

After performing those transplant, her colleagues and the hospital prosecuted her and banned her from performing surgery for more than 1 year. This past week, the HIV Organ Policy Equity (HOPE) Act was approved by the US Congress, permitting donation from HIV-positive organs to HIV-positive recipients. It took time but she is now recognized as a pioneer in the field and her courage to perform those surgeries were remarkable. The law that passed will help expand the availability of organ donors to HIV positive patients and will help with organ shortage.

Some challenges though still remain. HIV resistance is much higher in the States (~19%) and HIV+ transplant recipients experience a higher rate of rejection and significant difficulties with drug-drug interactions (P450 inhibitors). Details about a recent trial can be reviewed on this prior blog. In contrary to the idea of over-immunosuppression, recent paper suggests that ATG may be a better induction therapy choice for these patients. Closely monitoring of these patients will be essential as we learn more about HIV and transplantation. By bending rules, Elmi changed a transplant policy and made history.

Naoka Murakami
Leo Riella

Aristolochic Acid Nephropathy

Aristolochic acids (AA) are found in products derived from the aristolochia genus of plants which are used extensively in herbal medicines, particularly in Asia. Nephrotoxicity resulting from AA exposure was originally described in a case series of women taking diet supplements in Belgium but has subsequently been identified in the US, Europe and Asia. Consumption of products containing AA remains endemic in some areas with an estimated exposure in up to 40% of the Taiwanese population. The disease known as Balkan endemic nephropathy – described the population living around tributaries of the Danube river- is now thought to result from contamination of wheat flour with seeds of plants containing AA.

Patients with AA nephropathy typically present with renal insufficiency and anemia. Urinalysis reveals a few red cells and mild proteinuria. The rate of decline of renal function varies but may depend on the cumulative dose of AA. Renal histology is characterized by extensive interstitial fibrosis with tubular atrophy and low numbers of inflammatory cells. There is a very high incidence of urothelial atypia and carcinoma. Exposure to AA can be confirmed by the presence of AA-DNA in biopsy tissue. 

Therapy consists of routine management of CKD alongside regular screening for urothelial malignancy. A trial of steroids can be considered in selected patients. The risk of urothelial malignancy is so high that some consider patients for bilateral nephrouretecomy once RRT as been established.

Despite being banned in many countries, products containing AA remain available. The true incidence of CKD and urothelial malignancy resulting from AA exposure remains unknown. It is possible that a lack of awareness means that a significant proportion of AA resulted morbidity remains undiagnosed.  For a comprehensive review of the subject see here.

Image from Wikipedia.

Posted by Jonathan Dick

Abatacept for Glomerular Diseases: A New Era of Intelligent immunosuppression?

At ASN Kidney Week there was some interest in abatacept as a targeted therapy for glomerular diseases. T-cell activation requires 2 signals; (i) binding of the T-cell receptor to the antigen-MHC complex on the antigen-presenting cell and (ii) a co-stimulatory signal involving CTLA-4 on the T-cell and B7-1 on the antigen presenting cell. Abatacept is a fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of CTLA-4 which inhibits the T-cell co-stimulatory pathway via B7-1 binding. 

          FSGS

The headlines must go to the small case series of abatacept in FSGS published in NEJM. The rationale for its use was the observation that B7-1 expression is not apparent in normal human podocytes but is found in certain diseased podocytes including a subset of FSGS patients. The series included 4 patients with recurrent FSGS post-transplantation (rituximab-resistant) and one with glucocorticoid-resistant primary FSGS. All patients achieved either partial or complete remission.

In vitro studies demonstrated that α3-Integrin knockout mice constitutively expressed B7-1 in podocytes and abatacept blocked B7-1 mediated podocyte migration in these cells. The molecular mechanism of B7-1-induced podocyte dysfunction was shown to be disruption of activation of the glomerular protein β1-integrin. The authors conclude that B7-1 immunostaining of biopsies may identify a subgroup of patients who would benefit from treatment with abatacept.

2       Lupus Nephritis

The late-breaking session included a randomized controlled trial of Euro-lupus regime cyclophosphamide (i.e. low dose IV) with or without abatacept for proliferative lupus nephritis [Access Trial]. Azathioprine was introduced at 3 months and stopped at 6 months in the abatacept group if they had achieved a remission. Overall, there was no difference in remission rate between the groups. Despite the neutral outcome, 2 points should be taken from the study: (i) The Euro-lupus regime appeared to work in a US cohort of patients where almost 80% were either Hispanic or African American. (ii) Abatacept patients who achieved remission maintained this at 1 year despite coming off immunosuppression at 6 months. However, with the growing confidence in Mycophenolate-based therapy for lupus nephritis and the lack of improved remission with Abatacept in this study, its place in the treatment of proliferative lupus nephritis remains uncertain.

3       Diabetic Nephropathy

An oral presentation on abatacept in Diabetic Nephropathy [FR-OR010] reported increased B7-1 expression in both murine podocytes cultured in high-glucose and on human glomerular podocytes from biopsy specimens. The use of Abatacept in diabetic mice prevented an increase in albuminuria.

Bottom Line: The FSGS case series beautifully illustrates how targeted therapies may be applied to immune-mediated renal diseases. While this case series is very small, it demonstrates the potential for reclassifying disease based on pathogenesis (i.e. B7-1-mediated) rather than crude pathological patterns (focal segmental sclerosis). This is similar to the recent re-classification of MPGN into complement or immune complex-mediated forms. With new targeted therapies like abatacept (and eculizumab for complement mediated glomerulopathies), we may be entering an era of intelligent immunosuppression based on molecular pathogenic signals rather than crude histological patterns.

Ultrasound and Nephrologists

Registration has opened for the Spring session of the Ultrasound course for Nephrologists at Emory University. It will be held on Feb 1-2 2014, in Atlanta.

The brochure for the upcoming course is available here.

Management of CMV after transplantation

Pre-transplant:

All the donors and recipients of kidney transplants (both living and deceased) should be tested for status of CMV by CMV IgG in the blood. If there is history of recent transfusion, pre-transfusion status should be regarded as the true status of CMV. The status of both donor and recipient for a given pair. should be documented in the record post-transplant

Post-transplant:

Prophylaxis:

• CMV related illness is common in the KTRs and the risk is highest in D+/R- group and the least in D-/R-. 
• We do prophylaxis KTRs with Valganciclovir (Valcyte) 900 mg daily (adjusted for renal function) for 6 months in D+/R- group, and 450 mg daily for 3 months for R+ group regardless of the donor status. No CMV prophylaxis is required for the D-/R- group (this group receives acyclovir for prophylaxis of other opportunistic viruses like HSV and HZV).
• Leukopenia is a side effect of Valcyte and the anti-metabolites. If leukopenia is encountered, valcyte dose or dose of the anti-metabolite (eg MPA derivative, azathioprine, or TOR inhibitor) or both be adjusted based on the physician’s discretion (consider checking for CMV pcr). Consider use of G-CSF if the absolute neutrophil count is less than 500. If Valcyte dose must reduced or discontinued for more than one week, weekly monitoring of CMV Quantitative (blood PCR) could be considered for a total of 3-4 months from the time of transplant.
• Routine CMV PCR testing is NOT recommended in patients receiving full doses of prophylactic therapy unless there is some other clinical suspicion for breakthrough CMV infection.

Treatment - CMV related illness is divided into:

1. CMV infection:

Active viral replication (based on blood PCR) without any symptoms attributable to CMV. It is recommended to start treatment even at a low level of viral load. It should be noted that a change of viral load less than or greater than three times the previous value (0.5 times log 10) does not mean a true change in the viral load. 

Valcyte at treatment dose (900 mg BID), adjusted for renal function) is recommended for treatment. Weekly Quantitative PCR in plasma is recommended while on treatment and duration of treatment to continue at least for two consecutive negative Quantitative PCRs, and not less than a total of 2 weeks. Secondary prophylaxis at the end of treatment (at prophylaxis dose of Valcyte) for a month or two after finishing treatment can be considered if suspicion for relapse is high.

2. CMV disease:

Active viral replication plus symptoms: Either 1) a flu-like illness with fever and general malaise,  often associated with leukopenia or 2) tissue invasive disease (commonly GI but also including hepatitis, pulmonary and rarely uveitis and encephalitis).

Treatment either with Valcyte at treatment dose or IV Ganciclovir at treatment dose (for life threatening illness and GI disease). IV Ganciclovir can be switched to corresponding dose of Valcyte at any time during the therapy if considered appropriate. Monitoring for response and duration of treatment are similar to CMV infection treatment. Please note that tissue invasive disease can rarely occur with negative quantitative PCR in blood (especially when disease is limited to the GI tract). In that situation, duration of therapy should consist of at least two weeks of the antiviral or longer as guided by clinical response. Secondary prophylaxis at the end of treatment with Valcyte for a month or two (at prophylaxis dose of valcyte) can be considered if suspicion for relapse is high. 

Lowering of immunosuppression should be considered starting with the anti-metabolite (definitely for life threatening illness) at the discretion of physician. If leukopenia is encountered, it is recommended to lower anti-metabolite rather than lowering valcyte dose to avoid failure of therapy and resistance of CMV to valcyte.

CMV resistance, although rare, should be suspected if no response to therapy even after a total duration of 5 weeks with Valcyte. If CMV resistance is confirmed, consider foscarnet for treatment, the dose of which should be also adjusted based on renal function

CrCl (ml/min)	Maintenance/Prophylaxis	Treatment
Valcyte
>60	900 mg q day	900 mg bid
40-59	450 mg q day	450 mg bid
25-39	450 mg q 2 days	450 mg q day
10-24	450 mg twice weekly	450 mg q 2 days
<10	100 mg 3 times a week, after HD	200 mg 3 times a week, after HD
IV Ganciclovir
>70		5 mg/kg q 12 hr
50-69		2.5 mg/kg q 12 hr
25-49		2.5 mg/kg q 24 hr
10-24		1.25 mg/kg q 24 hr
<10		1.25 mg/kg 3 times a week after HD

 

Posted by Raj Sabaru

Tolvaptan and the FDA - A patient's perspective

Over at the Atlantic this week, an article was published written by one of the people who took part in the early trials of tolvaptan for APKD. The article shows just how much hope people with this disorder were putting on this drug and the disappointment felt in the APKD community now that the FDA has rejected its use for this indication. Given the lack of new therapies that are available for renal diseases in general it is understandable that patients and their doctors are unhappy with this decision.

However, it should be said that there are substantial questions that remain to be answered about the use of this drug. The large trial published in the NEJM last year showed that tolvaptan reduced the rate of growth in kidney size while also leading to a slowdown in the rate of GFR decline. However, these are surrogate endpoints and we have been burned by surrogate endpoints in nephrology before (see Bardoxolone). Also, the majority of patients had good renal function at baseline. Not all patients with PCKD will develop ESRD and there is no indication at this time who should be treated with this drug and for how long. It should also be said that there was a high rate adverse events in the treatment group (primarily related to thirst and polyuria) and 23% of participants discontinued the drug. It is extremely expensive and it is important that there are clear guidelines for its use. As mentioned in this post, copeptin levels may be useful in determining who will respond to tolvaptan.

That said, it is always interesting and revealing to know the patient's point of view on this difficult issues.