Contrast-Induced Nephropathy (CIN): An Update from the Cardiology Literature

Happy new year to all! I’ve been thinking about how much Nephrology content there is in non-renal journals and how much we miss by just reading the usual renal periodicals each month. You cannot be expected to read every Cardiology/Endocrinology/Rheumatology journal every month so I thought I would bring you what I’ve noticed in the non-Nephrology literature recently. Today I’m focusing on CIN. If the post proves popular, we may run a regular literature watch from non-Nephrology journals on RFN.

Since, N-acetylcysteine (NAC) has fallen out of favor, all we have in our armamentarium for CIN prevention is IV volume expansion. There were 3 recent publications in the Journal of the American College of Cardiology which you may have missed regarding novel therapies for CIN prevention. Firstly, the PRATO-ACS study which was a RCT of rosuvastatin in >500 consecutive statin-naïve patients presenting with a NSTEMI who proceed to cardiac catheterization. Greater then 50% of patients were diabetic and mean eGFR was 82mls/min. The incidence of CIN was significantly lower in the rosuvastatin group (6.7 vs 15.1%) as were other renal, cardiac events and mortality. In the same issue, a study of 3000 diabetic CKD (Stage 2 or 3) patients randomized patients to either rosuvastatin or placebo 5 days before intra-arterial contrast. The rosuvastatin group had a significantly lower incidence of CIN compared to controls (2.3% vs 3.9%). Statins are postulated to improve CIN by their anti-inflammatory and positive endothelial effects. These large scale prospective RCTs support a meta-analysis from 2012 suggesting a benefit in statin use for CIN.

A meta-analysis of trials using ascorbic acid for the prevention of CIN was also recently published in J Am Coll Card. Over 1500 patient were included from 9 RCTs and it was demonstrated that receiving ascorbic acid (mix of oral and IV) had 33% less risk of CIN compared to the control group. Six of the 9 studies had significantly p values themselves. The postulated mechaism of action of ascorbic acid is similar to the theory behind NAC, antioxidant free-radical scavenger i.e who knows?

Verdict: The 2 statin trials are good sized prospective studies in high risk populations (ACS & diabetic CKD) receiving intra-arterial contrast and do support short term statins in this circumstance. Knowledge gaps exist for lower risk patients and those already on statins (a lot of patients these days) as well as dose, duration and the benfit of other statins. The Vitamin C meta-analysis looks interesting but given the study heterogeneity and the NAC story, I remain skeptical until well powered RCTs are performed.

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.

Statins and Chronic Kidney Disease

There is an excellent review of the use of statins is CKD in KI from last month. The authors point out that the association between LDL cholesterol and CVD is not as strong in patients with CKD, particularly in stages IV and V. In fact, the clearer association between hypertriglyceridemia, low HDL and CVD in patients with advanced CKD suggests that statins may not be the best treatment in this setting. The results of clinical trials are conflicting. However, the authors of the current study came up with some suggested guidelines for the management of hyperlipidemia in CKD reproduced below:

1. LDL cholesterol-lowering strategies include either statins or ezetemibe, or both, and target the reduction of LDL to <70 mg/dl as recommended for patients with CVD or an equivalent disorder in the general population
2. Start LDL cholesterol-lowering treatment in stages 1-4 CKD patients with preexisting CV events or those with multiple risk factors and at high risk for coronary heart disease and LDL cholesterol > 70 mg/dl
3. Continue LDL cholesterol-lowering strategies in patients developing CKD stage 1 or more or those starting dialysis who were previously on such treatment
4. Do not use LDL cholesterol-lowering strategies in CKD patients with inflammation/malnutrition, nor start such treatment in dialysis patients who are treatment-naive until additional literature data in favor of a different therapeutic approach become available

What do you think? Do these recommendations make sense?

FDA, Statin and Transplantation - A conundrum

We are facing a conundrum in post-transplant lipid management after the recent warning from the FDA, which updated the label of simvastatin. This drug is now contraindicated in patients taking cyclosporine due to the potential for liver dysfunction and myopathy.


Just to remind you, statins are metabolized by the hepatic cytochrome P450 3A4, similarly to calcineurin inhibitors and mTOR inhibitors. In the presence of these immunosuppressive agents, statin levels are raised and risk of myopathy is increased. This danger has always existed, however, the FDA has taken a harder stance lately with creating a “contraindication”. Moreover, simvastatin doses greater than 20 mg/day are also not recommended anymore in patients receiving amlodipine, which is the vast majority of transplant recipients (this is new since prior literature solely reported non-dihydropyridine CCB like diltiazem and verapamil as important interactions). Nonetheless, there is nothing listed when simvastatin is co-administered with tacrolimus, sirolimus and/or everolimus. However, the potential for a similar drug-interaction and adverse events exists. So what do we do?


First, let’s do a brief review of dyslipidemia post-transplantation. Elevated cholesterol levels are very prevalent in transplant recipients reaching above 80% of kidney recipients in some reports. Immunosuppressive drugs play a major role, with all the following classes glucocorticoids, calcineurin inhibitors (cyclosporine greater than tacrolimus) and mTOR inhibitors having deleterious effects. Among them, the effect of mTOR inhibitors is different since it causes predominantly elevated hypertriglycerides due to blockade of insulin-stimulated lipoprotein lipase.


The importance of dyslipidemia in the transplant population is related to the most common cause of death with a functioning allograft - cardiovascular disease (~40%). Similar to the dialysis data, statin trials in transplantation are limited to one prospective randomized trial (ALERT) with fluvastatin in kidney transplant recipients that showed lower cholesterol levels in the treatment arm compared to placebo, however there was only a non-significant trend towards reduction of composite cardiovascular events. Nonetheless, secondary outcomes of this trial, observational, long-term follow ups and post-hoc analyses have suggested some beneficial effects.


Most of our transplant patients are taking tacrolimus which is extensively metabolized by the cytochrome P450 family enzymes in the liver and excreted into the bile. Therefore, what should we do? Should we stop completely using simvastatin?


I think there is no straight answer here, especially since we have been using statins for a long time in combination with tacrolimus, monitoring in those settings LFTs and symptoms of myalgia. But now with the formal contraindication with cyclosporine, physicians will get more careful in prescribing even the sister CNI with simvastatin. Insurers will likely change their policies facilitating the use of other statins as well. So which statins are safe to use?


Fluvastatin and Pravastatin (both generic) have minimal drug interaction with CNIs/amlodipine and should be considered for mild hypercholesterolemia, since both are weaker statins (see strength and interconversion table above that I simplified from the FDA version). Atorvastatin should be the chosen statin for moderate-severe hypercholesterolemia, since it has increased potency requiring a lower dose and has a favorable safety profile despite some metabolism by P450. Rosuvastatin, a novel potent statin, could also be the agent of choice since it is not metabolized by cytochrome P450, though preliminary results from the PLANET trials have reported a higher risk of proteinuria when higher doses were administered. Therefore, it is wise to wait until final results are published.

The debate is open and would love to hear how others would face this dilemma.

Stopping statins in dialysis patients

It can often be difficult to stop something once it's been started; take statins for example. It seems that despite consistent evidence from two large, randomized controlled trails demonstrating the lack efficacy of statins for preventing cardiovascular mortality in dialysis patients, there has been little impact on the prescribing habits of nephrologists. This study shows that in the 2 years following the negative 4D result, the rate of statin prescription in diabetic hemodialysis patients actually increased by 10%.

There are probably several reasons for this practice, such as scepticism about the result in ESRD patients given the proven efficacy of statins in other groups, or a reluctance to engage in therapeutic nihilism. Personally, I worry about precipitating a cardiovascular event by stopping these drugs; the 4D and Aurora trials do not address the issue of discontinuation. With such a high rate of cardiovascular events in this population, aren't you just asking for trouble by drawing a line through the Lipitor on the medsheet? It's a thorny question, and one we may put to poll on this blog next week.

Statin-induced proteinuria

In the past I've struggled to get my head around the question of the role of statins in CKD. On the one hand they appear to slow progression, and people with lots of proteinuria often show some reduction in this measure over time. However, the effects on urinary protein excretion are at best variable, and there's no doubt that in some patients proteinuria actually increases. Despite this, the beneficial effects on preservation of renal function seem pretty consistent.

This paper from Sydney, Australia clears up how, on the one hand, statins can increase proteinuria while still preserving renal function in the long run.
It all has to do with mevalonate. In order prevent the 200 or so steps in cholesterol synthesis, statins nip the process in the bud by inhibiting HMGcoA at the beginning of the mevalonate synthetic pathway. Mevalonate is a precursor of isoprenoid pyrophosphates, which are necessary for G-protein prenylation of proteins involved in receptor-mediated endocytosis of albumin in the proximal tubule. Hence, the more potent the statin, the more it inhibits this reuptake pathway, causing albuminuria. This is why albuminuria is more frequently seen with newer, more potent statins such as rosuvastatin. As this is effectively an artefactual finding, patients with heavy proteinuria at baseline may show a reduction over time via improved endothelial function in their renal vascular bed. Admit it, that's pretty interesting. Shut up, it is.