CKD and high blood lipids

Hello Dr. Agar. I know that people with CKD have high blood lipids/cholesterol. Back when I was first diagnosed with fsgs in 1992, no one told me about the effects of CKD other than hypertension for which I was eventually treated. But it wasn’t until I moved from the UK back to the US that I had a full workup done, and imagine my complete and utter shock to discover that despite my efforts to keep fit and eat healthily, my cholesterol and triglyceride levels were stratospheric. My doc said that he had never seen levels so high in someone who wasn’t diabetic (I asked for a prize but didn’t get one. Harumph.). I was told, and I quote, that I could eat cardboard for the rest of my life but would still have high lipid levels if left untreated. Of course, I am now on statins, etc and have normal lipid levels, but I don’t really understand WHY impaired renal function leads to high lipid levels.

It is my understanding that the high incidence of cardiovascular problems in kidney patients are due more to phosphates than to cholesterol; is that true?

Still, I would very much like to better understand the link between CKD and high cholesterol/triglyceride levels.

Thank you.

You ask very difficult questions!

And, on this topic, it is embarrassing to say that something seemingly so common could be so little understood – but nowehere in medicine is this more true than of the cause(s) of the lipid (blood fat) abnormalities of CKD.

I guess I might start by saying that while almost all patients with CKD have disordered lipid metabolism, there are 3 main populations of lipid abnormality in CKD … those with CKD due to diabetes, those with CKD resulting from (or complicated by) the nephrotic syndrome, and those with neither diabetic nor nephrotic CKD.

The second ‘explanatory note’ is to remind the reader of this note that lipids are not just restricted to the blood cholesterol … the other major blood fat – triglyceride – is just as important and as much of a problem as is cholesterol. Further, there are a squillion sub-types of lipid – often classified by their ‘density’ into high-density lipoproteins, low-density lipoproteins, very low density lipoproteins and, even more complex, there are lots of other lesser known or appreciated lipid structures like the apo-lipoproteins, the cell membrane component phospholipids etc. The list seems endless.

I plan to restrict this to a brief discussion about cholesterol and triglyceride in CKD: if I don’t, the answer will become a book in itself!

Having said that, I return to my first statement: that, sadly, lipid abnormalities in CKD are poorly understood. Most think that the reason why lipids – and especially triglycerides - are elevated in general, all-cause CKD is due to reduced ‘clearance’. This, of itself, leads to elevated triglyceride levels (hypertriglyceridemia) – the result of both (1) an alteration in the mix of the triglyceride subsets and (2) also from reduced levels of ‘lipase’ activity. The lipases are enzymes that originate in the liver and which help to break lipids down into smaller, less troublesome fragments.

The obvious question is ‘why should lipase activity be diminished in CKD’?

Well, again, no-one really knows for sure, but it maybe that increased inhibition of their action results from the switched-on parathyroid activity of CKD with a resulting increase in calcium levels inside the liver cells. Note the ‘maybe’, as this is supposed, yet not known for certain.

Good cholesterol is reduced, too, in CKD – possibly due to the fact that the manufacture of these ‘good’ lipid substances is also ‘inhibited’ in CKD through enzyme inhibition.

You see, enzyme systems – mainly but not exclusively liver-originating – are required both to make good lipids and to break down nasty ones – and these enzymes either (1) don’t work as well, or (2) work in incorrect proportions under the influence of some of the waste imbalances of CKD.

While most lipids are broken down either in the liver or in the cells of the body, some are also cleared by normal kidney function … a clearance function that increasingly diminishes as CKD progresses.

In nephrotic syndrome, the mechanism is different – at least in part. Here, when the albumin level falls as albumin is lost by the nephrotic kidneys, the ‘oncotic pressure’ of the blood falls. Oncotic pressure is that effect of the circulating plasma proteins (especially albumin) that ‘holds’ or ‘attracts’ fluid from the interstitial space into the circulation and thus which maintains blood volume.

A low oncotic pressure directly stimulates some of the hepatic genes to make lipids. I always have imagined this to be a kind of last-ditch effort to sustain the plasma oncotic pressure by making something ‘oncotic’ to replace the lost albumin – for lipids do exert an oncotic effect. Its as if the body is saying … “hey, if I don’t sustain my blood volume, I am gonna die! I have to make something to replace the lost albumin of I am done for … so, what could I make that might do the same job? Ah. I know … lipids!” And, away it goes.

Is that the right interpretation? … who knows … but you may get the idea.

It is way more complex that that, too: there is enhanced synthesis of cholesterol by the liver: there is decreased cholesterol breakdown: there is mis-directed metabolism where, for some reason, the wrong mix and distribution of lipids are made with a preponderance of low density vs high density lipoprotein manufacture … … indeed the whole shooting-match is totally screwed up.

In diabetes (type II), insulin resistance plays a key role. Insulin resistance is accompanied by high circulating insulin levels. This, in turn, promotes higher triglyceride levels and lower good, high-density lipoprotein levels. In addition, as triglycerides are made from a combination of glucose and free fatty acids – both of which are in far more abundant and plentiful supply – the end result is a high triglyceride concentration.

It’s a massively complex area. It’s poorly understood. The range and number of lipid fragments, enzymes and synthetic (manufacturing) and degradation (eliminating) pathways is staggering and I certainly don’t understand the half of it.

At the end of the day, the patient is left with lipid abnormalities – often profound - that endanger vascular health. In many respects, these are way beyond simple dietary measures to correct. As they are not dietary but metabolic abnormalities in origin, diet is commonly unsuccessful in their management.

I commonly have my patients bemoaning their lipid problems with … ‘ but I am being good’.

And, I know that they are … and feel doubly sorry for them, for I know how hard they are trying.

Nature, their metabolism and their CKD - and all three are potent forces - are armed against them.

I appreciate any doctor who is able to say, “We just are not sure.” I can accept that as a valid answer.

I know FOR SURE that “being good” with your diet alone does not solve the problem. I’m on three different meds for lipid problems, and I am happy to say that they have been extremely (and quickly) effective. My tryglycerides went from an untreated 2100 to a treated 230 (still high, I know, but not 2100!), and cholesterol from an untreated 550 to a treated 165, so I can’t complain. If I were your patient and presented these numbers, how much less at risk would you judge me to be from vascular problems?

If you had to put a number on it, how much cardiovascular disease in CKD patients is due to high blood lipids, and how much is due to calcification/phosphate problems? I know that vascular disease is so much more prevalent in this population, but I am not sure exactly why.

Does optimal dialysis in and of itself improve blood lipid levels? Or do you find that even in the best dialyzed patients, high lipid levels remain a problems and still must be treated with statins or other types of meds?

Off to talk @ ISBP (Beijing)

Dear MooseMum

I am off in the next day or so to give a couple of talks to the Int Soc Blood Purification annual meeting in Beijing.

I appreciate the question and will answer when/as I can (maybe from the plane) but you may have to wait a little while for the answer … sorry - but things are pretty hectic at the office at present! Hope you can be patient.

What? You’d rather talk to The International Society of Blood Purification than answer my question??? Well…OK. I’ll allow it. This particular patient can be patient…

Good luck with your talks. I’m sure your audience will come away with a lot of valuable and well-delivered information. Travel safely.

Measurement of lipids (cholesterol, triglycerides and the component lipids like low density lipoproteins (LDL cholesterol), high density ‘good’ lipoproteins (HDL cholesterol), the ratio of LDL to HDL cholesterol etc … all these are used along with a range of other cardiovascular risk assessments (which include blood pressure, ECG, exercise ECG, echocardiography etc.) to determine the health (or otherwise) of your cardiovascular system and your relative risk of cardiovascular events – like heart attack and stroke.

All sorts of risk assessment tools have been developed to use these ‘markers’ to gauge risk. They are used either singly or in combination – and your primary care doctor (GP) will likely have applied these to your circumstances already.

None of these risk-assessment tools are perfect and most simply refer to ‘additional risk factors’ - like the presence of CKD - as complicating factors … whereas we now know that CKD is an amplifier of all cardiovascular risk, and not just another factor.

What an ‘amplifier’ means is that an amplification factor (like CKD) ramps up the collective risk and shouldn’t be added in as just another risk factor.

As with the previous post, triglycerides are the major form of fat found in the body. The function of triglyceride is to provide energy for the cells. The ideal levels of these substances will vary a little, lab vs lab – as methods for their determination vary, but – broadly – the levels thought to be ideal are:

• Cholesterol <200 mg/dL (5.2 mmol/L)
• HDL-cholesterol > 40 mg/dL (1.05 mmol/L)
• LDL-cholesterol <100 mg/dL* (2.6 mmol/L)
• Triglycerides <150 mg/dL (1.7 mmol/L)

NB: I hope I have those conversions right as we use mmol/l here in Australia. Furthermore, our cardiology colleagues continually pull the upper level of cholesterol down and we shoot, now, for <4.5 mmol/l (not <5.2).

Assessing ‘risk’ is both far more complicated and far more imprecise then you might imagine. Risk assessment is never ‘you’. Risk assessment is, at best, a population risk. Risk assessment can never predict ‘you’ apart from ‘the population. ‘You’ may vary in all sorts of ways from a population … you may have diabetes, be a smoker, be short, overweight and be sedentary. Just as likely, you are an ex-swimmer who has never smoked, has no diabetes (nor family history of it), and be built like a thoroughbred … but … have an horrendous and life-long blood pressure issue. We all vary from societal means in idiosyncratic and individual ways. These variations always pepper risk assessment with ‘ifs and buts’.

That said … there are some risk assessment tools around.

One is put out by the NIH and is contained in the 3rd Report of the National Expert Panel on Cholesterol Education … and was developed from the Framingham (Mass) Heart Study

It can be found at:

Remember, applying such tools does not take into account the ‘you’ in the equation … they are tools developed for ‘them’, the population … but as much as you fit the average of ‘them’, the assessments can be roughly applied to ‘you’.

I am glad you have accepted the ‘we just don’t know’ as a valid answer – because, here it comes again. As regards the benefits of optimum dialysis – and by optimum dialysis, I am meaning more than just 3 x week x variants of 4 hr duration treatments – I think the fairest answer is ‘we just don’t know.

In patients without CKD, there does appear to be a relationship between the blood cholesterol and the risk of coronary artery disease – the greater the degree of CKD, the greater the risk. Several big trials in CKD patients have shown that with statin therapy, the risk of a cardiovascular event – be that cardiovascular death, heart attack (myocardial infarction) or stroke – is reduced as lipid levels improve.

But – and disappointingly - two large studies in dialysis patients … the 4-D trial (atorvastatin in ~1250 dialysis patients) and the AURORA trial (rosuvastatin in nearly 2800 dialysis patients) … found that despite significant lowering of the LDL cholesterol levels in both trials, there appeared to be no reductions in the usual cardiovascular end points of cardiovascular death, myocardial infarction (heart attack) or stroke between the treated and the non-treated groups.

Perhaps a little encouragingly, the SHARP study, which combined two triglyceride and cholesterol-lowering drugs, simvastatin and ezetimibe and was carried out in end-stage CKD and haemodialysis patients, showed a 17% lowering of ‘major atherosclerotic events’. So, while the jury is still out, there is no agreed recommendation to use statins in dialysis patients with only a mild to modest elevation of LDL-cholesterol.

Confusing, isn’t it. And even if you aren’t … I still am – and I am supposed to treat people.

As for optimum dialysis – and here I mean long, slow, frequent dialysis therapies – there are no trials and no group data to say whether optimum dialysis itself has any lipid-lowering effects though I suspect the answer is likely a ‘no’.

But – and it is a very important ‘but’ – long, slow, frequent dialysis regimens do … repeat ‘do’ … control phosphate beautifully – and, via phosphate control, the calcium:phosphate product. Long, slow, frequent dialysis regimens do result in lowered PTH levels, better bone physiology and the reabsorption of extra-osseus (non-bone) calcium deposition.

As the cause of much of the vascular calcification seen in CKD and dialysis patients is circumferential calcification of blood vessels as well as the calcification of existing cholesterol ‘plaques’, one has to be hopeful that reabsorption of calcium deposits from lipid plaques might result from optimal dialysis … and if so, then long, slow, frequent ‘optimal’ dialysis should benefit vascular health.

Andreas Pierratos (Toronto) has reported extra-osseus calcification reabsorption with NHD while Chris Chan (also Toronto) has reported that coronary calcification has been ‘stalled’ by NHD … though there was no control group and these reports are case study reports only and, as such, need to be interpreted with caution.

Intuitively, though, one would have to surmise that better dialysis, with normalized phosphate levels and a normal calcium:phosphate product should be beneficial for vascular health.

Now … shush, till I get back from Beijing!

OK, I’ll shush up now, but first I need to say “thank you!” I hope that’s allowed!

安全的旅行 Dr Agar

Thanks Bill (I think) … did that just read “sock it 'em John” … or is my Mandarin rusty. One nice thing is that I will be seeing Chris Blagg there.

And, by the way, I can retire from here. I just read your very nice explanation about sodium, sodium modeling and the inaccuracies of the dialysate sodium setting by machines at the ‘I Hate Dialysis’ site. Seems I and the others can relax into our G&T’s now. Well done.

As for MooseMum … I meant no offence by the ‘shush’! I enjoy the interest you show.

Ooooooh, who’s the clever clogs?! Is that Mandarin for “sodium modeling”? lol

Yes, it WAS good, wasn’t it!

As for MooseMum … I meant no offence by the ‘shush’! I enjoy the interest you show.

Oh, I didn’t take offense, but I do have to admit that most of your answers just lead me to more questions. Not that your answers are incomplete or incoherent…quite the opposite. It’s the burden I bear for having an inquisitive mind. lol!

What I know I learned from you so I hope it is right heh Dr Agar is an IHD lurker

安全的旅行 = safe travels (: