Understand NICE CKD: know why

My name is Fernando Florido and I am a GP in the United Kingdom. In this episode I go through some of the statements made by NICE in the guidelines “Chronic kidney disease: assessment and management” or NG203, published on 25 August 2021, explaining why these statements were made.

There is a Youtube version of this and other videos that you can access here:

·      @nicegp: (1) NICE GP - YouTube

Resources and transcript

Resources:

Full NICE guideline on CKD:

·      Website: https://www.nice.org.uk/guidance/ng203or as

·      Or download here: https://1drv.ms/b/s!AiVFJ_Uoigq0lgvjCLLzwi5sLeq7?e=JC2Z0g

CKD visual summaries:

• Websites:
• Identifying CKD: 

https://www.nice.org.uk/guidance/ng203/resources/visual-summary-identifying-chronic-kidney-disease-in-adults-pdf-9206256493

• Managing proteinuria: 

https://www.nice.org.uk/guidance/ng203/resources/visual-summary-chronic-kidney-disease-g15-a13-managing-proteinuria-pdf-9206256495

• Phosphate binders:

https://www.nice.org.uk/guidance/ng203/resources/visual-summary-chronic-kidney-disease-stages-4-and-5-phosphate-binders-pdf-9206256494

·      Or download here:  

o  Identifying CKD: https://1drv.ms/b/s!AiVFJ_Uoigq0lgxMqWAve0P2Uqmw?e=r9Gaj2

o  Managing proteinuria:

https://1drv.ms/b/s!AiVFJ_Uoigq0lg2n86ZBA-LtN8Sx?e=3iUfe7

o  Phosphate binders:

https://1drv.ms/b/s!AiVFJ_Uoigq0lg62GGYNQmkebxqF?e=nG7cm6 

CKD tables- 1&2

·      Download:https://1drv.ms/u/s!AiVFJ_Uoigq0lhN1Hnk7TV08C5lC?e=FaLGZo 

NICE HTA guideline:

·      Full guideline: https://youtu.be/dELO3enIhsI

·      Flowchart: https://youtu.be/Ffa6IYrZWeo

·      Shorts: 

o  https://youtu.be/qmLJtwu677I 

o  https://youtu.be/Izo_eSuECEU 

o  https://youtu.be/BnbcUPriJ9g

SGLT2 inhibitors for adults with CKD and type 2 diabetes, see chronic kidney disease in NICE's guideline on type 2 diabetes in adults.  

·      Summary of guidance: CKD section of diabetes guideline 1.8.17 

For adults with type 2 diabetes and CKD who are taking an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), offer an SGLT2 inhibitor (in addition to the ARB or ACE inhibitor) if:

·      ACR is over 30 mg/mmol and

·      they meet the criteria in the marketing authorisation (including relevant estimated glomerular filtration rate [eGFR] thresholds).

·      Website: Diabetes guideline: 

https://www.nice.org.uk/guidance/ng28/chapter/Recommendations#chronic-kidney-disease 

NICE's technology appraisal guidance on dapagliflozin for treating chronic kidney disease.  

·      Website:

https://www.nice.org.uk/guidance/ta775

·      Or download here:

https://1drv.ms/b/s!AiVFJ_Uoigq0lg_O0S-awCfFqpI_?e=rrscuF

 

NICE's technology appraisals on sodium zirconium cyclosilicate and patiromer.  

·      Website:

o  Zirconium: https://www.nice.org.uk/guidance/ta599

o  Patiromer: https://www.nice.org.uk/guidance/ta623

·      Or download here:

o  Zirconium:

https://1drv.ms/b/s!AiVFJ_Uoigq0lhLUkpx5T4E0mrE_?e=XcfIQt

o  Patiromer: https://1drv.ms/b/s!AiVFJ_Uoigq0lhARwG8vfMNKvISz?e=VEsKLm 

NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification for the use of statins in adults with CKD. 

·      Website: https://www.nice.org.uk/guidance/cg181

·      Or download here:

https://1drv.ms/b/s!AiVFJ_Uoigq0lhEqiQX4EhaMN2A3?e=7u5KIK

MHRA safety advice on recombinant human erythropoietins:

·      Website:

 https://www.gov.uk/drug-safety-update/recombinant-human-erythropoietins-new-advice-for-prescribing

·      Summary of advice: 

Recombinant human erythropoietins: new advice for prescribing:

Over-correction of haemoglobin concentration may increase the risk of death and serious cardiovascular events in patients with chronic kidney disease; it may increase the risk of thrombosis and related complications in patients with cancer.

4-variable Kidney Failure Risk Equation

·      Download:

https://1drv.ms/x/s!AiVFJ_Uoigq0lhS5kRhCr7qSz8vm?e=mDkKEY  

Intro / outro music: Track:

Halfway Through — Broke In Summer [Audio Library Release]  

Music provided by Audio Library Plus  

Watch: https://youtu.be/aBGk6aJM3IU (https://www.youtube.com/watch?t=0s&v=aBGk6aJM3IU) 

Free Download / Stream: https://alplus.io/halfway-through (https://www.youtube.com/redirect?event=video_description&q=https%3A%2F%2Falplus.io%2Fhalfway-through&redir_token=QUFFLUhqbVNpZlBNM0lCeDIxQzRkU29qUnJGQy15WEtTQXxBQ3Jtc0tuUUFSMkZwSEVuaHdUTWlYV21fZmpjWS1WRXI3R0hZU056MkpmRFpKdXdGYm1La3BlazhUemZ5SkVMTFdaWWRvSG9Ucy1neWpudTJ0MUIxNnl2NmhvR0lmdzduWXEwUUg0alduYkRNdjlWWTNsMnhzaw&v=aBGk6aJM3IU) 

Transcript

Hello everyone and welcome. My name is Fernando Florido and I am a GP in the United Kingdom.

In today’s episode we are going to look at some of the statements made by NICE in their guideline on CKD and I will try to explain the reasons for these statements. We will look at the aetiology, pharmacology and pathophysiology in the expectation that, if we understand why the recommendations have been made, it will be easier for us to remember them.

Remember that there is also a Youtube version of these episodes so have a look in the description below.

The first thing that I want to say is that in this episode I am not doing a summary of the guideline. For that, please have a look at the corresponding episode on this channel. Instead, we will look at several recommendations made by NICE, which I will review in more details explaining why they may have been made.

I have picked 15 statements, so, let’s get started.

1-NICE says that “reduced muscle mass leads to an overestimation of eGFR and increased muscle mass leads to an underestimation of the eGFR”  

Right, we all see in our patients’ test results that high creatinine levels normally come with low eGFR readings. That is obvious because renal impairment causes creatinine to rise and GFR to decrease. But we must also be aware that we are not talking about real GFR values but about the eGFR, that is the estimated value, which is based on a relatively complex formula that takes into account a number of parameters, including creatinine. The effect of the creatinine in the formula means that the higher the creatinine, the lower the estimated GFR. 

Now, creatinine is a breakdown product of muscle metabolism. Because formation happens almost exclusively in the muscle, creatinine will be higher in, for example, body builders. They, because of the formula would have a lower estimated GFR. On the other hand, a reduction in muscle mass is associated with lower creatinine levels, resulting in a higher estimated GFR. So don’t be fooled by bodybuilders with a borderline low eGFR or by, for example, malnourished elderly patients with a relatively high eGFR, as this may just be the effect of muscle mass on their readings. 

2- NICE also recommends that we should advise patients “not to eat any meat in the 12 hours before having a blood test for eGFRcreatinine”.  

And this is because dietary protein intake can affect creatinine concentrations too. We have just seen that creatinine is a breakdown product of creatine in the muscle. Therefore, ingestion of creatine (either via red meat or supplementation) can increase muscle creatine “pools,” raising the creatinine levels. So, eating less (or no meat) will cause the creatinine to fall and consequently, the eGFR to improve.  This is important because, if we are going to tell a patient that their eGFR is slightly low, we just want to make sure that it is not real and not just that they have binged on red meat for the last few days. 

3- NICE also says that we should “recheck a high ACR between 3 - 70 in a subsequent early morning sample to confirm the result”.

This is because it has been noted in research that the use of early morning urine gives more accurate ACR readings and, additionally, early morning urines allow the exclusion of orthostatic or postural proteinuria. In orthostatic proteinuria significant urinary protein is excreted when standing, but when lying down the urinary protein is completely normal. This usually occurs in young adults, and is a benign condition with no long-term consequences. 

4- NICE also recommends that “after starting or increasing the dose, we will not modify the dose of an ACEI or ARB if either: 

• the eGFR decrease from baseline is less than 25% or 
• the serum creatinine increase from baseline is less than 30%”.  

Right, so let’s remember a little bit of anatomy. The glomerulus receives its blood supply from an afferent arteriole and, unlike most capillary beds, the glomerular capillaries exit into efferent arterioles rather than venules. Let’s also remind ourselves that ACEI prevent the conversion of angiotensin I to angiotensin II, and ARBs block the effect of angiotensin II. This results in relative vasodilation, which preferentially reduces efferent or postglomerular resistance. Consequently, this will lower intraglomerular pressure which will reduce the glomerular filtration rate  or GFR and cause a subsequent rise in creatinine.

An increase in creatinine of up to 30% and a decrease of eGFR of up to 25% are acceptable and. in the absence of renovascular disease, creatinine levels will frequently return to baseline or below if blood pressure is lowered, despite the continued use of an ACEI or ARB.

5- NICE also says that “we will offer antiplatelet therapy only for the secondary prevention of cardiovascular disease, but we need to be aware of the increased risk of bleeding in CKD patients”.   

Why is this? The real cause for the association between CKD and bleeding is not well known but research studies have shown that CKD has been associated with a 1.5-fold increased risk of bleeding. This has been associated with platelet dysfunction and activation of the fibrinolytic system which can lead to a higher risk of bleeding episodes.

However, we also know that the function of the coagulation system in patients with CKD is abnormal because, although some patients are prone to bleeding, other patients may also develop excessive clot formation. Little is known about the reasons why one patient develops bleeding problems, while another tends to head towards excessive clotting.  

So, in summary, for the secondary prevention of CVD, we definitely need to give aspirin, but being aware of the risks.   

6- NICE talks quite a bit about anaemia of CKD and says that “if eGFR is below 30 we will note that anaemia is often caused by CKD”.   

So, let’s have a look at the causes of anaemia of CKD. Anaemia of CKD is generally a normocytic normochromic, hypoproliferative Anaemia. Although the widely accepted aetiology is a decreased renal production of erythropoietin (EPO), the hormone responsible for stimulating red cell production, anaemia of CKD is of multifactorial origin. Other mechanisms include uraemia, folate and vitamin B12 deficiency, iron deficiency, a shortened lifespan of red blood cells and bleeding due to dysfunctional platelets. But we have to emphasise that CKD patients are at significant risk of iron deficiency; therefore, we must always consider iron supplementation as part of their treatment with erythropoietin stimulating agents.

7- NICE says that in CKD patients “treated with iron, ferritin levels should not rise above 800 and that we will review the dose of iron when ferritin reaches 500”.  

So what this means is that we are going to keep giving iron to our patients even when their ferritin is well above the normal range. Why? This is because, in addition to true iron deficiency, CKD patients also have a functional iron deficiency, which is a type of cell iron blockade which results in reduced iron release from body stores which is then unable to meet the requirement for erythropoiesis. By having a higher than normal ferritin level we would expect iron to be released for erythropoiesis more easily. 

8- NICE also states that “we will offer intravenous iron therapy to people on haemodialysis”. 

Why? This is simply because it has been shown that haemodialysis patients also have impaired intestinal iron absorption, which is why intravenous iron is preferred.  

9- The guideline also says that “we will treat clinically relevant hyperparathyroidism to improve the management of the anaemia”.   

Now, this is a little bit more complex. First of all, Anaemia  has been recognized as a possible complication of primary hyperparathyroidism. So, if the hyperparathyroid state can induce Anaemia in patients with normal kidney function, the high PTH levels also found in hyperparathyroidism secondary to CKD will also have an unfavourable effect. 

So, let’s look at the PATHOGENESIS OF RENAL ANAEMIA ASSOCIATED WITH SHPT

Studies have shown that this is mediated via multiple pathways  

1.   Bone marrow fibrosis: a direct effect of the excess secretion of PTH.

2.   Inhibition of EPO synthesis: although the molecular mechanism through which PTH negatively regulates EPO synthesis is mostly unknown.

3.   Inhibition of bone marrow erythroid progenitors: It is suggested that the excessive PTH downregulates the erythropoietin receptors on progenitor cells in the bone marrow. Therefore, physiologic concentrations of EPO can no longer sustain normal red cell counts, so normocytic and normochromic anaemia follows.

4.   A shortened RBC lifespan: because an excessive PTH level increases the osmotic fragility of RBC through enhanced calcium entry into them. 

Moreover, recent clinical studies have shown that the treatment of SHPT either with medication or parathyroidectomy leads to an improvement of the Anaemia, supporting the role of PTH in renal Anaemia. 

10- NICE also indicates that we should “avoid blood transfusions in people in whom kidney transplant is an option”.  

This is because exposure to multiple blood donations may cause alloimmunisation to human leucocyte antigen or HLA class I on white blood cells. HLA antibodies can then react with the transplanted kidney leading to higher rates of acute rejection and poorer long-term graft survival. However, the risk of alloimmunisation has reduced since the introduction of universal leucodepletion of blood components.  

11- The next statement warns us that “the use of ACEIs or ARBs may lead to increase in ESA therapy”.   

Now, why is this? Various mechanisms have been offered to explain this. First, it has been shown that angiotensin II directly increases the proliferation of erythroid progenitor cells in vitro. Therefore, any agent decreasing angiotensin II levels or its effect could potentially have a negative impact on erythropoiesis. Also, ACE inhibitors and ARBs have been found either to increase substances that inhibit erythropoiesis or to reduce others that stimulate it. I will not go into more detail about this because it is quite a complex area.

12- NICE also tells us that “hyperphosphataemia in CKD stage 4 or 5 can be common”  

Now, by way of introduction, we must know that hyperphosphatemia is seen as the "silent killer" because of its dramatic effect on vascular calcifications. Also, hyperphosphatemia explains, at least in part, the onset of the complex mineral and bone disorders associated with CKD, together with hypocalcemia, low vitamin D levels and secondary hyperparathyroidism.  

So, why does this happen? Hyperphosphataemia in CKD tends to occur in the later stages (that is, 4 and 5) because of insufficient excretion of phosphate by the poorly functioning kidneys, leading to an accumulation of phosphate in the body. 

Surprisingly, and not generally adequately considered, the skeleton contributes to the hyperphosphatemia in CKD through the effects of abnormal bone remodelling. This causes excess bone resorption and thereby, they contribute to the hyperphosphatemia by effectively blocking the skeleton from exerting its normal reservoir function of phosphate. 

13- NICE also talks about the effect of CKD “on bone metabolism and osteoporosis”.  

So what is CKD mineral bone disease? It is the disturbed mineral metabolism caused by uraemic toxins or secondary hyperparathyroidism which disturbs bone mineralization and makes it difficult for calcium and phosphate to enter the bones, resulting in increased serum calcium and phosphate.  

The negative balance between bone formation and resorption in CKD results in bone loss and in those cases, bone densitometry will detect osteopenia or osteoporosis. The prevalence of osteoporosis in the population with CKD certainly exceeds the prevalence in the general population.

As we have explained previously, when bone resorption exceeds bone formation, phosphorus and calcium are released and contribute to hyperphosphatemia and hypercalcemia. This is an important stimulus to heterotopic calcifications, especially in the vasculature, which can lead to cardiovascular events and mortality.  

And because of this vascular calcification and osteoporosis are the most common complications related to CKD-MBD.  

And because vitamin D deficiency plays an important role in renal osteodystrophy, vitamin D supplements are important in treating both osteoporosis and vascular calcification at the same time.  

14- Following on this, NICE says that if vitamin D deficiency has been corrected with cholecalciferol or ergocalciferol and symptoms of CKD–mineral and bone disorders persist, “we will offer alfacalcidol or calcitriol to people with a GFR of less than 30 and we will monitor the calcium and phosphate levels”.   

For this we have to understand a bit the vit D metabolism in the human body. The proximal tubular cells in the kidney converts 25 Vit D (that is 25-hydroxy-cholecalciferol, 25-hydroxy-ergocalciferol), into the active form calcitriol also known as 1,25-dihydroxycholecalciferol. Now, as kidney disease worsens, there is a reduction in the renal 1α-hydroxylase activity for converting Vit D into the active form calcitriol. 

Whilst you would think that giving calcitriol straightaway would be the solution, we also know that treatment with vitamin D (that is ergocalciferol or cholecalciferol) has been shown to increase calcitriol levels in both stage 3 and 4 CKD. So this, together with the other benefits of Vit D that we have discussed, is the reason why cholecalciferol and ergocalciferol remain the main therapeutic approach initially.  

However, treatment with ergocalciferol or cholecalciferol has not always lowered PTH levels which can contribute to the persistent CKD mineral and bone disorder symptoms. And this is why therapy with calcitriol or alfacalcidol, which is an analogue of vitamin D, can be used in these cases as second line. 

15-Finally, NICE says that we will need to consider “oral sodium bicarbonate supplementation for if both: 

• the eGFR is less than 30 (GFR category G4 or G5) and 
• a serum bicarbonate concentration of less than 20”.  

 

Now, why is this? We know that metabolic acidosis has been associated with CKD due to reduced renal acid excretion. Chronic metabolic acidosis is a common complication of CKD and it also appears to contribute to the progression of kidney disease. Existing evidence from clinical trials suggests that alkali therapy, that is treatment with sodium bicarbonate, could slow down the progression of CKD and this is why it is recommended even if the acidosis is not particularly symptomatic.  

We have come to the end of this episode. I hope that you have found it useful. Thank you for listening and good-bye.