CHRONIC KIDNEY DISEASE: A

BIOCHEMICAL BREAKDOWN
First, let’s consider a fairly common scenario:

A 78 year old woman presents to her GP having been unwell for several weeks with a cough, nausea and
anorexia. Her GP performs some blood tests, which show the following abnormalities:

Hb 9.8 g/dl [11.5-14.5]

Na 138 mmol/l [130-140]

K 5.4 mmol/l [3.5-5.5]

Urea 34 mmol/l [0-11]

Creatinine 450 mmol/l [60-120]
Calcium 2.05 mmol/l [2.1-2.6]
Phosphate 2.2 mmol/l [0.8-1.5]
This patient has a raised creatinine, meaning that she has kidney disease. This can be acute (occurring over the
course of a few hours or days), or chronic (developing over the course of months). Her anaemia, hypocalcaemia
and hyperphosphataemia are all features of the latter: but what’s the mechanism behind these abnormalities?

Why is she anaemic?

Our patient has a low haemoglobin, a feature that tends to develop around stage 3 CKD. There’s no single
answer to why this occurs, but several mechanisms have been proposed, each with some supporting evidence in
human and/or animal studies. The real reason is probably a combination of the following factors:

o Decreased intake and absorption of iron, including decreased iron reabsorption by the failing kidney.

o Bone marrow toxicity due to uraemia, leading to reduced red cell production.

o Increased red blood cell destruction, due to fragile capillaries and poor platelet function (another

consequence of uraemia). Patients on haemodialysis seem to have a particular problem here, which might be

due to RBC damage from the dialysis membranes (peritoneal dialysis causes fewer problems).
Anaemia is a real problem. A reduced oxygen-carrying capacity means the cardiac output has to increase to
ensure adequate oxygen delivery to the tissues, and in the long term this contributes to hypertrophy – increased
muscle bulk – of the left ventricle. Fibrosis and re-modelling of the heart occurs, and the end-stage of this
process is cardiac failure. Fortunately, a recombinant version of the hormone erythropoietin (EPO) can be used
to treat anaemia in CKD to reduce the risk of getting to this stage. EPO is normally secreted by the kidney in
response to hypoxia to stimulate red blood cell production, and became notorious after being used by athletes
and cyclists to cheat, by artificially boosting their red cell production and hence oxygen-carrying capacity.
However, endogenous levels of EPO aren’t actually low in patients with CKD. It’s a bit like taking paracetamol for
a headache – it treats the symptoms, but it doesn’t mean that headache is caused by paracetamol deficiency!

What’s happening with her calcium and phosphate?

The kidney is intimately involved in calcium and phosphate regulation, and this is a bit more complex. I think the
easiest way to understand this part is to think of it as a sequence of events.

o As the GFR falls, phosphate excretion can’t happen as effectively.

 o This means that the serum phosphate level rises, i.e. hyperphosphataemia.

o A high phosphate causes release of parathyroid hormone (PTH) from the parathyroid gland. In a normal

setting, PTH promotes phosphate excretion, and raises the serum calcium by causing bone resorption to

occur. This phenomenon is known as secondary hyperparathyroidism.

o Normally, vitamin D causes phosphate and calcium to be absorbed from the gut. But since the phosphate

level is now high, vitamin D production becomes suppressed.

o Since vitamin D is the only hormone that stimulates calcium absorption from the GI tract, our patient now

isn’t absorbing calcium. She becomes hypocalcaemic.

o This is made worse since 1-a-hydroxylase, one of the many hormones involved in producing vitamin D, is

present in the kidney, and its activity goes down in CKD.

Or, if you prefer it as a diagram:

If this isn’t treated, she’s going to develop bone disease, which is known as “renal osteodystrophy”. Textbooks
often use a range of terminology that can be confusing, but really the bone problems in CKD can be separated
into just two categories.

o (1) Disease due to high turnover of bone. This is called osteitis fibrosa cystica. It occurs because the high

PTH levels are causing continuous bone breakdown, which the body is attempting to replace.
 o (2) Disease due to low turnover of bone. This is called osteomalacia. It occurs because vitamin D levels are

low, and vitamin D is required for bone ‘mineralisation’ – i.e. incorporation of calcium and phosphate into

the bone matrix.

If you understand the pathology, then knowing the treatment here is very simple. Just think about what goes
wrong, and then correct the underlying problem:

Finally, why is her potassium normal, when everything else has gone wrong?
This is something I found slightly puzzling as a medical student. In acute kidney injury, hyperkalaemia is a severe
and life-threatening complication that occurs with disease. However, patients with CKD retain the ability to keep
their potassium level in the normal range until very late in the disease. Why should this be?

The best explanation I’ve found is that potassium regulation happens in a lot of other ways apart from via the
renal route. If you think about it, the normal serum K+ is 5 mM, in a volume of around 3 litres for the “average” 70
kg man. Intracellular K+, on the other hand, is much higher, at around 150 mM in 25 litres. When you work out
the total mass of K+ in each compartment, our hypothetical person only has 0.4% of their total body K+ sitting in
the blood: if kidney function falls off gradually, some of that can easily be taken up into their cells to keep the
blood level constant.

So, to summarise:

o Chronic kidney disease is a common clinical problem.

o Complications include anaemia and renal osteodystrophy.

o The biochemical abnormalities that occur include the following:

 ACID BASE DISTURBANCE

The kidney plays a critical role in the regulation of acid-base, potassium, and sodium balance, a role that can be

compromised by a decrease in kidney function caused by CKD (defined as an eGFR < 60 mL/min/1.73 m2).

Because of the high prevalence of type II diabetes and hypertension, progressive damage to the kidney resulting

in CKD is increasingly common in the world's population. Furthermore, it is likely that the prevalence of CKD will
only increase as the population ages.

The disturbances in acid-base, potassium, and sodium balance that develop with CKD can have a significant

impact on a patient's clinical well-being and also contribute to increased mortality.1 Therefore, recognizing and

managing these disturbances in acid-base and electrolyte balance will remain a significant challenge for both the

general physician and renal specialist. Indeed, the recognition that abnormalities in these parameters can

emerge at an early stage of CKD (a time when the patient may be cared for almost exclusively by a general
internist) emphasizes the importance for all clinicians to understand the pathophysiology of these disturbances,

their epidemiology, their adverse effects on patient's well-being, and the most efficacious and cost-effective
methods of treatment.

In this themed issue of Advances in Chronic Kidney Disease, experts in the field explore the pathogenesis of

disorders of acid-base potassium and sodium balance as a foundation for description of their frequency,

relationship to stage of kidney failure, adverse effects on cellular function and patient's well-being, approach to
their diagnosis, and new and innovative methods of treatment.
First, Drs Nagami and Hamm nicely summarize our current knowledge of the factors that contribute to regulation

of acid-base balance and particularly the contribution of the kidney to this process. The impact of progressive

CKD to impair renal regulation of acid-base balance is described and the most efficient methods of evaluating

acid-balance in these patients is presented. Of great importance, it appears that despite adaptive changes in

tubular function, acid excretion falls below acid production at a relatively early point of the course of CKD causing

positive acid balance.2 This positive acid balance might initially only accumulate in interstitial tissues, and only
later on cause hypobicarbonatemia and a reduction in blood pH. 3

Drs Chen and Abramowitz examine the current literature and existing large databases to provide the clinician

with a full picture of the prevalence and nature of acid-base disorders observed in the course of CKD. Particularly

important, they describes when in the time course of CKD alterations in acid-base balance might be encountered

and the effect of various types of kidney diseases on their prevalence. They also discuss the value of serum [

] alone compared with venous or arterial blood gases in assessing these patients. This information is

particularly important in guiding the clinician as to when and how to assess acid-base balance in patients seen at
all stages of CKD.

Metabolic acidosis developing in the course progressive CKD, even when mild in degree, can have significant

adverse effects on cellular function.4 Indeed, some studies indicate cellular dysfunction can occur early in the

course of CKD when there might be acid retention, but hypobicarbonatemia is absent (so-called

eubicarbonatemic metabolic acidosis).2 I and Dr Madias summarize the nature of the major adverse effects of

metabolic acidosis on various organs systems including development or exacerbation of bone disease, impaired

growth in children, muscle wasting, hypoalbuminemia, acceleration of the progression of CKD, increased

inflammation, and increased mortality. We explore the underlying mechanisms of individual adverse effects with
the idea that revealing their nature could lay the foundation for targeted therapy.

One of the major challenges faced by the clinician is determining the most cost-effective, safe, and tolerable

treatment of the metabolic acidosis accompanying CKD. Drs Goraya and Wesson, pioneers in this area, nicely

summarize the animal and human data on the indications for treatment, impact of treatment on the adverse

consequences of metabolic acidosis, and current methods available for treatment. 3, 5 Particularly interesting for

the clinician are studies from their group showing that changes in dietary intake of fruits and vegetables can
complement and in some cases even substitute for administration of base in treatment. 5, 6

Regulation of potassium balance is a critical function of the kidney to prevent both hyperkalemia and

hypokalemia. Dr Dubose summarizes our current knowledge of the regulation of potassium balance in health and

with CKD. He discusses the pathogenesis of abnormalities in potassium handling as a foundation for the

understanding of potential new therapies. He also provides a structured approach to the evaluation of
disturbances of potassium balance summarizing the benefits and limitations of current methods.
The normal Western diet is relatively high in potassium averaging 80-100 mEq/d putting patients with CKD at risk

for development of hyperkalemia. Increased ingestion of fruits and vegetables as a possible adjunctive treatment

of the metabolic acidosis of CKD raises the quantity of potassium ingested and the potential for hyperkalemia.

Furthermore, treatment with many of the medications routinely prescribed by the clinician to control hypertension

and slow the progression of CKD, particularly converting enzyme inhibitors or angiotensin receptor blockers can

impair renal potassium excretion and worsen hyperkalemia. 7 In contrast, patients with CKD are often treated with

diuretics which can cause large losses of potassium and hypokalemia which can also have adverse effects.

Therefore, the patient with CKD is often at risk for both hyperkalemia and hypokalemia. Dr Raphael summarizes

the epidemiology of disturbances of potassium balance and describes the correlation between eGFR and

abnormalities of potassium balance and also summarizes the potential adverse effects that might be
encountered. He also comments on the development of hypokalemia and its possible consequences.

Treatment of disturbances of potassium balance has remained a challenge for the clinician. Both acute and

chronic hyperkalemia and acute and chronic hypokalemia can cause significant abnormalities in organ function

particularly involving the myocardium. The methods available for treatment of hyperkalemia in the past were often

limited and sometimes associated with significant potential side effects. For example, the ischemic colitis

described with Kayexalate treatment, although infrequent, was a real concern for the clinician. 8 Newer agents that

enhance potassium elimination with less side effects promise to simplify treatment of these patients. 9 Drs Palmer

and Clegg describe the indications for treatment of both acute and chronic hyperkalemia and the methods

presently available including these new agents. They also nicely summarize the approach to treatment of
hypokalemia including simple methods to estimate the potassium deficit and the most appropriate therapy.

Salt and water retention in patients with CKD is extremely common and plays a critical role in the genesis of

hypertension and development of congestive heart failure in these patients. Because cardiac disease often

accompanies the evolution of CKD, treatment of disordered sodium metabolism in these patients to control

hypertension and improve cardiac function without causing worsening CKD can be a real challenge. Drs Soi and

Yee summarize the mechanisms underlying dysregulation of sodium balance with CKD and its impact on cellular
function and patient's well-being.

Given the difficulty often encountered by the clinician to treat disorders of sodium balance in patients with CKD, it

is important to understand the various methods used, their side effects, and value in treatment. Dr Ellison

provides an organized and nuanced approach to treatment of extracellular volume expansion in patients with

CKD which is designed to be effective while minimizing side effects and preserving glomerular filtration rate.
Their approach can serve as a model for all clinicians caring for these patients.

In summary, disturbances in acid-base, potassium, and sodium balance are frequent in patients with CKD and

remain a challenge for the clinician, whether he/she is a generalist or specialist in kidney disease. The

epidemiology, pathogenesis, adverse effects, and treatment of acid-base and electrolyte disturbances occurring
in patients with CKD is an area of intense investigation. We hope this themed issue of Advances in Chronic
Kidney Disease is of interest to physiologists and clinicians alike and encourages more basic and clinical

research designed to provide evidence based treatment of these important disorders.