Nephropathy - Part 1 - Diabetic Kidney Disease


Diabetes is a leading cause of kidney failure, and diabetic nephropathy affects upto 40% of people with diabetes. Kidney disease is closely associated with heart disease and high blood pressure - together these factors significantly increase the risk of death.

In New Zealand, over 40% of all patients requiring renal replacement therapy - i.e. dialysis or a kidney transplant - are as a result of the damaging effects of diabetes. This is about on par with average figures for 'westernised' countries including the UK and US (figures range from about 40 - 50%, depending on source data)

However, importantly, research data suggests that Maori and Pacific peoples are 3.5 times more likely to develop kidney failure.

The story doesn't end here; numbers are expected to increase dramatically over the next ten years... Clearly, diabetic kidney disease is a problem affecting individuals and nations, and it requires attention.

 




What's covered on this page



Normal Kidney Function and the Effects of Diabetes

Diagnosing Nephropathy - Chronic Kidney Disease (CKD) - in Diabetes

Complications of Chronic Kidney Disease



Normal Kidney Function

The kidneys filter out waste products, toxins and surplus nutrients from the blood. Excess fluid is also excreted by the kidneys and collectively all of this 'waste' makes up our urine. Urine drains from the kidneys into the bladder, where it is collected and stored until we decide it is time to 'go'.

The kidneys play an important role in cleansing our bodies, maintaining the optimum environment for us to function. They control the fluid and salt content of the blood, and play an important role in maintaining blood pressure.

The kidneys also produce hormones that affect the function of other organs. For example, a hormone produced by the kidneys stimulates red blood cell production (erythropoietin (EPO); see also Anaemia and Erythropoietin below). Other hormones produced by the kidneys help to regulate blood pressure and control calcium metabolism in the body.

In Summary

What our kidneys do for us

  • Remove waste products
  • Remove or metabolise some types of drugs
  • Help to maintain correct levels of salts and other substances in the blood
  • Balance the body's fluid levels
  • Produce hormones that regulate blood pressure
  • Produce active Vitamin D, essential for healthy bones
  • Control production of red blood cells

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How do the kidneys normally work?

We each have two kidneys; they are bean-shaped, about the size of a fist, and are found on either side of the spine at the lowest level of the rib cage. Blood enters the kidneys through one main blood vessel, known as the renal artery. The artery then splits up into numerous small blood vessels, each ultimately ending up at a nephron. The nephrons are the individual filtering units of the kidney. A human kidney contains well over a million nephrons.

Each nephron contains a glomerulus and a renal tubule. The glomerulus consists of a network of fine capillaries (very small blood vessels). The cells lining these blood vessels form a special porous layer (the glomerular basement membrane) and selectively allow fluid and other components of the blood to be filtered through. The fluid then runs along the tubule and from here, some important substances and some fluid are reabsorbed into the blood. The remaining fluid - containing the waste, unwanted chemicals, and excess water - becomes urine, and goes on to collect in the bladder.

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What goes wrong in people with diabetes?

High blood glucose levels damage the small blood vessels that supply the tiny filtering units - nephrons - in the kidney. This happens through a number of mechanisms, some of which are not entirely understood.


Possible Mechanisms of Kidney Damage in Diabetes

  • Genetics
  • High blood glucose levels*
  • High blood pressure
  • Glomerular hyperfiltration
  • Renal renin-angiotensin system (RAS)
  • Proteinuria
  • Altered blood lipids?

>> More details

*also see "Hyperglycaemia - Long Term Effects"

 

The damaging effects of diabetes on the kidneys can be dramatically slowed down with appropriate medication and tight blood glucose and blood pressure control. There are no symptoms in the early stages of diabetic kidney disease, so it can only be detected through regular lab tests and medical check-ups (see "Annual Review" and "Laboratory Tests" in the section, "Your Diabetes Care").

Gradually, over many years, the kidneys may become progressively less able to work properly, finally resulting in kidney failure (also termed 'renal failure'). Symptoms then may include tiredness, itchy skin, loss of appetite, restless legs,swollen ankles, shortness of breath, and feeling cold. See Part 2 for more information about treatment options in kidney failure.

However, not all people with diabetes are destined for dialysis...

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Genetics and your risk of developing diabetic nephropathy

Some people with diabetes will go on to develop diabetic neuropathy regardless of their degree of blood glucose control. Genetic factors are undoubtedly involved in the risk of developing diabetic nephropathy, and in particular, with regards to the risk of it progressing towards kidney failure.

Although there does appear to be familial clustering, little progress has been made in terms of identifying exactly which genes confer what risk and to who.

Genetic linkage studies have so far identified specific areas on three chromosomes (3q, 10q and 18q) which may be related to an increased susceptibility for diabetic kidney disease in some people (1).

Equally, the strength of the genetic factor is not known - so even if you have a close family member with diabetes who goes on to develop kidney failure, it is by no means certain that you will do so as well. Many other factors are important in preventing the progression of diabetic nephropathy, and these may override genetic susceptibility in some cases.

That said, we do know from population studies, that people from some ethnic backgrounds have a higher risk of developing nephropathy - for example, African Americans, Asians, Maori and Pacific Island peoples.

We obviously don't know the full stury yet; but, even if you are at an increased risk because of genetic factors, there are still things that you can do to decrease your risk.

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Preventing diabetic nephropathy

If you have diabetes then you are at risk of developing kidney damage after about 5 years (earlier if you had diabetes for a while before it was diagnosed, which is not uncommon in people with Type 2 diabetes). However, there are a number of things that you can do to help to reduce that risk:

 

REDUCE THE RISK

  • Tight control of blood glucose and blood pressure
    are your best defences against the development of nephropathy
  • Take your medications as prescribed
  • If you smoke, then take steps to STOP SMOKING
  • Eat regularly and make healthy food choices
  • Exercise regularly

 Making healthy lifestyle choices and making the most of your health care team will help you to achieve these goals.

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Diagnosing Nephropathy - Chronic Kidney Disease (CKD) - in Peole with Diabetes

Normally, protein should not be excreted in the urine. Early on, diabetc nephropathy can be diagnosed when small amounts of protein are found in the urine - this is after other possible causes of proteinuria, such as infection, have been discounted (a process known as 'differential diagnosis').

Sometimes, if there is any doubt, an ultrasound is performed, in order to provide an image of the kidneys that will help to differentiate urinary tract obstruction, kidney stones and polycystic kidney disease.

Screening for diabetic kidney disease should take place at least once a year at the Annual Review; a urine sample is collected and analysed at the laboratory for protein. A blood test to measure the level of creatinine is also recommended on an annual basis. (In addition to the information below, see "Laboratory Tests" in the section, "Your Diabetes Care").

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Microalbuminuria --- Protein in the urine

Microalbuminuria is a medical mouthful meaning, "small amounts of protein in the urine". It is classically the first sign of diabetic nephropathy.

Urine samples may be tested for protein by a number of ways. A dip-stick can be used as a screening test to provide a positive or negative indication of protein in the urine. Spot samples of urine may be tested at the lab for an accurate measurement of the protein in that sample. More acurate determinations of protein excretion by the kidneys may be made using timed urine collections.

Larger amounts of protein in the urine is termed macroalbuminuria.

Proteinuria - protein in the urine

Microalbuminuria

20 - 200 ug/min

30 - 300 mg/24hr

30 - 300 mg/g*

Macroalbuminuria

> 200 ug/min

> 300 mg/24hr

> 300 mg/g*

*Albumin:creatinine ratio

See "Laboratory Tests" in the section, "Your Diabetes Care" for more details.

 

"Normal" levels; still "at risk"?

There is more and more evidence to support the fact that the risk of developing nephropathy (and cardiovascular disease) is increased, even when microalbuminuria levels are only very slightly raised, and still within the "normal" range (i.e. 0 - 20 ug/min).

What does this mean? Well in simple terms, two things:

(a) you are 'at risk' from the word "Go" (i.e. diagnosis or before), and

(b) your kidneys may be affected by diabetes before it is clinically evident (i.e. before demonstrated by recognised routine diagnostic tests, namely small amounts of protein detected in urine)

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Serum Creatinine Levels

The level of creatinine in the blood gives a good indication of kidney function. As kidney function worsens, the kidneys are less able to excrete creatinine and creatinine levels in the blood rise.

By the time serum creatinine levels reach 150 umol/l (micromoles per litre) you should have been referred to a kidney specialist (nephrologist) - usually at the hospital - for specialist care.

In the very early stages of kidney disease, serum creatinine levels are usually normal; it is only when kidney function is affected that the level of creatinine in the blood is increased. For this reason, serum creatinine levels are not a good marker of early kidney disease. Early detection and treatment of diabetic kidney disease improves the outcome in most cases, so it has been suggested that estimated glomerular filtration rate (eGFR) may be a better tool in the screening for and diagnosis of diabetic nephropathy (2,3).

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Creatinine Clearance and the Glomerular Filtration Rate (GFR)

Glomerular filtration rate (GFR) is a good measure of kidney function. The glomeruli are the actual filters in the kidney (see above); the glomerular filtration rate refers to the amount of blood that is filtered per minute. Measuring the 'real' GFR accurately is complex; so, more often, a reasonably accurate estimate is made - the eGFR.

The eGFR is a calculated estimate of the actual glomerular filtration rate, based on the blood (serum) creatinine concentration (see above). A formula is used to calculate GFR - this takes age, gender, height, and weight into consideration* (*see footnote).

Compared to measuring serum creatinine levels alone, the eGFR more reliably detects kidney disease in its early stages. However, in reality the calculation works best for estimating reduced renal function, so in the US the National Kidney Foundation suggests only reporting actual results once values are < 60 ml/min (normal values are 90-120 ml/min, according to the NKF). An eGFR below 60 ml/min suggests that some kidney damage has occurred (see Stages of Nephopathy below).

MDRD is now the more commonly used calculator to estimate kidney function (eGFR) from the individual's age and blood test for serum creatinine. The result calculated is more accurate below a result of 60ml/min/1.73m2 body surface area.

Values between 60 and 90ml/min/1.73m2 ,may require professional renal physician explanation, and normal values of GFR (kidney function) vary with age, gender and race. Specialist renal advice is recommended prior to further investigation.

If the result is above 90ml/min/1.73m2 BSA, no absolute value is reported by this calculator. Values above 90 are usually normal, but the MDRD calculator is less accurate at estimating kidney function; other tests may be more appropriate.


Creatinine Clearance Test

GFR can also be determined using 'creatinine clearance' (see "Laboratory Tests" in the section, "Your Diabetes Care") however, in addition to the serum creatinine, this test requires a timed urine collection (usually over 24 hours) and may be liable to more errors as a result, although it does give a reliable measurememnt of GFR and kidney function.

 

GFR in Diabetic Nephropathy

The GFR is usually stable or even slightly increased in the very early stages of diabetic nephropathy (alongside microalbuminuria).

However, as the kidney damage worsens, the GFR decreases gradually (see Stages of Nephopathy below).

 

* With some eGFR formulas, ethnicity (race) is also incorporated into the calculation.

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Typical stages of nephropathy

Diabetic nephropathy is categorised into stages, based on kidney function as measured by glomerular filtration rate (GFR). It may take up to 20-25 years to progress from stage I to stage V, although progression to stage V is not inevitable - early detection and treatment can help to prevent worsening of the condition.

 

Stage /
Urinary albumin
excretion (UAE)

These values cover the different ways in which protein in the urine may be measured

Glomerular
Filtration Rate
(GFR)

measured as:
ml min-1 1.73m-2

Description

I

Microalbuminuria

20 - 200 ug/min

30 - 300 mg/24hr

30 - 300 mg/g

 

> 90

Kidney damage with normal or high GFR

GFR may starts to decrease as proteinuria increases

Not all people progress from this stage... some even regress back to "normal"

II

Macroalbuminuria

> 200 ug/min

> 300 mg/24hr

> 300 mg/g

 

60 - 90

Kidney damage with mild reduction in GFR

Reduced number of nephrons (filtering units in the kidney, see above) leads to vicious circle of damage

>> More detail

III 30 - 59 Kidney damage with moderate reduction in GFR
IV 15 - 29 Kidney damage with severe reduction in GFR

V

End Stage Renal Failure (ESRF)

Commonly known as Kidney Failure

 

<15

At this stage, dialysis and/or a kidney transplant are necessary
>> see Part 2

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Early treatment for nephropathy

There are a number of faces to the treatment for diabetic nephropathy. If we look at the sequence of events occuring in figure 2 below, we can see a number of potential places to intervene:

Click on the figure to open in a new window

Prevention of diabetes is an area not covered in this section of the web site. This is, however, an important aspect of public health, and health policy directives should acknowledge the close links between diabetes and kidney failure.

The prevention of the onset of nephropathy in people with longstanding diabetes has been discussed above.

Here, we look at the treatment options at the onset of microalbuminuria, which is usually the stage at which kidney damage becomes clinically evident. At this stage, the main objective of treatment is to prevent or slow down further damage in order to prevent or delay the onset of kidney failure, requiring dialysis and/or a kidney transplant.

 

FIRST LINE TREATMENT APPROACH = ANTIHYPERTENSIVES

i.e. Blood pressure control

TYPE 1 DIABETES - ACE Inhibitors e.g.

TYPE 2 DIABETES - ARBs e.g.

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Complications of Chronic Kidney Disease

The very early stages of kidney disease in diabetes are symptomless and cause minimal discomfort to the patient. However, as the kidney damage progresses, not only do symptoms start to develop, but other problems also start to become evident...

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Renal Bone Disease (Osteodystrophy)

One of the additional functions of the kidney is to produce substances that help make the bones strong and healthy. And therefore, it is an almost inevitable consequence that most people with kidney failure develop some degree of renal bone disease.

Detecting Renal Bone Disease

Abnormal* levels of calcium, phosphate, and vitamin D in the blood can be detected early on in kidney failure:

low vitamin D Failing kidneys produce less Vitamin D.
low calcium Less Vitamin D results in less calcium being absorbed by intestines.
hgh phosphate

[High phosphate levels may be the root cause of that itchy skin.]

increased parathyroid hormone (PTH) As a result of the changes above, PTH secretion is increased. This casuses loss of calcium from the bones.

 *See "Laboratory Tests" in the section on "Diabetes Care"

 

Parathyroid hormone (PTH) levels are increased and as a result calcium moves from the bones into the blood in an attempt to increase the serum calcium levels. As calcium is lost, the bones become weak. The weakened bones are vulnerable and may break or "fracture" easily. Renal bone disease also leads to pain in the bones, particularly in the spine, hips, legs and knees. Treatment should be started early in order to prevent serious weakening of the bones.

Treating Renal Bone Disease

Treatment of renal bone disease aims to correct the deficiencies in calcium and vitamin D, and to lower the phosphate level:

Phosphate binders and Vitamin D analogs (to reduce PTH levels).

In the past, treatment frequently included the removal of the parathyroid glands.

 

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Anaemia and Erythropoietin (EPO)

Anaemia is the condition caused by a lack of red blood cells. It results in tiredness, weakness, and often a feeling of apathy, or lack of motivation to "do" anything. Pale skin and a poor appetite are also associated with anaemia. Red blood cells contain haemoglobin, which carries oxygen from the lungs to various organs and tissues in the body. A lack of red blood cells means a reduced oxygen supply to all parts of the body.

There are numerous reasons why people develop anaemia at various stages during their lives. For people with chronic kidney disease it is often 'par for the course'... This is because the kidneys play an important part in regulating the production of red blood cells. Red blood cells are normally produced in the bone marrow (the fluid part in the centre of bones) and their production is largely controlled by the substance erythropoietin (EPO), which is produced by the kidneys.

Synthetic (artificially manufactured) EPO is now available for kidney patients, and helps to address the propblem of anaemia for those people on dialysis, awaiting a transplant (usually, EPO can be stopped after transplantation).

Anaemia starts long before the need to initiate dialysis, however some doctors prefer to delay EPO therapy until after dialysis treatment has started.

It sounds contrary to common sense, but the theory is that the dialysis treatment removes toxins that have been building up, and that have been inhibiting bone marrow production of red blood cells.

Talk to your doctor about EPO, and find out what the preferences are at your renal unit.


CAUTIONARY NOTES

  • EPO treatment may increase blood pressure;
  • EPO treatment will not work if there is an iron deifiency. Blood ferritin levels provide an indication of iron stores in the body.

 

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High Blood Pressure

The relationships between kidney disease are blood pressure are complex. The kidneys do play a vital role in controlling blood pressure, but the association extends to the relationship between kidney disease and heart disease (see below).

High blood pressure is common in people with kidney failure. In addition to kidney falure contributing to high blood pressure, high blood pressure itself contributes to kidney failure failure. The association is immediately confusing!

Early on in the disease process, people with diabetes-related kidney disease are encouraged to take anti-hypertensive drugs, which lower prood pressure, and have a protective effect on the kidneys in relation to the advancement of diabetic nephropathy.

Diabetic nephropathy: first line treatment = antihypertensives

For more detail see, "Treatment for Nephropathy", above

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Heart Disease

Heart disease and kidney disease are closely related.

Sometimes complications caused by CKD can also make cardiovascular disease more likely. These include:

  • Excess calcium or phosphorus in the blood, which can stiffen and narrow the blood vessels
  • High homocysteine levels, which some evidence suggests can damage artery walls and encourage dangerous clots
  • Systemic inflammation, which is inflammation that's not in just one part of the body but has spread generally and can lead to heart attacks and strokes

CKD patients are also prone to anemia (see above). Prolonged anemia can cause the heart to develop a left ventricular hypertrophy, which means the muscle on the left side of the heart becomes abnormally thick. This can lead to congestive heart failure.

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References

1. SG Satko, BI Freedman, S Moossavi S. Genetic Factors in end-stage renal disease. Kidney International 2005; 94 (supp) S46-S49

2. American Diabetes Association. Standards of Medical Care in Diabetes–2006. Diabetes Care 2006; 29:S4-S42.

3. JP New, DJ O'Donoghue, RJ Middleton, A Rudenski, I Dasgupta, RW Bilous, SM Marshall. Time to move from serum creatinine to eGFR [Editorial]. Diabetic Medicine 2004; 23 (10) 1047-9.


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