Type 2 Diabetes & Renal Impairment

Denise Blanchfield

Advanced Nurse Practitioner Diabetes & Renal Impairment.

Diabetes Department St Luke's General Hospital Kilkenny

How does hyperglycaemia cause the complications associated with Type 2 diabetes ?

Complication: Nephropathy How to assess renal function. Proteinuria/haematuria. Renal anaemia Targets for care Guardian drugs

Agenda

Strong evidence is present to show that the severity of complications in both Type1+2 diabetes is associated the duration and degree of high blood glucose.

High blood glucose results in a process which causes damage to nerve endings ,blood vessels and circulation How?

At least three distinct metabolic pathways are involved in the pathogenesis of long term complications, although the primacy of any one of these pathways has not been established.

Why do Complications commonly occur with hyperglycaemia?

Increased Polyol pathway flux: This refers to the increased flux of glucose and other sugars

through the polyol pathway which focuses on the enzyme aldose reductase.

Aldose reductase normally has the function of reducing toxic aldehydes in the cell to inactive alcohols, but when the glucose concentration in the cell becomes too high, aldose reductase reduces glucose to sorbitol increasing susceptibility to intracellular oxidative stress and damage

Pathways involved in the development of diabetic complications

Polyol pathway

aldose reductase

High glucose level

Sorbital accumulation

Intracellular stress & damage

Increased Intracellular & Extra cellular advanced glycation end products (AGEs):

• AGEs are formed by the reaction of glucose and other glycating compounds resulting in irreversible intracellular and extracellular damage such as:

Pathways involved in the development of diabetic complications

AGE’s formed by the

reaction of glucose &

other glycating

compounds

Irreversible intracellular

& extracellular damage such

as:

Basement membrane thickening

Increased adhesion of

inflammatory cells to the

endothelium = increased vascular

permeability.

Activation of AGE receptors = production of inflammatory cytokines and growth factors,

which in turn cause vascular pathology.

Basement membrane: a sheet of extracellular material upon which the basal surfaces of epithelial cells rest; it is also associated with muscle cells, Schwann cells, fat cells, and capillaries, interposed between the cellular elements and the underlying connective layer.

Basement membrane

Increased Protein kinase C activation (PK)C (PK)C are a family of enzymes which are involved

in controlling the function of other proteins.

Cardiovascular pathologies of diabetes have an effect on microvenules, arteries, and myocardium. It is believed that hyperglycemia is one of the most important metabolic factors in the development of both micro- and macrovascular complications in diabetic patients.

Pathways involved in the development of diabetic complications

Chronic activation by hyperglycemia of protein kinase (PK)C has been associated with vascular alterations such as increases in permeability, contractility, extracellular matrix synthesis, cell growth, apoptosis and cytokine activation and inhibition.

These perturbations in vascular cell homeostasis caused by (PK)C are linked to the development of pathologies affecting large vessel (atherosclerosis, cardiomyopathy) and small vessel (retinopathy, nephropathy and neuropathy) complications.

Pathways involved in the development of diabetic complications

Why are some cells more vulnerable to the tissue damaging effects of hyperglycaemia ?

Circulation Eyes

Kidneys Peripheral Nerves

Hyperglycemia results in damage to a particular subset of cell types: capillary endothelial cells such as the circulatory system & retina, mesangial cells in the renal glomerulus, and neurons and Schwann cells in peripheral nerves.

Why does damage occur only in the few cell types involved in diabetic complications? What is distinct about these cells that makes them so vulnerable to hyperglycemia when all of the body is exposed to elevated blood glucose ?

Why are some cells more vunerable to the tissue damaging effects of hyperglycaemia ?

The reason for this is that most cells are able to reduce the transport of glucose inside the cell when they are exposed to hyperglycemia, so that their internal glucose concentration stays constant. In contrast, the cells damaged by hyperglycemia are those that cannot do this efficiently.

Thus, diabetes selectively damages cells, like endothelial cells and mesangial cells, whose glucose transport rate does not decline rapidly as a result of hyperglycemia, leading to high glucose inside the cell

Why are some cells more vunerable to the tissue damaging effects of hyperglycaemia ?

The tiny structures that do the work in your kidneys arecalled nephrons. Each nephron has 3 parts: a small blood vessel that brings in unfiltered blood, a GLOMERULUS that filters the blood. a small blood vessel that returns filtered blood to the body.

Complications: Nephropathy

The main pathology of the diabetic kidney affects both the glomerulus and the tubular institium.

Glomerular enlargement occurs initially due to increased capillary length and surface filtering area.

The kidney then tries to compensate by adaptive compensatory mechanisms in the surviving glomeruli.

Complications:Nephropathy

The earliest detectable change in glomeruli is thickening of the thin basement membrane. This is part of the filter that separates the blood from the urine.

Damage to this membrane causes proteins to leak from the blood into the urine.

Complications: Nephropathy

Diabetes also can cause progressive scarring of glomeruli.

This is called Glomerulosclerosis. This scarring oftenproduces nodules (lumps) of scar in the glomeruli and thus is called nodular diabetic glomerulosclerosis.

Complications: Nephropathy:Glomerulosclerosis

The Modification Diet in Renal Disease formula (MDRD)estimates glomerular filtration rate (eGFR) using Creatinine, race, age and sex.

There are 5 stages of Chronic Kidney disease & 3 ACR stages (outline next slide).

Please consider: eGFR can be interpreted as the percentage of normal kidney function such that an eGFR of 50 ml/min/1.73 m2 approximates 50% of normal kidney clearance.

National Institute for Health and Clinical Excellence (NICE) (July 2014) Chronic Kidney Disease guideline 182.

How to assess renal function:

The diagnosis of CKD is entirely based eGFR on criteria once the value is less than 60/ml/min/1.73 m2.

However earlier stages of CKD require other laboratory or clinical features so as to appropriately apply the label of CKD. 

Other evidence of chronic kidney damage may include any of the following:

Other evidence of chronic kidney damage:

Persistent Microalbumuria.

Persistent proteinuria.

Persistent Haematuria (after exclusion of other causes, e.g. urological disease).

Structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiological testing e.g. polycystic kidney disease, reflux nephropathy.Biopsy proven chronic glomerulonephritis.

Patients found to have an eGFR OF 60-89/ml/min/1.73 m2 without one of the above markers: Should not be considered to have CKD and should not be subjected to further investigation. 

Define accelerated progression of CKD as: a sustained decrease in GFR of 25% or more and a change in

GFR category within 12 months or a sustained decrease in GFR of 15 ml/min/1.73 m2 per year. In patients with CKD 4 or 5, forearm and upper arm veins

suitable for placement of vascular access should not be used for Venepuncture or IV, subclavian or peripherally inserted central catheter lines (PICCs).

In people with CKD the chronic use of NSAIDs may be associated with progression and acute use is associated with a reversible decrease in GFR. Exercise caution when treating people with CKD with NSAIDs over prolonged periods of time. Monitor the effects on GFR, particularly in people with a low baseline GFR and/or in the presence of other risks for progression

Progression of Chronic Kidney Disease (CKD)Take the following steps to identify progressive CKD

Obtain a minimum of 3 GFR estimations over a period of not less than 90 days.

In people with a new finding of reduced GFR, repeat the GFR within 2 weeks to exclude causes of acute deterioration of GFR – for example, acute kidney injury or starting renin–angiotensin system therapy

Be aware that people with CKD are at increased risk of progression to end-stage kidney disease if they have either of the following:

a sustained decrease in GFR of 25% or more over 12 months or

a sustained decrease in GFR of 15 ml/min/1.73 m2 or more over 12 months.

Take the following steps to identify the rate of progression of CKD:

Albumin is the principle component of Glomular disease. To detect and identify Proteinuria, use of urine ACR is preference as it has greater sensitivity for low levels of proteinuria and is recommended method for people with diabetes.

Falsely elevated ACR values can occur which influence the appearance of albumin in the urine; these include such metabolic perturbations as ketosis & hyperglycaemia and hemodynamic factors such as exercise, dietary protein intake, diuresis, and the presence of a urinary tract infection and semen.

For the initial detection of proteinuria, if the ACR is between 3 mg/mmol and 70 mg/mmol, this should be confirmed by a subsequent early morning sample. If the initial ACR is 70 mg/mmol or more, a repeat sample need not be tested.

Regard a confirmed ACR of 3 mg/mmol or more as clinically important proteinuria.

Proteinuria:

When testing for the presence of Haematuria, use reagent strips rather than urine microscopy. Do not use urine microscopy to confirm a positive result.

Evaluate further if there is a result of 1+ or more on urinalysis: correspondence to General Practitioner to evaluate and arrange appropriate referral as necessary.

When there is a need to differentiate persistent invisible Haematuria in the absence of proteinuria from transient Haematuria regard 2 out of 3 positive reagent strips as confirmation of persistent haematuria.

Assessment of Haematuria

Persistent invisible Haematuria, with or without proteinuria should require prompt investigation for urinary tract malignancy in appropriate age groups. These patients should be discussed with either the Consultant Diabetologist or General Practitioner and appropriate referral made.

In situations where prompt, appropriate investigation for urinary tract malignancy has been undertaken and out ruled persistent invisible Haematuria in the absence of proteinuria should be followed up annually with repeat testing for Haematuria, GFR and blood pressure monitoring as long as the Haematuria persists.

Assessment of Haematuria

damaged kidney

impaired production of erythropoietin

reduced number of red blood cells

anaemia

Renal anaemia:

Normocytic/normochromic anemia is present in the majority of patients who have a reduction in kidney function.

Primary cause:◦ Reduced erythropoietin

production from diseased kidney.

◦ This leads to a progressive decline in red blood cell production and subsequent drop in haemoglobin.

Anaemia of Chronic Kidney Disease: What to expect:

Erythropoietin :Glycoprotein hormone

Stimulated by hypoxia/reduced Hb or RBC levels.

Controlled by negative feedback and inhibited when hypoxia/Hb/RBC production is corrected.

Detected when blood is passing through peritubular capillaries Approx. 90% produced in the kidney

10% production in liver

Haemoglobin Normal levels are: Men: 13.5-16.5 g/dl Women: 12.1-15.1 g/dl Children: 11-16 g/dl Pregnant women: 11-12 g/dl Renal Impairment Diabetic Population

haemoglobin level recommendations:Hb: 9.5-11.5 g/dl

Haematinics

HaematinicsIn order to maintain the haem component of the red blood cell, available iron is crucial. Iron is available from:

Ferritin: • Stored iron, found in all tissues but especially liver, bone

marrow and spleen (reticuloendothelial stores).

• Serum ferritin concentrations become elevated during episodes of inflammation, can hinder ability to diagnose iron deficient anaemia in renal disease.

• May check C-reactive proteins which indicate inflammation.

• A serum ferritin < 12ng/ml is an unequivocal indicator of diminished iron stores.

Transferrin: The iron transport protein:o The transferrin saturation rate (Tsat) is the amount of

immediate available iron in the blood for the bone marrow and RBC production.

o A persistently low Tsat is associated with iron deficient erythropoiesis.

Renal Anaemia Screen: Urea & Electrolytes. Full Blood count Aim Hb:9.5-11.5g/dl Transferrin saturation rate (Tsats): Aim > 20% B12, Ferritin Serum Folate(As per laboratory reference

range) Thyroid function test. Liver Function Tests.

Haematinics

Blood Pressure:130/80 mmhg. Renal Impairment: Blood Pressure:125/85 mmhg Body Mass Index< 25 HbAIC below 7% (DCCT 1993). ACR/Microalbumuria within normal limits. Cholesterol below 4.0 triglycerides below 1.8 Hb 9.5-11.5 G/dl Tsats > 20%.Commence oral iron therapy if Tsats

< 20%, as Hb will begin to drop if Tsats low.

Targets for Care

All patients over 40 years of age should be commenced on: NSA Statin, Ace inhibitor

The purpose of these pharmacological interventions isTo prevent/halt progression of the complicationsassociated with Diabetes.

(UK Prospective Diabetes Study Group UKPDS 1998)

Guardian Drugs

Circulation Research.2010; 106: 1319-1331doi:10.1161/ CIRCRESAHA.110.21711

Diabetes Care A Desktop Guide to Type 2 Diabetes. European Policy Group. International Diabetes Federation, Brussels.

K/DOQI Anaemia management guidelines. (2006) Clinical Guidelines 1,2,5,11,20. National Institute for Health and Clinical Excellence (NICE) (September 2008) Chronic

Kidney Disease guideline 73 Pickup. and Williams. (1999 & 2010) Handbook of Diabetes 2nd edition. Blackwell

Science. Oxford Renal Association (2005) United Kingdom Guidelines for Identification, Management

and Referral of Chronic Kidney Disease in Adults. United Kingdom The Diabetes Control and Complications Trial Research Group DCCT (1993). The Effects

of Intensive treatment of diabetes in the development and progression of long term complications in insulin dependent diabetes mellitus. The New England Journal of Medicines 329 (14), 978 – 984.

The International Diabetes Federation European Region. (1999) Guidelines for Diabetes The Irish Nephrology Society (2007).Chronic Kidney Disease Information Pack (document developed by Irish Nephrologists ,general practitioner and endocrinologists and endorsed by the Irish Nephrology Society).

UK Prospective Diabetes Study Group UKPDS. (1998) Tight blood pressure control and risk of microvascular complications in Type 2 diabetes. UKPDS 38.British Medical Journal 317; 703-713.

References