Proteinuria and Chronic Kidney Disease:

Chickens and EggsDr Steph Stringer

Clinical research fellow, UHB

Introduction

• Definition of proteinuria• Pathogenesis of proteinuria• Relevance of proteinuria and CKD• Strategies to reduce proteinuria

What is proteinuria?• The hallmark of glomerular disease• The presence of variable quantities of protein

in the urine• Traditionally measured in 24 hour urine

collections• Thus expressed as mg/24hr• Recent movement away from 24hr collections• Emergence of spot urine collections,

measurement of PCR or ACR

Normally....

• Normal protein excretion <150mg/24hours• This is composed of:

20-30mg albumin10-20mg LMW protein that are freely filtered40-60mg secreted proteins such as IgA and Tamm-

Horsfall Protein

But sometimes....

• Excretion 30-300mg albumin/dayMicroalbuminuria, equivalent to ACR 0.03-0.3

• Excretion urine total protein <3.5g/dayNon-nephrotic proteinuria, numerous causes, may

be non-glomerular • Excretion >3.5 g/day

Nephrotic range proteinuria, only nephrotic syndrome with hyperlipidaemia and hypoalbuminaemia

Pathogenesis of proteinuria

• Overflow proteinuriaTypically urinary light chain excretion, MM

• Tubular proteinuriaUsually low grade (<2g/day) loss of tubular

proteins and also some albumin due to impaired re-absorption

• Glomerular proteinuriaMay be the result of single nephron pressure,

orthostatic or intrinsic glomerular disease

Some causes of proteinuriaDisease Amount of proteinuria

Minimal change Nephrotic range

FSGS Nephrotic range

Membranous nephropathy Nephrotic range

Membranoproliferative Nephrotic range

Amyloidosis Nephrotic range

Diabetes Micro-albuminuria through to nephrotic range

Hypertensive/ischaemic nephropathy Usually micro-albuminuria to non-nephrotic range

Identification of proteinuria

• Urine Dip a commonly used screening testResult Significance

Negative Unlikely to be proteinuria present

Trace 15-30mg/dL

1+ 30-100mg/dL

2+ 100-300mg/dL

3+ 300-1000mg/dL

4+ >1000mg/dL

30-100mg/dl is equivalent to 300mg/24hours if urine volume is 1L

Limitations of urine dip tests

• False positives; Presence of blood or

semen Alkaline urine Detergents/disinfectants Radio-contrast agents High spec. Gravity

(>1.030)

• False negatives; Low spec. gravity

(<1.010) High salt concentration Acidic urine Non-albumin

proteinuria

How to quantify proteinuria?

• Definitive quantification from 24 hr collections• Take account of variable excretion rates

during the day• However unreliable because of compliance

issues• When GFR stable the excretion of creatinine

and protein is stable• This has lead to spot collections for protein

quantification

• Smaller variations seen when PCR used compared to spot protein excretion measurement alone

• Timing of spot samples not crucial, though some authors recommend early morning urines

• Spot samples more cost effective and acceptable method of quantifying proteinuria

ACR vs. PCR

• PCR a measure of all types of protein excreted• However microalbuminuria is prognostic in

diabetes/hypertension• Measurement of ACR has greater sensitivity at

lower levels of proteinuria• NICE recommend ACR for diabetics• However they state that PCR can be used for

monitoring of proteinuria in other patients

Why does proteinuria matter?

• Is proteinuria a cause or a consequence of renal injury?

• Proteinuric GN characterised by loss of size selectivity of the glomerular barrier to protein filtration

• The site of protein excretion (the glomerular capillary wall) is the place where glomerular sclerosis begins

• The injury is transmitted to the interstitium• This results in progressive nephron

destruction

5,0000.1<15Kidney Failure5

10,0000.215-30Severe decrease in GFR4

215,0004.330-60Moderate decrease in GFR

3(A&B)

150,0003.060-90Slight decrease in GFR + other evidence of kidney damage

2

165,0003.3>90normal or increasedGFR with evidence of kidney damage

1

No in West Midlands(4.5 x 106)

Prevalence(%)

GFRml/min/1.73m2

DescriptionStage

Use the suffix ‘p’ to donate the presence of proteinuria

Staging Chronic Kidney Disease

Proteinuria and progressive CKD

• Proteinuria a cause of progressive renal damage

• A poor prognostic indicator in all causes of CKD, especially diabetes

• A risk factor for renal decline and cardiovascular events

• A demonstrated risk factor, independent of the cause of the proteinuria

Why does progressive CKD matter?

O'Hare, A. M. et al. J Am Soc Nephrol 2007

Age 18 to 44 years: risk of ESRD exceeded the risk of death if eGFR < 45 ml/min/1.73 m2 Age 65 to 84 years: risk of ESRD exceeded the risk of death if eGFR 15 ml/min/ 1.73 m2

Go A et al. N Engl J Med 2004

Age-Standardized Rates of Death from Any Cause (Panel A), Cardiovascular Events (Panel B), and Hospitalization (Panel C), According to the Estimated GFR among 1,120,295 Ambulatory AdultsExcess mortality in CKD:

cardiac and vascular events

Proteinuria and CV risk

Why is proteinuria associated with CV events?

• A small amount of albuminuria unlikely to have a direct effect

• But albuminuria related to other factors that may be causal or linked to CV disease;

Hyperglycaemia (diabetic or non-diabetic) Hypertension Renal dysfunction Dyslipidaemia Hyperhomocysteinaemia Smoking

Thus Albuminuria likely to reflect underlying vascular disease

STRIPPOLI et al J Am Soc Nephrol 15: 411–419, 2004

An evidence base for nephrology?

As a result......

• There are only 3 evidence based interventions in CKD management– ACEi/ARB in proteinuria– BP control– Target HbA1C <7% in diabetics

Strategies to reduce proteinuria

• Low protein dietsNo longer recommended

• Management of BP• Drugs• Low salt diets

BP and proteinuria

• Does reducing BP by any method reduce proteinuria or does the agent used matter?

RAAS blockade• RAAS has a crucial role in progressive CKD and

proteinuria• Effects mediated via reduction in intra-glomerular

pressure and salt/water balance

ACEi/ARB

• Shown to reduce proteinuria and improve renal outcomes in diabetics and non-diabetics with proteinuria

• Effect independent of BP lowering • Mechanism is via reduction of GFR and

intraglomerular pressure• Initial enthusiasm for synergistic effect of ACEi

+ ARB now not justified

ACEi/ARB notes of caution

• Hyperkalaemia in advanced renal disease or with other drug combinations

• Presence of RAS• Potential for ARF in the setting of acute

intercurrent illness• Combination of ACEi/ARB potentiates risks• Their increasing use in non-proteinuric

hypertension – not recommended as 1st line by NICE

Spironolactone

• K+ sparing diuretic• Aldosterone receptor antagonist• Through this effect reduces proteinuria• May be additionally effective in combination

with ACEi/ARB• But obvious concerns about hyperkalaemia

present

Calcium channel blockers

• The anti-proteinuric effect limited to the non-dihydropyridines (Diltiazem, Verapamil)

• They cause changes to the glomerular membrane size selectivity

• The dihydropyridines reduce systemic BP by afferent arteriolar dilatation, this actually increases intra-glomerular pressure

Statins

• Known to have beneficial effects on endothelial function

• Improving renal perfusion• Reducing abnormal permeability to plasma

proteins• As yet not indicated for use as anti-proteinuric

agents• However many patients with CKD will have

other indications for their use

The role of salt restriction• High salt diets blunt the anti-proteinuric effects

of ACEi/ARB/CCB• Even when the BP reduction seems appropriate• Mechanism is via the relative volume depletion in

low salt diets that makes the glomerular microcirculation more sensitive to the effects of ATII

• Recommended intake of <70meq/day (equivalent to 1.5-2g)

This bought curry could contain as much as 20.5g of salt

In conclusion

• Many causes of proteinuria• Complex pathogenesis, subtle interactions• Regardless of cause it confers a poor

prognosis• Progressive renal decline• Cardiovascular events• Should be considered and attempts made to

reduce