Proteinuria and Chronic Kidney Disease: Chickens and Eggs

Dr 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 albumin 10-20mg LMW protein that are freely filtered 40-60mg secreted proteins such as IgA and TammHorsfall Protein

But sometimes....
Excretion 30-300mg albumin/day
Microalbuminuria, equivalent to ACR 0.03-0.3

Excretion urine total protein <3.5g/day

Non-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 proteinuria
Typically urinary light chain excretion, MM

Tubular proteinuria
Usually low grade (<2g/day) loss of tubular proteins and also some albumin due to impaired re-absorption

Glomerular proteinuria
May be the result of single nephron pressure, orthostatic or intrinsic glomerular disease

Some causes of proteinuria

Disease Minimal change FSGS Membranous nephropathy Membranoproliferative Amyloidosis Diabetes Hypertensive/ischaemic nephropathy Amount of proteinuria Nephrotic range Nephrotic range Nephrotic range Nephrotic range Nephrotic range Micro-albuminuria through to nephrotic range Usually micro-albuminuria to nonnephrotic range

Identification of proteinuria
Urine Dip a commonly used screening test
Result Negative Significance Unlikely to be proteinuria present

Trace 1+ 2+
3+ 4+

15-30mg/dL 30-100mg/dL 100-300mg/dL

300-1000mg/dL >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

Staging Chronic Kidney Disease

Stage Description GFR
ml/min/

Prevalence (%)

1.73m2

No in West Midlands (4.5 x 106) 165,000 150,000

1 2

normal or increased GFR with evidence of kidney damage Slight decrease in GFR + other evidence of kidney damage Moderate decrease in GFR Severe decrease in GFR

>90 60-90

3.3 3.0

3(A&B) 4 5

30-60 15-30 <15

4.3 0.2 0.1

215,000 10,000 5,000

Kidney Failure

Use the suffix p to donate the presence of proteinuria

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?

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

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 Adults

Excess mortality in CKD: cardiac and vascular events

Go A et al. N Engl J Med 2004

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

An evidence base for nephrology?

STRIPPOLI et al J Am Soc Nephrol 15: 411419, 2004

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 diets
No 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 nondihydropyridines (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