Proteinuric renal disease

‘Functional’ proteinuria

Transient subnephrotic proteinuria, ‘functional proteinuria’, can occur following exercise or in association with fever or heart failure. It is benign and probably mediated by glomerular haemodynamic changes.⁴

Overflow proteinuria

Overflow proteinuria is caused by the increased filtration of low molecular weight proteins through a normal glomerular barrier. It is most commonly associated with increased free light-chain production in myeloma (Bence Jones proteinuria). It should be suspected if the urine dipstick is negative (dipsticks are albumin specific) when other tests indicate significant proteinuria.

Tubular proteinuria

Injury to the tubulointerstitial compartment results in the loss both of the proteins that are normally filtered and reabsorbed and of those released by tubular epithelial cells in response to injury.⁵

Orthostatic proteinuria

Orthostatic proteinuria is a benign condition characterised by proteinuria only when in the upright position. Proteinuria is absent in early morning samples but appears in samples collected later in the day. It is not associated with haematuria, the glomerular filtration rate (GFR) is preserved, and the prognosis is uniformly good.⁶

Glomerular proteinuria

Glomerular disease causes an increase in the permeability of the glomerular capillary wall to macromolecules (particularly albumin) and results in glomerular proteinuria. It is persistent and may be associated with haematuria and reduced GFR.

Asymptomatic proteinuria

Most patients with proteinuria are asymptomatic and are identified when the urine is tested either as part of the:

• evaluation for some key life event (eg life insurance application, armed forces recruitment), or

• screening process for high-risk individuals (Table 1).

Symptomatic proteinuria

Nephrotic syndrome. The nephrotic syndrome comprises the following constellation of symptoms:

• heavy proteinuria: above 50 mg/kg/day (ie >3.5 g/day in a 70 kg adult)

• hypoalbuminaemia

• oedema

• hyperlipidaemia (and lipiduria).

Patients typically present with oedema, characteristically observed in a periorbital distribution on waking. Progressive oedema then develops with ankle, sacral and genital involvement. Pleural effusions and ascites may also develop. Leukonychia results from hypoalbuminuria, and xanthelasma may also be seen.⁷ Patients with this level of proteinuria may describe frothing of the urine on micturition. The common causes of nephrotic syndrome are shown in Table 2.

Nephritic syndrome. The nephritic syndrome comprises:

• oedema

• hypertension

• proteinuria with significant hematuria

• reduced GFR.

Patients typically present with reduced urine output, and often describe urine as having a smokey or Coca-Cola colour. Ankle oedema is often present but is less marked than in the nephrotic syndrome. Hypertension is usual and may be severe. Nephritic syndrome often occurs with evidence of systemic disease (see Table 2).⁸

Quantification

Quantification of proteinuria has historically been performed on 24-hour urine collections; these are inconvenient for patients and therefore inaccurate. Current best practice involves measuring the albumin and/or protein concentration in a ‘spot’ urine sample (ideally, an early morning sample).¹⁰

To correct for the effects of urine concentration (hydration state), the albumin/protein concentration is normalised to the creatinine concentration and expressed as the albumin to creatinine ratio (ACR) and protein to creatinine ratio (PCR), respectively (expressed as mg albumin or protein/mmol creatinine). An average person excretes approximately 10 mmol of creatinine per day, so the ACR and PCR can be multiplied by 10 to give an estimate of the daily albumin/protein loss (in mg). The ACR is more sensitive than the PCR, so the former measurement is recommended for the detection and identification of proteinuria while the PCR is reserved for quantification and monitoring.

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Fig 1.

Algorithm for the evaluation of non-diabetic patients with asymptomatic proteinuria. ACEI = angiotensin-converting enzyme inhibitor; ACR = albumin to creatinine ratio; BP = blood pressure; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; PCR = protein to creatinine ratio; rpt = repeat. Reproduced with permission from NICE.

Excretory renal function

The excretory renal function should also be determined (plasma creatinine concentration and the calculated estimated GFR (eGFR)). The patient can then be categorised according to their stage of chronic kidney disease (CKD) (Fig 1; Table 3).⁹

Normal

Normal protein excretion is less than 150 mg per day – equivalent to a urine PCR of less than 15 mg/mmol.

Nephrotic-range proteinuria

The nephrotic range of proteinuria is more than 3.5 g a day (PCR >350 mg/mmol). A protein that is predominantly albumin (ie dipstick-positive or high urine ACR) is characteristic of glomerular disease.

Non-nephrotic proteinuria

A situation in which there is a urine PCR of 15–350 mg/mmol (ie 150 mg to 3.5 g of proteinuria per day) is defined as non-nephrotic proteinuria. This can result from a wide variety of conditions including glomerular disease, non-glomerular parenchymal renal disease and urinary tract disease outside the kidney.

Microalbuminuria

Microalbuminuria defines an albumin excretion of 30–300 mg/day. The microalbuminuric range in the urine ACR is 2.5–30 mg/mmol for men and 3.5–30 mg/mmol for women. This level is below the detection threshold for conventional dipsticks and is used to identify early diabetic nephropathy. Arguably, it may also be used to assess cardiovascular risk in at-risk populations (eg patients with hypertension).

General measures

Patients should be encouraged to take exercise, achieve a healthy weight and stop smoking.⁹

Blood pressure control and proteinuria reduction

Non-diabetic patients. The aim in non-diabetic patients is to keep systolic blood pressure below 140 mmHg (target 120–139 mmHg) and diastolic below 90 mmHg. For those with an ACR above 30 mg/mmol, an angiotensin-converting enzyme inhibitor (ACEI) should be first-line therapy for hypertension. An angiotensin receptor blocker (ARB) may be used if the patient is intolerant of ACEIs. If the ACR is over 70 mg/mmol (PCR >100 mg/mmol), there is evidence that a combination of an ACEI and ARB provides an additional antiproteinuric and renoprotective effect.^11,12 Patients with an ACR above 70 mg/mmol without hypertension also derive renoprotection from combined ACEI and ARB treatment.

Diabetic patients. The threshold for commencing ACEIs/ARBs is lower in patients with diabetes. An ACR above 2.5 mg/mmol in men or above 3.5 mg/mmol in women justifies the use of ACEIs or ARBs, even in the absence of hypertension.

When used, the dose of either the ACEI or ARB should be increased to the maximum tolerated dose before adding a second agent. For maximum antiproteinuric effect, dietary sodium should be limited to 50–70 mmol/day. About 1–2 weeks after commencing or increasing the dose of an ACEI or ARB, the serum potassium and eGFR should be checked. If the serum potassium rises to over 6.0 mmol/l or the eGFR decreases by more than 25% from baseline (or plasma creatinine increases by more than 30%) without any other explanation, the ACEI or ARB should be discontinued.