pathophysiology of proteinuria & the nephrotic syndrome...focal and segmental glomerulosclerosis...

Dr Angharad Marks – Renal Consultant

Pathophysiology of proteinuria & the nephrotic syndrome

Renal teaching – 1st October 2019

1315-1415

Dr Angharad Marks

Renal Consultant



Curriculum: To undertake a specialist assessment, investigate and manage a patient with proteinuria and nephrotic syndrome • Outlines the pathophysiology of proteinuria and nephrotic syndrome

• Differentiates between physiological and pathological causes of proteinuria

• Lists the causes of proteinuria and define the relationship to systemic diseases

• *Describes the risk of extrarenal complications of nephrotic syndrome

• *Lists the range of treatment options (including potential adverse effects) available for management of proteinuria and associated extrarenal complications


Proteinuria

• Total urinary protein excretion in the normal adult should be less than 150 mg/day

• Proteinuria is consequence of two mechanisms: the abnormal transglomerular passage of proteins due to increased permeability of glomerular capillary wall and their subsequent impaired reabsorption by the epithelial cells of the proximal tubuli• Glomerular

• Tubular

• Overflow

• “Post-renal”


Kidney International (2011) 79, 1331–1340

Kidney International (2011) 79, 1331–1340


Figure 2. Schematic representation of transglomerular transfer to the tubular lumen, reabsorption by the tubular cells and excretion in the urines of plasma proteins of low-molecular-weight (LMW), intermediate-molecular-weight [mainly albumin ALB)], and high-molecular-weight (HMW) in physiologic conditions and in pathologic conditions characterized by progressively increasing permeability of the glomerular barrier and reabsorptive load of the tubular cells. (A) In physiologic conditions, all LMW proteins and a fraction of albumin cross the glomerular barrier and are completely reabsorbed by the tubular cells. (B) The alteration of the permeability of the glomerular barrier is moderate, involving mainly a loss of restriction to passage of negatively charged proteins (especially albumin); albumin and a small fraction of HMW proteins reach the tubular lumen and saturate the reabsorptive capacity of tubular cells, inducing the loss in the urines of a fraction of LMW proteins and albumin, together with a very small fraction of HMW proteins (selective proteinuria).(C) A more severe damage progressively increases size permeability of the glomerular barrier, and, due to the saturation of the reabsorptive mechanisms of tubular cells, a greater percentage of HMW proteins is excreted in the urines (nonselective proteinuria). (D) Permeability of the glomerular barrier is further increased, and the massive and protracted reabsorptive load of the tubular cells induces toxic lesions of these cells and reduces their reabsorptive capacity; excretion with the urines of all three classes of proteins and, in particular, of LMW and HMW proteins, is increased,and represents a valid marker of the severity of the glomerular and tubular damage

D’Amico & Bazzi Pathophysiology of proteinuria KI 63 (3) 2003809-825 https://doi.org/10.1046/j.1523-1755.2003.00840.x

https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-proteins

https://www.sciencedirect.com/topics/medicine-and-dentistry/albumin

https://doi.org/10.1046/j.1523-1755.2003.00840.x


How to measure proteinuria

• Reagent strips are a useful screening tool for proteinuria although they are not sensitive for detecting low levels of proteinuria and are only semi-quantitative.

• ACR (or PCR) measurements should usually be performed in preference to 24 hr urine collections for determining urinary protein excretion. Units are mg/mmol(mg protein: mmol creatinine).

• ACR is more sensitive for detecting low levels of proteinuria (i.e. negative/1+ protein on reagent strip) and is the recommend method for screening and measuring proteinuria in patients with diabetes.

• Measurement of ACR forms the basis of the NICE grading system for CKD – see CKD stages

• For quantification and monitoring of higher levels of proteinuria (e.g. ACR > 70 mg/mmol) PCR may be preferable.

• A PCR of 100, or ACR of 70, is approximately equal to 1g of protein per 24 hr; below this level the conversion is non-linear.

https://renal.org/information-resources/the-uk-eckd-guide/ckd-stages/


Samal & Linder The Primary Care Perspective on Routine Urine Dipstick Screening to Identify Patients with Albuminuria Clin J

Am Soc Nephrol 8: 131–135


What to do about it• A number of thresholds have been recommended, as summarised here

• The degree of proteinuria can provide an important clue regarding the likely aetiology. An ACR>70 (or PCR>100 mg/mmol) is strongly suggestive of glomerular pathology.

• Patients with proteinuria are at increased risk of developing cardiovascular disease, in addition to progressive renal disease, and cardiovascular risk factor reduction strategies should be considered.

ACR (mg/mmol)

PCR (mg/mmol)

Implication

ACR> 3 >15Abnormal and adequate to define CKD G1 or G2. Commence ACEI/ARB if diabetic(**). Suffix A2 if ACR > 3 mg/mmol on CKD stage

30 50Favour ACE inhibitor/ ARB if hypertensive Suffix A3 if ACR > 30 mg/mmol on CKD stage

70 100 Stricter BP limits apply Referral threshold in non-diabetics

>250 >300Sometimes referred to as “nephrotic range” proteinuria In the presence of oedema and hypoalbuminaemia, sufficient to define the “nephrotic syndrome”


APPROACH TO THE PATIENT WITH PROTEINURIA• Rule out transient proteinuria

• Persistent isolated proteinuria

• Role of kidney biopsy


• 1 million glomeruli in each human kidney

• glomerulus – tuft of capillary loops supported by the mesangium and enclosed in a pouch-like extension of the renal tubule (4 Glomerular cells and visiting white cells etc• Mesangial cell

• glomerular endothelial cell

• visceral epithelial cell (podocyte)

• parietal epithelial cell lining Bowman basement membrane.

• leukocytes patrol the glomerulus in health and mediate injury in disease

• Glomerulo-nephr-itis


What the glomerular filtration barrier achieves –glomerular anatomy and physiology

• Various models


Kitching & Hutton The Players: Cells Involved in Glomerular Disease Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215

• three layers of the glomerular capillary wall, participate in the maintenance of the glomerular filtration barrier (GFB)• fenestrated endothelium and its associated

glycocalyx,

• glomerular basement membrane (GBM),

• podocyte foot processes with their slit diaphragms


For info - Some causes of Glomerulo-nephr-itis & urine findings (Nephrotic / Nephritic)

Protein Haem

Minimal change disease causes most cases of nephrotic syndrome in children but can cause it in adults too. However, it is unlikely to cause renal failure

++++ -

Focal and segmental glomerulosclerosis (FSGS) can cause nephrotic syndrome in adults. Those with other types of FSGS can progress to renal failure ++++ -

Membranous nephropathy causes proteinuria or nephrotic syndrome. Its cause is usually unknown, but it can sometimes be brought on by some medicines, other diseases or cancer. In some cases, patients with membranous nephropathy get better; others deteriorate.

+++ -

Diabetes, after many years, can cause the kidneys to begin to leak protein. This is more likely to happen if the blood sugar level or blood pressure is poorly controlled

+++ -

Amyloid a protein is deposited in the kidney. It can cause nephrotic syndrome and renal failure ++++ -

Lupus is a common cause of glomerulonephritis in young women. It can cause different types of glomerulonephritis. The worst cases need powerful treatment to prevent irreversible kidney damage

+++ + to +++

Mesangio capillary glomerulonephritis can be caused by persistent infections (for example, endocarditis, and hepatitis B or C), other diseases, or it can occur alone

++ ++

IgA nephropathy is the most common cause of glomerulonephritis worldwide +/- ++

Post-infectious glomerulonephritis is uncommon in the developed world. It occurs after an infection, often a streptococcal throat or skin infection. Leads to haematuria, proteinuria, high BP, fluid retention and reduced GFR. It usually gets better if the infection clears up

+ +++

Vasculitis is inflammation of small blood vessels in the glomerulus. It is often caused by diseases that also affect other organs (for example, microscopic polyangiitis and Wegener’s disease). If severe, vasculitis can cause crescentic nephritis

+ ++++

Crescentic nephritis is also known as rapidly progressive glomerulonephritis. It is a severe and usually very acute type of kidney inflammation that can cause loss of kidney function within days to weeks. It is important to make the diagnosis quickly so that kidney function can be saved

+ ++++

Key: ++++ = heavy proteinuria/haematuria; + = slight proteinuria/haematuria; - = usually no proteinuria/haematuria; +/- = slight or no proteinuria/haematuria

Copied from Kerr & Turner“What I tell my patients about Glomerulonephritis” BRITISH JOURNAL OF RENAL MEDICINE 2008; Vol 13 No 1, 15-18 http://www.bjrm.co.uk/patient-information.aspx


Kitching & Hutton The Players: Cells Involved in Glomerular Disease Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215


• Kitching & Hutton The Players: Cells Involved in Glomerular Disease Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215


Am J Kidney Dis. 2011;58(4):666-677


• three layers of the glomerular capillary wall, participate in the maintenance of the glomerular filtration barrier (GFB)• fenestrated endothelium and its associated

glycocalyx,

• glomerular basement membrane (GBM),

• podocyte foot processes with their slit diaphragms


Nephrotic syndrome

• Proteinuria

• Hypoalbuminaemia

• Oedema

• Hyperlipidaemia

• Hypovaolaemia

• Thrombembolism

• AKI

• Infection


Causes (pathology) of nephrotic syndrome -adults• Primary renal disease (70%)

• Membranous (Spanish study 24%) 33%

• Minimal change disease (Spanish study 16%) 15%

• FSGS (Spanish study 12%) increasing 35%

• Membranoproliferrative (Spanish study 7%)

• IgA (Spanish study 6%)

• Systemic disease (30%) • Diabetes

• Amyloidosis (Spanish study 6%)

• SLE (Spanish study 14%)


Secondary causes (process) of nephrotic syndrome - adults• Cancer (CJASN 7: 1701–1712, 2012)

• Paraproteins (CJASN 11: 2288-2294 2016)

• Infections

• Drugs (CJASN 10: 1300-1310, 2015)


Membranous

• Secondary -MN 20-30% secondary to SLE/ infections/drugs/cancer

• Prevalence of cancer 6-22% (CJASN 7: 1701–1712, 2012)

• Drug assoc 14% (Gold, Penicillamine, Tiopronin, Captopril, NSAIDs)

• Primary -PLA2RAb


A case… to discuss

• April 2019: Please can you assess this 48 year old male he ha multiple PEs in sept 18 then other emboli to legs embolectomy and amputation due emboli Nov 18 on warfarin and gabapentin Alb 18 and gross oedema BP 140/90 Urine Pro 4+ Bld trace INR 3.5. Presented beccause increasing oedema of stump and unable to fit prosthesis

pathophysiology of proteinuria & the nephrotic syndrome...focal and segmental glomerulosclerosis...

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