Aetiology

Nephrotic syndrome, defined as the presence of proteinuria (>3.5 g/24 hours), hypoalbuminaemia (<30 g/L), and peripheral oedema, is a relatively rare but important manifestation of kidney disease.

Despite the presence of heavy proteinuria and lipiduria in patients with nephrotic syndrome, the urine contains few cells or casts. This differs from nephritic syndrome, which is typically defined as the presence of acute kidney injury (renal dysfunction), hypertension, and an active urinary sediment (red cells and red cell casts).

In the US, annual incidence of nephrotic syndrome among children is reported to be 2-7 cases per 100,000.[12][13][14][15][16][17]​ In adults, nephrotic syndrome incidence is approximately 3-4 cases per 100,000 each year.[18][19]

Aetiology: children

The most common cause of nephrotic syndrome in young children is minimal change disease (MCD). Renal biopsy is not usually performed if children with MCD are steroid-sensitive (steroid-sensitive nephrotic syndrome).[20] Children with steroid-resistant nephrotic syndrome (SRNS) undergo renal biopsy, with the pathology most likely to be focal segmental glomerulosclerosis (FSGS). In older children/adolescents, the incidence of MCD starts to decrease, and other causes of nephrotic syndrome become more common.

Aetiology: adults

There are many possible differential diagnoses in adults presenting with nephrotic syndrome. A renal biopsy is necessary in the vast majority of cases to obtain the diagnosis. Data from the US and Europe suggest that FSGS is a common cause of nephrotic syndrome in adults; FSGS incidence is similar to, or greater than, membranous nephropathy in some studies.[21][22][23]​ In one series of renal biopsies in adults with unexplained nephrotic syndrome, the relative aetiological frequencies were: 35% FSGS; 33% membranous nephropathy; 15% MCD; 9% IgA nephropathy; 4% amyloidosis; and 4% other.[21]

In older people, membranous nephropathy is the most common cause of nephrotic syndrome.[23][24][25][26]​ Diabetic nephropathy is the most common cause of nephrotic syndrome in adults with a history of long-standing diabetes.

Many of the diseases that cause nephrotic syndrome in adults (e.g., membranous nephropathy) can cause the syndrome in children, but this is uncommon.

Aetiology: ethnicity

Causes of nephrotic syndrome can also differ by ethnicity; for example, in a US study of adults with primary nephrotic syndrome, the most common cause of nephrotic syndrome in black patients was FSGS, whereas the most common causes in white and Asian patients were membranous nephropathy and MCD, respectively.[27]

Conditions with features of nephrotic syndrome

Patients with IgA nephropathy, membranoproliferative glomerulonephritis (MPGN), and post-infectious glomerulonephritis may demonstrate some features of nephrotic syndrome (nephrotic range proteinuria with a low serum albumin). However, these causes of renal disease are predominantly nephritic and investigations will reveal haematuria, red cell casts, and possibly renal dysfunction.

Minimal change disease

MCD accounts for up to 90% of cases of nephrotic syndrome in children younger than 10 years.[28][29]​ This figure decreases to approximately 50% in older children, and to between 10% and 20% in adults.[26][28][29]​ MCD is frequently classified as SRNS as there is often no histological diagnosis.

MCD is a major cause of idiopathic nephrotic syndrome.[30][31]​ In a minority of cases, it may be associated with an underlying secondary cause, such as non-steroidal anti-inflammatory drug (NSAID) use or Hodgkin's lymphoma.[32][33]​ Infection is a recognised trigger in idiopathic nephrotic syndrome in children and adults.[34] In 20% to 30% of patients with MCD, there may be an associated acute kidney injury.[29] Risk factors for the development of acute kidney injury in patients with MCD include male sex, age >50 years, severe nephrotic syndrome, known hypertension, and arteriosclerosis.[29]

'Minimal change' refers to light microscopic findings that often reveal normal glomeruli, or mild mesangial proliferation with negative immunofluorescence and no immune complex deposition. Electron microscopy, however, classically demonstrates diffuse effacement of the epithelial cell foot processes. MCD is typically responsive to steroids. If steroid resistance is noted, alternative aetiologies should be considered, in particular FSGS.

Focal segmental glomerulosclerosis

FSGS can be either primary (idiopathic), secondary, or genetic. Differentiating between primary and secondary FSGS is key in determining management, as primary FSGS may respond to immunosuppression, while secondary causes are treated by reducing intraglomerular pressure (renin-angiotensin blockade).

Secondary causes of FSGS can be divided into those caused by:[24][25][35][36]

  • conditions such as HIV infection, reflux nephropathy, class III obesity (BMI 40 or above), chronic glomerular hyperfiltration from a solitary kidney, or any other cause of extensive nephron loss (e.g., renal obstruction, prior glomerulonephritis), or

  • certain drugs (such as pamidronate or heroin).

HIV is associated with collapsing FSGS, characterised by collapse and sclerosis of the entire glomerular tuft (non-segmental).

Genetic forms of FSGS usually present in childhood. A mutation in one of four genes (NPHS1, NPHS2, LAMB2, WT1) accounts for up to 85% of cases of SRNS presenting by 3 months, and up to 66% presenting in the first year of life.[3][37]

Genetic analysis may be offered when FSGS cannot be classified by clinicopathological assessment.[35] This is particularly relevant in young adult patients, especially when there is a strong family history. One cohort study demonstrated that a single-gene cause of SRNS was found in 29.5% of patients presenting before the age of 25.[3]

FSGS commonly presents with haematuria, hypertension, and reduced renal function. Oedema may be present. Light microscopy shows segmental areas of mesangial collapse and sclerosis affecting some but not all glomeruli (focal disease). Patients are often resistant to steroids and renal biopsy is required to confirm diagnosis.

Membranous nephropathy

Membranous nephropathy is the most common cause of nephrotic syndrome in older adults but is rare in children.[23][24][25][38]

The majority of cases of membranous nephropathy are primary (70%), with the remaining 30% associated with malignancy, chronic infections (e.g., hepatitis B, hepatitis C, syphilis, malaria, or tuberculosis), autoimmune disease (e.g., lupus membranous nephropathy), or certain drugs (e.g., gold, penicillamine, and NSAIDs).[25][39]

Primary membranous nephropathy

In primary membranous nephropathy, antibodies to M-type phospholipase A2 receptor (PLA2R) have been identified in 70% to 80% of patients.[40][41]​ Measurement of anti-PLA2R antibody titre is routine, contributing to diagnosis, treatment planning, and prognosis.[42][43]​ A negative anti-PLA2R antibody test (in the context of negative staining of the antigen, PLA2R, by immunohistochemistry in a renal biopsy) should provoke investigations for a secondary cause.

Microscopy demonstrates basement membrane thickening without associated cellular proliferation or infiltration in primary membranous nephropathy. Immunofluorescence reveals diffuse, granular IgG deposition throughout the capillary walls and electron microscopy shows electron dense deposits in the subepithelial space. New basement membrane growth between subepithelial immune deposits leads to the classic "spike and dome" appearance.

Secondary membranous nephropathy

The most common secondary cause of membranous nephropathy is malignancy. While this should be suspected in patients who present aged >60 years, subsequent investigations for underlying malignancy are determined on a case-by-case basis. A chest x-ray and a breast examination are reasonable, with other investigations (e.g., computed tomography chest, colonoscopy, mammography) guided by the symptoms.

Diabetic nephropathy

The most common cause of nephrotic syndrome in adults with long-standing diabetes. About 20% to 50% of patients with type 1 or type 2 diabetes develop evidence of diabetic nephropathy.[44][45][46]​ Non-diabetic renal disease is also common in adults with diabetes.[47][48]

Microalbuminuria (≥30 mg/day) constitutes early clinical evidence of diabetic nephropathy. Left untreated, persistent microalbuminuria will progress to frank proteinuria in a proportion of patients over the subsequent 10 to 15 years.[49][50]​ These patients are at risk of progressing to end-stage renal disease.

Patients with non-proteinuric diabetic kidney disease, such as hypertensive glomerulosclerosis or tubulointerstitial disease, are also at risk of decline in renal function.[51][52]

A combination of pathogenic processes occurs including glomerular hyperfiltration, hyperglycaemia, and glycation of matrix proteins. Rarely, heavy proteinuria caused by diabetic nephropathy can lead to nephrotic syndrome. Diabetic nephropathy is defined by characteristic mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis leading to the development of Kimmelstiel-Wilson nodules.

Sudden development of heavy proteinuria in patients with diabetes is not typical and may suggest an alternative underlying diagnosis. Microscopic haematuria may be present in diabetic nephropathy, but in a patient presenting with haematuria, proteinuria, and a rapid decline in renal function, an alternative diagnosis must be considered. Absence of diabetic retinopathy should also suggest an alternative diagnosis.

Amyloidosis

Amyloidosis is responsible for around 10% of nephrotic syndrome cases. The main subtypes of amyloidosis include:[53][54]

  • AL primary amyloid, a light-chain dyscrasia where monoclonal light chains form amyloid fibrils; can affect several organs and have differing presentations

  • AA amyloid, which is associated with chronic inflammation (e.g., rheumatoid arthritis, inflammatory bowel disease) and chronic infections; usually affects the kidneys

  • Hereditary amyloidosis, usually caused by transthyretin amyloidosis; a multi-symptom disease that most commonly presents with a neuropathy, but can cause nephropathy, gastrointestinal impairment, cardiomyopathy, or ocular deposition.

Investigations should search for the presence of a monoclonal paraprotein in the urine or plasma.

Membranoproliferative glomerulonephritis

MPGN is a relatively rare cause of nephrotic syndrome and occurs primarily in children and young adults.[55]

A pathophysiological classification has been proposed that splits MPGN into two major groups:[56][57]

  • Presence of immunoglobulins with or without C3: differentials include monoclonal gammopathy of renal significance, autoimmune diseases (mixed cryoglobulinaemia), and infections (hepatitis B and C, chronic bacterial infections), or

  • C3 staining without immunoglobulin deposition: C3 glomerulopathies such as C3GN or dense deposit disease (DDD). Both C3GN and DDD require investigation for genetic disorders of complement regulation.

Malignant hypertension

A rare cause of nephrotic syndrome; can be diagnosed on the basis of the blood pressure and, usually, fundoscopic signs. However, a presentation with proteinuria and raised blood pressure may be part of a nephritic syndrome, typically seen with acute glomerulonephritis, in which case there will be microscopic haematuria and red cell casts on urine microscopy.

Congenital nephrotic syndrome

Congenital nephrotic syndrome presents at birth or in the first 3 months of life. Infantile nephrotic syndrome presents between 3 and 12 months. The majority of children will have an underlying genetic cause of disease, be unresponsive to immunosuppression, and have a poor prognosis with respect to progression to end-stage renal disease.[37][58]

Other causes of nephrotic syndrome

Uncommon causes of nephrotic syndrome include fibrillary glomerulopathies (e.g., fibrillary glomerulopathy and immunotactoid glomerulopathy), multiple myeloma (light-chain deposition diseases), Fabry's disease, nail-patella syndrome, and Alport syndrome.

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