Characterized by massive proteinuria, hypoalbuminemia and oedema (also, hyperlipidemia).
Tetrad:
Nephrotic-range proteinuria (>3.5 g/day)
Dyslipidemia
Oedema
Hypoalbuminemia
Thromboembolic disease
Classification
Based on renal histological characteristics:
Minimal change nephrotic syndrome (MCNS) (M/C)
Nephrotic syndrome with significant lesions:
Membranous glomerulonephritis
Light microscopy: Diffuse thickening of GBM
Electron microscopy: Subepithelial immune deposits in GBM “spike & dome appearance”
Focal Segmental Glomerulosclerosis (Common in adults)
Features
Minimal lesion
Significant lesions
Age at onset
2-6 yr
Older children
Sex incidence
Higher in boys
Equal
Haematuria
Rare
Usual
Blood pressure
Normal
Normal or increased
GFR
Normal
Normal or decreased
Renal biopsy
Normal glomeruli; mild mesangial proliferation; often IgM deposits
Changes of varying severity; C3, immunoglobulin deposits
Serum C3
Normal
Low in MPGN
Selectivity of proteinuria
High
Low
Response to steroids
Remission in >95%
Unsatisfactory
Prognosis
Good; relapses stop by second decade
Variable progression of renal damage
Etiology
Primary (or idiopathic)
> 90% of childhood cases
Secondary causes:
Amyloidosis
Vasculitis
Systemic lupus erythematosus (SLE)
Postinfectious GN
Hepatitis B nephropathy
Diabetic nephropathy
Causes nodular glomerulosclerosis
Characterised by Kimmelstiel-Wilson nodules
Patient age and sex are associated with an increased probability of different types of podocytopathies related to different causes or risk factors that can frequently even combine in the same patient. For example, genetic causes are more frequent in children and young adults, whereas immunological causes are more frequent in male children. On the other hand, podocytopathies related to inhibition of vascular endothelial growth factor (VEGF) are observed during pre-eclampsia and are, therefore, more prevalent in pregnant women. Major risk factors for the development of a podocytopathy, such as increased single-nephron glomerular filtration rate for obesity or diabetes, are more frequently observed in adult middle-age patients, whereas a low nephron mass endowment can cause a podocytopathy during adolescence or early adulthood. Finally, a susceptibility gene, such as APOL1, is prevalent in Black adult patients. | HCV, hepatitis C virus; TH, T helper; Treg cell, regulatory T cell. | Kopp, J.B., Anders, HJ., Susztak, K. et al. Podocytopathies. Nat Rev Dis Primers 6, 68 (2020). https://doi.org/10.1038/s41572-020-0196-7
Presentation
The Calgary Guide | http://calgaryguide.ucalgary.ca/
Oedema
Insidious onset
Eyes → Legs → Generalised oedema
Soft, pitting type
Regional types:
Periorbital oedema
Peripheral oedema
Hydrothorax
Hydrocele
Ascites
Complications:
Infections: Due to progressive loss of LMW-complement proteins
Pneumococcal infections (M/C)
Thrombotic complications: Progressive loss of Antithrombin III
Procoagulant state: M/C Renal Vein Thrombosis
Acute Renal Failure
Steroid toxicity
Iron-deficiency Anemia
Chronic cases
Progressive loss of Transferrin
Diagnosis
Urine examination
Heavy (3-4+) proteinuria
Hyaline and granular casts
Significant glomerular lesions:
Gross hematuria/persistent microscopic hematuria
Blood:
Complete blood counts (CBC)
Urea & creatinine: Normal
↓ IgG, ↑ IgM, normal C3
↑ Albumin
↑ Cholesterol
Serology:
↓ Serum albumin (< 1 g/dl)
Milky appearance (due to hypercholesterolemia)
Tuberculin test
Additional tests:
Gross or persistent microscopic hematuria: C3 & Antistreptolysin O
Positive tuberculin test; history of contact with TB: Chest X-ray
Recent jaundice; raised levels of transaminases: Hepatitis B surface antigen
Nephrotic Syndrome: Pathology A spectrum of glomerular lesions can produce nephrotic syndrome. Minimal change disease (lipoid nephrosis) shows little or no change by light microscopy. Fused epithelial foot processes and occasional immunoglobulin (Ig) M deposits are seen by electron microscopy. If the disease is complicated by focal and segmental sclerosis, fused epithelial foot processes, capillary collapse, or mesangial expansion with γ-globulin deposits, response to immunosuppressive therapy deteriorates. Membranous nephropathy is characterized by thickened capillary walls, spikes in the basement membrane due to antigen-antibody complexes beneath the epithelial cells (membranous disease), and diffuse granular deposits of IgG and C3 (complement). Mesangioproliferative glomerulonephritis shows thickening of glomerular capillary walls complicated by mesangial proliferation and sclerosis with subendothelial deposits of C3 and IgG in a lumpy, nonlinear pattern. Focal segmental inflammatory necrosis and crescent formation signals a poor response to immunosuppressive therapy. | Clinical Gate. (2015). Kidneys, Ureters, and Urinary Bladder. [online] Available at: https://clinicalgate.com/kidneys-ureters-and-urinary-bladder/ [Accessed 6 Jun. 2017].
Pathology of podocytopathies: a | The lesion pattern of diffuse mesangial sclerosis occurs only in young children and is usually associated with severe nephrotic syndrome. The glomerulus shows diffuse mesangial sclerosis (arrow) with prominent mesangial consolidation, closure of the capillary loops and overlying prominent immature podocytes. Periodic acid–Schiff staining; magnification ×400. b | The lesion pattern of minimal changes on light microscopy shows a normal glomerulus. Haematoxylin and eosin staining; magnification ×200. c | On electron microscopy, minimal change disease foot process effacement (arrows) is visible. Minimal change lesions are usually associated with steroid-sensitive nephrotic syndrome but can also be associated with isolated proteinuria or, rarely, with steroid-resistant nephrotic syndrome, particularly in the early phases of the disease. d | The lesion pattern of focal segmental glomerulosclerosis (FSGS) is associated with diverse clinical presentations but most frequently with isolated proteinuria or steroid-resistant nephrotic syndrome. FSGS lesions (arrow) have been distinguished into five subtypes but the lack of accuracy to predict a specific cause of disease or outcome limits their clinical relevance264. In addition, particularly in maladaptive FSGS, lesions typically start in juxtamedullary nephrons, which are sensitive to haemodynamic injury and harbour fewer podocyte progenitors, which explains why FSGS starts and is more frequently observed in juxtamedullary glomeruli53. Perihilar and cellular variants share an intermediate prognosis and the former is associated with maladaptive (secondary) causes265. Coarse segmental staining for IgM and C3 can occur with minimal or FSGS lesions. At electron microscopy, limited effacement with narrow foot processes is frequent in maladaptive podocytopathy with secondary FSGS lesions197, whereas diffuse foot process effacement is typical of primary podocytopathies and virus-related or drug-related podocytopathy266,267,268. Masson’s trichrome staining; magnification ×200. e | The lesion pattern of collapsing glomerulopathy is less common and usually associated with severe steroid-resistant nephrotic syndrome. Traditionally, collapsing glomerulopathy has been associated with people of African descent and a fast rate of progression to end-stage kidney disease, whereas tip lesions (which are the result of proliferation of parietal epithelial cells at the urinary pole) are associated with white ethnicity, a low histological score at presentation and a better response to therapy. The collapse of the tuft is evident by the circular black lines (capillaries) and loss of the urinary space (arrows). Jones methenamine silver staining; magnification ×200. | Kopp, J.B., Anders, HJ., Susztak, K. et al. Podocytopathies. Nat Rev Dis Primers 6, 68 (2020). https://doi.org/10.1038/s41572-020-0196-7
Management
Management Principles
Management Principles of Nephrotic Syndrome | Khan, S. R., Pearle, M. S., Robertson, W. G., Gambaro, G., Canales, B. K., Doizi, S., Traxer, O. and Tiselius, H.-G. (2016) ‘Kidney stones’, Nature Reviews Disease Primers. Macmillan Publishers Limited, 2, p. 16008. Available at: http://dx.doi.org/10.1038/nrdp.2016.8.
Management of initial episode
Dietary management:
High protein
Salt restriction
No extra salt
Associated infections:
Antibiotics
Diuretics (if significant oedema):
Furosemide (1-4 mg/kg/day in 2 divided doses) ± spironolactone (2-3 mg/kg/day in 2 divided doses)
Corticosteroid regimen(International Study Group on Kidney Disease in Children):
Prednisolone
2 mg/kg/day in single/divided doses for 6 weeks
1.5 mg/kg/alternate-day (morning) for 6 weeks
Dose tapered over the next 8-12 weeks and stopped
Parent education
Disease progression after therapy:
Remission
Urine albumin nil/trace (or proteinuria <4 mg/m2 /hr) for 3 consecutive early morning specimens
Relapse
Urine albumin 3+/4+ (or proteinuria >4 mg/m2/hr) for 3 consecutive early morning specimens, having been in remission previously
Types:
Frequent relapses
≥2 in initial 6 months or ≥4 relapses in any 12 months
Steroid-dependence
2 consecutive relapses when on alternate-day steroids or within 14 days of its discontinuation
Steroid-resistance
Absence of remission despite therapy with daily prednisolone at a dose of 2 mg/kg per day for 4 weeks and alternate day for next 4 weeks.
Management of relapse (2-3 relapses)
Prednisolone
2 mg/kg/ day until protein is negative/trace for 3 consecutive days
1.5 mg/kg/alternate-day for 4 weeks
Long-term management frequent relapses and steroid dependence
Diagnosis and management of paediatric patients with proteinuria or nephrotic syndrome: In children with podocytopathies, persistent sub-nephrotic proteinuria of >0.5 g per day is treated with a renin-angiotensin system inhibitor (RASi), maximally titrated. Patients are longitudinally followed up. If the proteinuria is associated with other symptoms, such as hypertension, kidney biopsy is required to exclude other glomerular disorders, which are treated accordingly. The length and frequency of the follow-up is determined for each patient based on renal function and residual proteinuria but, at a minimum, yearly evaluation should be performed even in patients with long-standing complete remission and normal renal function. Paediatric patients with idiopathic nephrotic-range proteinuria or nephrotic syndrome are treated with steroids, the response to which defines further management. Steroid-resistant patients should undergo biopsy and genetic testing; treatment with second-line immunosuppressive agents can be started while awaiting the results of genetic testing and should be continued only if these tests are unrevealing. Uncertain or unexpected genetic diagnosis should be confirmed with re-evaluation of the patient and their family. When a genetic diagnosis is ascertained, management should be personalized on the gene identified. By contrast, paediatric patients with nephrotic-range proteinuria or nephrotic syndrome who achieve complete or partial remission should be followed up and re-treated with steroids in case of relapse. Steroid-sparing immunosuppressive agents should be considered only for frequently relapsing and steroid-dependent patients. Based on guidelines from Kidney Disease Improving Global Outcomes (KDIGO) and the International Pediatric Nephrology Association, updated and modified based on recent literature. | ANA, antinuclear antibody; CNI, calcineurin inhibitor; DMS, diffuse glomerulosclerosis; FSGS, focal segmental glomerulosclerosis; Ig, immunoglobulin; LM, light microscopy; MC, minimal changes (with foot process effacement); MMF, mycophenolate mofetil; sCr, serum creatinine. a≥2 relapses in 6 months or ≥4 relapses in 12 months. b<2 relapses in 6 months or <4 relapses in 12 months. | Kopp, J.B., Anders, HJ., Susztak, K. et al. Podocytopathies. Nat Rev Dis Primers 6, 68 (2020). https://doi.org/10.1038/s41572-020-0196-7
Diagnosis and management of adults with proteinuria or nephrotic syndrome: Renal biopsy, laboratory examinations and renal imaging (and, potentially, genetic testing) exclude other glomerular disorders and rule out secondary aetiologies of podocytopathies, which are treated according to the cause. Sub-nephrotic proteinuria is generally treated with a renin-angiotensin system inhibitor (RASi), maximally titrated; patients are longitudinally followed up based on renal function and residual proteinuria; a yearly evaluation should be performed even in patients with long-standing complete remission and normal renal function. Patients with idiopathic nephrotic-range proteinuria and nephrotic syndrome are treated with a course of steroids and with RASi. Response to steroids defines further management: steroid-resistant patients should undergo genetic testing and treatment with second-line immunosuppressive agents should be considered only if these tests are unrevealing. When a genetic diagnosis is ascertained, management should be targeted to the gene identified. Conversely, patients who achieve complete or partial remission should be followed up and re-treated with steroids in case of relapse. Steroid-sparing immunosuppressive agents should be considered only for frequently relapsing and steroid-dependent patients. Based on Kidney Disease Improving Global Outcomes (KDIGO) guidelines, updated and modified based on recent literature. | CNI, calcineurin inhibitor; FSGS, focal segmental glomerulosclerosis; MC, minimal changes (with foot process effacement); MMF, mycophenolate mofetil. a≥2 relapses in 6 months or ≥4 relapses in 12 months. b<2 relapses in 6 months or <4 relapses in 12 months. | Kopp, J.B., Anders, HJ., Susztak, K. et al. Podocytopathies. Nat Rev Dis Primers 6, 68 (2020). https://doi.org/10.1038/s41572-020-0196-7
Summary:
Podocytopathies are kidney diseases in which injury to podocytes (key cells of the glomerulus, which is the filter in the kidney) result in proteinuria or nephrotic syndrome. | Podocytopathies. Nat Rev Dis Primers 6, 67 (2020). https://doi.org/10.1038/s41572-020-0208-7
