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Renal System

Nephrotic Syndrome

Characterized by massive proteinuria, hypoalbuminemia and oedema (also, hyperlipidemia).

Introduction

Characterized by massive proteinuriahypoalbuminemia and oedema (also, hyperlipidemia).

  • Tetrad:
    1. Nephrotic-range proteinuria (>3.5 g/day)
    2. Dyslipidemia
    3. Oedema
    4. 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)
FeaturesMinimal lesionSignificant lesions
Age at onset2-6 yrOlder children
Sex incidenceHigher in boysEqual
HaematuriaRareUsual
Blood pressureNormalNormal or increased
GFRNormalNormal or decreased
Renal biopsyNormal glomeruli; mild mesangial proliferation; often IgM depositsChanges of varying severity; C3, immunoglobulin deposits
Serum C3NormalLow in MPGN
Selectivity of proteinuriaHighLow
Response to steroidsRemission in >95%Unsatisfactory
PrognosisGood; relapses stop by second decadeVariable 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.
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

Nephrotic syndrome
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
  • Suspected SLE: Antinuclear antibodies
  • Suspected UTI: Urine culture (suspected urinary tract infection)

Imaging:

  • X-ray (Chest)
    • Pleural effusion
    • Oedema
  • USG (Kidneys)

Renal biopsy:

  • Indications:
    • After 2-3 yr of continuous therapy
    • Steroid resistance
  • Light microscopy
    • General pathology
  • Immunofluorescence
    • Antibody
    • Immune complex stain
  • Electron microscopy
    • Detailed change in glomerular membrane
Nephrotic Syndrome: Pathology A spectrum of glomerular lesions can produce nephrotic syndrome
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
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
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

  • Prednisone
    • Small-dose alternate-day for 9-18 months
    • Relapses during treatment:
      • 2 mg/kg/ day until remission
      • Alternate-day therapy resumed at 1.5 mg/kg
  • Regimens:
    • Immunomodulator:
      • Levamisole (+ alternate-day prednisone) (3-6 months)
    • Alkylating agents:
      • Cyclophosphamide (+ alternate-day prednisone) (12-week)
    • Mycophenolate mofetil (+ tapering-dose prednisone) (12-36 months)
    • Calcineurin inhibitors:
      • Patients that fail to benefit with levamisole, cyclophosphamide and/ or mycophenolate mofetil:
        • Cyclosporine A
        • Tacrolimus
    • Monoclonal anti-CD20 antibody:
      • Rituximab

Steroid-resistant nephrotic syndrome

Immunosuppressive agent
(Calcineurin inhibitors: Cyclophosphamide/tacrolimus)
(12-36 months)
+
Alternate-day prednisolone
+
ACE-inhibitor

Other measures:

  • Hypertension:
    • ACE-inhibitors
  • IV Albumin
    • Indications:
      • Systematic hypovolemia
      • Symptomatic oedema
      • Marked ascites
  • Hypercholesterolemia:
    • HMG-CoA Reductase inhibitors
Diagnosis and management of paediatric patients with proteinuria or nephrotic syndrome
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
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
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

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