It is characterized by rapid deterioration of renal functions over days to weeks.

MANAGEMENT of RPGN-

We have elaborated “The regimen used by the Glomerular Disease Collaborative Network at the University of North Carolina at Chapel Hill”

•  Glomerular Disease Collaborative Network at the University of North Carolina at Chapel Hill Regimen is as follows:

  • Administer Methylprednisolone at 7 mg/kg/day IV (not to exceed 1 g) for 3 days,
  • Followed by oral prednisone at 1 mg/kg/d (not to exceed 80 mg) for 3 weeks,
  • Then oral prednisone at 2 mg/kg every other day (not to exceed 120 mg) for 3 months.
  • This dose is decreased by 25% every 4 weeks until the patient stops taking prednisone.

  Therapy for ANCA-associated disease ( Wegener granulomatosis and PAN) consists of a combination of corticosteroids and cyclophosphamide. Treatment with steroids alone results in a 3-fold increase in the risk of relapse compared to combination therapy.

  • Administer cyclophosphamide either intravenously or orally. Intravenous therapy is initially administered at a dose of 0.5 g/m², and the oral dose is 2 mg/kg. Both are adjusted according to a 2-week leukocyte nadir count (goal 3000-4000/µL). The maximum intravenous dose is 1 g/m².
  • Oral and intravenous cyclophosphamide appears to be equally efficacious. However, this remains an area of controversy, particularly in the case of Wegener granulomatosis, for which some advocate oral therapy.

  
• In Europe, azathioprine substitutues cyclophosphamide after a 3-month induction period. Azathioprine is administered at 2 mg/kg orally in a single daily dose. This is continued for 6-12 months.
• Methotrexate has been substituted for cyclophosphamide in the initial treatment of Wegener granulomatosis for mild disease and has been used for treatment after initial induction therapy with cyclophosphamide in more severe disease.
• Plasmapheresis may be a beneficial addition to therapy for patients who present with severe renal failure (serum creatinine >6 mg/dL) or those who progress despite treatment.
• Other medications have been used in an attempt to attain a remission, such as intravenous immunoglobulin, antithymocyte antibody, and humanized monoclonal antibody to CD4 and CD25. None of these therapies has been well studied. They appear in the literature as case reports.
  The only predictor of renal survival is the serum creatinine value at the time of diagnosis. Therefore, a high index of suspicion is imperative to establish the diagnosis quickly and to institute treatment as soon as possible. Renal failure requiring dialysis is not a contraindication to treatment. Many patients can be removed from Dialysis for an extended period (18 mo to 2 y).
  Resources-
  Medscape via
  
  
  Falk RJ, Hogan S, Carey TS, et al. Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network. Ann Intern Med. Nov 1 1990;113(9):656-63.
  Nachman PH, Hogan SL, Jennette JC, et al. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. Jan 1996;7(1):33-9.

Initiator of the disease process by:

1. Antibody mediated injury: immune complex deposition or cytotoxic antibodies
2. T-cell mediated immune injury: non-immune complex deposition mechanism

Secondary immunopathogenic mechanism:

Role of mediators of the disease:

A) Cells:

• Neutrophils and monocytes
• Macrophages, T lymphocytes and NK cells
• Platelets
• Resident glomerular cells (Mesagnial cells)

B) Soluble mediators:

• Complement components
• Eicosanoids, NO, angiotensin and endothelin
• Cytokines: IL-1 and TNF
• Chemokines: MCP-1, RANTES, TGF-B
• Coagulation system

Antibody Mediated Injury

Include:

1. Membranous glomerulonephritis
2. IgA nephropathy
3. Membranoproliferative glomerulonephritis
4. Postinfectious glomerulonephritis
5. Anti-glomerular basement membrane disease

Immune complexes activates complement pathway through classic pathway.

A) In-situ immune complex deposition

1. Fixed intrinsic tissue (Glomerular) antigens:

Mechanism: Circulating antibodies form immune complex against the normal glomerular components

• Glomerular basement mebrane antigens : NC1 domain of collagen type IV antigen (anti-GBM disease)
  • Immunofluorescence: Linear pattern immune-complex deposition
• Podocyte antigens: Heymann antigen (membranous glomerulonephritis)
  • Immunofluorescence: Granular pattern immune-complex deposition
• Mesangial antigens
• Others

2. Planted (Deposited) antigens

Mechanisms: Non-glomerular antigens are deposited in GBM from the circulation firstly and then the circulating antibodies form immune-complex.

Immunofluorescence: Granular pattern immune-complex deposition

• Exogenous antigens (infectious agents, drugs)
• Endogenous antigens (DNA, nuclear proteins, immunoglobulins, immune complexes, IgA)

Factors influencing antigen trapping are: size, charge, molecular configuration and carbohydrate content of antigens.

B) Circulating immune complex deposition

Immunofluorescence: Granular pattern immune-complex deposition

Mechanism: Type III hypersensitivity initiated by antigen-antibody complex formed in the circulation.

• Exogenous antigens (infectious products)
• Endogenous antigens (DNA, tumor antigens)

Localisation of complexes and Factors enhancing it:

Primary immune complex deposition in one site is often accompanied by deposition of lesser amounts in other sites. The factors influencing the localisation complexes are: molecular charge of complexes, size, avidity (strength of bond between antigen and antibody), blood flow, etc.

1. Subendothelial (between capillary endothelium and GBM):

• Charge: Highly anionic complexes excluded from GBM
• Size: Intermediate
• Avidity: High

2. Intramembranous (within GBM):

• Charge: Represents the transitional phase in which complexes migrate from subendothelial position to subepithelial
• Blood flow: Increased

3. Subepithelial (between epithelial cells and GBM):

• Charge: Highly cationic complexes
• Size: Smallest (pass freely through the glomerulus without being trapped)
• Avidity: Low

4. Mesangial (within mesangium):

• Charge: Neutral charge
• Size: Large
• Blood flow: Decreased

C) Cytotoxic antibodies

Cell mediated immune injury

Mechanism: Non-immune complex deposition glomerulonephritis

This may occur through regulation of B-cell differentiation and antibody production or by local cell-mediated immunity i.e. delayed-type hypersensitivity reaction. The later is initiated by CD4+ cells by activating monocytes/macrophages which produces cytokines: IL12, IL2, INF-γ and TNF-a which are powerful inflammatory mediators causing injury. CD8+ cells acts by their cytotoxic ability.

Includes:

1. Minimal Change Disease (Lipoid necrosis)
2. Focal segmental glomerulosclerosis

Activation of Alternative Complement Pathway

Alternative pathway of complement pathway is activated by complex polysaccharides.

Role of Complement: C₃ & C₅ are chemoattractant for leukocytes, neutrophils in particular which causes damage by releasing proteolytic enzymes and by generating reactive oxygen metabolites. Terminal complement components C₅b-9, membrane attack complex (MAC) causes injury by basement membrane lysis.

Non-immunologic Mechanism

Hemodynamic and physical forces that cause intraglomerular HTN and abnormal stress and strain on the vascular wall.

Relationship of Physiologic role of glomerular components with consequences of glomerular injury

A) Endothelial cells:

Physiologic function –> Consequence of injury –> Related Disease

1. Maintain glomerular perfusion –> Vasoconstriction –> Acute renal failure
2. Prevent leukocyte adhesion –> Leukocyte infiltration –> Focal/diffuse GN
3. Prevent platelet aggregation –> Intravascular microthrombi –> Thrombotic microangiopathies

B) Mesangial cells:

• Physiologic function: Control glomerular filtration
• Consequence of injury: Proliferation and increased matrix
• Related Disease: Membranoproliferative GN

C) Visceral epithelial cells (Podocytes):

• Physiologic function: Prevent plasma protein filtration
• Consequence of injury: Proteinuria
• Related disease: Minimal change disease, Focal Segemntal Glomerulosclerosis

D) Glomerular Basement Membrane (GBM):

• Physiologic function: Prevents plasma protein filtration
• Consequence of injury: Proteinuria
• Related disease: Membranous GN

E) Parietal epithelial cells:

• Physiologic function: Maintain Bowman’s space
• Consequence of injury: Crescent formation
• Related disease: Rapidly Progressive Glomerulonephritis (RPGN)

Summary:

a) Non-immune mechanisms are involved in Diabetic nephropathy

b) Detected anibody deposition pattern: Granular except in Anti-GBM Nephritis (Linear)

c) Sites of Immune complex or Antigen Deposition:

• Subepithelial: Poststreptococcal Glomerulonephritis
• Epimembranous: Membranous Glomerulonephritis
• Subendothelial: SLE, Type I Membranoproliferative Glomerulonephritis (MPGN)
• Mesangial: IgA Nephropathy
• Basement membrane: Type II MPGN

Patient with RA stenosis presents with:

A.Hypertension when it affects single kidney and as Renal failure when it affects bilateral kidneys. It is often a part of Atherosclerotic vascular disease.

B. Deterioration of Renal function on ACE inhibitors: A drop in GFR ie .20% rise in serum creatinine levels when patient is on ACEI , raises the possibility of RA stenosis .

C. Flash Pulmonary Edema- Acute pulmonary edema occurring repeatedly associated with Hypertension in absence of any other disease like MI, Arrythmia,thyrotoxicosis can occur in RA stenosis even in patient with Normal RFT and cardiac function. It usually follows sudden increase in BP.

Acute Renal Infarction- can occur causing acute loin pain with hematuria. Hypertension can occur but is not an always symptom. ARF is likely to occur.

Etiology

• Reduced Renal blood flow is associated with >70% RA stenosis usually with distal post-stenotic dilation.
• Atherosclerosis- most common cause mainly in elderly age group.
• Fibromuscular dysplasia in younger age group.
• Large vessel vasculitis- Takayasu’s Arteritis
• Medial sized vessel disease- Polyarteritis Nodosa

Investigations

• RFT usually deranged with increased rennin activity causing Hypokalemia.
• USG may show discrepancy in the size of two kidneys.
• Doppler USG can identify significant RA stenosis.
• Renal Isotope Scanning may show delayed uptake of isotope
• Captopril Renography- delayed DTPA excretion from kidney
• Renal Arteriography is the Definitive investigation- carries risk of Contrast nephopathy
• Non-invasive test like MR Angiography
• Spiral CT Angiography

Management

• Medical management with BP lowering, low dose aspirin and lipid lowering drugs.
• Angioplasty with placement of stent
• Surgical resection of stenosed section and reanastomosis (rare)
• The angioplasty is mostly widely used.

Mechanisms implicated for Anemia in CKD are-

1. Relative deficiency of Erythropoeitin: Also called hematopoietin or hemopoietin, it is produced by the peritubular capillary endothelial cells in the kidney and liver. It is the hormone that regulates red blood cell production. Production of EPO is decreased in CKD. When erythropoietin levels are low, an inadequate number of oxygen-carrying red blood cells are produced
2.Toxic effect of Uremia on marrow cells causing Erythropoeisis.
3. Reduced RBC survival: RBC survival is reduced, perhaps due to decreased RBC deformability.
4. Increased blood loss due to capillary fragility and poor platelet function : There is increased bleeding tendency in a patient with CKD.
5. Reduced dietary intake and absorption of iron and other haematinics.

Workup-

Management Of Anemia in CKD-

Recombinant Human Erythropoeitin is effective in correcting the anemia of CRF. The target Hb is usually 10-12 gm%. Erythropoeitin treatment may cause increase in Blood pressure and requires adjustment of Antihypertensive drugs. Increased incidence of blood coagulability and thrombosis of AV fistula is seen. Slow correction of anemia is thus required.

Iron deficiency should be treated and Iron supplementation should be give to keep Ferritin level >100 microgram/L and transferrin >20%. Epoetin is administered by subcutaneous or intravenous injection 1 to 3 times weekly

Pathogenesis of Hypertension in Erythropoeitin therapy is not well-understood but several mechanisms are suspected-

• High dose of EPO
• Prior personal or family history of hypertension
• Diminished production of nitric oxide
• Marked increase in intracytosolic calcium levels
• Enhanced vascular alpha adrenergic sensitivity
• Increased plasma endothelin levels
• Arterial remodeling through stimulation of vascular cell growth
• Activation of the renin-angiotensin system
• Elevation of the thromboxane:prostacyclin ratio in vascular tissue

Newer Therapies-

• Darbepoetin alfa, a second-generation erythropoiesis-stimulating agent, contains 2 amino acid substitutions, which provide the protein with greater metabolic stability in vivo and increase the elimination half-life when compared with intravenous epoetin alfa
• Third-generation erythropoiesis-stimulating agent continuous erythropoiesis receptor activator (CERA).
• Erythropoietin-mimetic peptides- Hematide

References-

1. Davidson’s Principle and Practice of Medicine.
2. http://www.uptodate.com/patients/content/topic.do?topicKey=~WiiZn1K1Dt5Kbu
3. http://www.ccjm.org/content/73/3/289.full.pdf+html
4. http://cme.medscape.com/viewarticle/549364