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.

Korotkoff sounds:

When the cuff pressure is great enough to close the artery during part of the arterial pressure cycle, a sound then is heard with each pulsation. These sounds are called Korotkoff sounds believed to be caused mainly by blood jetting through the partly occluded vessel. The jet causes turbulence in the vessel beyond the cuff, and this sets up the vibrations heard through the stethoscope.

As long as the pressure in the cuff is higher than the systolic blood pressure of the patient, blood doesn’t jet through the completely occluded artery, hence no sound is heard. If the pressure is dropped to a level equal to that of the patient’s systolic blood pressure, the first Korotkoff sound will be heard. As the pressure is further gradually lowered down, following korotkoff sounds are heard:

Phase 1 (K1): Clear tapping sounds representing systolic pressure
Phase 2 (K2): Softer tones
Phase 3 (K3): Louder once again
Phase 4 (K4): Muffled Tones sounds representing diastolic pressure
Phase 5 (K5): Tones cease

Auscultatory Gap:

An auscultatory gap also called as silent gap is the interval of pressure where korotkoff sounds indicating true systolic pressure fade away and reappear at a lower pressure point during the manual measurement of blood pressure by auscultatory method. The auscultory gap happens when the first Korotkoff sound fades out for about 20-50 mmHg only to return. It can result in following erroneous blood pressure reading:

1. Underestimation of systolic blood pressure
2. Overestimation of diastolic blood pressure

Example:

The patient’s actual systolic pressure is 200 with a gap from 170 to 140 and a diastolic of 110. You inflate the cuff to 170 and hear nothing until the manometer reaches 140, which you presume is the systolic pressure. Also if you, inflate the cuff to 200, you may read 170 as the diastolic pressure which is the beginning of auscultatory gap.

When recording a blood pressure with an auscultatory gap, always list your complete findings. eg. BP 200/110 with the auscultatory gap from 170 to 140.

Auscultatory gap has been found to occur due to venous pooling of blood. The auscultatory gap is most likely to appear in the obese arm, especially if the physician pumps up the cuff slowly and traps a great deal of blood in the arm’s venous compartment. Another way to trap blood is to pump the cuff 2nd time immediately after 1st determination, without allowing 1-2 minutes for the trapped blood to escape.

Auscultatory gap in Hypertension

An auscultatory gap is common in elderly hypertensive patients. It occurs in some hypertensive patients only. Auscultatory gaps are related to carotid atherosclerosis and to increased arterial stiffness in hypertensive patients, independent of age.

Types:

3 types of auscultatory gaps, have been identified by using wideband external pulse recording.

1. G1: occurs with cuff pressure just below systolic and is characterized by the presence of K1 and K2 with intermittent disappearance of K2. G1 gaps are related to a phasic decrease of arterial (systolic) pressure.
2. G2: are related to a phasic increase of arterial (diastolic) pressure, occur when cuff pressure is just above diastolic, and are characterized by the presence of K1, K2, and K3 with intermittent disappearance of K2.
3. G3: occurs with cuff pressure between systolic and diastolic and are characterized by an underdeveloped or blunted K2 signal.

Mechanism:

• The mechanism of origin of auscultatory gap has not been understood clearly.
• Cavallani recently showed that the early loss of audible sound during cuff deflation is associated with blunted high frequency K2 signals associated with korotkoff sound (detected by wideband external pulse recording) likely related to the altered physical properties of a stiffer arterial wall.

Precautions:

1. Determining systolic blood pressure by palpatory method before recording the blood pressure with auscultatory method.
2. Inflating the blood pressure cuff to 20-40 mmHg higher than the pressure required to occlude the brachial pulse.

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

Investigations to be done for all lupus patients (both groups):

1. Complete hemogram
2. Kidney function test
3. Liver function test
4. Chest xray
5. ECG
6. Urine routine examination
7. 24 hour urine albumin or urinary albumin: creatinine ratio
8. Urine for active sediments (ie dysmorphic RBCs, RBC and WBC casts)
9. Urine RBC morphology

The last three investigations are done if urine routine examination reveals more than trace proteinuria or hematuria. The investigations are primarily indicated to identify any subclinical organ involvment.

Investigations done in life threatening cases (in addition to above):

1. dsDNA titres
2. C3 and C4 levels
3. APS panel including anti-cardiolipin Ab (IgM and IgG), Lupus anti-coagulant and beta-2 glycoprotein-1 levels (espcially if anti-phospholipid syndrome is suspected)
4. Cultures from possible infected sites (Blood, urine, sputum, pleural fluid etc) if sepsis is a possibility. Most cases of lupus patient having sudden deterioration in their clinical condition are likely to have infective etiology (as a complication of immunosuppressive treatment)
5. HRCT chest or PFT with DLCO ( in acute presentation of ILD or alveolitis)
6. Bone marrow examination, coombs test , reticulocyte count in cases of cytopenias.

TREATMENT:

A) NON LIFE THREATENING:

This basically includes SLE diagnosed on the basis of joint and muco-cutaneous complaints. The subclinical renal involvement needs to be ruled out before labeling the patient as having non-life threatening disease. Treatment of this category will include:

1. Low dose prednisolone. May be started at 0.5mg/kg and gradually tapered over 3months.
2. Hydroxychloroquine sulfate 200mg twice daily
3. Non-steroidal anti-inflammatory drugs: for temporary control of pain and inflammation on as required basis only.
4. Sunscreen application with SPF >= 30 for skin rashes and photosensitivity.
5. Mild cutaneous involvement only may be managed by low potency topical steroids by dermatologists.

Some patients with mild cytopenias or refractory synovitis and those who are unable to taper steroids may require addition of immunosuppressant like azathioprine (1-2mg/kg/day) or cyclosporin (2-3mg/kg/day in divided doses)

B) LIFE THREATENING:

This is a condition when you need to treat the patient aggressively. Usually these patients require workup and treatment simultaneously.  After confirmation of lupus as the etiology for patient’s condition (be it rapidly progressing renal failure, worsening dyspnea, mesenteric ischemia, refractory or recurrent seizures) or if these manifestations are seen in a patient previously diagnosed as lupus (may be as non life threatening initially), then aggressive immnunosuppression needs to be instituited.

Intravenous methylprednisolone 1gm daily for 3 doses is the most rapid acting drug. This however needs to be followed by cyclophosphamide or rituximab as a definitive treatment. If you cannot rule out co-existing infection then it is always safe and pragmatic to put the patient on broad spectrum antibiotic coverage according to local sensitivity pattern.

Once the condition of the patient is stabilized, they should be maintained for a long time on immunosuppressant and be monitored regularly.

COMMON PRACTICAL ERRORS SEEN IN CLINICAL PRACTICE:

I was not sure whether I should write in this heading but then I thought the whole purpose is to clean up the mistakes we are doing by sharing them amongst us. So here are few of them:

1)      Waiting for renal biopsy report before starting high dose steroids in patients with RPRF (rapidly progressive renal failure). If you have adequate evidence that the disease is lupus, eg by compatible clinical picture and positive ANA and high titres DNA, then you should not wait to document the renal histology before saving the patient. An early administration of high dose steroids can be kidney and life saving in such situations. If you wait for creatinine and patient to stabilize before a biopsy then a diagnosis may be only documented at autopsy or little less the patient may land up with shrunken kidneys and dialysis for lifetime!

2)      Starting cyclophosphamide but not methylprednisolone: This again is seen quite commonly and the logic is ‘avoiding steroids’. Wow! We better save the organ first than think of osteoporosis years later. And, it is not the high dose given for few days that matter but the long toxic doses given cause all the harm. Also, it should be remembered that intravenous cyclophosphamide takes at least 15days to act and that is enough time for the disease to destroy the kidneys. Steroids given in pulse acts within 48hours to save it!

3)      Give options: There are other treatment options that are less toxic but extremely expensive. For example, rituximab, mycophenolate mofetil etc. Patients should be allowed to make an informed rational choice and we should not force them with our decision.

Dr. Binit Vaidya MBBS, MD (AIIMS), FACR

4)      You do not need to repeat ANA titres to monitor the disease. If really needed one may use dsDNA and C3 levels to monitor impending flare or renal activity. Most of the times, clinical features and ESR/CRP are adequate for managing them.

Once these patients are stabilized, they need maintenance immunosuppression adequate to control the baseline activity. They should be frequently monitored to look for both the toxicity of medicines as well as early evidence of disease flare.