who classification of lupus nephritis class iminimal mesangial glomerulonephritis - histologically...

WHO Classification of Lupus Nephritis

CLASS I Minimal Mesangial Glomerulonephritis- histologically normal on light microscopy but with mesangial deposits on electron microscopy

CLASS II Mesangial Proliferative Lupus Nephritis- typically responds completely to treatment with corticosteroids

CLASS III Focal Proliferative Nephritis- often successfully responds to treatment with high doses of corticosteroids

CLASS IV Diffuse Proliferative Nephritis- mainly treated with corticosteroids and immunosuppressant drugs

CLASS V Membranous Nephritis- characterized by extreme edema and protein loss

CLASS VI Glomerulosclerosis

International Society of Nephrology/Renal Pathology Society (INR/RPS) 2003 Classification of Lupus

NephritisCLASS I Minimal Mesangial Lupus Nephritis

- normal glomeruli by LM but mesangial immune deposits by IFCLASS II Mesangial Proliferative Lupus Nephritis

- purely mesangial hypercellularity of any degree or mesangial matrix expansion by LM, with mesangial immune deposits- may be a few isolated subepithelial or subendothelial deposits visible by IF or EM, but not by LM

CLASS III Focal Lupus Nephritis- active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations

III-(A) Active lesions: focal proliferative lupus nephritisIII-(A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritisIII-(C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis

(LM – Light Microscopy, IF – Immunofluorescence Microscopy, EM – Electron Microscopy)

Weening et. al. 2004. The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited. J Am Soc Nephrol 15:241-250.


NephritisCLASS IV Diffuse Lupus Nephritis

- active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations- this class is divided into:

1. diffuse segmental(IV-S) lupus nephritis when 50% of the involved glomeruli have segmental lesions

2. diffuse global (IV-G) lupus nephritis when 50% of the involved glomeruli have global lesions

- segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft- this class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation

IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritisIV-G (A) Active lesions: diffuse global proliferative lupus nephritisIV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritisIV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritisIV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis



NephritisCLASS V Membranous Lupus Nephritis

- global or segmental subepithelial immune deposits or their morphologic sequelae by LM and by IF or EM, with or without mesangial alterations- may occur in combination with class III or IV in which case both will be diagnosed- shows advanced sclerosis

CLASS VI Advanced Sclerosing Lupus Nephritis- 90% of glomeruli globally sclerosed without residual activity

(LM – Light Microscopy, IF – Immunofluorescence Microscopy, EM – Electron Microscopy)


3. Enumerate the side-effects of cyclophosphamide

• Side effects of Cyclophosphamide– diarrhea– lethargy– chemotherapy-induced nausea and vomiting– bone marrow suppression– darkening of the skin/nails– alopecia (hair loss) or thinning of hair– changes in color and texture of the hair– hemorrhagic cystitis

Reference: http://www.drugs.com/sfx/cyclophosphamide-side-effects.html

3. Enumerate the side-effects of cyclophosphamide

• Side effects of Cyclophosphamide – carcinogenic, potentially causing transitional cell

carcinoma of the bladder as a long-term complication

– lower the body's immune system – cause temporary or (rarely) permanent sterility.


Some side effects with cyclophosphamide are potentially serious and should be reported immediately to a healthcare

provider. These include but are not limited to:

• Signs of an infection, such as chills or a fever • Blood in the stool • Blood in the urine (which can be a sign of bladder damage) • Severe mouth sores • Signs of an allergic reaction, including unexplained rash, hives,

itching, and unexplained swelling. • Severe nausea, vomiting, or diarrhea • Decreased urination, which may be a sign of kidney damage • Difficulty breathing or water retention, which may be signs of

congestive heart failure • Any unusual moles, skin sores that do not heal, or unusual lumps

(which can be signs of new tumors or cancers)


Clinical and radiographic manifestations of musculoskeletal TB

TB of Bones and Joints

• Weight-bearing joints– spine 40%– hips 13%– knees 10%ff

• Phemister’s Triad– Juxta-articular osteoporosis– Peripherally located osseous erosions– Gradual narrowing of the intra-osseous space

Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

Pott’s Disease (Tuberculous Spondylitis)• most dangerous form of musculoskeletal TB– bone destruction, deformity, and paraplegia

• Progressive bone destruction, >2 adjacent vertebral bodies– leads to vertebral collapse and kyphosis (due to

collapse in anterior spine)• Spinal canal narrowing: abscesses, granulation

tissue or direct dural invasion– leading to SC compression and neurologic deficits


Clinical Manifestations

• Back pain, stiffness– thoracic and lumbosacral region most common

• Constitutional symptoms = fever, weight loss• Most deadly complication = paraplegia– due to abscess compressing the spinal cord


Radiographic Findings

• Lytic destruction of anterior portion of vertebral body• Increased anterior

wedging• Collapse of vertebral

body

Reference: Emedicine. 2009. Pott’s Disease. Retrieved February 16, 2010 from http://emedicine.medscape.com/article/226141-overview

CT Scan– provides better bony detail of irregular lytic

lesions, sclerosis, disk collapse and disruption of bone circumference

– reveals early lesions and is more effective for defining the shape and calcification of soft-tissue abscesses.

Reference: Emedicine. 2009. Pott’s Disease. Retrieved February 16, 2010 from http://emedicine.medscape.com/article/226141-overview

Radiographic Manifestation

CT scan demonstrating destruction of the right pedicle of T10 due to Pott's disease


Tuberculosis of Hip and Knee Joints• Unrecognized joint destruction• Hip joints– Involves the head of the femur (common)– Painful

• Knee joints– Pain and swelling

• Diagnosis: biopsy, tissue culture and synovial fluid exam (thick in appearance, high protein concentration and variable cell count)


Tuberculosis of the Hip

Lesion on femoral head and acetabulumKissing Lesion: hallmark of TB infection

Reference: Singh, Arun Pal. 2009. X-Ray of TB of Hip Joint. Retrieved February 16, 2010 fromhttp://boneandspine.com/muculoskeletal-radiology/xray-of-tuberculosis-of-hip-joint/

calcified debris in the supra-patellar bursa

Reference: Palmer & Reeder. 2009. The Imaging of Tropical Diseases. Retrieved February 16, 2010 from http://www.isradiology.org/tropical_deseases/tmcr/chapter5/lymphadenopathy.htm

Clinical, laboratory, radiographic manifestations of genitourinary TB


• Local symptoms predominate• Up to one third of patients may concomitantly

have pulmonary manifestations• Common symptoms include: – Urinary frequency– Dysuria– Nocturia– Hematuria– Abdominal and Flank pain

Harrison’s Principle of Internal Medicine, 17th ed. P1011-1012


• In females:– May affect the fallopian tubes and the

endometrium causing infertility, pelvic pain and menstrual abnormalities

• In males:– Primarily affects the epididymis, producing a slight

tender mass that may drain externally through a fistulous tract; orchitis and prostatitis.


Laboratory Manifestations

• Urinalysis:– Pyuria and Hematuria

• Urine Culture:– Pyuria but negative for common organisms

causing UTI– Culture of three morning urine specimens positive

for Mycobacterium tuberculosis is a definitive diagnosis.


Radiographic Manifestations

• Intravenous pyelography• Abdominal CT• MRI

Deformities, obstructions, calcifications and ureteral strictures are suggestive findings in genitourinary tuberculosis.


Side effects of anti-TB medications HREZ

Isoniazid• Isoniazid-induced hepatitis-most common major

toxic effect• Peripheral neuropathy• CNS toxicity-memory loss, psychosis,seizures• Fever and skin rashes• Drug-induced SLE• Hematologic abnormalities• Provocation of pyridoxine deficiency anemia• Tinnitus• Gastrointestinal discomfort

Katzung, B, Basic and Clinical Pharmacology 10th ed., McGraw Hill 2007, page 773

Rifampicin

• Orange urine, sweat and tears• Rashes• Thrombocytopenia• Nephritis• Light-chain proteinuria• Flu-like sydrome(fever, chills, myalgia, anemia

and thrombocytopenia)


Ethambutol

• Retrobulbar neuritismost common serious adverse eventLoss of visual acuity and red-green color blindness

• Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis)

• Fever and lymphadenopathy

http://www.drugs.com/sfx/ethambutol-side-effects.html


Pyrazinamide

• Hepatotoxicity-major adverse effect• Nausea• Vomiting• Fever• hyperuricemia


Anti-TB regimen in special situations of liver disease, renal impairment, and pregnancy.

Liver disease• Patients with pre-existing liver disease can receive the usual TB

regimens provided that there is no clinical evidence of chronic liver disease, hepatitis virus carriage, a past history of acute hepatitis, current excessive alcohol consumption.

• However, hepatotoxic reactions to anti-TB drugs may be more common among these patients and should therefore be anticipated

• The first-line drugs HRZ are all associated with hepatotoxicity.– Pyrazinamide is the most hepatotoxic

Treatment of tuberculosis: guidelines - 4th ed. WHO http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf

• The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used.

• In general, patients with chronic liver disease should not receive pyrazinamide. All other drugs can be used, but close monitoring of liver enzymes is advised.

If the serum AST level is more than 3 times normal before the initiation of treatment, the following regimens should be considered .

• Two hepatotoxic drugs (rather than the three in the standard regimen): 9 months of HRE2 months of HRSE followed by 6 months of HR6–9 months of RZE.

• One hepatotoxic drug: 2 months of HES, followed by 10 months of HE

• No hepatotoxic drugs: 18–24 months of streptomycin, ethambutol and a fluoroquinolone.

Renal impairment• The recommended initial TB treatment regimen for patients with

renal failure or severe renal insufficiency is 2 months of HRZE, followed by 4 months of HR.

• Isoniazid and rifampicin are eliminated by biliary excretion, so no change in dosing is necessary.

• There is significant renal excretion of ethambutol and metabolites of pyrazinamide and doses should therefore be adjusted.

• Three times per week administration of these two drugs at the following doses is recommended: pyrazinamide (25 mg/kg), and ethambutol (15 mg/kg)


Renal impairment• While receiving isoniazid, patients with severe renal insufficiency or

failure should also be given pyridoxine in order to prevent peripheral neuropathy.

• Streptomycin should be avoided in patients with renal failure because of an increased risk of nephrotoxicity and ototoxicity.

• If streptomycin must be used, the dosage is 15 mg/kg, two or three times per week, to a maximum of 1 gram per dose, and serum levels of the drug should be monitored.

Pregnancy• Women of childbearing age should be asked about current or

planned pregnancy before starting TB treatment. • A pregnant woman should be advised that successful treatment of

TB with the standard regimen is important for successful outcome of pregnancy.

• With the exception of streptomycin, the first line anti-TB drugs are safe for use in pregnancy– streptomycin is ototoxic to the fetus and should not be used during

pregnancy. • Pyridoxine supplementation is recommended for all pregnant

women taking isoniazid
