Glomerulonephritis

Dr Rasol M Hasan

MINIMAL CHANGE NEPHROPATHY AND PRIMARY FOCAL

SEGMENTAL GLOMERULOSCLEROSIS (FSGS) • Patients with minimal change nephropathy and a

subgroup of patients with FSGS can be seen as opposite ends of a spectrum of conditions causing idiopathic nephrotic syndrome . Minimal change disease occurs at all ages but accounts for nephrotic syndrome in most children and about one-quarter of adults. Proteinuria usually remits on high-dose corticosteroid therapy (1 mg/kg prednisolone for 6 weeks), although some patients who respond incompletely or relapse frequently need maintenance corticosteroids, cytotoxic therapy or other agents. Minimal change disease does not progress to CRF; the main problems are those of the nephrotic syndrome and complications of treatment.

• FSGS is a histological description with many causes. The primary FSGS group that present with idiopathic nephrotic syndrome and no other cause of renal disease typically show little response to corticosteroid treatment and often progress to renal failure; the disease frequently recurs after renal transplantation, and sometimes proteinuria recurs almost immediately. However, a proportion of patients with FSGS do respond to corticosteroids (a good prognostic sign). As FSGS is a focal process, abnormal glomeruli may not be seen on renal biopsy if only a few are sampled, leading to an initial diagnosis of minimal change nephropathy. Juxtamedullary glomeruli are more likely to be affected in early disease.

Cont.• In other patients with the histological

appearances of FSGS but lesser proteinuria, focal scarring reflects healing of previous focal glomerular injury, such as haemolytic uraemic syndrome, cholesterol embolism or vasculitis. In others, it seems to represent particular types of nephropathy: for example, those associated with heroin misuse, HIV infection and massive obesity. Associations with numerous other forms of injury and renal disorders are reported. There is no specific treatment for most of these.

MEMBRANOUS NEPHROPATHY • This is the most common cause of nephrotic

syndrome in adults. A proportion of cases are associated with known causes but most are idiopathic. Of this group, approximately one-third remit spontaneously, one-third remain in a nephrotic state, and one-third show progressive loss of renal function. Short-term treatment with high doses of corticosteroids and alkylating agents (e.g. cyclophosphamide) may improve both the nephrotic syndrome and the long-term prognosis. However, because of the toxicity of these regimens, most nephrologists reserve such treatment for those with severe nephrotic syndrome or deteriorating renal function.

IgA NEPHRO AND HENOCH-SCHÖN PURPURA • IgA nephropathy is the most commonly recognised

type of glomerulonephritis and can present in many ways . Haematuria is almost universal, proteinuria usual, and hypertension very common. There may be severe proteinuria and nephrotic syndrome, or in some cases progressive loss of renal function. The disease is a common cause of ESRF. A particular hallmark in some individuals is acute exacerbations, often with gross haematuria, in association with minor respiratory infections. This may be so acute as to resemble acute post-infectious glomerulonephritis, with fluid retention, hypertension and oliguria with dark or red urine. Characteristically, the latency from clinical infection to nephritis is short: a few days or less. These episodes usually subside spontaneously

IgA/ HSP• In children, and occasionally in adults, a systemic

vasculitis occurring in response to similar infections is called Henoch-Schönlein purpura. A characteristic petechial rash (cutaneous vasculitis, typically affecting buttocks and lower legs) and abdominal pain (gastrointestinal vasculitis) usually dominate the clinical picture, with mild glomerulonephritis being indicated by haematuria. When the disease occurs in older children or adults, the glomerulonephritis is usually more prominent. Renal biopsy shows mesangial IgA deposition and appearances indistinguishable from acute IgA nephropathy. Occasionally, IgA nephropathy progresses rapidly and crescent formation may be seen. The response to immunosuppressive therapy is usually poor. The management of less acute disease is largely directed towards the control of blood pressure in an attempt to prevent or retard progressive renal disease.

GLOMERULONEPHRITIS ASSO WITH INFECTION • CAUSES OF GLOMERULONEPHRITIS

ASSOCIATED WITH LOW SERUM COMPLEMENT

• Post-infection glomerulonephritis • Subacute bacterial infection-especially

endocarditis • SLE • Cryoglobulinaemia • Mesangiocapillary glomerulonephritis-

usually type II

• Bacterial infections, usually subacute (typically subacute bacterial endocarditis), may cause a variety of histological patterns of glomerulonephritis, but usually with plentiful immunoglobulin deposition and often with evidence of complement consumption (low serum C3. In the developed world, hospital-acquired infections are now a common cause of these syndromes. World-wide, glomerulonephritis associated with malaria, hepatitis B, hepatitis C, schistosomiasis, leishmaniasis and other chronic infections is very common. The usual histological patterns are membranous and mesangiocapillary lesions, although many other types may be seen. FSGS associated with HIV infection is prevalent in black races. Proving a causative relationship between renal disease and infection in individual cases is extremely difficult. Acute and chronic infections may also cause interstitial renal disease .

Acute post-infectious glomerulonephritis • This is most common following infection with certain strains of

streptococcus and therefore is often called post-streptococcal nephritis, but it can occur following other infections. It is much more common in children than adults but is now rare in the developed world. The latency is usually about 10 days after a throat infection or longer after skin infection, suggesting an immune mechanism rather than direct infection. An acute nephritis of varying severity occurs. Sodium retention, hypertension and oedema, are particularly pronounced. There is also reduction of GFR, proteinuria, haematuria and reduced urine volume. Characteristically, this gives the urine a red or smoky appearance. There are low serum concentrations of C3 and C4 and evidence of streptococcal infection (perform antistrepto-lysin O (ASO) titre, culture of throat swab, and other swab tests if skin infection is suspected). Renal function begins to improve spontaneously within 10-14 days, and management by fluid and sodium restriction and use of diuretic and hypotensive agents is usually adequate. Remarkably, the renal lesion in almost all children and most adults seems to resolve completely despite the severity of the glomerular inflammation and proliferation seen histologically.

RAPIDLY PROGRESSIVE GLOMERULONEPTIS • This describes an extreme inflammatory

nephritis which causes rapid loss of renal function over days to weeks. Renal biopsy shows crescentic lesions often associated with necrotising lesions within the glomerulus (focal segmental (necrotising) glomerulonephritis). It is typically seen in Goodpasture's disease, where there are specific anti-GBM antibodies, and in small-vessel vasculitides , but can also be seen in SLE and occasionally IgA and other nephropathies

INHERITED GLOMERULAR DISEASES • Alport syndrome• A number of uncommon diseases may affect the

glomerulus in childhood, but the most important one affecting adults is Alport's syndrome. Most cases arise from a mutation or deletion of the COL4A5 gene on the X chromosome which encodes type IV collagen, resulting in inheritance as an X-linked recessive disorder. Mutations in COL4A3 or COL4A4 genes are less common and cause autosomal recessive disease. The accumulation of abnormal collagen results in a progressive degeneration of the GBM. Affected patients progress from haematuria to ESRF in their late teens or twenties. Female carriers of COL4A5 mutations usually have haematuria but rarely develop significant renal disease. Some other basement membranes containing the same collagen isoforms are similarly affected, notably in the cochlea, so that Alport's syndrome is associated with sensorineural deafness and ocular abnormalities. No specific treatment has been devised to slow the progress of this condition, but patients with Alport's syndrome are good candidates for renal replacement therapy as they are young and usually otherwise healthy. Some of these patients develop an immune response to the normal collagen antigens present in the GBM of a transplanted kidney, and in a small minority anti-GBM disease develops and destroys the allograft

THIN GBM DISEASE • In 'thin GBM' disease there is glomerular

bleeding, usually only at the microscopic or stick-test level, without associated hypertension, proteinuria or reduction of GFR. The glomeruli appear normal by light microscopy, but on electron microscopy the GBM is abnormally thin. This autosomal dominant condition accounts for a large proportion of 'benign familial haematuria' and has an excellent prognosis. Some families may be carriers of autosomal recessive Alport's syndrome, but this does not account for all cases

TUBULO-INTERSTITIAL DISEASES • INTERSTITIAL NEPHRITIS A group of

inflammatory, inherited and other diseases affect renal tubules and the surrounding interstitium. The clinical presentation is often renal failure, but electrolyte abnormalities are common, especially hyperkalaemia and acidosis. Proteinuria (and albuminuria) is rarely > 1 g/24 hrs but low molecular weight proteinuria (e.g. retinol-binding protein, β2-microglobulin, lysozyme) with haematuria and pyuria are common.

ACUTE INTERSTITIAL NEPHRITIS (AIN)

• Acute inflammation within the tubulo-interstitium is most commonly allergic, particularly to drugs, but other causes include toxins and a variety of systemic diseases and infections . Renal biopsies show intense inflammation, with polymorphonuclear leucocytes and lymphocytes surrounding tubules and blood vessels and invading tubules (tubulitis), and occasional eosinophils (especially in drug-induced disease).

Cont.• CAUSES OF ACUTE INTERSTITIAL

NEPHRITIS Allergic• Penicillins • NSAIDs • Allopurinol • Many other drugs

Cont.• Immune• Autoimmune nephritis ± uveitis

• Infections• Acute bacterial pyelonephritis • Leptospirosis • Tuberculosis • Hantavirus

• Toxic• Myeloma light chains • Mushrooms (Cortinarius)

Cont.• Only a minority (perhaps 30%) of patients with

drug-induced AIN have a generalised drug hypersensitivity reaction (e.g. fever, rash, eosinophilia) and dipstick testing of the urine is usually unimpressive. However, leucocyturia is common, and eosinophils are found in the urine in up to 70% of patients. Deterioration of renal function in drug-induced AIN may be dramatic and resemble rapidly progressive glomerulonephritis. Renal biopsy is usually required to confirm the diagnosis. The degree of chronic inflammation in a biopsy is a useful predictor of the eventual outcome for renal function. Many patients are not oliguric despite moderately severe ARF, and AIN should always be considered in patients with non-oliguric ARF.

Cont.•Management Some patients with

drug-induced AIN recover following withdrawal of the drug alone, but corticosteroids (e.g. prednisolone 1 mg/kg/day) accelerate recovery and may prevent long-term scarring. Dialysis is sometimes necessary, but is usually only short-term. Other specific causes should be treated where possible

CHRONIC INTERSTITIAL NEPHRITIS • Aetiology Chronic interstitial nephritis (CIN) is

caused by a heterogeneous group of diseases, summarised in . However, it is quite common for the condition to be diagnosed late and for no aetiology to be apparent. Toxic causes of CIN The combination of interstitial nephritis and tumours of the collecting system is seen in Balkan nephropathy, so called because of where cases are found, and has been controversially attributed to ingestion of fungal toxins, particularly ochratoxin A, present in food made from stored grain. A plant toxin, aristolochic acid, has been blamed for a rapidly progressive syndrome caused by mistaken identity of ingredients in herbal preparations

Cont/CIN• CAUSES OF CHRONIC INTERSTITIAL NEPHRITIS

Acute interstitial nephritis• Any of the causes of AIN if persistent • • Glomerulonephritis• Varying degrees of interstitial inflammation

occur in association with most types of inflammatory glomerulonephritis

• Immune/inflammatory• Sarcoidosis • Sjögren's syndrome • SLE, primary autoimmune • Chronic transplant rejection

• Toxic • Mushrooms • Lead • Chinese herbs • Balkan nephropathy

• Drugs• All drugs causing AIN • Lithium toxicity • Analgesic nephropathy • Ciclosporin, tacrolimus

• Infection• Consequence of severe pyelonephritis

• Congenital/developmental• Vesico-ureteric reflux-is associated; causation not clear • Renal dysplasias-often associated with reflux • Inherited-now well recognised but mechanisms unclear • Other-Wilson's disease, medullary sponge kidney, sickle-cell nephropathy

• Metabolic and systemic diseases • Hypokalaemia, hyper-calciuria, hyperoxaluria • Amyloidosis

Cont.• Long-term ingestion (years to decades) of

analgesic drugs can cause renal papillary necrosis and CIN. As the papillae are at the end of the capillary distribution in the kidney, they become ischaemic most easily and may necrose in this condition, in sickle-cell disease and occasionally in diabetes and other conditions. Necrosed papillae may cause ureteric obstruction and renal colic. Papillary necrosis is difficult to identify other than on IVU or retrograde pyelography. In animals, lesions can be induced with almost any NSAID; however, there has been a dramatic fall in the incidence of this disease following withdrawal of phenacetin from compound analgesics. If it is diagnosed, cessation of analgesic intake may arrest progression

Cont.• Clinical and biochemical features Most patients

present in adult life with CRF, hypertension and small kidneys. CRF is often moderate (urea < 25 mmol/l or 150 mg/dl) but, because of tubular dysfunction, electrolyte abnormalities are typically more severe (e.g. hyperkalaemia, acidosis). Urinalysis abnormalities are non-specific. A minority of patients present with hypotension, polyuria and features of sodium and water depletion (e.g. low blood pressure and jugular venous pressure)-salt-losing nephropathy. Impairment of urine-concentrating ability and sodium conservation places patients with CIN at risk of superimposed ARF with even moderate salt and water depletion during an acute illness. Hyperkalaemia may be disproportionate in CIN or in diabetic nephropathy because of hyporeninaemic hypoaldosteronism . Renal tubular acidosis is seen most often in myeloma, sarcoidosis, cystinosis and amyloidosis.

Glomerulonephritis / Glomerulosclerosis

• Glomerulonephritis - An inflammatory condition that affects predominantly the glomeruli.

• Causes•IgA nephropathy• Streptococcus bacteria•Autoimmune

• Glomerulosclerosis - scarring of the glomeruli

GN/GSSigns and Symptoms• Blood or protein in urine• Frothy urine (signifying protein in

urine) • Dark or pink-coloured urine • Leg swelling • Systemic disease like diabetes or

autoimmune disease will have systemic manifestations, e.g. weight loss, arthritis, or skin rash

GN/GS

TreatmentSpecific•Suppression of inflammation may

be achieved by certain medications (eg steroids).

General•Medications to decrease

excretion of urinary protein •Control of blood pressure•Dietary modifications

Glomerulus – Anato / Histo

Nephr I / O tic ????• NephrOtic

(PrOtein)• 3 Systemic Diseases

• Diabetes• SLE• Amyloidosis

• 1 “membrane”• Membranous GN

• 2 others• Minimal Change• Focal Segmental

• NephrItic (RBC +/-casts)• 3 Autoimmune

• Poststrep GN (Type III)

• IgA Nephropathy (Type III)

• Goospasture’s (Type II)

• 1 “membrane”• Membranoproliferative

• 2 others• Crescentic• Alport’s (collagen IV

defect)

Hypersensitivity Essentials of GN

• Type I – IgE cross-linking on presensitizes mast cells inflammatory mediators released

• Type II – Antibodies directed against specific “enemies.” Damage cells via complement mediated “MAC” Inflammatory response NOT necessarily present

• Type III – Immune complex deposits (eg SLE) activates complement C5a chemotactic to neutrophils damage

• Type IV – T-cell mediated

NephrOtic

• Membranous (#1)– Type III HS• Immune deposits IN the GBM• Assoc w/ hepatitis B antigenemia, autoimmune

diseases, thyroiditis, malignancies, pharm (gold, penicillamine, captopril, NSAIDs).

• Minimal Change Disease (#1 Kids)• “lipoid nephrosis (why???)”• Tx w/ steroids

• Focal Segmental Glomerulosclerosis• Presents w/ acute onset; Glomerular “scarring” • Mutliple etiology: Podocyte injury, Nephron loss,

Renal vasodilatation (diabetic nephropathy, sickle cell, obesity, Von Gierke’s, Pregnancy, Obesity, Healing of prior inflammatory injury)

NephrOtic – Systemic Disease

•Diabetes – (1) GBM thickening, (2) KW Nodules, (3) DIFFUSE glomerular sclerosis

•SLE (Type III) – SubENDOthelial deposits

•Amyloidosis “apple green”

NephrItic – Autoimmune• Poststrep GN (#1 acute) – type III

(“small” – subepithelial “humps”) – follows sore throat or cellulitis •Peripheral & periorbital edema (autoimmune)

• IgA – post-infectious – type III•Mild, self-limiting, assoc w/ Henoch-Sch

• Goodpastures – type II•Men in mid 20’s

NephrItic – Other 3• Membranoproliferative – MESANGIAL

CELLS proliferate. Assoc w/ Hep C, SLE, a1-antitrypsin.

• Crescentic GN – Fibrin deposition in Bowman’s. Assoc w/ post-strep & membranous GN.

• Alport’s – Hereditary, type IV collagen defect, CN VIII defective

Membranoproliferative“tram-tracking”

Linear – Type IIGoodpasture’s(anti-GBM)Capillary BM of glomerulus & alveolar walls

Granular – Type IIIIgA Nephropathy(mesangial deposits)

Post-Strep GN(Subepithelial)

Membranous GN(deposits are in the GBM)

SLE GN(Subendothelial)

Colon CA (anti-CEA deposits)