Lecture 2

 Minimal change disease occurs at all ages but accounts for nephrotic syndrome in most children and about one­quarter of adults. It is caused by reversible dysfunction of podocytes.  The presentation is with proteinuria or nephrotic syndrome, which typically remits with high­dose corticosteroid therapy (1 mg/kg prednisolone for 6 weeks).  Minimal change disease does not progress to CKD but can present with problems related to the nephrotic syndrome and complications of treatment.

 The primary, idiopathic form of MCD is very responsive to steroids. Up to 95% of patients achieve complete remission, defined as proteinuria declining to levels below 300 mg/day with stable renal function.  Some patients who respond incompletely or relapse frequently need maintenance corticosteroids, cytotoxic therapy or other agents.  Secondary forms of MCD should be treated by focusing on removal or mitigation of the inciting insult, such as discontinuation of a certain drug or treatment of an underlying malignancy.

 Primary focal segmental glomerulosclerosis (FSGS) can occur in all age groups. In some patients, FSGS can have specific causes, such as HIV infection, podocyte toxins and massive obesity, but in most cases the underlying cause is unknown (primary FSGS).  Patients with primary FSGS present with massive proteinuria and idiopathic nephrotic syndrome.

 Histological analysis shows sclerosis affecting segments of the glomeruli, which may also show non specific traping staining deposits of C3 and IgM on immunofluorescence.  Since 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.

 Although nephrotic syndrome is typical, some patients present with the histological features of FSGS but less proteinuria.  In these patients, the focal scarring may reflect healing of previous focal glomerular injury, such as HUS, cholesterol embolism or vasculitis. These examples of secondary FSGS have different course and treatments.

 Primary FSGS can respond to high­dose corticosteroid therapy (0.5–2.0 mg/kg/day) but most patients show little or no response.  Immunosuppressive drugs, such as ciclosporin, cyclophosphamide and mycophenolate mofetil, have also been used.  Progression to CKD is common in patients who do not respond to steroids and the disease frequently recurs after renal transplantation, with an almost immediate return of proteinuria following transplant in some cases.

 membranous nephropathy, is the most common cause of nephrotic syndrome in adults. It is caused by antibodies (usually autoantibodies) directed at antigen(s) expressed on the surface of podocytes.  Recent studies suggest that one such antigen is the M­type phospholipase A2receptor1 (antiPLAR2 Abs).  A proportion of cases are associated with other causes, such as heavy metal poisoning, drugs, infections and tumours and but most are idiopathic.  Approximately one­third of patients with idiopathic membranous glomerulonephritis undergo spontaneous remission; one­third remain in a nephrotic state, and one­third go on to develop CKD.

 Short­term treatment with high doses of corticosteroids and cyclophosphamide may improve both the nephrotic syndrome and the long­term prognosis. However, because of the toxicity of these regimens, many nephrologists reserve such treatment for those with severe nephrotic syndrome or deteriorating renal function.

 This is one of the most common types of glomerulonephritis and can present in many ways. Haematuria is the earliest sign and is almost universal, and hypertension is also very common.  Proteinuria can also occur but is usually a later feature. In many cases, there is slowly progressive loss of renal function leading to ESRD. Clinical presentations are protean and vary with age.  A particular hallmark of IgA nephropathy in young adults is the occurrence of acute self­limiting exacerbations, often with gross haematuria, in association with minor respiratory infections.

 This may be so acute as to resemble acute post­infectious 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.  Asymptomatic presentations dominate in older adults, with haematuria, hypertension and loss of GFR. Occasionally, IgA nephropathy progresses rapidly and crescent formation may be seen.  The prognosis is usually good, especially in those with normal blood pressure,normal renal function and absence of proteinuria at presentation.Surprisingly, recurrent macroscopic haematuria is a good prognostic sign.

 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.  There is some evidence for additional benefit from several months of high­dose corticosteroid treatment in high­risk disease, but no strong evidence for other immunosuppressive agents.  Allpatients with or without hypertensionand proteinuria, should receive ACE inhibitor and/or angiotensin II receptor antagonist which enhances reduction of proteinuria and preservation ofrenalfunction.

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Lecture 3

 This condition most commonly occurs in children but can also be observed in adults. It is characterised by a systemic vasculitis that often arises in response to an infectious trigger.  The presentation is with a characteristic petechial rash typically affecting buttocks and lower legs, and abdominal pain due to the occurrence of vasculitis involving the gastrointestinal tract. 

 The gastrointestinal disease, which occurs secondary to submucosal edema and hemorrhage, may be limited to pain and vomiting. Some patients, however, may experience more significant complications, such as frank gastrointestinal hemorrhage or intussusception.  Less common systemic manifestations include scrotal pain or swelling, as well as central nervous system disease (i.e., headache, seizures).

 The presence of glomerulonephritis is usually indicated by the occurrence of haematuria. When Henoch–Schönlein purpura occurs in older children or adults, the glomerulonephritis is usually more prominent and less likely to resolve completely. Renal biopsy shows mesangial IgA deposition and appearances that are indistinguishable from acute IgA nephropathy.  Treatment is supportive in nature; in most patients, the prognosis is good, with spontaneous resolution, but some, particularly adults, progress to develop ESRD.

 MPGN is characterised by an increase in mesangial cellularity with thickening of glomerular capillary walls and subendothelial deposition of immune complexes and/or components of the complement pathway.  The typical presentation is with proteinuria and haematuria.

It can be classified into two main subtypes.  The first is characterised by deposition of immunoglobulins within the glomeruli. This subtype is associated with chronic infections, autoimmune diseases and monoclonal gammopathy.  The second is characterised by deposition of complement in the glomeruli and is associated with inherited or acquired abnormalities in the complement pathway. Within this category is so­ called ‘dense deposit disease’”DDD”, which is typified by deposition of electron­dense deposits within the GBM.  The third subtype is recognised, in which neither immunoglobulins nor complement are deposited in the glomeruli. This is associated with healing following thrombotic microangiopathies, such as HUS and TTP.

 Treatment of MPGN associated with immunoglobulin deposits consists of identifying and treating the underlying disease, if possible, and the use of immunosuppressive drugs such as mycophenolate mofetil or cyclophosphamide.  There is no specific treatment for MPGN associated with deposition of complement in the glomeruli or for dense deposit disease.

 Glomerulonephritis may occur in connection with infections of various types, including subacute bacterial endocarditis.  The most common histological pattern in bacterial infection is mesangiocapillary glomerulonephritis, often associated with extensive immunoglobulin deposition in the glomeruli with evidence of complement consumption (low serum C3).In the developed world, hospital­acquired infections with various organisms are a common cause of these syndromes.  Worldwide, glomerulonephritis more commonly follows hepatitis B, hepatitis C, schistosomiasis, leishmaniasis, malaria and other chronic infections. Infection with HIV may be associated with FSGS, particularly in people of African descent.

 This is a specific subtype of post­infectious glomerulonephritis. It is much more common in children than adults.  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.

 Serum concentrations of C3 and C4 are typically reduced, reflecting complement consumption, and evidence of streptococcal infection (High “antistreptolysin O “ASO titer) may be found.  Renal function begins to improve spontaneously within 10–14 days, and management by fluid and sodium restriction with diuretic and antihypertensive agents is usually adequate.  Remarkably, the renal lesion in almost all children and many adults seems to resolve completely, despite the severity of the glomerular inflammation and proliferation seen histologically.

 Rapidly progressive glomerulonephritis (also known as crescentic glomerulonephritis) is characterised by rapid loss of renal function over days to weeks.  Renal biopsy shows crescentic lesions, often associated with necrotising lesions within the glomerulus, termed focal segmental (necrotising) glomerulonephritis. It is typically seen in Goodpasture’s disease, where the underlying cause is the development of antibodies to the glomerular basement membrane (anti­GBM antibodies), and in small­vessel vasculitides.  It can also be observed in SLE and occasionally IgA and other nephropathies. Rapid onset disease may be associated with relatively little proteinuria.

 Management depends on the underlying cause but immunosuppressive drugs are often required. Patients with anti­GBM disease should be treated with plasma exchange combined with corticosteroids and immunosuppressants (cyclophosphamide).  Patients with renal involvement secondary to ANCA­associated vasculitis and SLE should also be treated with corticosteroids and immunosuppressants.  Plasma exchange:to remove circulating antibodies  Steroids: to suppress inflammation from antibody already depositedin the tissue.  Cyclophosphamide: to suppress further antibody synthesis

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