Title All Urinary Disorders.pdf ✅

Glomerular diseases • 397 15 Most types of glomerulonephritis are immunologically mediated and several respond to immunosuppressive drugs. Deposition of antibody occurs in many types of glomerulonephritis and testing for circulating or glomerular deposition of antibodies may aid diagnosis (see Fig. 15.11 and Boxes 15.8 and 15.10). In small-vessel vasculitis, no glomerular antibody deposition is observed (pauci-immune), but the antibodies may be indirectly pathogenic by activating neutrophils to promote endothelial injury (Fig. 15.11). Glomerulonephritis is generally classified in terms of the histopathological appearances, as summarised in Box 15.15 and Figure 15.12. Many non-specialists find the terminology used in describing glomerulonephritis to be confusing; some definitions are provided in Box 15.16. It is important to stress that the histological appearance rarely confirms a specific renal disease but rather suggests a limited range of diagnoses, which may be confirmed by further investigation. Conversely, some diseases, such as lupus, are associated with more than one histological pattern of injury. The most common histological subtypes may be categorised according to their typical clinical presentation, as discussed below. Genetic disorders associated with glomerular disease are described later (p. 403). pathological cause. Investigation and management of suspected diabetes insipidus are described on page 688. Nocturia Nocturia is defined as waking up at night to void urine. It may be a consequence of polyuria but may also result from increased fluid intake or diuretic use in the late evening (including caffeine). Nocturia also occurs in CKD, and in prostatic enlargement when it is associated with poor stream, hesitancy, incomplete bladder emptying, terminal dribbling and urinary frequency due to partial urethral obstruction (p. 437). Nocturia may also occur due to sleep disturbance without any functional abnormalities of the urinary tract. Urinary incontinence Urinary incontinence is defined as any involuntary leakage of urine. It may occur in patients with a normal urinary tract, as the result of dementia or poor mobility, or transiently during an acute illness or hospitalisation, especially in older people (see Box 15.54, p. 436). The pathophysiology, investigation and management of urinary incontinence are discussed in detail later in the chapter (p. 436). Glomerular diseases Glomerular diseases account for a significant proportion of acute and chronic kidney disease. Most patients with glomerular disease do not present acutely and are asymptomatic until abnormalities are detected on routine screening of blood or urine samples. There are many causes of glomerular damage, including immunological injury, inherited diseases such as Alport’s syndrome (p. 403), metabolic diseases such as diabetes mellitus (p. 757), and deposition of abnormal proteins such as amyloid in the glomeruli (p. 81). The glomerular cell types that may be the target of injury are shown in Figure 15.11. Proteinuria is the hallmark of glomerular disease; however, the response of the glomerulus to injury and hence the predominant clinical features vary according to the nature of the insult, ranging from fulminant nephrotic syndrome to rapidly progressive glomerulonephritis (see Fig. 15.9). Several prognostic indicators are common to all causes of glomerulonephritis (Box 15.14) and may be helpful in assessing the need for immunosuppressive therapy. Glomerulonephritis While glomerulonephritis literally means ‘inflammation of glomeruli’, the term is often used more broadly to describe all types of glomerular disease, even though some of these (e.g. minimal change nephropathy) are not associated with inflammation. Fig. 15.11 Glomerulonephritis associated with antibody production. Antibodies and antigen–antibody (immune) complexes may target or be deposited in specific components of the glomerulus, resulting in different patterns of histological injury and clinical presentation. Testing for antibody deposition in the glomerulus by immunofluorescence (IF) on renal biopsy tissue or for antibodies in the serum may aid diagnosis. Diagnostic tests are shown in italics. (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; dsDNA = double-stranded DNA; GBM = glomerular basement membrane; IgA = immunoglobulin A; SLE = systemic lupus erythematosus) Endothelium (indirectly) Small-vessel vasculitis ANCA (serum) GBM Goodpasture's disease Anti-GBM antibody (serum + IF on biopsy; see Fig.15.12H) Podocyte Membranous nephropathy Anti-phosphilipase A2 receptor 1 (serum + IF on biopsy; experimental at present; see Fig.15.12F) Planted antigens SLE – ANA, anti-dsDNA (serum) Post-infectious glomerulonephritis Circulating immune complexes Cryoglobulinaemia (Cryoglobulins in serum) Serum sickness Endocarditis Mesangium IgA nephropathy (polyclonal rise in serum IgA in 50% patients; IF on biopsy; see Fig.15.12G) 15.14 Poor prognostic indicators in glomerular disease • Male sex • Hypertension • Persistent and severe proteinuria • Elevated creatinine at time of presentation • Rapid rate of decline in renal function • Tubulo-interstitial fibrosis observed on renal biopsy
398 • NEPHROLOGY AND UROLOGY discussed elsewhere, including diabetic nephropathy (p. 757) and amyloid (p. 81). Minimal change nephropathy Minimal change disease occurs at all ages but accounts for most cases of nephrotic syndrome (see Box 15.15) in children and about one-quarter of adult cases. It is caused by reversible dysfunction of podocytes. On light microscopy, the glomeruli appear normal (Fig. 15.12A), but fusion of podocyte foot processes is observed on electron microscopy. The presentation is with nephrotic syndrome, which typically is severe; it remits Diseases typically presenting with nephrotic syndrome In these diseases, the injury is focused on the podocyte and there is little histological evidence of inflammation or cell proliferation in the glomerulus (non-proliferative, Fig. 15.12). Minimal change and primary focal segmental glomerulosclerosis (FSGS) typically present with fulminant nephrotic syndrome, whereas in membranous nephropathy and secondary FSGS, the nephrosis tends to be more indolent in nature. Other causes of nephrotic syndrome due to systemic disease are 15.15 Glomerulonephritis categorised by clinical presentation and histological classification Histology Immune deposits Pathogenesis Associations Comments Nephrotic presentation Minimal change Normal, except on electron microscopy, where fusion of podocyte foot processes is observed (non-specific finding) None Unknown; probable circulating factor promoting podocyte injury Some cases are genetic (p. 403) Atopy Drugs, most commonly NSAIDs Haematological malignancies Acute and often severe nephrotic syndrome Good response to glucocorticoids Dominant cause of idiopathic nephrotic syndrome in childhood Focal segmental glomerulosclerosis (FSGS) Segmental scars in some glomeruli No acute inflammation Podocyte foot process fusion seen in primary FSGS Non-specific trapping in focal scars Unknown; circulating factors may increase glomerular permeability Injury to podocytes may be common feature Some cases are genetic (p. 403) APOL1 variant in people of West African descent Causes of secondary FSGS include: Healing of previous local glomerular injury HIV infection Heroin misuse Morbid obesity Chronic hypertension Primary FSGS presents as idiopathic nephrotic syndrome but is less responsive to treatment than minimal change; may progress to renal impairment, and can recur after transplantation Secondary FSGS presents with variable proteinuria and outcome Membranous nephropathy Thickening of GBM Progressing to increased matrix deposition and glomerulosclerosis Granular subepithelial IgG Antibodies to a podocyte surface antigen (commonly phospholipase A2 receptor 1), with complement- dependent podocyte injury HLA-DQA1 (for idiopathic) Drugs: Penicillamine, NSAIDs, heavy metals Hepatitis B virus Malignancy Lupus1 Common cause of adult idiopathic nephrotic syndrome One-third progress, one-third spontaneously remit and one-third remain stable; may respond to glucocorticoids and immunosuppressants Mild glomerulonephritic presentation IgA nephropathy Increased mesangial matrix and cells Focal segmental nephritis in acute disease Mesangial IgA (and C3) Unknown Mucosal infections (e.g. helminths) may be involved Usually idiopathic, flares triggered by upper respiratory infection Liver disease Coeliac disease Common disease with range of presentations, usually including haematuria and hypertension Henoch–Schönlein purpura is an acute IgA variant common in children Mesangiocapillary glomerulonephritis Immunoglobulin type Immunoglobulins Deposition of circulating immune complexes or ‘planted’ antigens Infections, autoimmunity or monoclonal gammopathies Most common pattern found in association with subacute bacterial infection, but also with cryoglobulinaemia ± hepatitis C virus, and others Complement type Complement components Complement abnormalities, inherited or acquired Dense deposit disease is associated with abnormal activation of alternative complement pathway Complement gene mutations C3 nephritic factor and partial lipodystrophy In dense deposit disease, intramembranous deposits No proven treatments Continued
Glomerular diseases • 399 15 15.15 Glomerulonephritis categorised by clinical presentation and histological classification – continued Histology Immune deposits Pathogenesis Associations Comments Rapidly progressive glomerulonephritis presentation Focal necrotising glomerulonephritis Segmental inflammation and/or necrosis in some glomeruli ± crescent formation Variable according to cause but typically negative (or ‘pauci- immune’) Small-vessel vasculitis, often ANCA-mediated Primary or secondary small-vessel vasculitis Often occurs in systemic disease Responds to treatment with glucocorticoids and immunosuppressants Diffuse proliferative glomerulonephritis 2 Infection-related diffuse proliferative glomerulonephritis 3 Diffuse proliferation of endothelial and mesangial cells Infiltration by neutrophils and macrophages ± crescent formation Subendothelial and subepithelial Immune complex-mediated (e.g. to streptococcal infection with presumed cross-reactive epitopes) Post-streptococcal Concurrent infection with staphylococci, endocarditis Presents with severe sodium and fluid retention, hypertension, haematuria, oliguria Usually resolves spontaneously Anti-glomerular basement membrane disease Usually crescentic nephritis Linear IgG along GBM Autoantibodies to α3 chain of type IV collagen in GBM HLA-DR15 (previously known as DR2) Associated with lung haemorrhage but renal or lung disease may occur alone Treat with glucocorticoids, cyclophosphamide and plasma exchange 1 Systemic lupus erythematosus can cause almost any histological injury pattern, most commonly membranous nephropathy or diffuse proliferative glomerulonephritis. 2 In addition to the association with infection and anti-GBM disease, a diffuse proliferative glomerulonephritis picture may also be seen with lupus and occasionally IgA nephropathy. 3 Infection may also present with mesangioproliferative glomerulonephritis and membranous nephropathy (HIV). (ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; APOL1 = apolipoprotein L1; GBM = glomerular basement membrane; HLA = human leucocyte antigen; IgA = immunoglobulin A; NSAIDs = non-steroidal anti-inflammatory drugs) Fig. 15.12 Histopathology of glomerular disease. ( A – E Light microscopy) A A normal glomerulus. Note the open capillary loops and thinness of their walls. B Focal segmental glomerulosclerosis (GS). The portion of the glomerulus arrowed shows loss of capillary loops and cells, which are replaced by matrix. C Focal necrotising glomerulonephritis (GN). A portion of the glomerulus (N = focal necrotising lesion) is replaced by bright pink material with some ‘nuclear dust’. Neutrophils may be seen elsewhere in the glomerulus. There is surrounding interstitial inflammation (I). This is most commonly associated with small-vessel vasculitis and may progress to crescentic nephritis (see E ). D Membranous glomerulonephritis. The capillary loops (C) are thickened (compare with the normal glomerulus) and there is expansion of the mesangial regions by matrix deposition (M). However, there is no gross cellular proliferation or excess of inflammatory cells. E Crescentic glomerulonephritis. The lower part of Bowman’s space is occupied by a semicircular formation (‘crescent’, Cr) of large pale cells, compressing the glomerular tuft. This is seen in aggressive inflammatory glomerulonephritis. Antibody deposition in the glomerulus. ( F – H Direct immunofluorescence) F Granular deposits of IgG along the basement membrane in a subepithelial pattern, typical of membranous GN. G Immunoglobulin A (IgA) deposits in the mesangium, as seen in IgA nephropathy. H Ribbon-like linear deposits of anti-GBM antibodies along the glomerular basement membrane in Goodpasture’s disease. The glomerular structure is well preserved in all of these examples. (A, C, D, E) Courtesy of Dr J.G. Simpson, Aberdeen Royal Infirmary. (F, G, H) Courtesy of Dr R. Herriot. A B C D E F G H Normal glomerulus Focal segmental GS Focal necrotising GN Membranous GN Crescentic GN Membranous GN IgA nephropathy Anti-GBM disease C N I Cr M
400 • NEPHROLOGY AND UROLOGY rarely exhibit full-blown nephrotic syndrome. Management of secondary FSGS is focused on treating the underlying cause and reducing proteinuria by inhibiting the renin–angiotensin system (p. 417). Membranous nephropathy Membranous nephropathy is the most common cause of nephrotic syndrome in Caucasian adults. It is caused by antibodies (usually autoantibodies) directed at antigen(s) expressed on the surface of podocytes, including the M-type phospholipase A2 receptor 1. While most cases are idiopathic, a proportion are associated with other causes, such as heavy metal poisoning, drugs, infections, lupus and tumours (see Box 15.15 and Fig. 15.12D and F). Approximately one-third of patients with idiopathic membranous nephropathy undergo spontaneous remission, one-third remain in a nephrotic state, and one-third develop progressive CKD. High doses of glucocorticoids and cyclophosphamide may improve both the nephrotic syndrome and the long-term prognosis. However, because of the toxicity of these regimens, many nephrologists reserve such treatment for those with severe nephrotic syndrome or deteriorating renal function. Treatment of secondary membranous nephropathy is directed at the underlying cause. Diseases typically presenting with mild nephritic syndrome Patients with mild glomerulonephritis typically present with non- visible haematuria and modest proteinuria, and their renal disease tends to follow a slowly progressive course. IgA nephropathy and mesangiocapillary glomerulonephritis (MCGN) typically fall in this category. Their presentation is highly variable, however; IgA nephropathy occasionally presents with rapidly progressive glomerulonephritis while MCGN may present with nephrotic syndrome. Other diseases that present with haematuria, modest proteinuria and slow progression include Alport’s syndrome (p. 403). IgA nephropathy This is one of the most common types of glomerulonephritis and can present in many ways. Haematuria is the earliest sign and non-visible haematuria is almost universal, while hypertension is also very common. These are often detected during routine screening: for example, at occupational medical examinations. Proteinuria can also occur but is usually a later feature. In many cases, there is slowly progressive loss of renal function leading to end-stage renal disease (ESRD). A particular hallmark of IgA nephropathy in young adults is the occurrence of acute self-limiting exacerbations, often with visible 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. Asymptomatic presentations dominate in older adults, with non-visible haematuria, hypertension and reduction in GFR. Occasionally, IgA nephropathy progresses rapidly in association with crescent formation on biopsy. Management is largely directed towards the control of blood pressure, with renin–angiotensin system inhibitors preferable in those with proteinuria. There is some evidence for additional benefit from several months of high-dose glucocorticoid treatment in those at high-risk of progressive disease (see Box 15.14), but no strong evidence for other immunosuppressive agents. A role for other therapies, such as fish oil, remains uncertain. with high-dose glucocorticoid therapy (1 mg/kg prednisolone for 6 weeks), though the response to therapy is often less satisfactory in older patients. Some patients who respond incompletely (glucocorticoid-resistant) or relapse frequently need maintenance glucocorticoids (glucocorticoid dependence), cytotoxic therapy or other agents. Glucocorticoid resistance in children warrants a biopsy to exclude an alternative diagnosis, but if minimal change is confirmed, a genetic cause should be considered (p. 403). Minimal change disease typically does not progress to CKD but can present with problems related to the nephrotic syndrome (see Box 15.11) and complications of treatment. Focal segmental glomerulosclerosis Primary focal segmental glomerulosclerosis (FSGS) (Fig. 15.12B) can occur in all age groups but is particularly common in people of West African descent, who, compared with other ethnicities, have a much higher carriage rate of an apolipoprotein L1 (APOL1) gene variant that is associated with increased risk of FSGS. Histological analysis shows sclerosis initially limited to segments of the glomeruli, which may also show positive staining for 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. In most cases the underlying cause is unknown (primary FSGS) and these patients typically present with abrupt onset of severe nephrotic syndrome. Primary FSGS may respond to high-dose glucocorticoid therapy (0.5–2.0 mg/ kg/day) but the response is rarely as rapid or complete as for minimal change disease. Immunosuppressive drugs, such as ciclosporin, cyclophosphamide and mycophenolate mofetil, have also been used but their efficacy is uncertain. Progression to CKD is common in patients who do not respond to glucocorticoids and the disease frequently recurs after renal transplantation. FSGS may also be secondary to other diseases such as human immunodeficiency virus (HIV) renal disease (particularly in African Americans), morbid obesity or chronic hypertension. In addition, it may reflect scarring from previous focal glomerular injury resulting from HUS, cholesterol embolism or vasculitis. Patients with secondary FSGS typically present with more modest proteinuria than those with primary disease and 15.16 Terminology used in glomerulonephritis Light microscopy • Focal: affecting some but not all glomeruli • Diffuse: affecting > 50% of glomeruli • Segmental: affecting a portion of a glomerulus • Global: affecting all of the glomerulus • Necrotising: severe injury leading to an area of necrosis, usually associated with vasculitis • Crescentic: a crescent-shaped area of inflammatory cells responding to severe glomerular injury Electron microscopy • Subendothelial immune deposits: found between the endothelial cell and the GBM – often found in nephritic presentations • Intramembranous immune deposits: found within the GBM – found in the dense deposit variant of mesangiocapillary glomerulonephritis • Subepithelial immune deposits: found between the epithelial cell and the GBM – often found in nephrotic presentations, including membranous presentation of lupus (GBM = glomerular basement membrane)