Glomerularnephritis (PDF)

Chapter objectives 1. After studying this chapter, you should be able to:  2. Describe the components of acute nephritic syndrome and its variations.  3. Describe other forms of presentation of glomerulonephritis (GN) and their classification by clinical presentation, renal biopsy...

Chapter objectives 1. After studying this chapter, you should be able to:  2. Describe the components of acute nephritic syndrome and its variations.  3. Describe other forms of presentation of glomerulonephritis (GN) and their classification by clinical presentation, renal biopsy appearance and cause.  4. Understand the pathogenesis of post-streptococcal GN.  5. Differentiate acute nephritis occurring with post-streptococcal GN, IgA disease and systemic diseases.  6. Discuss the consequences of glomerular disease.  7. Describe the parameters of urinary sediment examination.  8. Discuss the natural history of post-streptococcal GN.  Introduction Acute glomerulonephritis (GN) refers generally to inflammatory renal diseases affecting the glomeruli of some or all of the million nephrons of each kidney. Although this classification is based largely on the pathological appearance of glomeruli, other components of the nephron, blood vessels and renal interstitium are involved to a variable extent. Many of the acute glomerulonephritides are primary or idiopathic, whereas, with others, a secondary cause is identified. The pathogenesis of GN varies with the diagnosis and may involve multiple factors. With many forms, it is only partially understood. In this chapter, the pathogenesis of GN will be explained by a discussion of the presentation and diagnosis of a case of acute nephritic syndrome. There are a bewildering number of types of primary and secondary GN, and the systems of classification are overlapping and confusing. For this reason, the student is urged to concentrate on the common or classic forms of disease which are discussed in this chapter (see  [Case 7.1: 1](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#b0020) ).  **CASE 7.1** **Glomerulonephritis and the acute nephritic syndrome: 1** Nephritic syndrome Michael is a 22-year-old man who presented to the local hospital of a small country town complaining of headache and dark urine. He had also noticed a reduction in urine output (oliguria) even though he had a normal fluid intake. In the past, Michael has had frequent sore throats and skin infections. Approximately 2 weeks before the presentation, he had another sore throat which resolved spontaneously after 8 days. The resident doctor noted that he had facial swelling and blood pressure of 165/105 mmHg. His jugular venous pressure was raised 2 cm, and rales (sounds produced by the passage of air through fluid in the lower respiratory tract) were heard on auscultation at the bases of both lungs. There was a creamy exudate on his tonsils and mild pharyngeal erythema. Dipstick analysis of urine revealed blood +++ and protein +. The doctor suspected that Michael had acute GN. The important clinical features in this patient include the occurrence of oliguria, dark urine, hypertension, and fluid overload 2 weeks after a sore throat. The questions that arise from this clinical history include the following:1. What is the pathophysiology of each of the clinical features? 2\. Are the clinical features interrelated? 3\. What is the relationship of the sore throat to the acute illness which followed 2 weeks later? 4\. What made the doctor suspect a diagnosis of GN? The answers to these questions will be revealed in the initial sections of this chapter. Before this, however, we must discuss the examination of urinary sediment, the first and one of the most important tests in a suspected case of renal disease, which provides a non-invasive glimpse of the inflammatory processes which occur within the kidney. Save to collection Share Urinary sediment examination To confirm the presence of renal inflammation, a sediment examination should be performed on a centrifuged sample of fresh urine. Although these techniques are now routinely performed by experienced pathology laboratories, microscopic examination of spun urine sediment is still manually performed by nephrologists and their trainees. To allow quantification of the urinary abnormalities, this should be done in a standardised fashion. Ten mL of urine is centrifuged for 5 min, 9.5 mL of the urine is then discarded, the sediment is resuspended in the remaining 0.5 mL of urine by gentle tapping of the test tube, and this resuspended sediment is examined under a microscope. Normal urine may contain up to ten red blood cells, ten white blood cells and one to two hyaline (but not granular or cellular) casts per high power field. The finding of an excess number of red or white cells may be explained by abnormalities anywhere in the urinary tract. It should be noted that a positive dipstick test for blood indicates the presence of haem pigment, whereas microscopy is required to confirm the presence of red blood cells (this is discussed in more detail in  [Chapter 12  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000129)). When cells or cellular debris aggregate in the tubular lumen, they may form casts of the tubule. Granular or cellular (epithelial, red, or white cell) casts indicate the presence of renal parenchymal disease, whereas hyaline casts are formed from Tamm-Horsfall protein and tend to be a non-specific finding. An 'active' sediment contains elements consistent with renal inflammation and/or cell necrosis, whereas a 'benign' sediment may contain a few cells and only hyaline casts. Urine should be examined as a fresh sample because casts may break down within 1 to 2 h.  [Fig. 7.1](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0010) shows examples of urinary casts. See  [Case 7.1: 2](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#b0025) .  **INTERESTING FACTS** Healthy individuals pass on average up to two million erythrocytes in their urine per day, with the actual number in an individual varying from four-fold less to more than this. These cells generally come from the kidney and are thus 'dysmorphic' in appearance. As urinary dipsticks for haem pigment can detect as few as 5--20 erythrocytes/µL, normal urinary blood should usually not be detectable by dipstick testing. A close-up of a microscope Description automatically generated Fig. 7.1 Urinary casts: (A) hyaline, (B) red cell. Casts form within the tubular lumen and therefore take on the shape of the lumen with parallel sides. (Photographs courtesy of Prof. J. Lawrence.)  Fig. 7.2 Renal biopsy of the patient with post-streptococcal glomerulonephritis. \(A) Light microscopy showing proliferation of intrinsic glomerular cells and infiltrating neutrophil leucocytes. (B) Electron microscopy showing large immune deposits ('humps' H) projecting into the Bowman's space (B) between the glomerular basement membrane (∗) and glomerular epithelial cell (arrows). (C) Immunofluorescence microscopy showing a coarse granular pattern for IgG along the glomerular capillary wall. **CASE 7.1** **Glomerulonephritis and the acute nephritic syndrome: 2** Initial investigations Urinary sediment examination showed more than ∗100 red cells/µL and a moderate number of white cell and red cell casts. Serum creatinine was elevated at ∗160 µmol/L. Based on this, the doctor told Michael he had 'nephritis'. The obvious question to be asked at this stage is: which of the clinical and laboratory features of the patient are diagnostic, characteristic, or consistent with the nephritic syndrome (or nephritis)? ∗Values outside the normal range; see Appendix. Save to collection Share Presentation and consequences of glomerular disease Patients with glomerular disease may present in several different ways; these are listed in  [Box 7.1](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#b0010) . The spectrum of the presentation includes asymptomatic microscopic haematuria and/or proteinuria discovered on a routine medical check, acute or chronic kidney disease (CKD), hypertension, or full-blown (or a limited form of) nephrotic or nephritic syndromes. The nephrotic syndrome is described in  [Chapter 6  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000063). It is important to be able to recognise these different presentations and to predict the pathologic condition associated with each one and possible underlying causes.  **BOX 7.1** **Presentation of glomerular disease** Nephritic syndrome∗ Nephrotic syndrome† Asymptomatic proteinuria and/or microscopic haematuria Macroscopic haematuria Acute kidney injury (acute renal failure) Progressive chronic kidney disease Hypertension ∗Haematuria, hypertension, renal functional impairment, and oliguria.†Heavy proteinuria, hypoalbuminaemia, and oedema. The nephritic syndrome consists of haematuria, hypertension, and renal functional impairment (reduced glomerular filtration rate (GFR), reflected by the raised serum creatinine), as was found in the present case. The haematuria and active urinary sediment are indicative of renal inflammation; oliguria and renal functional impairment are a consequence of glomerular infiltration with inflammatory cells and release of vasoactive hormones and cytokines, and hypertension is the result of salt and water retention and vasoactive hormone release. The consequences of glomerular disease and the underlying pathophysiology of each feature are described in  [Table 7.1](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0010) . Renal functional impairment in glomerular disease is multifactorial and arises because of the acute inflammatory process (proliferation of intrinsic glomerular cells, glomerular infiltration with leucocytes, and haemodynamic changes induced by vasoactive hormones and cytokines) and chronic renal scarring (caused by continuing inflammation, hypertension, proteinuria, and other factors). Hypertension occurs in acute nephritis because of salt and water retention (a consequence of the reduction of GFR), glomerular capillary and arteriolar scarring, and neurohumoral changes, in particular activation of the renin--angiotensin system.  Table 7.1 Consequences of glomerular disease Feature Pathophysiology ------------------ ------------------------------------------------------------------------- Proteinuria Impaired filtration barrier function of GCW Haematuria Leak into Bowman's space across GCW or into the tubular lumen Renal impairment Structural and/or functional damage to glomeruli and tubulointerstitium Hypertension Salt and water retention, activation of the renin--angiotensin system GCW, glomerular capillary wall. The diagnosis of glomerular disease and, specifically, nephritic syndrome can almost always be established by a combination of clinical features, serological tests, and renal biopsy. This was the case with the current patient. These clinical and laboratory features also give clues to the pathogenesis of the disease and its complications. See  [Case 7.1: 3](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#b0030) .  **CASE 7.1** **Glomerulonephritis and the acute nephritic syndrome: 3** Diagnostic investigations The history of a sore throat 14 days before the onset of acute nephritis was consistent with a diagnosis of post-streptococcal GN. Serum antistreptococcal O titre (ASOT) was elevated, and serum concentration of the third complement component (C3) was low, indicating complement activation, and was consistent with the presumed diagnosis. In this disease, the renal lesion represents an immunological reaction to nephritogenic antigens in the microorganism responsible for the sore throat. The patient was referred to a nephrologist who arranged a renal biopsy (  [Fig. 7.2](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0015) ). On light microscopy, all glomeruli were infiltrated with neutrophil leucocytes, and there was a proliferation of mesangial and endothelial cells. Electron microscopy showed large electron-dense deposits lying between the podocytes of the visceral glomerular epithelial cells and the glomerular basement membrane. Immunofluorescence microscopy was positive for IgM, IgA, and C3 in a granular capillary wall pattern. (A renal biopsy is frequently unnecessary in this situation because the clinical and other laboratory features can be highly suggestive of the diagnosis and the long term prognosis is usually good.) The results of these diagnostic investigations lead to several questions which will be answered in the following sections of this chapter: 1\. Which serological tests are necessary to establish the diagnosis and classification of GN? 2\. Which renal biopsy features are useful or necessary to classify GN? 3\. What insights do these features give to the pathogenesis of the renal lesion? Save to collection Share Investigation of glomerulonephritis Several serological tests are useful for establishing, confirming, or supporting a specific diagnosis in patients with GN (  [Table 7.2](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0015) ). A positive test result suggests the primary diagnosis but does not prove that it is the cause of renal disease. Some of these serological abnormalities are actually involved in the pathogenesis of the renal lesion and will be discussed in more detail later in this chapter.  Table 7.2 Important diagnostic serological tests for glomerulonephritis Test Diagnosis --------------------------------------------- -------------------------------------------------------------- **Serum complement ** Low C3 Post-streptococcal GN, mesangiocapillary GN Low C3 and C4 Systemic lupus erythematosus **Others ** ANA, anti-double-stranded DNA antibody, ENA Systemic lupus erythematosus ANCA Microscopic polyangiitis or granulomatosis with polyangiitis Anti-GBM antibody Goodpasture's syndrome ASOT Post-streptococcal GN HBsAg Hepatitis B Anti-HCV Hepatitis C HIV HIV associated kidney disease and AIDS VDRL Syphilis Anti-phospholipase A2 receptor Primary membranous GN ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ASOT, antistreptococcal O titre; GBM, glomerular basement membrane; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; VDRL, Venereal Disease Research Laboratory (serological test for syphilis); ENA, extractable nuclear antigens. A renal biopsy usually establishes the diagnosis definitively. The components of renal biopsy examination are discussed in  [Chapter 6  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000063)(  [Table 6.3  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000063#t0020)). In the current patient, the history, positive ASOT, low serum C3, and renal biopsy appearances were all consistent with a diagnosis of post-streptococcal GN. Save to collection Share Differential diagnosis of acute glomerulonephritis GN may occur in isolation or as part of a multisystem disease. Amongst diseases in which GN is the sole manifestation, a specific precipitant is recognised in only a few. In the current case, the precipitant was a streptococcal throat infection occurring 2 weeks before the onset of GN. This once-common disease is seen less frequently nowadays, except in underprivileged populations. The streptococcal infection may also be a skin infection. A similar type of GN can be seen following bacterial infections of other types (postinfectious GN). Many patients presenting with other types of GN give a history of respiratory illness in the preceding days to weeks. Only in some patients is the respiratory illness of definite pathogenetic significance. A common form of GN that needs to be distinguished from post-streptococcal GN is IgA disease (or mesangial IgA nephropathy). IgA disease is a common type of GN, characterised by acute nephritis and, in particular, macroscopic haematuria occurring at the time or within a few days of a viral sore throat. The shorter prodrome and its frequently recurrent nature help to distinguish it at the presentation from post-streptococcal GN (  [Table 7.3](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0020) and  [Fig. 7.3](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0020) ).  Table 7.3 Clinical and pathological differences between post-streptococcal glomerulonephritis (GN) and IgA disease ***Post-streptococcal GN *** ***IgA disease *** ------------------------ -------------------------------------------- ----------------------------------------------------------------------------------------------------------------------- Antecedent pharyngitis Yes, 10--14 days Yes, 0--4 days Acute nephritis Yes Yes Other presentations No Yes  [^∗ ^](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#tbl7_3fnlowast) Recurrence No Yes Long term prognosis Excellent Variable **Diagnostic tests ** Serological Low C3, positive ASOT -- Renal biopsy Glomerular neutrophil infiltration (LM) Mesangial IgA (IF)  [† ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#tbl7_3fndagger) Subepithelial electron-dense deposits (EM) Mesangial electron-dense deposits (EM) ASOT, antistreptococcal O titre; LM, light microscopy; EM, electron microscopy; IF, immunofluorescence microscopy. ∗ Other presentations of IgA disease include macroscopic haematuria, nephrosis (uncommon), hypertension, chronic kidney disease. † See  [Fig. 7.3  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0020). A green glowing substance on a black background Description automatically generated Fig. 7.3 Immunofluorescence of renal biopsy from a patient with IgA disease, showing positive immunofluorescence for IgA in a mesangial distribution. Contrast this with the 'capillary wall' distribution in Figs 7.2C and 7.4. Acute nephritic syndrome can occur in several conditions that are either restricted to the kidney or involve multiple organs (systemic diseases). Some of the important examples are listed in  [Box 7.2](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#b0015) . Amongst these, IgA disease is the only common disease. Nevertheless, it is important to consider the other conditions because, without rapid treatment, irreversible renal failure may develop. Rapidly progressive GN, in which renal failure develops over a period of days to weeks, is characteristic of several of these conditions, including primary crescentic GN, microscopic polyangiitis, and Goodpasture's syndrome.  **INTERESTING FACTS** IgA disease is the most common form of GN worldwide. Its presentation is very variable, ranging from isolated microscopic haematuria to (rarely) a rapidly progressive GN. Although the clinical course is benign in the majority of patients, IgA disease is so common that it is (after diabetes) the second most frequent condition causing end-stage kidney disease. **BOX 7.2** **Important causes of acute nephritic syndrome** Primary Post-streptococcal glomerulonephritis Post-infectious glomerulonephritis IgA disease∗ Mesangiocapillary (membranoproliferative) glomerulonephritis Crescentic glomerulonephritis Secondary to systemic disease Systemic lupus erythematosus Microscopic polyangiitis and granulomatosis with polyangiitis ∗Can present less commonly as a systemic vasculitis with skin, joint, gastrointestinal, and renal involvement (Henoch--Schönlein purpura). Save to collection Share Pathogenesis of acute glomerulonephritis Current classification systems for GN are confusing, which is not surprising given the incomplete knowledge of the pathogenesis and the overlapping morphological characteristics of many types of GN. Important concepts regarding classification will be outlined below. GN may be initiated by an immune response to an exogenous antigen such as a microbial product (including streptococcal products as in the current case) or an endogenous antigen (such as DNA with systemic lupus erythematosus; SLE). Less commonly, it may be initiated by an autoimmune response to a renal antigen, such as a component of the glomerular basement membrane in Goodpasture's syndrome (  [Figs 7.4A and 7.5](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0025) ). The antibodies involved in these responses may form the basis for diagnostic serological tests for these diseases (see  [Table 7.2](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0015) ). Several other effector mechanisms involving leucocytes, platelets, complement, coagulation factors, and humoral products of intrinsic and infiltrating cells act in concert with these immune mechanisms to cause glomerular injury.   Fig. 7.4 Immunofluorescence pattern of a renal biopsy specimen of glomerulonephritis initiated by: (A) autoimmune response to glomerular antigen (linear), and (B) immune response to circulating or planted extrarenal antigen (granular) and (C) staining for phospholipase A2 receptor, the antigen in most cases of membranous glomerulonephritis. Half of the glomerulus in (A) is replaced by a glomerular crescent which is not immunofluorescent. In both (A) and (B), the immunofluorescence is in a glomerular capillary wall distribution. Diagram of a diagram showing the sequence of a sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of sequence of Description automatically generated Fig. 7.5 Schematic representation of immunopathogenetic mechanisms of acute glomerulonephritis and the influence of other cellular and humoral mediators. Antigens may be deposited on the glomerular basement membrane before antibody deposition or as part of circulating antigen--antibody complexes or may be self-antigens (usually modified) in the glomerular basement membrane. When the antigen forms part of a circulating immune complex or is deposited in the kidney (e.g. on the glomerular capillary wall) to form an immune complex  *in situ,* the immunofluorescence pattern is discontinuous or granular (  [Fig. 7.4B](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0025) ). In this case, corresponding electron-dense deposits are seen with electron microscopy. This pattern is seen, for example, in membranous GN, post-streptococcal GN and SLE. In most cases, it is unclear whether the immune complex forms primarily in the circulation or in the kidney. In contrast, when the antibody is directed against an intrinsic renal antigen, the immunofluorescence pattern is continuous or linear, as seen in Goodpasture's syndrome (  [Fig. 7.4A](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0025) ). In the latter situation, there should be no electron-dense deposits seen with electron microscopy. Whether or not immune complex formation leads to the development of GN depends on numerous factors, including the nature of the antigen, the size of the complex, the antibody, the clearance of complexes by phagocytic cells, and other glomerular haemodynamic, cellular, and humoral influences (  [Fig. 7.5](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0030) ). Save to collection Share Pathology of acute glomerulonephritis The glomerulus may be altered in multiple ways in GN. Intrinsic cells (endothelial, mesangial, and epithelial) may proliferate; circulating leucocytes may infiltrate; platelets may accumulate; mesangial matrix may expand; the glomerular basement membrane may change; and scarring may develop. A hallmark of severe disease is the development of a glomerular crescent, which is a cellular, fibrinous and, later, fibrous lesion in Bowman's space, arising from the proliferation of extracapillary cells including glomerular epithelial cells and macrophages (  [Fig. 7.6](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0035) ). The greater the size and the number of crescents, the more severe the disease. Crescents may be seen in many forms of GN and, when large and numerous (in more than 50% of glomeruli), they are associated with a rapidly progressive clinical course in certain forms of vasculitis and in primary crescentic GN (  [Table 7.4](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0025) ). The presence of crescents is associated with reduced glomerular filtration by virtue of its association with more severe glomerular damage and mechanical blockage of filtration through Bowman's space.   Fig. 7.6 Cellular crescent (∗) occupying three-quarters of the circumference of a glomerulus and compressing the glomerular tuft. Table 7.4 Important types of glomerulonephritis (GN) and their usual clinical picture Asymptomatic haematuria/proteinuria can occur with almost all listed conditions. Presentation Primary Secondary -------------------------- ------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------ Nephrotic syndrome Minimal change disease Diabetes mellitus  [^∗ ^](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#tbl7_4fnlowast) Membranous nephropathy Amyloidosis  [^∗ ^](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#tbl7_4fnlowast) Focal segmental glomerulosclerosis (also known as focal sclerosing GN) Systemic lupus erythematosus Mesangiocapillary GN Acute nephritic syndrome Postinfectious GN Systemic lupus erythematosus Post-streptococcal GN IgA disease Mesangiocapillary GN Rapidly progressive GN Crescentic GN Microscopic polyangiitis Granulomatosis with polyangiitis (formally known as Wegener's granulomatosis) Goodpasture's syndrome ∗ These conditions are associated with non-inflammatory glomerulopathy rather than true glomerulonephritis. The glomerulus contains a capillary network and can thus be regarded as an 'extension' of the circulatory system, so it is not surprising that processes that cause systemic immune injury to blood vessels ('vasculitis') commonly cause GN. An example of this is antineutrophilic cytoplasmic antibody (ANCA) positive GN which can cause injury in the kidneys, lungs, or less often other tissues. Save to collection Share Outcome of glomerulonephritis Given that glomerulonephritides presenting with an acute nephritic picture may have a guarded prognosis, it is logical to ask about the natural history of this particular patient and whether treatment could alter the clinical course. See  [Case 7.1: 4](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#b0035) .  **CASE 7.1** **Glomerulonephritis and the acute nephritic syndrome: 4** Outcome The patient received antihypertensive therapy and a loop diuretic to control fluid accumulation. Within weeks his serum creatinine returned to normal, and his oedema and hypertension resolved. After 6 months, his urinary sediment was inactive. Thus, the patient's acute nephritis settled without specific treatment of the renal inflammation. But does this apply to other forms of acute nephritis? The outcome of acute GN varies greatly with the type of disease. In diseases in which the inciting antigen or event disappears spontaneously (as in the current case) or with treatment, the renal disease may resolve. In some circumstances, such as IgA disease and SLE, the disease may smoulder on or recur. When the disease remains active, smoulders on, or recurs, the tendency is for progressive kidney scarring and kidney failure to occur over a variable period of time. Save to collection Share Clinicopathological correlations in glomerulonephritis No current system of classification lends itself ideally to the study of GN and so understanding the condition can be a daunting task. Some primary and secondary glomerulonephritides are usually associated with nephrotic syndrome, as discussed in  [Chapter 6  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000063). Other forms of GN, such as postinfectious GN and IgA disease, may present with an acute nephritic syndrome, whilst others, such as SLE and mesangiocapillary GN, may present with either acute nephritis or nephrosis. In the context of an acute nephritic presentation, clinical clues should be sought to the presence of an underlying systemic condition (  [Fig. 7.7](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#f0040) ). As mentioned above, it is important to recognise the rare cases of rapidly progressive GN as they require emergency treatment.  A diagram of a person\'s body Description automatically generated Fig. 7.7 Signs diagnostic of nephritic syndrome or suggestive of an underlying systemic condition. JVP, jugular venous pressure; PSGN, post-streptococcal glomerulonephritis; GPA, granulomatosis with polyangiitis; GS, Goodpasture's syndrome; SLE, systemic lupus erythematosus; HSP, Henoch--Schönlein purpura; MPA, microscopic polyarteritis. GN can therefore be described as a combination of findings distilled from clinical presentation (acute kidney injury (AKI) vs chronic kidney disease, nephrotic vs nephritic), renal biopsy appearance (e.g. mesangial hypercellularity) and cause. Some diseases fit neatly into this paradigm (e.g. nephritic syndrome associated with mesangiocapillary GN because of antibodies against streptococcal antigen) whilst others do not (e.g. lupus nephritis can present as AKI or CKD, nephritic or nephrotic syndrome, mesangiocapillary, membranous or focal segmental glomerulosclerosis (FSGS) pattern on renal biopsy). The significant overlap in these aspects of diagnosis of GN make its study especially difficult. Use of the worksheet in the accompanying e-book will assist in understanding the classification of GN. Thus, medical students should limit their studies to the most common and/or clinically important diseases. These are listed in  [Table 7.4](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0025) . Some important diagnostic features of the glomerular pathology in these diseases are listed in  [Table 7.5](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0030) . These characteristic morphological and immunological features are sufficient to allow a definitive histological diagnosis to be made in the majority of cases. Further discussion of each condition included in  [Table 7.5](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000075#t0030) is beyond the scope of this text.  **INTERESTING FACTS** Granulomatosis with polyangiitis was formally known as Wegener's granulomatosis, named after the physician who described the condition in 1936. However, the use of the term 'Wegener's granulomatosis' has fallen out of favour because of the discovery that Dr. Friedrich Wegener was a member of the Nazi party before and during World War II. **CLINICAL SKILLS BOX: URINALYSIS** The examination of urine is a key aspect of the assessment of kidney health. The diagnosis of kidney disease can be quickly made by examining its colour, turbidity, and odour. In addition, the urine dipstick provides a rapid assessment of urinary characteristics. The dipstick comprises a series of colorimetric pads on a stick which is dipped into a jar of urine, ideally midstream, and then left for up to 1 min to enable testing, either visually or using an automated detection system. Key characteristics include:  - -  Colour -- urine should be a clear to somewhat yellow colour. Red urine suggests haematuria but can also be because of myoglobinuria or colourings from ingested beetroot or medications such as rifampicin (in which case the microscopy shows no significant red blood cells). Urine may also be pink (because of Propofol), green (methylene blue), black (haemoglobinuria), or purple (significant bacteriuria).  -  Turbidity -- because of infection, crystalluria or chyluria.  -  Odour -- pungent (because of infection) or other unusual smells with aminoaciduria.  -  Specific gravity (SG) -- usually between 1.005 to 1.030, with higher SG corresponding to higher concentrations of solutes. Dehydration is a common cause, but glycosuria may also cause a high SG.  -  pH -- usual range is 4.5 to 8. This is most useful when diagnosing renal tubular acidosis, where an inappropriately high urinary pH (\>5.5) is usually found. A high urinary pH may be found in patients with urinary tract infection (UTI) because of urease-producing organisms.  -  Heme (blood) -- is positive in the presence of heme pigment, usually because of Hb in red blood cells, but also where there is free Hb (haemoglobinuria) or myoglobin (as in rhabdomyolysis).  -  Leukocyte esterase ('leukocytes') -- is positive in the presence of neutrophils or macrophages but may be falsely negative if proteinuria or glycosuria is present.  -  Nitrite -- is detected in the presence of organisms that produce the enzyme nitrate reductase (e.g. Enterobacteriaceae). Therefore, the presence of nitrites is relatively specific but not that sensitive to UTIs.  -  Protein -- is present when there is significant proteinuria. However, kidney disease may present early with albuminuria, in which case the total protein content in urine may not reach the threshold for protein detection by dipstick. It is usually reported as trace, 1+, 2+, 3+.  -  Glucose -- is present in glycosuria. In patients with normal kidney function, glycosuria does not usually appear until the plasma glucose exceeds 10 mmol/L, but patients with tubular dysfunction may have urinary loss of glucose because of lack of glucose reabsorption.  **INTERESTING FACTS** Goodpastures syndrome is named after Ernest Goodpasture, a pathologist who described two cases of GN complicated by severe idiopathic pulmonary haemorrhage at the height of the 1918--19 influenza pandemic. Forty years later, two Australian physicians described a series of nine similar cases and recalled Goodpastures classic description, naming the disease after him. Table 7.5 Principal diagnostic glomerular appearances of important types of glomerulonephritis (GN) ***Light microscopy *** ***Electron microscopy *** ***Immunofluorescence *** -------------------------------------- ----------------------------------------------- --------------------------------------------- ----------------------------------- Minimal change disease Normal Diffuse foot process fusion Negative Membranous nephropathy Thick GCW without glomerular hypercellularity Subepithelial EDD ('lumps') Finely granular, CW Focal sclerosing GN Focal segmental GS Diffuse foot process fusion IgM (segmental) Mesangiocapillary GN Thick GCW with glomerular hypercellularity Subendothelial EDD, mesangial interposition CW Ig and C Postinfectious/post-streptococcal GN Hypercellular glomerulus Subepithelial EDD ('humps') CW Ig and C3 IgA disease Mesangial proliferation Mesangial EDD Mesangial IgA Diabetes mellitus GS Thick GBM, mesangial expansion CW pseudolinear Amyloidosis Variable Amyloid fibrils -- Negative birefringence with Congo Red stain Systemic lupus erythematosus Various patterns EDD -- multiple sites CW and mesangial, Ig, C3, C1q Rapidly progressive GN Crescents Variable CW negative or granular or linear C, complement; CW, capillary wall; EDD, electron-dense deposits; GBM, glomerular basement membrane; GCW, glomerular capillary wall; GS, glomerular sclerosis. Rapidly progressive GN is a rare medical emergency. It can occur as primary kidney disease or as part of a systemic illness such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis, Goodpasture's syndrome, and, rarely, Henoch--Schönlein purpura (a multisystem variant of IgA disease) or SLE. It is characterised clinically by a nephritic picture with rising serum creatinine and histologically by the presence of glomerular crescents. With appropriate early treatment, the disease may be halted or even cured; without treatment, end-stage kidney failure occurs quickly. Save to collection Share Summary - 1.  Acute nephritic syndrome comprises a constellation of proteinuria, haematuria, mild oedema, and hypertension. It may present as AKI or CKD.  - 2.  GN is a condition that can be described by clinical presentation (nephritic vs nephrotic, AKI vs CKD), renal biopsy appearance (e.g. mesangioproliferative, membranous, glomerulosclerosis) and cause (e.g. post-streptococcal infection, abnormally structured IgA deposits).  - 3.  Management of GN comprises supportive therapy (e.g. blood pressure control, management of electrolyte disturbances) and targeting of the underlying abnormality (e.g. targeting B-lymphocytes to reduce aberrant antibody production).  **SELF-ASSESSMENT CASE STUDY** Joe Shapiro, an 18-year-old man, presented to his local practitioner with macroscopic haematuria. Three days before his presentation, he had had a sore throat. At 15 and 16 years old, he had a similar episode of macroscopic haematuria. After studying this chapter, you should be able to answer the following questions: Q1. Explain how urinary examination would help narrow the differential diagnosis in this case. Q2. Based on the other clinical features, what is the most likely diagnosis? Q3. What other clinical features are required to make a diagnosis of 'the nephritic syndrome'? What is the pathogenesis of each feature? Q4. What are the main renal histopathological features of this disease? **SELF-ASSESSMENT CASE STUDY ANSWERS** A1. The presence of red blood cells (especially dysmorphic), casts and protein in the urine would all point to an upper urinary tract (i.e. renal parenchymal) origin for the bleeding; red blood cells without the other urinary abnormalities would point to a lower tract origin; positive dipstick for blood without red cells on microscopy would point to pigmenturia (i.e. haemoglobinuria or myoglobinuria). A2. The recurrent nature of the haematuria and sore throat occurring only a few days before presentation points to a diagnosis of mesangial IgA disease rather than post-streptococcal or postinfectious glomerulonephritis. A3. The nephritic syndrome consists of macroscopic haematuria, elevated serum creatinine and hypertension. The haematuria is caused by the leakage of the red cells from the glomerulus into the tubular lumen. Hypertension is because of renal salt and water retention and, in part to the release of vasoactive hormones. Reduced renal function is caused by structural damage (e.g. proliferation within the glomerulus and tubulointerstitial inflammation and scarring) and intrarenal haemodynamic changes because of vasoactive hormone release. A4. Mesangial proliferation on light microscopy; mesangial electron-dense deposits on electron microscopy; IgA in mesangial distribution on immunofluorescence microscopy. **SELF-ASSESSMENT QUESTIONS AND ANSWERS** Q1. What are the diagnostic clinical features of acute nephritic syndrome? Describe their pathogenesis. A1. Haematuria (because of leakage of blood cells across the glomerular capillary wall), hypertension (caused by salt and water retention and activation of the renin--angiotensin system), renal functional impairment (because of vasoactive hormone release and structural injury). See  [Table 6.2  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000063). Q2. List three conditions causing acute glomerulonephritis (GN) in which the serum concentration of complement components C3 and/or C4 may be reduced. A2. Post-streptococcal GN, mesangiocapillary GN, systemic lupus erythematosus (SLE). Q3. Which diagnostic serological tests are also involved in the immunopathogenesis of SLE, granulomatosis with polyangiitis, Goodpasture's syndrome, hepatitis B and C, respectively? A3. Anti-dsDNA antibody, ANCA, anti-GBM antibody, HBsAg, anti-HCV antibody, respectively. Q4. Describe five clinical features that may distinguish post-streptococcal GN from IgA disease. A4. See  [Table 6.4  ](https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702082924000063#t0025). Q5. List three ways in which antibodies may be associated with the glomerular basement membrane in acute GN. A5. In situ immune complex formation, deposition of circulating immune complex, reaction with intrinsic glomerular antigen.