Glomerulonephritis

Article Author:
Ahmad Kazi
Article Editor:
Muhammad Hashmi
Updated:
8/10/2020 9:07:06 PM
PubMed Link:
Glomerulonephritis

Introduction

The structural and functional unit of the kidney, the 'nephron' consists of a renal corpuscle (glomerulus surrounded by a Bowman capsule) and a renal tubule. Each kidney in an adult human contains around 1 million nephrons.[1]

A fenestrated endothelium forms the inner glomerular layer, followed by a layer composed of various extracellular proteins forming a meshwork called the glomerular basement membrane (GBM). The outer layer has visceral epithelial cells or podocytes, along with mesangial cells. The intricate arrangement provides the basis of the continuous plasma volume filtration that occurs at the glomerular level.

The term "glomerulonephritis" encompasses a subset of renal diseases characterized by immune-mediated damage to the basement membrane, the mesangium, or the capillary endothelium, resulting in hematuria, proteinuria, and azotemia.

Acute forms of glomerulonephritis can result from either a primary renal cause or a secondary illness that causes renal manifestations. Most forms of glomerulonephritis are considered progressive disorders, which without timely therapy, progress to chronic glomerulonephritis (characterized by progressive glomerular damage and tubulointerstitial fibrosis leading to a reduced glomerular filtration rate). This leads to the retention of uremic toxins with subsequent progression into chronic kidney disease (CKD), end-stage renal disease (ESRD) along with their associated cardiovascular diseases.[2]

Etiology

Etiological classification can be made on the basis of clinical presentation, which can range from severe proteinuria (>3.5 g/day) and edema qualifying for nephrotic syndrome, to a nephritic syndrome where hematuria and hypertension are more prominent while proteinuria is less pronounced.  

Nephrotic Glomerulonephritis

  • Minimal change disease
  • Focal segmental glomerulosclerosis
  • Membranoproliferative glomerulonephritis
  • Membranous nephropathy
  • HIV associated nephropathy
  • Diabetic nephropathy
  • Amyloidosis

Nephritic Glomerulonephritis

  • IgA nephropathy
  • Henoch Schonlein purpura (HSP)
  • Post streptococcal glomerulonephritis.
  • Anti-glomerular basement membrane disease
  • Rapidly progressive glomerulonephritis
  • Granulomatosis with polyangiitis
  • Eosinophilic granulomatosis with polyangiitis
  • Polyarteritis nodosa
  • Idiopathic crescentic glomerulonephritis
  • Goodpasture syndrome
  • Lupus nephritis
  • Hepatitis C infection
  • Membranoproliferative glomerulonephritis (typical presentation is with acute nephritic syndrome, however, sometimes features resembling nephrotic syndrome may occur, additionally)[3]

Epidemiology

Glomerulonephritis is a prominent cause of renal impairment. It leads to 10 to 15% of end-stage renal disease cases in the USA. In most instances, without timely intervention, the disease becomes progressive, eventually leading to morbidity.[4] This makes chronic glomerulonephritis the third most common cause of end-stage renal disease in the United States following diabetes mellitus and hypertension, accounting for 10% of patients on dialysis.

Acute glomerulonephritis affects males more than females with a male-to-female ratio of 2 to 1. IgA nephropathy is the commonest cause of glomerulonephritis worldwide.

Pathophysiology

The underlying pathogenetic mechanism common to all of these different varieties of glomerulonephritis (GN) is immune-mediated, in which both humoral as well as cell-mediated pathways are active. The consequent inflammatory response, in many cases, paves the way for fibrotic events that follow.

The targets of immune-mediated damage vary according to the type of GN. For instance, glomerulonephritis associated with staphylococcus shows deposits of IgA and C3 complement.[5]

One of the targets is the glomerular basement membrane itself or some antigen trapped within it, as in post-streptococcal disease. Such antigen-antibody reactions can be systemic with glomerulonephritis occurring as one of the components of the disease process, such as in systemic lupus erythematosus (SLE) or IgA nephropathy. On the other hand, in small vessel vasculitis; instead of antigen-antibody reaction, cell-mediated immune reactions are the main culprit. Here, T lymphocytes and macrophages flood the glomeruli with resultant damage.

These initiating events lead to the activation of common inflammatory pathways, i.e., the complement system and coagulation cascade. The generation of pro-inflammatory cytokines and complement products, in turn, results in the proliferation of glomerular cells. 

Cytokines such as platelet-derived growth factor (PDGF) are also released, ultimately causing glomerulosclerosis. This event is seen in those situations where the antigen is present for longer periods of time, for example, in hepatitis C viral infection. 

When the antigen is rapidly cleared as in post-streptococcal GN, the resolution of inflammation is more likely.[6]

Histopathology

Diffuse endocapillary proliferative changes are usually seen. The most common histological patterns observed in the descending order of prevalence are diffuse, focal, and mesangial proliferative glomerulonephritis.[7] Of the different histopathological patterns, one of the following may be seen.

  • Under light microscopy, a glomerular morphology that is within the normal limits; while a loss of foot processes on electron microscopy (EM).
  • Hypercellular glomeruli resulting from increased mesangial, endothelial, or parietal epithelial cells population; acute and chronic white blood cells may also be seen in diffuse proliferative glomerulonephritis (GN) while in crescentic GN, crescents made up of leukocytes and epithelial cells may be present.
  • Basement membrane thickening, a feature highlighted by Periodic acid–Schiff (PAS) stain and electron microscopy. EM will demonstrate electron-dense deposits of immune complexes in or adjacent to the basement membrane. The most common pattern of these deposits is sub-epithelial.
  • Sclerosis of glomeruli, the end result of glomerular damage from various causes.[8]

History and Physical

As the glomerular filtration rate (GFR) is decreased, symptoms like edema and hypertension occur, majorly due to the subsequent salt and water retention caused by the activation of the renin-angiotensin-aldosterone system.

A) Some symptoms occur primarily and include:

  • Hypertension
  • Edema (peripheral or peri-orbital) - initially in the dependent areas/areas with low tissue tension
  • Abnormal urinary sedimentation
  • Hematuria – microscopic or gross[9]
  • Oliguria
  • Azotemia
  • Shortness of breath or dyspnea on exertion
  • Headache - secondary to hypertension
  • Confusion - secondary to malignant hypertension
  • Possible flank pain

B) Or there can be symptoms specifically related to an underlying systemic disease:

  • Triad of sinusitis, pulmonary infiltrates, and nephritis – Wegener granulomatosis
  • Nausea, vomiting, abdominal pain, purpura -  Henoch-Schönlein purpura
  • Arthralgias - systemic lupus erythematosus (SLE)
  • Hemoptysis - Goodpasture syndrome or idiopathic progressive glomerulonephritis
  • Skin rashes – in hypersensitivity vasculitis, SLE, cryoglobulinemia, Henoch-Schönlein purpura [10]

Additionally, acute renal failure with a reduced glomerular filtration rate (GFR) can also be the presenting picture.

Evaluation

Following investigations guide not only in the determination of the potential cause but also in the assessment of the extent of the damage: 

Blood

  • Complete blood count
  • Serum electrolytes
  • Renal function tests
  • Liver function tests
  • Immunoglobulins
  • C-reactive protein (CRP)
  • Electrophoresis
  • Complement (c3,c4 levels)
  • Autoantibodies [ANA, ANCA, anti-ds-DNA, anti-Glomerular basement membrane (GBM)]
  • Blood culture
  • Antistreptolysin O Titer (ASOT)
  • Hepatitis serology

 Urine

  • Microscopy, culture, and sensitivity
  • Bence Jones protein
  • Albumin: creatinine/protein: creatinine
  • RBC casts

Imaging

  • Chest X-ray (helps to see for evidence of pulmonary hemorrhage, if any)
  • Renal ultrasound (helps in assessing the size and anatomy for biopsy)

Renal Biopsy

The examination of glomerular lesions via a renal biopsy provides the diagnosis of glomerulonephritis by answering the following queries:

  • Approximate proportion of involved glomeruli (focal vs. diffuse)
  • Approximate involvement of each glomerulus (segmental vs. global)
  • Presence of hypercellularity
  • Any evident sclerosis
  • Any deposits on immunohistology (immunoglobulins, light chains, complement)
  • Electron microscopy findings - precise localization of deposits. Exact ultrastructural appearance. Podocyte appearance
  • Presence of tubulointerstitial inflammation, atrophy or fibrosis
  • Evident vessel-related pathology[11]

Treatment / Management

Secondary glomerular diseases associated with a systemic disease, mostly resolve with the management of the underlying cause. Primary glomerulonephritis is managed supportively, and by specific disease-modifying therapy. The outcome mainly depends on the timely intervention, which, if not done, may lead to a progressive sequence of events causing glomerulonephritis to develop into chronic kidney disease (increasing the risk for simultaneous development of cardiovascular disease), the sequence finally culminates into end-stage renal disease (ESRD). 

The management of glomerulonephritis broadly follows two modalities.

A) Specific management revolves around immunosuppression, which in turn is governed by factors like

  • Histological diagnosis
  • Disease severity
  • Disease progression
  • Comorbidities 

 The available options include: 

  • High-dose corticosteroids
  • Rituximab (a monoclonal antibody that causes the lysis of B-lymphocytes)
  • Cytotoxic agents (e.g., cyclophosphamide, along with glucocorticoids are of value in severe cases of post-streptococcal glomerulonephritis)
  • Plasma exchange (glomerular proliferative nephritis, pauci-immune glomerulonephritis – used temporarily till chemotherapy takes effect)

B) With progression into chronicity, general management is done on the lines of CKD:

  1. By keeping track of the renal function tests (RFTs), serum albumin, and urine protein excretion rate.
  2. By controlling the BP and inhibiting the renin-angiotensin axis, through Loop diuretics, which serve two purposes; the removal of excess fluid and also the correction of hypertension.
  3. For individuals with severe/refractory hypertension with/without encephalopathy, vasodilators (e.g., nitroprusside, nifedipine) can be used.
  4. By managing the complications associated with progressive chronic disease, including anemia, bone mineral disorders, acidosis, cardiovascular disease, restless legs/cramps.
  5. Appropriate counseling regarding diet.
  6. Preparation for renal replacement therapy (RRT), if needed.

Nephritic Glomerulonephritis

IgA nephropathy: ACE inhibitors/ARBs (3-6 months) are used as they reduce proteinuria. Corticosteroids and fish oil can be prescribed if proteinuria exceeds 1 gm (provided GFR>50) even after the initial therapy. Henoch Schonlein purpura (HSP) is managed on the same lines. Steroids are helpful for gastrointestinal tract (GIT) related symptoms here, too.

Post Streptococcal GN: Supportive treatment and antibiotics to get rid of nephritogenic bacteria.

Anti-GBM Disease: The available options include plasma exchange, corticosteroids, and cyclophosphamide.

Rapidly progressive glomerulonephritis (RPGN): RPGN is treated with corticosteroids and cyclophosphamide.

Plasma exchange is used for anti-GBM/ANCA vasculitis.

For lupus nephritis, monoclonal antibodies are effective. 

Nephrotic Glomerulonephritis

Minimal change disease: Prednisolone 1 mg/kg (4 to 16 weeks). If relapsing, immunosuppression with greater intensity or for longer durations can be used. Cyclophosphamide and calcineurin inhibitors are effective options.

Focal segmental glomerulosclerosis: Treatment is done initially with ACE inhibitors/ARBs and by controlling BP. Calcineurin inhibitors are 2nd line. Plasma exchange and rituximab are helpful for recurrence in transplants. For primary (idiopathic) disease, corticosteroids should be used.

Membranoproliferative GN: Treatment is done initially with ACE inhibitors/ARBs and by controlling BP. Immunosuppression is useful if no underlying cause is found. Work is currently ongoing to block or modify C3 activation.

Differential Diagnosis

Based on the clinical presentation, differentiation needs to be drawn between the nephrotic or the nephritic spectrum. This is important as it helps to narrow down the differentials of the underlying glomerular pathology.

Also, depending on the age group and clinical picture, differential diagnoses will include primary versus secondary causes.

Primary glomerulonephritis presenting as the nephrotic syndrome in young patients is likely to be minimal change disease, while in adults, membranous variety is more likely. In the secondary category, diabetes mellitus has to be ruled out.

When the nephritic syndrome is the main presentation, in children, it is likely to be post-streptococcal. In adults, however, IgA nephropathy should be considered.

When systemic vasculitis involves glomeruli, the cause in the younger age group is Henoch Schonlein purpura, while in adults, Wegener granulomatosis should be suspected.

Lupus nephritis is seen more commonly in young women (20 to 30 years).[12]

Prognosis

Among the Nephritic Spectrum Diseases

  • Recovery is likely in children with post-streptococcal glomerulonephritis, while adults have a greater tendency to develop rapidly progressive glomerulonephritis (RPGN) and chronic kidney disease (CKD). 
  • IgA nephropathy can lead to three possible outcomes; spontaneous clinical remission in a third of patients, end-stage renal disease (ESRD), in 20 to 40% while the rest have a state of chronic microscopic hematuria. 
  • Henoch Schonlein purpura (HSP) usually results in recovery, if the hematuria is microscopic and the proteinuria minimal. Those who have nephrotic syndrome would more likely develop CKD and, ultimately, ESRD. The simultaneous presence of both nephrotic and nephritic symptoms indicates a very poor prognosis.
  • With timely and avid treatment, pauci-immune GN usually remits (75% cases). But if left untreated, it carries a very poor prognosis.
  • Membranoproliferative glomerulonephritis progresses to ESRD inevitably, despite therapy. Also, the frequency of recurrence is high even after a kidney transplant.

Among the Nephrotic Spectrum Diseases

  • Minimal change disease rarely progresses to ESRD.
  • Approximately a third of patients with membranous nephropathy who have subnephrotic proteinuria, respond to conservative management. Spontaneous remission has also been seen in cases of heavy proteinuria. However, in others with features of nephrotic syndrome, remission may take up to 6 months, provided adequate treatment is given.
  • Appropriate treatment does slow the progression of HIV associated nephropathy, but with progression into ESRD, a kidney transplant may be needed.
  • Amyloid light-chain (AL) amyloidosis takes 2 to 3 years for progression towards ESRD, while for amyloid A (AA) amyloidosis, remission can be achieved by identifying and managing the underlying disease.[9]

Complications

Glomerulonephritis may either lead to acute kidney injury (AKI) or may progress gradually to chronic renal failure. AKI is sometimes the initial presentation in rapidly progressive glomerulonephritis with crescent formation. Similarly, vasculitis and Goodpasture syndrome represent other conditions where AKI is associated with glomerulonephritis. Most cases, however, would show progression into chronic glomerulonephritis and eventually lead to CKD and ESRD, requiring the need for dialysis.[13]

Deterrence and Patient Education

It is important to cut down salts from the diet during the acute disease.

For progressive disease, dietary restrictions (2 g sodium, 2 g potassium, 40 to 60 g protein; a day) help to reduce the build-up of wastes and also prevent states of fluid overload.

Cessation of smoking is also paramount in decreasing the aggravation of renal disease.

Education in countering diabetes and elevated blood pressures is also important, through adequate lifestyle modifications and standardized therapy. Patients must also be counseled regarding the control of hyperlipidemias.

Problems with respect to sexual health (e.g., loss of libido) usually can occur in kidney disease, especially in men. Hence, appropriate guidance regarding the same should be provided to the patient.

Patients with nephrotic syndrome and especially those with progression into chronic kidney disease (CKD) are vulnerable to infections, so a seasonal flu vaccine and pneumococcal vaccines are of help for them.

Enhancing Healthcare Team Outcomes

In most instances, the disease follows a progressive course, and the patients often have associated co-morbidities, so the involvement of multiple disciplines and interprofessional communication is of prime importance. While the nephrologist is almost always involved in the treatment of patients with glomerulonephritis, the role of a physician cannot be undermined, considering the fact that the patients usually have other diseases simultaneously. Patients presenting in the outpatient departments with proteinuria/hematuria or both would need further evaluation.

A renal biopsy following the initial laboratory and radiological investigations may be needed to reach a diagnosis. This requires a collective approach involving histopathologists, immunologists, radiologists, and at times, the surgeons. Nurses are important in dispensing appropriate treatment and also assist with the education of the patient and family. Patients with chronic disease need assessment of renal function at regular intervals, so linking up with a local community doctor is important. Those with markedly decreased renal function require dialysis with appropriate scheduling, and so, interacting with the dialysis unit is pivotal. All in all, to improve outcomes, prompt consultation with specialists is recommended, and timely interprofessional communication is imperative to ensure quality health-care.



  • Image courtesy S Bhimji MD
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