Glomerulonephritis

Overview

The term "glomerulonephritis" refers to a group of renal disorders defined by immune-mediated destruction to the basement membrane, mesangium, or capillary endothelium, which results in hematuria, proteinuria, and azotemia.

Anatomy

Anatomy of Glomerulonephritis

The 'nephron' is the anatomical and functional unit of the kidney, consisting of a renal corpuscle (glomerulus surrounded by a Bowman capsule) and a renal tubule. An mature human kidney includes approximately 1 million nephrons.

The inner glomerular layer is formed by a fenestrated endothelium, which is followed by a layer made of diverse extracellular proteins that form a meshwork known as the glomerular basement membrane (GBM). Visceral epithelial cells or podocytes, as well as mesangial cells, make up the outer layer. The complicated structure serves as the foundation for continuous plasma volume filtration at the glomerular level.

Glomerulonephritis definition

Glomerulonephritis is an inflammation of your kidneys' small filters (glomeruli). Glomeruli are cells in your kidneys that remove excess fluid, electrolytes, and waste from your circulation and excrete them in your urine. Glomerulonephritis can develop quickly (acute) or gradually (chronic).

Acute glomerulonephritis can be caused by either a primary renal cause or a secondary illness with renal signs. The majority of kinds of glomerulonephritis are considered progressive illnesses that, if not treated promptly, proceed to chronic glomerulonephritis (characterized by progressive glomerular damage and tubulointerstitial fibrosis leading to a reduced glomerular filtration rate). This results in the retention of uremic toxins, which leads to the development of chronic kidney disease (CKD), end-stage renal disease (ESRD), and the accompanying cardiovascular disorders.

Epidemiology

Glomerulonephritis (GN) is a common cause of kidney damage. It accounts for 10% to 15% of all instances of end-stage renal disease in the United States. In most cases, if the disease is not treated promptly, it progresses, finally leading to morbidity. Chronic glomerulonephritis is the third most frequent cause of end-stage renal disease in the United States, after diabetes and hypertension, accounting for 10% of dialysis patients.

Glomerulonephritis accounts for 25% to 30% of all instances of end-stage renal failure. A fifth of the patients had nephritic syndrome. In most cases, progression is rapid, and end-stage renal failure can occur within weeks or months following the onset of acute nephritic syndrome.

IgA nephropathy has been identified as the leading cause of glomerulonephritis worldwide. However, in most of the developed world, the prevalence of post-streptococcal glomerulonephritis has decreased. According to Japanese experts, the incidence of postinfectious glomerulonephritis peaked in the 1990s. Postinfectious glomerulonephritis, which accounted for nearly all cases of postinfectious GN in the 1970s, has decreased to about 40-50 percent since the 1990s, while Staphylococcus aureus–related nephritis has increased to 30 percent, and hepatitis C virus–associated glomerulonephritis has also increased.

Post-streptococcal glomerulonephritis is still far more common in places like the Caribbean, Africa, India, Pakistan, Papua New Guinea, South America, and Malaysia. In Port Harcourt, Nigeria, acute glomerulonephritis in children aged 3 to 16 years was 15.5 cases per year, with a male-to-female ratio of 1.1:1; the situation is not much different today. According to an Ethiopian study from a regional dialysis clinic, acute glomerulonephritis was the second most common cause of acute renal failure needing dialysis, accounting for approximately 22% of cases.

Demographics by Age, Gender, and Race

Acute nephropathy can occur at any age, even infancy. Post-streptococcal glomerulonephritis most commonly affects children aged 5 to 15 years. Only 10% of instances involve patients above the age of 40. Outbreaks are common in youngsters aged 6 to 10 years.

Males are affected more than females by acute glomerulonephritis, with a male-to-female ratio of 2 to 1. There is no racial or ethnic preference for postinfectious glomerulonephritis.

Etiology

Etiological classification can be formed based on clinical presentation, which can range from severe proteinuria (>3.5 g/day) and edema qualifying for nephrotic syndrome to a nephritic syndrome with more pronounced hematuria and hypertension but less pronounced proteinuria.

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)

Pathophysiology

The basic pathogenetic process that underpins all of these distinct types of glomerulonephritis (GN) is immune-mediated, with both humoral and cell-mediated pathways at work. In many circumstances, the resulting inflammatory reaction pave the way for fibrotic events to occur.

The immune-mediated damage targets differ depending on the kind of GN. For example, glomerulonephritis caused by Staphylococcus aureus has IgA and C3 complement deposits.

The glomerular basement membrane itself, or an antigen trapped inside it, is one of the targets, as in post-streptococcal illness. Such antigen-antibody interactions can be widespread, with glomerulonephritis appearing as one of the disease's components, as in systemic lupus erythematosus (SLE) or IgA nephropathy. Cell-mediated immune reactions, rather than antigen-antibody reactions, are the principal culprit in small vessel vasculitis. T cells and macrophages infiltrate the glomeruli, causing injury.

These initiating events activate common inflammatory pathways, such as the complement system and the coagulation cascade. The production of pro-inflammatory cytokines and complement products, in turn, causes glomerular cell growth.

Platelet-derived growth factor (PDGF) and other cytokines are also released, resulting in glomerulosclerosis. This occurs in cases where the antigen is present for extended periods of time, such as in hepatitis C virus infection. When the antigen is swiftly removed, as in post-streptococcal GN, inflammation is more likely to resolve.

Structural Changes

Cellular proliferation increases the cellularity of the glomerular tuft structurally due to an excess of endothelial, mesangial, and epithelial cells. There are two types of proliferation:

Endocapillary - within the glomerular capillary tufts
Extracapillary - in the Bowman space including the epithelial cells

Extracapillary proliferation occurs when parietal epithelial cells multiply, resulting in the production of crescents, which is seen in some cases of fast progressing glomerulonephritis.

On light microscopy, glomerular basement membrane thickening shows as thicker capillary walls. However, using electron microscopy, this may appear to be a result of basement membrane thickening, such as diabetes, or electron-dense deposits on either the epithelial or endothelial side of the basement membrane. Subendothelial, subepithelial, intramembranous, and mesangial electron-dense deposits can all correspond to a region of immune complex deposition.

Irreversible damage is characterized by hyalinization or sclerosis, which can be localized, diffuse, segmental, or global. Changes in Function The following functional modifications have been implemented:

Proteinuria
Hematuria
Reduction in creatinine clearance, oliguria, or anuria
Active urine sediments, such as RBCs and RBC casts

This leads to intravascular volume expansion, edema, and systemic hypertension.

Symptoms of glomerulonephritis

Symptoms of glomerulonephritis

A comprehensive history must be obtained, with the goal of identifying some underlying reason, such as systemic disease or a recent infection. The majority of patients with acute glomerulonephritis are children aged 2-14 years who develop periorbital puffiness and face swelling as a result of a post-streptococcal infection. Urine is frequently black, foamy, or scanty, and blood pressure is elevated. Generalized weakness, fever, stomach ache, and malaise are nonspecific symptoms.

The patient with acute glomerulonephritis linked with staphylococcal infection is more likely to be a middle-aged man or older, sometimes with diabetes mellitus. The infection, such as pneumonia, endocarditis, or osteomyelitis; or a skin infection caused by methicillin-resistant Staphylococcus aureus, may cause the onset. Hematuria is frequently seen.

A history of the disease's inception and duration should be collected. The onset of symptoms is frequently abrupt. A latent period of up to three weeks before clinical appearance is common in acute postinfectious GN. However, the latent period varies; it is normally one to two weeks for instances that occur after a pharyngeal infection and two to four weeks for cases that arise after a postdermal infection, such as pyoderma. When nephritis develops within one to four days of streptococcal infection, it usually indicates previous kidney damage.

It is critical to identify a likely causative agent. A recent fever, sore throat, arthralgias, hepatitis, valve replacement, travel, or intravenous drug usage could all be factors. It is also critical to evaluate the illness process's results, such as loss of appetite, pruritis, weariness, nausea, facial swelling, peripheral edema, and dyspnea.

As the glomerular filtration rate (GFR) decreases, symptoms such as edema and hypertension develop, owing to the following salt and water retention induced by renin-angiotensin-aldosterone system activation.

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
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 – granulomatosis with polyangiitis
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

Patients' physical examinations are frequently ordinary, although they may appear with a triad of edema, hypertension, and oliguria. The following indicators of extra fluid in the body should be looked for by the provider:

Periorbital and/or peripheral edema
High blood pressure
Fine inspiratory crackles due to pulmonary edema
Raised jugular venous pressure
Ascites and pleural effusion

Other signs to look for include the following:

Vasculitic rash (as with Henoch-Schönlein purpura, or lupus nephritis)
Pallor
Renal angle fullness or tenderness
Abnormal neurologic examination or altered sensorium
Arthritis

Diagnosis

Glomerulonephritis Diagnosis

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 - A decreased hematocrit may suggest a dilutional type of anemia. In the background of an infectious cause, pleocytosis may be apparent.
Serum electrolytes - Potassium levels may be raised in patients with severe renal impairment.
Renal function tests - BUN and creatinine levels are raised, demonstrating a degree of renal impairment. The glomerular filtration rate (GFR) may be low.
Liver function tests - May point towards the underlying etiology.
Immunoglobulins
C-reactive protein (CRP)
Electrophoresis
Complement (C3, C4 levels) - Differentiation may enable the supplier to reduce the disparities. Cryoglobulinemia, systemic lupus erythematosus, infective (bacterial) endocarditis, and shunt nephritis all have low complement levels. Certain renal disorders, such as membranoproliferative GN or poststreptococcal GN, may also be taken into account. Normal complement levels indicate an abscess, polyarteritis nodosa, Henoch-Schönlein purpura, Goodpasture syndrome, idiopathic fast progressive GN, immunological complex illness, and immunoglobulin G or immunoglobulin A nephropathy. Anti-factor B autoantibodies may assist identify new-onset poststreptococcal GN from hypocomplementemic C3 glomerulonephritis in individuals with new-onset nephritis and low C3 levels, according to Chauvet et al.
Autoantibodies [ANA, ANCA, anti-ds-DNA, anti-Glomerular basement membrane (GBM)] to outrule collagenopathy as the underlying cause of GN.
Blood culture - When there is a fever, immunosuppression, intravenous drug misuse, indwelling catheters, or shunts, a blood culture is recommended.
Antistreptolysin O titer (ASOT) - In 60-80% of cases, it grows. The surge takes one to three weeks to begin, peaks in three to five weeks, then returns to baseline in six months. It has no bearing on the degree, duration, or prognosis of renal disease.
Hepatitis serology

Urine

With RBCs and RBC casts, the urine is usually black and has a specific gravity more than 1.020. Urinary protein excretion and creatinine clearance over 24 hours may be useful in determining the degree of renal impairment and proteinuria. The following parameters are frequently useful:

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
Presence of tubulointerstitial inflammation, atrophy, or fibrosis
Evident vessel-related pathology

Aside from determining the etiology, the biopsy also aids in determining the severity of the condition. It may also indicate additional lesions that are connected to the GN.

Management

Glomerulonephritis Management

Secondary glomerular disorders associated with a systemic disease usually disappear when the primary cause is treated. Primary glomerulonephritis is treated with supportive care as well as disease-modifying treatment. The outcome is primarily determined by timely intervention, which, if not performed, may result in a progressive sequence of events that causes glomerulonephritis to progress into chronic kidney disease (increasing the risk of concurrent development of cardiovascular disease), and the sequence eventually culminates in 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 chronic kidney disease:

By monitoring renal function tests (RFTs), serum albumin, and urine protein excretion rate.
By lowering blood pressure and blocking the renin-angiotensin axis, loop diuretics perform two functions: elimination of excess fluid and correction of hypertension.
Vasodilators (e.g., nitroprusside, nifedipine) can be administered in patients with severe/refractory hypertension with/without encephalopathy.
By addressing the comorbidities of chronic illness progression, such as anemia, bone mineral abnormalities, acidosis, cardiovascular disease, and restless legs/cramps.
Appropriate dietary counseling.
If necessary, preparation for renal replacement therapy (RRT).

Differential Diagnosis

Following are some important differentials to be considered while making the diagnosis of glomerulonephritis:

Acute kidney injury
Crescentic glomerulonephritis
Diffuse proliferative glomerulonephritis
Focal segmental glomerulonephritis
Glomerulonephritis associated with nonstreptococcal infection
Goodpasture syndrome
Lupus nephritis
Membranoproliferative glomerulonephritis
Poststreptococcal glomerulonephritis
Rapidly progressive glomerulonephritis

The following renal syndromes frequently mimic the early stages of acute GN:

Idiopathic hematuria
Chronic GN with an acute exacerbation
Anaphylactoid purpura with nephritis
Familial nephritis

Prognosis

Among the Nephritic Spectrum Diseases

Children with post-streptococcal glomerulonephritis are likely to recover, whereas adults are more likely to develop rapidly progressive glomerulonephritis (RPGN) and chronic kidney disease (CKD).
IgA nephropathy can result in one of three outcomes: spontaneous clinical remission in one-third of patients, end-stage renal disease (ESRD) in 20 to 40% of patients, and persistent microscopic hematuria in the remaining patients.
If the hematuria is tiny and the proteinuria is modest, Henoch Schonlein purpura (HSP) frequently results in recovery. Those with nephrotic syndrome are more prone to develop CKD and, eventually, ESRD. The presence of both nephrotic and nephritic symptoms at the same time implies a very unfavorable prognosis.
Pauci-immune GN usually resolves on its own with prompt and rigorous therapy (75 percent cases). However, if left untreated, it has an extremely terrible prognosis. Despite treatment, membraneproliferative glomerulonephritis eventually leads to end-stage renal disease (ESRD). Furthermore, even after a kidney transplant, the recurrence rate is significant.

Among the Nephrotic Spectrum Diseases

Minimal change illness seldom develops to end-stage renal disease (ESRD)
Conservative therapy helps about one-third of individuals with membranous nephropathy who have subnephrotic proteinuria. In situations of severe proteinuria, spontaneous remission has also been observed. However, in others with nephrotic syndrome symptoms, remission may take up to 6 months if sufficient treatment is not received.
Appropriate treatment slows the progression of HIV-associated nephropathy, but if the condition progresses to ESRD, a kidney transplant may be required.
Amyloid light-chain (AL) amyloidosis progresses to ESRD in 2 to 3 years, but amyloid A (AA) amyloidosis can be cured by detecting and controlling the underlying disease.

Complications

Glomerulonephritis can cause either acute kidney damage (AKI) or progressive chronic renal failure. AKI is occasionally the first symptom of quickly developing glomerulonephritis with crescent development. Other disorders where AKI is associated with glomerulonephritis include vasculitis and Goodpasture syndrome. The majority of cases, however, would proceed to chronic glomerulonephritis and eventually to CKD and ESRD, necessitating dialysis.

Conclusion

The word "glomerulonephritis" refers to a group of kidney illnesses marked by immune-mediated destruction to the basement membrane, mesangium, or capillary endothelium, resulting in hematuria, proteinuria, and azotemia.

In most cases, the condition progresses, and patients frequently have linked co-morbidities, therefore the engagement of various disciplines and interprofessional communication is critical. While a nephrologist is nearly always involved in the treatment of patients with glomerulonephritis, the importance of a physician cannot be underestimated, given that the patients frequently have other diseases at the same time. Patients who present to outpatient departments with proteinuria, hematuria, or both will require further assessment.

Following the first laboratory and radiographic studies, a kidney biopsy may be required to make a diagnosis. This necessitates a collaborative effort combining histopathologists, immunologists, radiologists, and, in certain cases, surgeons. Nurses have a crucial role in providing appropriate care as well as educating the patient and family.

Patients with chronic diseases require regular assessments of renal function, therefore establishing a relationship with a local community doctor is critical. Those with significantly reduced renal function require dialysis on a regular basis, therefore engaging with the dialysis unit is critical. Overall, rapid consultation with specialists is recommended to improve outcomes, and timely interprofessional communication is critical to ensuring quality health care.