Nephritic syndrome

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Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Nephritic syndrome from other Diseases
Epidemiology and Demographics
Natural History, Complications and Prognosis
History and Symptoms
Physical Examination
Laboratory Findings
Renal Biopsy
Echocardiography or Ultrasound
Treatment
Medical Therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Yazan Daaboul, Serge Korjian, Dildar Hussain, MBBS [3]

Synonyms and keywords: Acute nephritis syndrome; Acute glomerulunephritis

Overview

Nephritic syndrome is defined as the inflammation of the renal glomeruli. It is characterized by the presence of glomerular microscopic or gross hematuria with active sedimentation of dysmorphic red blood cells in the urine. Due to renal involvement, the syndrome includes a reduced glomerular filtration rate (GFR), oliguria, azotemia, high blood pressure, and edema. Unlike nephrotic syndrome, proteinuria in nephritic syndrome is not very significant, although frequently present nonetheless. Nephrotic and nephritic syndromes can both still occur concomitantly.

Historical Perspective

The symptoms of glomerulonephritis were first described by Richard Bright in 1827 when he discovered that several patients died with generalized edema were found to have renal disease. It was not until 1914 that Volhard and Fahr classified renal diseases in Die Brightsche Nierenkrankheit to 3 main categories: nephroses, nephritis, and arteriosclerotic disease. Acute post-streptococcal glomerulonephritis is thus considered the earliest nephritic syndrome to be described. In 1908, C.F. Wahrer described an epidemic of hemorrhagic nephritis preceded by scarlet fever in 35 patients. Epidemics of nephritis continued in 1915 among British troops during World War I. Clinical and pathological findings from both epidemics were similar. Hemolytic streptococci were isolated from cultures of the oropharynx in many patients.

Classification

The acute nephritic syndrome can be classified according to the etiology of the underlying disease (renal vs. non-renal etiology). Similarly, acute nephritis may be classified as idiopathic vs. secondary to other conditions. Finally, diseases may be classified according to the proliferative vs. non-proliferative changes seen on pathology.

Renal vs. Non Renal

Renal Diseases

• Acute post-streptococcal glomerulonephritis
• Membranoproliferative glomerulonephritis - Type 1 and 2
• IgA nephropathy
• Idiopathic rapidly progressive glomerulonephritis
  • Anti-GBM disease
  • Pauci-immune disease
  • Immune-deposit disease

Systemic Diseases

• Systemic lupus erythematosus
• Cryoglobulinemia
• Subacute bacterial endocarditis
• "Shunt" nephritis
• Polyarteritis nodosa
• Wegener granulomatosis
• Hypersensitivity vasculitis
• Henoch-Schonlein purpura
• Goodpasture's syndrome
• Visceral abscesses

Primary vs. Secondary

Classification of Glomerular Diseases

Type of Disorder	Proliferative Changes	No Proliferative Changes
Primary Renal Disorder	IgA nephropathy IgM nephropathy Other mesangioproliferative glomerulonephritides Crescentic glomerulonephritis With immune deposits Pauci-immune Membranoproliferative glomerulonephritis	Focal segmental glomerulosclerosis Membranous glomerulopathy Minimal-change disease Thin basement membrane disease
Secondary Disorder	Lupus nephritis Post-infectious glomerulonephritis Glomerulonephritis related to hepatitis B or C Systemic vasculitides Wegener's granulomatosis Polyarteritis nodosa Henoch-Schonlein purpura Idiopathic	Diabetic nephropathy Amyloidosis Light-chain nephropathy Human immunodeficiency virus nephropathy Alport's syndrome Drug-induced glomerulopathies

^{Adapted from Hricik DE, Chung-Park M, Sedor JR. Glomerulonephritis. N Engl J Med. 1998;339(13):888-99}

Renal vs. Non Renal

Renal Diseases

• Acute post-streptococcal glomerulonephritis
• Membranoproliferative glomerulonephritis - Type 1 and 2
• IgA nephropathy
• Idiopathic rapidly progressive glomerulonephritis
  • Anti-GBM disease
  • Pauci-immune disease
  • Immune-deposit disease

Systemic Diseases

• Systemic lupus erythematosus
• Cryoglobulinemia
• Subacute bacterial endocarditis
• "Shunt" nephritis
• Polyarteritis nodosa
• Wegener granulomatosis
• Hypersensitivity vasculitis
• Henoch-Schonlein purpura
• Goodpasture's syndrome
• Visceral abscesses

Primary vs. Secondary

Classification of Glomerular Diseases

Type of Disorder	Proliferative Changes	No Proliferative Changes
Primary Renal Disorder	IgA nephropathy IgM nephropathy Other mesangioproliferative glomerulonephritides Crescentic glomerulonephritis With immune deposits Pauci-immune Membranoproliferative glomerulonephritis	Focal segmental glomerulosclerosis Membranous glomerulopathy Minimal-change disease Thin basement membrane disease
Secondary Disorder	Lupus nephritis Post-infectious glomerulonephritis Glomerulonephritis related to hepatitis B or C Systemic vasculitides Wegener's granulomatosis Polyarteritis nodosa Henoch-Schonlein purpura Idiopathic	Diabetic nephropathy Amyloidosis Light-chain nephropathy Human immunodeficiency virus nephropathy Alport's syndrome Drug-induced glomerulopathies

^{Adapted from Hricik DE, Chung-Park M, Sedor JR. Glomerulonephritis. N Engl J Med. 1998;339(13):888-99}

Pathophysiology

Role of Antibodies

Immunological mechanisms mediated by antibodies are required in the pathogenesis of glomerulonephritis. Antibodies are thought to bind either intrinsic glomerular components or specific compounds with unique physiochemical features that are present surrounding the glomerulus. Type IV collagen is an intrinsic glomerular component involved in Goodpasture's syndrome; whereas histone-DNA complexes in systemic lupus erythematosus are not intrinsic compounds to the glomerulus. However, presence of antibodies alone is not sufficient for glomerular inflammation. Complexes formed by the antibody-antigen complexes must in fact be able to evade clearance by the reticuloendothelial system to effectively deposit at the glomerulus.

Role of Neutrophils

When complement pathway is activated, complement-derived neutrophil chemotactic factors facilitate the infiltration of neutrophils. Neutrophils undergo respiratory burst to release toxic oxygen metabolites that are nephritogenic. Hydrogen peroxide interacts with myeloperoxidase enzyme derived form the neutrophils leading to a direct injury to the glomerular basement membrane. Damage to the capillary wall and proteinuria have also been shown to be induced by elastase and cathepsin G, both of which are serine proteases derived from neutrophils.

Role of Platelets

Platelets play a role in the neutrophil-mediated injury as well. It is believed that platelets exacerbate the injury caused by neutrophils in a mechanism that is yet to be understood.

Role of Macrophages

Macrophages are involved in glomerular injury through the release of oxidants and proteases. These compounds help in the synthesis of tissue factor that leads to deposition of fibrin material on the glomerulus. Subsequently, cytokines and growth factors, such as IL-1 and TGF-B, are released and cause the abnormal production of extracellular matrix.

Role of T Cells

T cells are important for inducing glomerular hypercellularity. T cells are present in both proliferative and non-proliferative glomerular diseases. Pro-inflammatory pathways are activated following initial injury to induce further synthesis of cytokines, complement activation, influx of circulating leukocytes, release of proteolytic enzymes, and activation of coagulation pathway. These changes make the glomerular cell itself, in addition to the infiltrating glomerular cells, an active component of destruction and subsequent restoration.

Matrix Remodeling

Matrix remodeling is in part involved in the activation and proliferation of glomerular cells. The resident and the infiltrating cells will both receive unique signals following matrix remodeling that are involved in the activation of pro-inflammatory pathways in these cells. Autocrine activation of platelet-derived growth factors (PDGF) B-chain and B-receptors is believed to cause the proliferation of mesangial cells during glomerular injury. Growth factors ultimately cause the increase in proteinase synthesis and matrix expansion.

Adaptive Mechanisms

Due to ongoing injury, adaptive changes take place in order to help in the resolution of glomerulonephritis. Hyperfiltration, intraglomerular hypertension, and irregular intravascular stress and shear are all processes that may on one hand worsen the renal injury, but are also crucial for the remainder of the functioning glomerulus.

Resolution of Disease

Apoptosis, defined as programmed cell death, plays a significant role in defining the resolution of disease and in the renal scarring following glomerulonephritis.

Causes

• Causes of nephritic syndrome vary by age. Causes of nephritic syndrome include post-infectious glomerulonephritis, IgA nephropathy (Berger disease), thin basement membrane disease, and rapidly progressive glomerulonephritis.
• Age plays an important role in identifying the cause of nephritic syndrome. Nonetheless, age should not be the only factor in defining the etiology of nephritic syndrome.

Common Causes of Nephritic Syndrome by Age

Age (Years)	Cause of Nephritic Syndrome
< 15	Post-infectious glomerulonephritis IgA nephropathy (Berger disease) Thin basement membrane disease Alport's syndrome (hereditary nephritis) Henoch-Schonlein purpura Lupus nephritis
15-40	IgA nephropathy (Berger disease) Thin basement membrane disease Lupus nephritis Alport's syndrome (hereditary nephritis) Rapidly progressive glomerulonephritis Post-infectious glomerulonephritis
> 40	IgA nephropathy (Berger disease) Rapidly progressive glomerulonephritis Vasculitis Post-infectious glomerulonephritis

^{Adapted from Rose BD. Pathophysiology of renal diseases, ed. 2. New York, McGraw-Hill, 1987,p. 167}

• There are a number of different causes of nephritic syndrome such as:

Primary renal diseases	Secondary renal diseases	Multi-system disease	Allergy
Immunoglobulin A nephropathy (Berger disease) Membranoproliferative glomerulonephritis Idiopathic rapidly progressive crescenteric glomerulonephritis	Subacute bacterial endocarditis Infected ventriculoperitoneal shunt Glomerulonephritis with visceral abscess Glomerulonephritis with bacterial, viral or parasitic infections	Systemic lupus erythematosus (SLE) Wegener’s granulomatosis Goodpasture’s syndrome Microscopic polyarteritis Mixed cryoglobulinaemia Henoch-Schonlein purpura Haemolytic uraemic syndrome	Acute allergic tubulointerstitial nephritis

Differential Diagnosis

• The clinical differentiation between nephritic and nephrotic syndromes is crucial to establish the proper differential diagnosis and determine the appropriate management. In addition, the clinical history and prognosis of nephritic syndrome is different from that of nephrotic syndrome.
• The following table summarizes the key differences between nephrotic syndrome and nephritic syndrome:

Distinguishing Nephritic Syndrome from Nephrotic Syndrome

Clinical Feature	Nephritic Syndrome	Nephrotic Syndrome
Hematuria	Yes	Yes / No
Proteinuria	< 3.5 g/24 hrs	> 3.5 g/24hrs
Red Cell Casts	Yes	No
Hypoalbuminemia	Yes / No	Yes
Hypertension	Yes	Yes / No
Progression	Insidious	Abrupt

Epidemiology and Demographics

Approximately 25% of patients with acute glomerulonephritis present with nephritic syndrome. Acute glomerulonephritis accounts for 10-15% of glomerular diseases in the USA. The reported incidence of glomerulonephritis in adults varies between 0.2 to 2.5/100,000 annually with a male to female ratio reaching 2 to 1. The most common cause of glomerulonephritis worldwide is IgA nephropathy (Berger disease). Approximately 25-30% of patients eventually develop end-stage renal disease (ESRD). The yearly variation of incidence of glomerulonephritis is not validated. While some studies report a decrease in the incidence due to improved healthcare and socioeconomic status, others report an increase in the reported incidence due to increased number of biopsies. Additionally, the true incidence is difficult to predict because the disease might present subclinically.

Natural History, Complications, and Prognosis

Prognosis, complications, and outcome depend on the underlying etiology. Generally, nephritic syndrome is characterized by an abrupt onset. The course of the disease varies greatly.

History and Symptoms

Symptoms of nephritic syndrome include change in the urine color, decreased urine output, nocturia, and fatigue. In patients with secondary etiologies of glomerular diseases, the clinical presentation might be consistent with the etiology of the disease. Patients must always be inquired about recent illnesses, symptoms of vasculitides or other organ involvement, and constitutional symptoms. Symptoms of nephritic syndrome include change in the urine color, decreased urine output, nocturia, and fatigue. In patients with secondary etiologies of glomerular diseases, the clinical presentation might be consistent with the etiology of the disease. Patients must always be inquired about recent illnesses, symptoms of vasculitides or other organ involvement, and constitutional symptoms.

Symptoms

• Red urine (or dark urine)
• Headache and blurred vision due to high blood pressure
• Oliguria, defined as low urine output <400 mL/day
• Nocturia
• Edema may or may not be present
• Fatigue and lethargy

Physical Examination

The physical examination of patients with nephritic syndrome due to a primary glomerular disease is usually not very remarkable. Nonetheless, a few signs on physical exam might still be present such as high blood pressure in a minority of patients and signs of fluid overload (peripheral or periorbital edema, pulmonary edema, ascites, and jugular venous distention). A full physical examination is required when patients present with nephritic syndrome in search for causes of secondary glomerular pathology.

Laboratory Findings

Laboratory work-up must be directed to first identify the exact diagnosis of nephritic syndrome by ruling out common etiologies, and to monitor disease progression and renal function. Work-up might be different from one individual to another based on the patient's presentation and medical history and physical examination findings.

Initial Work-Up

Blood Work-up

• Complete blood count (CBC)

• Serum electrolytes

• Serum creatinine

• Blood urea nitrogen (BUN)

• Erythrocyte sedimentation rate (ESR) and C-reactive protein

Findings associated with glomerulonephritis include anemia, leukocytosis, and electrolyte disturbances such as hyperkalemia. Creatinine and BUN are required to monitor renal function, calculate eGFR, and possible renal deterioration.

Inflammatory markers, such as CRP and ESR, may or may not be elevated in acute glomerulonephritis. They may be helpful in the diagnosis of systemic illnesses, such as malignancies or vasculitides.

Urinalysis

A urinalysis is always recommended in acute glomerulonephritis, looking for:

• Hematuria

• Proteinuria

• RBC casts

• Urine culture

Further Work-Up

A more extensive work-up may be necessary for patients who present with symptoms of signs consistent with secondary glomerulonephritis. Work-up includes, but is not limited to:

• Complement levels

• Blood culture

• Streptozyme test (ASO titer)
• Streptococcal antigens, such as nephritis-associated protease (NAPR), DNase, streptolysin O, streptokinase, and hyaluronidase
• ANA profile
• c-ANCA and p-ANCA
• HBV and HCV serologies

Renal Biopsy

A renal biopsy may be helpful to differentiate etiologies of renal disease, monitor disease progression, and estimate prognosis. Not all cases of nephritic syndrome require renal biopsy. The procedure itself is invasive and may be associated with its own risks. As such, renal biopsy is only indicated if benefit will outweigh the risks. Renal biopsies for patients with initial presentation of nephritic syndrome may be affected greatly by age, progression of symptoms, clinical suspicion, and response to empirical therapy.

Echocardiography or Ultrasound

Renal ultrasound is useful to estimate the kidney size and echogenicity. Decreased renal size (eg. less than 8 cm) is consistent with irreversible renal injury. Echocardiography is indicated when a cardiac murmur is noted on physical examination or when there is a high suspicion of bacterial endocarditis causing renal involvement and nephritic syndrome.

Medical Therapy

Management and therapy vary greatly according to the diagnosis of nephritic syndrome. While most causes of nephritic syndrome are self-resolving and do not require medical intervention, such as post-infectious streptococcal glomerulonephritis, other etiologies require high doses of steroids and immunotherapy, such as rapidly progressing glomerulonephritis. In secondary etiologies of nephritic syndrome, management of the underlying disease is the mainstay of the management.