Glomerulonephritis

Published on 06/06/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 6026 times

62 Glomerulonephritis

Glomerulonephritis (GN) is a term used to describe an inflammatory insult to the kidney’s glomeruli. A clinical pattern of hematuria, proteinuria, hypertension, red blood cell (RBC) casts, azotemia, oligoanuria, and edema occurs in various combinations. The inciting process varies from infectious to immunologic and from autoimmune to hereditary. Prompt recognition of GN is important because this disease can result in hypertensive emergency, hyperkalemia, heart failure, pulmonary edema, and renal failure. In addition, early diagnosis of GN permits prompt medical treatment of destructive subtypes that can cause long-term renal damage. Supportive care consists of strict attention to fluid and electrolyte management and blood pressure control. Certain types of GN require specific medical management to combat renal inflammation. An understanding of the diagnosis and management of GN ensures the best chance at reducing immediate morbidity and mortality as well as reducing the likelihood of progression to chronic kidney disease (CKD).

Etiology and Pathogenesis

Most glomerulonephritides result from either circulating immune complex deposition within the glomerulus or in situ immune complex formation. This activates complement, as well as cellular and humoral pathways of inflammation. Within the glomerulus, there can be endothelial, epithelial, and mesangial hypercellularity, infiltration of leukocytes, thickening or duplication of the glomerular basement membrane, and necrosis (Figure 62-1). This results in loss of capillary integrity and obstruction of blood flow through the glomerular capillary loops. This capillary injury and obstruction of glomerular blood flow leads to the fluid overload, oligoanuric renal failure, hematuria, and RBC casts.

Figure 62-1 Hypothesis of pathogenesis of acute glomerular injury by circulating immune complexes (schematic).

Differential Diagnosis

The two most common causes of GN in children are acute postinfectious GN (APIGN) and IgA nephropathy (IgAN). Other less common but important causes of GN include Henoch-Schönlein purpura (HSP), membranoproliferative GN (MPGN), rapidly progressive GN (RPGN), antineutrophilic cytoplasmic antibody– (ANCA-) positive vasculitis, systemic lupus erythematosus (SLE), and hemolytic-uremic syndrome (HUS).

Acute Postinfectious Glomerulonephritis

Acute poststreptococcal GN (APSGN) is the most common cause of APIGN in children and has a higher incidence in developing countries (Figure 62-2). APSGN is caused by nephritogenic forms of Lancefield group A streptococci. In most cases, there is clinical or laboratory evidence of antecedent streptococcal infection. APSGN must be confirmed or ruled out before looking for less common causes of post infectious GN (Staphylococcus aureus, Streptococcus viridans).

Figure 62-2 Acute poststreptococcal glomerulonephritis.

APSGN is characterized by sudden onset and variable presentation of hypertension, periorbital, lower extremity edema, oliguria, and painless gross hematuria. Urine microscopy reveals RBC casts. The glomerular damage in APSGN is immune mediated, with antigen–antibody reactions occurring in the circulation or in situ in glomeruli. These antigen–antibody reactions activate the alternative complement pathway cascade with reduction in the serum C3 concentration.

By light microscopy, findings in APSGN include glomerular enlargement, mesangial cell expansion and proliferation, and neutrophil exudation (see Figure 62-2). Electron microscopy (EM) reveals discrete subepithelial deposits.

IgA Nephropathy

IgA Nephropathy (IgAN) is an immune complex–mediated GN. Its course is highly variable and can range from asymptomatic microhematuria to recurrent episodes of gross hematuria to hypertension and acute and chronic renal failure. In Japan, of the children found by mass screening to have IgAN, 70% had asymptomatic microscopic hematuria. In these cases, IgAN is clinically silent. However, in up to 20% of patients who are referred to a pediatric nephrologist, IgAN will progress over decades to chronic renal failure.

The etiology of this disease is unknown. Although many children with IgAN present 1 to 2 days after the beginning of an upper respiratory infection, no infectious etiology has ever been identified. Most IgAN is sporadic, although an autosomal dominant form with incomplete penetrance has been found. Abnormally glycosylated IgA1 is found in the circulation and deposits in the skin and mesangium of the kidneys. The deposition of IgA in the mesangium causes activation of cytokines and growth factors, leading to mesangial expansion and extracellular matrix deposition.

Light microscopic findings show cellular and matrix expansion of the mesangium with deposition of IgA by immunofluorescence. Electron microscopy reveals electron dense deposits within the mesangium that may extend along capillary loops.

Henoch-Schönlein Purpura Nephritis

HSP nephritis is a small vessel vasculitis caused by IgA deposition within the glomeruli in the context of systemic HSP. Renal manifestations may present weeks after the onset of systemic HSP; rarely is it the first feature manifested in this syndrome. Prevalence of renal manifestations is subject to observer bias. Pediatric nephrology centers report that 50% of children with HSPN have hematuria and proteinuria, 8% have acute GN (AGN), 13% have nephrotic syndrome, and 29% have a mixed nephritic and nephrotic syndrome. Treatment of HSP nephritis is controversial because of a high rate of spontaneous remission and the lack of rigorous studies regarding treatment. Prognostic features are noted in Table 62-1.

Table 62-1 Poor Prognostic Features of Selected Glomerulonephritides and Recommended Treatment

Disease	Poor Prognostic Features	First-Line Treatment
IgAN	Proteinuria >1 g/24 h, hypertension, azotemia, interstitial fibrosis, sclerotic glomeruli	If medical treatment,- corticosteroid ACEI
HSP	Presence of nephritic or nephrotic syndrome, renal failure, nephrotic-range ongoing proteinuria, interstitial fibrosis, sclerotic glomeruli	If medical treatment needed, corticosteroids, immunosuppressive agents
SLE	Diffuse proliferative GN (WHO Class IV), ↑ creatinine, persistent HTN, chronic anemia, nephrotic-range proteinuria	Corticosteroid therapy, cyclophosphamide, azathioprine, MMF
ANCA+ vasculitis or pauci-immune GN	Crescents on biopsy, frequent relapses	Corticosteroid therapy, azathioprine, MMF, cyclophosphamide
MPGN	Type II disease, nephrotic-range proteinuria	Corticosteroid therapy

ANCA, antineutrophilic cytoplasmic antibody; AZA, azathioprine; CCS, corticosteroids; GN, glomerulonephritis; HSP, Henoch-Schönlein purpura; HTN, hypertension; IgAN, IgA nephropathy; MMF, mycophenolate mofetil; MPGN, membranoproliferative glomerulonephritis; SLE, systemic lupus erythematosus; WHO, World Health Organization.

Rapidly Progressive Glomerulonephritis

Rapidly progressive glomerulonephritis (RPGN) may be idiopathic or secondary to Goodpasture’s syndrome, HSP, Wegener’s granulomatosis, SLE, APSGN, or IgAN. It is associated with rapidly deteriorating renal function. Glomerular crescents are present on biopsy. Patients with RPGN require renal biopsy to provide appropriate therapy.

Membranoproliferative Glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN) is a form of GN with variable presentation, from asymptomatic proteinuria and hematuria to acute nephritis. MPGN requires prolonged therapy and can lead to CKD. It is an important differential diagnosis to consider in cases of presumed APSGN in which the serum C3 concentration does not revert to normal 6 to 8 weeks after the initial presentation.

Antineutrophilic Cytoplasmic Antibody–Positive Vasculitis/Pauci-Immune Glomerulonephritis

These are small vessel vasculitides (SVVs) that include Wegener’s granulomatosis, microvascular polyangiitis, and Churg-Strauss syndrome. The pathogenesis involves antimyeloperoxidase and antiserinase 3 ANCAs (c-ANCA and p-ANCA). These patients may present with night sweats, fever, weight loss, cough, and hemoptysis. More than 50% present with a pulmonary–renal syndrome. The GN associated with SVV can be severe, with rapid progression to end-stage renal failure.

Clinical Presentation

The clinical presentation of AGN is variable. Some children are asymptomatic and are found on screening, and others present to the emergency department with hypertensive emergency, edema, and acute renal failure. On history, the child’s urine may be cola or iced tea colored; there usually is no associated dysuria. The child’s face, abdomen, or legs may look swollen. One-third of patients will complain of cough, sore throat, fever, or headache. The most common physical examination findings are any combination of hypertension, edema, and gross hematuria. Nausea, vomiting, and abdominal pain are seen less often. Presentation with anuria, seizures, pulmonary edema, and symptoms of congestive heart failure occurs infrequently.

Evaluation

Performing a directed patient history and physical examination focused toward the major causes of GN and targeted use of laboratory tests will help the practitioner with diagnosis.

Recent Illnesses or Exposures

It is important to elicit the temporal relationship to any recent illnesses or exposures. ASPGN occurs after group A streptococcal infection of the throat (7-21 days later) or skin (14-28 days later). There may be a recent history of documented streptococcal pharyngitis or sore throat. Families may report that others in the family recently had sore throats but that the patient seemed unaffected. It is important to ask if there have been any skin infections (impetigo, infected bug bite, cellulitis) within the past month.

In IgA nephropathy, gross hematuria begins concurrently or 1 to 2 days after the start of an upper respiratory infection. A recent history of a visit to a zoo or farm or ingestion of undercooked hamburgers or unwashed fruits and vegetables might suggest HUS.

Other Symptoms and Review of Systems

Questions to ask in the review of symptoms include:

• Does the patient have abdominal pain or purpuric lesions that would suggest HSP nephritis?

• Is there a malar rash, pleuritic chest pain, neurologic changes, or other stigmata of SLE?

• Is there concomitant bloody diarrhea or a lobar pneumonia that would be seen in Shiga toxin or pneumococcal HUS, respectively?

• Is there any hemoptysis or sinusitis suggesting Wegener’s granulomatosis or Goodpasture syndrome?

• Does the child have any hearing loss that would suggest a diagnosis of Alport’s syndrome?

• Has the child fainted, felt dizzy, or had heart palpitations that could be indicative of arrhythmias caused by electrolyte imbalance?

Family History

In a child with suspected GN, it is also important to obtain a detailed family history, focusing on inherited forms of GN, especially Alport’s syndrome (also known as hereditary nephritis). In all of these cases, it is important to construct a family tree because Alport’s syndrome is usually X-linked. Questions to ask include:

• Has anyone else in the family ever had gross hematuria?

• Has anyone in the family been told that he or she has microscopic hematuria?

• Is there a history of renal failure, dialysis, or renal transplant in the family?

Physical Examination

In AGN, it is important to determine the degree of intravascular volume overload and to look for findings suggestive of the cause for the GN.

Intravascular Volume Status

It is important to determine whether there is fluid overload that is compromising the child’s cardiorespiratory status. Intravascular volume overload is suggested by weight gain in presence of elevated blood pressure; jugular venous distension; gallop rhythm; reduced oxygenation by pulse oximetry; increased work of breathing, rales, or crackles; hepatomegaly; and peripheral edema. The edema in AGN varies in severity. Hypertensive children may present with seizures, but headache and nonspecific behavioral changes are more common.

Other Physical Examination Findings

Physical examination findings that may indicate specific etiologies of AGN are detailed in Table 62-2.

Table 62-2 Types of Glomerulonephritis with Possible Associated Physical Examination Findings

Disease	Notable Physical Examination Findings
ASPGN	Pharyngitis, healing or healed impetigo or ecthyma
IgAN	Coryza, congestion, pharyngitis, cough
HSP	Abdominal pain, palpable purpura
SLE	Malar or discoid rash, painless oral ulcers, neurologic changes, arthritis, serositis
ANCA positive: pauci-immune GN	Weight loss, fever, myalgias, sinusitis, hemoptysis (pulmonary–renal syndrome)
HUS: Shiga toxin positive Pneumococcal	Bloody diarrhea Lobar pneumonia

ANCA, antineutrophilic cytoplasmic antibody; APSGN, acute poststreptococcal glomerulonephritis; HSP, Henoch-Schönlein purpura; HUS, hemolytic-uremic syndrome; IgAN, IgA nephropathy; SLE, systemic lupus erythematosus.

Laboratory Evaluation

Laboratory evaluation is required to assess renal function and serum electrolyte concentrations, evaluate for the presence of GN, and determine the etiology of the glomerular inflammation. The presence of RBC casts should be determined in a fresh urine specimen examined by microscopy. The serum C3 concentration helps differentiate among the many causes of GN. A low serum C3 concentration is present in APSGN and MPGN. Patients with SLE may have low serum concentrations of C3 and C4. In those with IgAN, SVV, HUS, Alport syndrome, and HSP nephritis, the serum C3 concentration is normal. The serum C3 concentration should return to normal in 6 to 8 weeks in children with APSGN. If this does not occur and the patient remains symptomatic, then a biopsy should be considered to evaluate for MPGN. Studies used to differentiate among the glomerulonephritides are detailed in Table 62-3.

Table 62-3 Laboratory Tests Important in Distinguishing Etiology of Glomerulonephritis

Disease	Laboratory Evaluation
APSGN	C3, ASOT, Streptozyme, rapid strep or throat culture
IgAN	Glycosylated IgA1, renal biopsy
SLE	C3, C4, ANA, anti-Smith, anti dsDNA, and renal biopsy
ANCA+ Vasculitis/Pauci-Immune glomerulonephritis	ANCA titers, anti-PR3 Ab, anti-MPO Ab, and renal biopsy
HUS	Stool culture for Escherichia coli O157, stool Shiga toxin
MPGN	C3, C4, hepatitis panel (secondary causes of MPGN)
Alport’s syndrome	Genetic test for mutations in type IV collagen gene COL4A5 and renal biopsy

ANCA, antineutrophil cytoplasmic antibody; ANA, antinuclear antibodies; APSGN, acute poststreptococcal glomerulonephritis; ASOT, antistreptolysin titer; C3/4, complement 3/4; HSP, Henoch-Schönlein purpura; HUS, hemolytic-uremic syndrome; IgAN, IgA nephropathy; MPGN, membranoproliferative glomerulonephritis; PR3, serine protease 3; MPO, myeloperoxidase; SLE, systemic lupus erythematosus.