Glomerular diseases are a group of kidney disorders primarily characterized by hematuria, proteinuria, edema, hypertension, and varying degrees of renal dysfunction. These conditions typically involve both kidneys and represent a major cause of chronic renal failure. The etiology, pathogenesis, pathological changes, clinical manifestations, disease course, and prognosis of glomerular diseases vary significantly. Based on etiology, they can be classified into three main categories: primary, secondary, and hereditary.
Primary glomerular diseases refer to those with unknown causes.
Secondary glomerular diseases are those caused by systemic diseases, such as lupus nephritis or diabetic nephropathy.
Hereditary glomerular diseases result from genetic mutations, such as Alport syndrome.
This section focuses on primary glomerular diseases.
Classification
Primary glomerular diseases can be classified based on clinical presentation and renal biopsy pathology.
Clinical Classification
The clinical classification of primary glomerular diseases is based on clinical manifestations, which are grouped into corresponding clinical syndromes. Each syndrome may encompass multiple types of diseases or pathological changes. Detailed information can be found in related sections.
- Acute glomerulonephritis (AGN).
- Rapidly progressive glomerulonephritis (RPGN).
- Chronic glomerulonephritis (CGN).
- Asymptomatic hematuria and/or proteinuria.
- Nephrotic syndrome (NS).
Pathological Classification
The pathological classification of glomerular diseases is based on the nature and extent of the lesions.
Lesions involving fewer than 50% of glomeruli are classified as focal, while those involving 50% or more glomeruli are classified as diffuse.
Lesions affecting less than 50% of the capillary loops within a glomerulus are termed segmental, while those involving 50% or more of the capillary loops are termed global.
Minor Glomerular Lesions
Minor glomerular lesions include minimal change disease (MCD).
Focal Segmental Lesions
Focal segmental lesions include focal segmental glomerulosclerosis (FSGS) and focal glomerulonephritis.
Diffuse Glomerulonephritis
Diffuse glomerulonephritis:
- Membranous Nephropathy (MN).
- Proliferative Glomerulonephritis:
- Mesangial proliferative glomerulonephritis.
- Endocapillary proliferative glomerulonephritis.
- Mesangial capillary glomerulonephritis, including:
- Membranoproliferative glomerulonephritis (MPGN) types I and III.
- Dense deposit disease (DDD), also known as MPGN type II.
- Crescentic glomerulonephritis.
- Sclerosing Glomerulonephritis.
Unclassified Glomerulonephritis
There is a certain correlation between the clinical and pathological classifications of glomerular diseases, but the two are not necessarily directly aligned. Identical clinical presentations may arise from different pathological types, while the same pathological type may present with varying clinical manifestations.
Renal biopsy remains an essential method for determining the pathological type and extent of lesions in glomerular diseases. Accurate pathological diagnosis must be closely integrated with clinical findings. In clinical practice, initial classification is typically based on clinical syndromes, followed by pathological evaluation under appropriate circumstances.
Pathogenesis
The pathogenesis of primary glomerular diseases remains incompletely understood. Most glomerular diseases are immune-mediated inflammatory disorders. It is generally believed that immune responses serve as the initiating mechanism of glomerular diseases, with inflammatory mediators (such as complement, cytokines, and reactive oxygen species) contributing to the process, ultimately leading to glomerular injury and clinical symptoms. Non-immune and non-inflammatory mechanisms are also involved in the chronic progression of glomerular diseases. Additionally, genetic factors play an important role in disease susceptibility, severity, and response to treatment.
Immune Responses
Immune responses include both humoral and cellular immunity. The roles of humoral immunity, such as circulating immune complexes (CICs), in situ immune complexes, and autoantibodies, in the pathogenesis of glomerular diseases are well-established. Cellular immunity has also been increasingly recognized in certain types of glomerular diseases.
Humoral Immunity
Deposition of Circulating Immune Complexes (CICs)
Exogenous antigens (e.g., components of nephritogenic streptococci) or endogenous antigens (e.g., degradation products of DNA) can stimulate the production of corresponding antibodies, forming CICs in the bloodstream. These CICs may deposit in the glomeruli or be trapped by glomerular structures, activating inflammatory mediators and causing glomerular damage. Factors such as the formation of lattice-like structures by multiple antigen-antibody molecules, impaired phagocytosis by the mononuclear phagocyte system, reduced mesangial clearance, or complement deficiencies can increase the likelihood of CIC deposition in the glomeruli. CICs primarily deposit in the mesangial region and/or subendothelial space.
Formation of In Situ Immune Complexes
This involves the binding of circulating antibodies (or antigens) to intrinsic glomerular antigens (e.g., glomerular basement membrane [GBM] antigens or podocyte antigens) or planted exogenous antigens (or antibodies) in the glomeruli. These immune complexes form locally in the kidneys and cause tissue damage. In situ immune complexes are mainly deposited on the epithelial side of the GBM. Idiopathic membranous nephropathy (IMN), in addition to classic anti-GBM nephritis, is a disease primarily mediated by in situ immune complexes. The M-type phospholipase A2 receptor (PLA2R) on podocytes is the major target antigen in IMN. Specific circulating anti-PLA2R antibodies bind to this receptor, forming in situ immune complexes that activate complement, leading to podocyte injury and proteinuria.
Autoantibodies
Autoantibodies, such as anti-neutrophil cytoplasmic antibodies (ANCAs), can interact with neutrophils, vascular endothelial cells, and complement activation to induce immune-inflammatory responses in the glomeruli, resulting in typical pauci-immune glomerulonephritis.
Cellular Immunity
Cellular immunity has been increasingly recognized as a key factor in the pathogenesis of glomerulonephritis. Evidence from animal models of nephritis and some human glomerulonephritis cases supports this role. In minimal change disease (MCD), there is no evidence of humoral immune involvement within the glomeruli. Instead, the disease is characterized by T-cell dysfunction. In vitro studies have shown that lymphocytes from patients can release vascular permeability factors, causing podocyte foot process effacement. Recent research has also highlighted the role of imbalances between different subsets of helper T cells in the development of glomerular diseases.
Inflammatory Responses
Immune responses must trigger inflammatory responses to cause glomerular injury and clinical symptoms. The inflammatory system consists of inflammatory cells and inflammatory mediators. Inflammatory cells produce mediators, while mediators recruit and activate inflammatory cells. These interactions form a complex network of interdependent processes.
Inflammatory Cells
Inflammatory cells include neutrophils, monocytes/macrophages, sensitized T lymphocytes, eosinophils, and platelets. These cells produce various inflammatory mediators, resulting in glomerular inflammation. Recent studies have shown that intrinsic glomerular cells (e.g., mesangial cells, endothelial cells, and podocytes) possess receptors for immunoglobulins and inflammatory mediators. These cells can also secrete inflammatory mediators and extracellular matrix (ECM), actively participating in immune-mediated glomerular inflammation rather than being passive victims.
Inflammatory Mediators
Inflammatory mediators influence local renal hemodynamics and glomerular capillary permeability by inducing vasoconstriction or vasodilation. They act on different renal cells, including glomerular and tubulointerstitial cells, affecting cell activation, proliferation, autocrine, and paracrine signaling. These processes regulate ECM accumulation and degradation, mediating inflammatory damage and sclerosis.
Non-Immune Factors
While immune-mediated inflammation plays a primary and/or initiating role in glomerular diseases, non-immune mechanisms contribute to chronic disease progression. These include intraglomerular capillary hypertension, proteinuria, and hyperlipidemia. These factors can perpetuate and exacerbate kidney damage.
After renal parenchymal injury, surviving nephrons undergo hemodynamic changes, leading to increased intraglomerular capillary pressure, which promotes glomerular sclerosis. Furthermore, heavy proteinuria is an independent risk factor for the progression of glomerular disease.
Clinical Manifestations
Proteinuria
The normal glomerular filtration membrane allows proteins with a molecular weight of less than 20,000–40,000 Da to pass through easily. As a result, the primary urine filtered by the glomerulus mainly contains small molecular proteins, such as lysozyme, β2-microglobulin, and light chain proteins. In contrast, larger proteins like albumin (molecular weight 69,000 Da) and immunoglobulins are present in much smaller amounts. Over 95% of the proteins filtered into the primary urine are reabsorbed in the proximal tubules, resulting in very low protein levels in the final urine of healthy individuals (<150 mg/day). Approximately half of the proteins in normal urine are Tamm-Horsfall proteins secreted by the distal tubules and ascending loop of Henle, as well as other tissue proteins secreted by the urinary tract. The other half consists of plasma proteins, including albumin, immunoglobulins, light chain proteins, β2-microglobulin, and various enzymes. Routine urinalysis in healthy individuals usually does not detect protein. Proteinuria is defined as the presence of more than 150 mg/day of protein in the urine, which results in a positive qualitative urine protein test. If the daily urinary protein excretion exceeds 3.5 g, it is referred to as massive proteinuria.
The glomerular filtration membrane consists of glomerular capillary endothelial cells, the basement membrane, and visceral epithelial cells (podocytes). Its filtration barrier function includes:
- Molecular Barrier: The glomerular filtration membrane only permits the passage of smaller protein molecules.
- Charge Barrier: The endothelial cell and podocyte membranes contain sialoproteins, while the basement membrane contains heparan sulfate, imparting a negative charge to the filtration membrane. This negative charge repels negatively charged plasma proteins, such as albumin, and prevents their filtration.
Damage to any of these barriers can lead to proteinuria. Glomerular proteinuria is often primarily composed of albumin. In minimal change disease, where glomerular structure appears normal in light microscopy, massive proteinuria is primarily due to damage to the charge barrier. When the molecular barrier is disrupted, larger plasma proteins, such as immunoglobulins and C3, may also appear in the urine, indicating more severe structural damage to the glomerular filtration membrane.
Hematuria
Hematuria is defined as the presence of more than 3 red blood cells (RBCs) per high-power field in a centrifuged urine sediment under a microscope. Gross hematuria can occur when 1 mL of blood is present per liter of urine. Hematuria associated with glomerular diseases, particularly glomerulonephritis, is often painless, occurs throughout the entire urinary stream, and may present as microscopic or gross hematuria, either persistently or intermittently. Hematuria can occur alone or be accompanied by proteinuria and/or casts. The presence of significant proteinuria and/or casts (especially RBC casts) in a patient with hematuria strongly suggests glomerular origin.
Two diagnostic methods help differentiate the source of hematuria:
- Phase-contrast microscopy of fresh urine sediment: Dysmorphic RBCs in the urine suggest a glomerular origin, while uniformly shaped RBCs are more likely to be non-glomerular in origin. However, in severe glomerular damage (e.g., crescentic glomerulonephritis), uniformly shaped RBCs may also be observed.
- Urinary RBC volume distribution curve: Hematuria of glomerular origin often shows an asymmetric curve, with the peak RBC volume smaller than that of venous RBCs. Non-glomerular hematuria tends to show a symmetric curve, with the peak RBC volume larger than that of venous RBCs.
The primary cause of glomerular hematuria is GBM rupture. As RBCs pass through the rupture site, they are subjected to intravascular pressure, leading to damage. These damaged RBCs are further altered by the osmotic pressure and pH changes in different segments of the renal tubules, resulting in dysmorphic RBCs, reduced RBC volume, and even RBC fragmentation.
Edema
The fundamental pathophysiological mechanism of renal edema is water and sodium retention. In glomerular diseases, edema can be classified into two main types:
Nephrotic Edema
This is primarily caused by prolonged and massive proteinuria, leading to hypoalbuminemia and reduced plasma oncotic pressure. Fluid shifts from the intravascular space to the interstitial space, resulting in edema. Additionally, a decrease in effective blood volume stimulates the activation of the renin-angiotensin-aldosterone system and increases antidiuretic hormone secretion, promoting water and sodium reabsorption in the renal tubules and further exacerbating edema. Recent studies suggest that certain factors originating from the distal nephron may contribute to water and sodium retention in nephrotic edema, independently of the renin-angiotensin-aldosterone system.
Nephritic Edema
This occurs primarily due to a decrease in glomerular filtration rate (GFR) while tubular reabsorption remains relatively normal. This "glomerulotubular imbalance" and a reduced filtration fraction (GFR/renal plasma flow) lead to water and sodium retention. In nephritic edema, blood volume is often increased, with reduced renin-angiotensin-aldosterone system activity and decreased antidiuretic hormone secretion. Factors such as hypertension and increased capillary permeability further contribute to the persistence and worsening of edema. Nephrotic edema is characterized by low protein content in the interstitial fluid and typically begins in the lower extremities, whereas nephritic edema has a higher protein content in the interstitial fluid and often starts in the eyelids or face.
Hypertension
Hypertension commonly accompanies glomerular diseases, with a prevalence of approximately 61% in patients with chronic glomerulonephritis and 90% in those with chronic renal failure. The mechanisms underlying hypertension in glomerular diseases include:
- Water and Sodium Retention: Increased blood volume leads to volume-dependent hypertension.
- Increased Renin Secretion: Renal ischemia stimulates the renin-angiotensin system, causing arteriolar constriction, increased peripheral resistance, and renin-dependent hypertension.
- Reduced Production of Intrarenal Vasodilators: Damage to the renal parenchyma reduces the production of vasodilatory substances, such as prostaglandins and kinins, contributing to renal hypertension.
Other factors, such as atrial natriuretic peptide, the sympathetic nervous system, and various endocrine hormones, may also directly or indirectly contribute to renal hypertension. Hypertension caused by glomerular diseases is often volume-dependent, though renin-dependent hypertension can also occur. The two types of hypertension frequently coexist and may be difficult to distinguish.
Renal Dysfunction
Some cases of acute glomerulonephritis may present with transient azotemia or acute kidney injury. Rapidly progressive glomerulonephritis often leads to severe and rapid deterioration of renal function, potentially resulting in kidney failure. In chronic glomerulonephritis, progressive renal dysfunction of varying degrees is common, and some patients eventually develop end-stage renal disease (ESRD).
To be continued