Primary renal diseases affect the four functional units of the kidney: glomeruli, tubules, interstitium, and blood vessels. Glomerular diseases tend to be immunologically mediated and the others due to toxic insult or infection. Pathology of all for components is what defines end-stage kidney disease.

1 Clinical manifestations of renal disease

Azotemia describes elevated blood urea nitrogen (BUN) and creatinie: clinical signs of decreased glomerular filtration rate (GFR)—which may be a consequence of acute or chronic kidney injury (primary or secondary). Prerenal and postrenal azotemia are used to describe hypoperfusion and obstruction of urine flow distal to the kidney that impair renal function without parenchymal damage, respectively. Uremia describes a more advanced state of azotemia that is associated with additional signs, symptoms, and biochemical abnormalities.

Nephritic syndrome defined as grossly visible hematuria or microscopic hematuria with dysmorphic red cells and red cell casts, proteinuria, reduced glomerular filtration rate, and hypertension. Classically, it is the presentation of acute poststreptococcal glomerulonephritis.

Nephrotic syndrome is also due to disease of the glomeruli and is characterized by proteinuria (urine protein content > 3.5 gm/day), hypoalbuminemia, edema, hyperlipidemia, and lipidurea.

Asymptomatic hematauria or protinurea are signs of mild glomerular dysfunction.

Acute kidney injury describes an acute decline in glomerular filtration rate (seen as retention of creatinine and urea on urinalysis), fluid and electrolyte dysregulation, oliguria, or anuria.

Chronic kidney disease is defined by a glomerular filtration rate ≤ 60mL/min/1.73m2 or albuminuria for at least 3 months. Presentation my be insidious but mild changes or with severe uremia.

End-stage renal disease is defined by a glomerular filtration rate that is 5% of normal i.e terminal uremia.

Renal tubular defects most often manifest as polyuria, nocturia, and electrolyte disorders.

Urinary tract obstruction and renal tumors are not defined by their clinical manifestation as it has high variance however obstruction due to infection manifests as bactiuria and pyuria (leukocytes in urine).

Nephrolithiasis or renal stones are known for severe pain and hematuria.

2 Glomerular disease

Disease of the glomerulus is the most common source of chronic kidney disease and has a large number of secondary etiologies: systemic lupus erythematosus, diabetes mellitus, or Fabry disease–that tend to be systemic in nature. Primary diseases are termed glomerulopathies or glomerulonephritis, when involving inflammation.

2.1 Structure of the glomerulus

The glomerulus consists of the following elements:

The glomerulus is highly permeable to water and small solutes but impermeable to molecules as at least as large as albumin. Moreover, anionic molecules are impermeable due to the charge of the glomerular basement lamina.

The slit diaphragm of the visceral epithelium acts as size-selective diffusion barrier distal to the basement lamina. Nephrin is a transmembrane with a large extracellular, Ig-like domains that associate with each other across the foot process of the podocytes. Within the cell, nephrin associates with a membrane bound protein, podocin and CD2-associated protein that ultimately connects with the actin skeleton of the podocyte.

2.2 Pathological responses to injury

The glomerulus can respond in some of the following ways to injury, which can then lead to pathology.

Hypercellularity. Inflammatory disease of the glomerulus can cause various forms of hypercellularity.

Basement lamina thickening. Evidence of basement lamina thickening includes:

Hyalinosis and sclerosis. Hyalinosis describes insudated, eosinophilic, amorphous plasma proteins in glomerular structures; it is often due to endothelial or capillary wall injury and is a often the end result of glomerular damage.

Sclerosis refers to deposition of collagenous extracellular matrix of the mesangial areas or capillary loops.

2.3 Etiology of glomerular injury

Immunologic dysfunction underlies most forms of primary glomerulopathy though cell-mediated injury and activation of complement are also known etiologies. In general, antibody mediated injury can occur in situ or by deposition of circulating antibody-antigen complexes (the former is a major cause of the latter).

2.3.1 Diseases of in situ formation of immune complexes

Immune complexes of self-antigens and antibodies form or antibodies can form complexes with self-antigen that was previously deposited in glomerular tissue. Antibodies are typically generated against proteins on the basal surface of visceral epithelial cells and subsequently formation of complexes activate compliment. A granular pattern of antibody deposition (in contrast to a linear pattern) can be appreciated by immunoflorescence. Basement membrane thickening is a common result.

2.3.1.1 Antibodies against deposited antigens

Antigens that localize and are deposited in glomerular tissues can be: cationic molecules bound to anionic portions of the glomerulus; DNA, nucleosomes, or other nuclear proteins; bacterial products; large protein aggregates; and immune complexes. Children who develop antibodies against bovine albumin (from drinking cow’s milk) present with sings of glomerulonephritis—the bovine albumin cannot pass through the slit diaphragms allowing for immune complexes to form.

2.3.2 Disease caused by antibodies directed at normal components of the glomerular basement lamina

In contrast to in situ formation of immune complex, formation of antibodies to components of the glomerular basement lamina arrange as a diffuse linear pattern along the entire length of the basement lamina when stained with immunoflorescense. When these antibodies cross react with the basement membrane of the alveoli giving rise to the sequela of Goodpasture syndrome. The antigen implicated in this disorder is part of the noncollagenous domain (NC1) of the α3-chain of type 4 coallagen. Cresent formation is seen as a consequence to this injury and causes rapidly progressive, necrotizing glomerulonephritis.

2.3.3 Glomerulonephritis resulting from deposition of circulating immune complexes

Preformed antigen-antibody complexes circulating in plasma can get trapped with in the glomerular apparatus allowing for a number of mechanisms of immune-mediated injury to occur. Disease that are commonly associated with this etiology are systemic lupus erythamatosis; IgA nephropathy; complexes formed with bacteria, viruses, T. pallidum, P. falciparum, or streptococcal proteins; HVC or HVB surface antigens; or tumor antigens.

2.3.4 Mechanisms of glomerular injury following immune complex formation

As discussed earlier in situ or deposition of antigen-antibody immune complexes elicit the inflammatory response. Complement activation is one important response as well as engagement of the Fc receptor on leukocytes by glomerular mesangial cells or others. Reactions can be short lived and never remit (as seen in cases of poststreptoccal glomerulonephritis) or chronically remittent (as seen in cases of SLE), which can leading to pathological changes to the structures of the glomeruli. Structure and change play an important role in localization and nature of the inflammatory response:

While pathology due to formation of antibodies for antigens directed at intrinsic components of the basement lamina can be identified by a neat diffuse linear pattern on immunoflorescense, the granular pattern does not serve as a discriminate between in situ deposition or deposition of circulating antibody-antigen complexes. Moreover, deposition of circulating complexes can induce in situ complex formation.

2.3.5 Cell-mediated immunity in glomerulonephritis

2.3.6 Activation of complement pathway

2.3.7 Mediators of glomerular injury

2.4 Mechanisms of progression in glomerular diseases

Independent of the original etiology of renal disease, once the glomerular filtration rate is 30-50% of baseline, progression to end-stage failure becomes a steady, regular decline.

Focal segmental glomerulosclerosis. Focal segmental glomerulosclerosis is defined by progressive fibrosis of parts of some glomeruli—seen on a pictomicrograph—after many types of renal injury and manifests clinically with proteinuria. Sclerosis is thought to be an adaptive change due to changes in fluid dynamics. Injury to endothelial and visceral epithelia injury that denudes the glomerular basement lamina of its overlaying foot processes leads to increased protein permeability. Accumulation of proteins in the mesangial layer stimulates proliferation and macrophage infiltration is the basis of segmental and global sclerosis. Chronic inflammation induces fibrosis and remodeling; notably by TGF-β.

Tubulointerstitial fibrosis. Local insult to the tubular cells or damage secondary to glomerulonephritis can cause them to secrete pro-inflammatory cytokines and growth factors causing fibrosis.

2.5 Nephritic syndrome