Mechanisms of Chronic Kidney Disease Progression

Much of what we understand about the mechanisms involved in the progression of CKD has been obtained through “experimental kidney disease.” Progression of CKD may be considered as a process of “glomerular adaptation.” In experimental models, adaptation is characterized by an increased workload per nephron, and this is manifested as increased “single nephron GFR (SNGFR).” The increase in SNGFR is initially “adaptive,” but eventually becomes “maladaptive,” because it leads to further nephron injury. There are several theories that have been suggested to account for this:

• 1. Hemodynamic hypothesis
• 2. Abnormal permeability to macromolecules
• 3. Growth Factor Hypothesis

Hemodynamic Hypothesis

In experimental settings, ablation of kidney mass is achieved through a unilateral nephrectomy followed by ligation of the renal artery branches in the remaining functioning kidney, thereby causing an infarction of approximately two-thirds of said kidney. By reducing the number of nephrons to one-sixth, GFR reduction ensues. Following a reduction in the number of functioning nephrons, the remaining nephrons experience hyperfiltration and glomerular capillary hypertension. Although these changes are initially adaptive to maintain GFR, over time they are deleterious to renal function because of pressure-induced capillary stretch and glomerular injury. Histopathologically, this progression of events is manifested as glomerular and tubular hypertrophy followed by eventual focal glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Damage caused by glomerular hyperfiltration is notably important in the pathophysiology that underlies diabetic nephropathy.

Another experimental kidney disease model mimicking diabetes mellitus utilizes alloxan or streptozotocin to chemically ablate pancreatic islet cells. The hyperfiltering state induced by hyperglycemia upregulates local expression of the renin-angiotensin-aldosterone system (RAAS) and contributes to progressive kidney damage. In this instance, stimulation of the RAAS causes glomerular injury by further raising glomerular capillary pressure through angiotensin II (AII)-driven efferent arteriolar vasoconstriction and facilitating pressure and stretch injury in the capillaries. Taken together, these effects lead to endothelial injury, stimulation of profibrotic cytokines by the mesangium, and detachment of glomerular epithelial cells.

Abnormal Permeability to Macromolecules

Another consequence of renal injury and activation of the RAAS is proteinuria. Glomerular capillary hypertension, caused by hyperfiltration and AII effect on efferent arterioles, leads to an increase in glomerular permeability and excessive protein filtration. Pore size is altered by AII, increasing protein leak across the glomerular basement membrane. An activated RAAS may also cause proteinuria through novel effects on neph- rin expression in kidney. Nephrin, a transmembrane protein located in the slit diaphragm of the glomerular podocyte, is thought to play a key role in the function of the glomerular filtration barrier. By maintaining slit diaphragm integrity, nephrin limits protein loss across the glomerular basement membrane. When its expression is disrupted, proteinuria and its consequences may result. Data in rat models of proteinuric kidney disease suggest an important interaction between the RAAS and nephrin in modifying glomerular protein permeability. Although proteinuria is a marker for renal disease risk, it is also likely that excess protein in urine contributes to progressive kidney damage. Proteins present in the urine are toxic to the tubules, and can result in tubular injury, tubulointerstitial inflammation, and scarring. Tubular damage is caused by protein overloading of intracellular lysosomes, stimulation of inflammatory cytokine expression, and extracellular matrix protein production. These processes induce renal tubulointerstitial fibrosis and glomerular scarring. Remission or reduction in proteinuria is often associated with renoprotection and slowed progression of kidney disease.

Growth Factor Hypothesis

Although it is known that elevated glomerular capillary pressure and capillary stretch lead to scar formation in the glomerulus, an activated RAAS and other inflammatory mediators cause irreversible damage in the kidney through other mechanisms. Proinflammatory and profi- brotic effects of AII and aldosterone underlie the injury that develops in the renal parenchyma.

Advanced glycation end-products (AGEs) accumulate in the mesangial area and glomerular capillary walls in diabetic nephropathy patients, and as such may have a role in perpetuating renal injury. AGEs are a heterogeneous group of compounds that are produced by nonenzymatic, sequential glycation and oxidation reactions of sugars with free amino groups on proteins, peptides, or amino acids. There are several pathways by which AGEs cause renal injury:

• 1. AGEs interfere with extracellular matrix proteins (collagen, elastin, and laminin) leading to alterations in both structure (induces fibrosis) and function (hydro- phobicity, charge, elasticity, and turnover).
• 2. AGE-RAGE interactions. AGE may also produce cellular injury by a cascade of receptor-dependent (RAGE) events that leads to transformation of tubular cells into myofibroblasts, leading to development of tubular atrophy and interstitial fibrosis.
• 3. AGEs are also involved in receptor-independent interactions that lead to intracellular generation of reactive oxygen species (ROS). ROS activate signaling pathways (eg, mitogen-activated protein kinases, protein kinase C, Janus kinase/signal transducers and activators of transcription), which lead to proinflammatory (eg, nuclear factor kappa B [NF-xB], monocyte chemoattractant protein-1, tumor necrosis factor [TNF]-Gf) and profibrotic (eg, transforming growth factor [TGFJ-Д connective tissue growth factor, platelet-derived growth factor [PDGF]) effects.
• 4. Accumulation of AGEs also leads to endothelial dysfunction (indirectly), increased thrombogenicity and accelerated atherosclerotic changes, and subsequent end-organ hypoperfusion.

Another maladaptive consequence is increased ammo- niagenesis per remnant nephron. This effect promotes complement cascade activation and enhanced injury to the tubulointerstitium. These effects are thought to be related to the actions of excess aldosterone and endothelin-1 stimulated by impaired elimination of the daily acid load and subsequent acid retention (inherent in CKD). This concept has led to the notion that dietary alkali therapy may have a potential role in preserving GFR and delaying progression of CKD.

These various mediators promote fibrosis and scarring in the kidney through multiple untoward effects such as toxic radical formation, enhanced cellular proliferation, and collagen deposition in the glomerulus and tubuloin- terstitium. Ultimately, glomerulosclerosis and tubulointerstitial fibrosis occur and promote CKD.

I* TABLE 16-2. Risk Factors associated with Initiation and Progression of Chronic Kidney Disease

• RISK FACTORS FOR PROGRESSION OF CKD

The risk factors for CKD progression can be classified into (Table 16.2):

• 1. Susceptibilityfactors—These are the factors that predispose to CKD. These include genetic and familial predispositions, race, maternal-fetal factors, age, and gender.
• 2. Initiation factors—These are the factors that precipitate injury to the kidneys.
• 3. Progression factors—These are the factors associated with progression of damage to established kidney disease.

These factors are further classified as either modifiable or nonmodifiable, based on feasibility for intervention. Below are the modifiable risk factors for progression.