Abstract
The pathophysiology of chronic kidney disease (CKD) is dependent on the inciting cause, but irrespective of the etiology, there is a consistent pattern of ongoing damage across most forms of CKD. These harmful adaptations lead to progressive kidney dysfunction and can be divided into hemodynamic and nonhemodynamic injury. The renin-angiotensin-aldosterone system (RAAS) is mainly responsible for perpetuating this progression through its profibrotic actions and increasing glomerular and systemic hypertension. Robust clinical evidence supports blockade of the RAAS system to help delay progression in most forms of CKD, especially in those with proteinuria. Treating the underlying cause, use of RAAS blockers, controlling blood pressure, avoiding acute kidney injury (AKI), and attempting cardiovascular risk reduction are the most important goals for the physicians treating patients with CKD.
Keywords
chronic kidney disease, pathophysiology, progression, proteinuria, diabetic nephropathy, hyperfiltration, glomerular hypertension, fibrosis, systemic hypertension, renin-angiotension-aldosterone blockade
Chronic kidney disease (CKD) is defined as abnormal measurements of the actual or estimated glomerular filtration rate (GFR) for a minimum of 3 months ( Box 51.1 ), or situations where the GFR is normal but pathology in the kidney is still present, such as radiographically imaged cysts in polycystic kidney disease or isolated proteinuria in early glomerular disease (see Chapter 52 ). The most commonly reported causes of CKD and end-stage renal disease (ESRD) ( Table 51.1 ) are diabetic nephropathy ( Fig. 51.1 ) and hypertensive nephrosclerosis, although the diagnosis of “hypertensive nephrosclerosis” has recently been questioned in reference to APOL1 genetic abnormalities ( Chapter 37 ). However, many other conditions can cause CKD, including primary glomerular diseases (e.g., IgA nephropathy, membranous glomerulopathy), secondary glomerular diseases (e.g., lupus nephritis, amyloidosis), and tubulointerstitial, vascular, cystic, and hereditary kidney diseases. Each of these has specific pathophysiologic mechanisms for kidney damage; therefore the treatments developed for these diseases are unique and aimed at controlling or reversing the primary disease process.
- 1.
Chronic kidney disease (CKD) is currently defined by a reduction in glomerular filtration rate over a period of time or evidence of kidney damage.
- 2.
The most commonly reported causes of CKD are diabetes mellitus and hypertension, and less frequent causes are primary glomerular, tubulointerstitial, and cystic diseases.
- 3.
The pathophysiology of chronic kidney damage is related to the underlying disease, but it is accelerated by glomerular hypertension, systemic hypertension, inflammation, and fibrosis.
- 4.
Risk factors for progression are hypertension, proteinuria, and recurrent acute kidney injury.
- 5.
Treatment for CKD is disease specific, but several generalized methods can be applied to almost all kidney diseases. The goal is slowing or reversing progression with therapies aimed at correcting the pathophysiologic patterns. These involve blocking the renin-angiotensin-aldosterone system (RAAS) with medications, controlling blood pressure, and reducing albuminuria when present. This goal is attempted while also targeting cardiovascular risk reduction. Novel methods, which require further study, involve attacking the inflammatory and fibrotic effects of the pathophysiology.
| Disease | Percentage (%) |
|---|---|
| Diabetes mellitus type 1 | 3.9 |
| Diabetes mellitus type 2 | 41.0 |
| Hypertension | 27.2 |
| Primary glomerulonephritis | 8.2 |
| Tubulointerstitial | 3.6 |
| Hereditary or cystic | 3.1 |
| Secondary glomerulonephritis or vasculitis | 2.1 |
| Neoplasm or plasma cell dyscrasias | 2.1 |
| Miscellaneous | 4.6 |
| Unknown | 5.2 |
The idea, then, that CKD could be generalized into one disease process is an oversimplification, because the primary processes causing kidney damage are protean. However, the pathophysiology of progression of many of these disorders involves similar pathways, and generic treatments aimed at slowing this progression have been applied across a wide variety of kidney diseases effectively and safely. Over the last 20 years, treatments have been developed and proven to delay progression to ESRD, and other therapies continue to be studied. Therefore early recognition of CKD becomes important to help implement therapy that may delay or reverse this progression and reduce the associated morbidity and mortality.
Pathophysiologic Mechanisms of Chronic Kidney Disease
The pathophysiology of CKD is complex and in large part dependent on the primary cause. After a primary acute or chronic insult occurs, such as in diabetic nephropathy or lupus nephritis, many common pathways are activated to perpetuate and exacerbate glomerular and tubulointerstitial injury ( Fig. 51.2 ). These harmful adaptations, occurring because of an initial injury, can be broadly categorized into those that are hemodynamically mediated or those that are nonhemodynamic.
Hemodynamic Injury
Much of the work in hemodynamic-mediated injury stems from the 5/6 nephrectomy animal model. Following unilateral nephrectomy and 2/3 removal of the contralateral kidney in rats, hypertension, proteinuria, and progressive decline in GFR ensue. Pathologic examination of the remaining tissue exhibits hyperfiltration injury, as evidenced by glomerular hypertrophy and focal segmental glomerular sclerosis (FSGS). The process occurs at a linear rate in proportion to the greater reduction in kidney mass. Micropuncture techniques reveal an increase in renal plasma flow and hyperfiltration of the remaining nephrons. Systemic and glomerular hypertension, from activation of the renin-angiotensin-aldosterone system (RAAS), causes progressive glomerular damage and proteinuria. As a result of these changes, efferent arteriolar tone increases more than afferent tone. This net efferent vasoconstriction increases intraglomerular and filtration pressure further, perpetuating hyperfiltration injury. Animal models of other primary kidney diseases, such as that of diabetic nephropathy in the rat, reveal similar pathophysiologic changes of glomerular hypertension, hypertrophy, and hyperfiltration.
These maladaptive hemodynamic effects are mediated by the RAAS ( Figs. 51.2 and 51.3 ). With nephron loss, adaptation leads to release of renin from the juxtaglomerular apparatus because of decreased perfusion pressure and low solute delivery to the macula densa. Renin converts angiotensinogen to angiotensin I, which is converted to angiotensin II (AII) under the influence of angiotensin converting enzyme (ACE). AII, in addition to increasing aldosterone production from the adrenal gland, is the main perpetrator of glomerular hemodynamic maladaptation. Through an increase in sympathetic activity, AII is a potent vasoconstrictor, especially predominant in the efferent arterioles. It also exhibits a role in salt and water retention, both directly through proximal tubular sodium reabsorption and indirectly through aldosterone-dependent distal sodium reabsorption. Finally, it stimulates the posterior pituitary to release antidiuretic hormone (ADH).
The net effect of all these mechanisms is an integral component of autoregulation, helping to maintain GFR when perfusion is decreased. However, in the setting of nephron loss through a primary kidney insult or CKD, the effect of continuous AII overactivity is perpetual maladaptation by creating systemic and, notably, glomerular hypertension. This glomerular hypertension increases the filtration fraction, increases the radius of the pores in the glomerular basement membrane (GBM) through an increase in hydrostatic pressure, and eventually results in clinical proteinuria and glomerular destruction.
The best example of a human model of decreased nephron mass or number is unilateral renal agenesis. Ashley and Mostofi originally reported 232 patients with unilateral renal agenesis in the 1960s, and, although the pathology was not described, 16% of the patients died from kidney failure. Later, in the 1980s, autopsy series and case series confirmed the association of unilateral renal agenesis with hypertension, proteinuria, progressive kidney disease, glomerulomegaly, and FSGS ( Fig. 51.4 ). Besides renal agenesis, another human example is the condition known as oligomeganephronia. This is a form of congenital renal hypoplasia in which the number of nephrons is reduced. The glomeruli hypertrophy in compensation for the reduced nephron number. The sequelae of this include hypertension, proteinuria, and FSGS related to hyperfiltration and progressive kidney failure. Other clinical human examples of disease that support this mechanism of kidney injury include obesity-related glomerulomegaly and nephropathy, dysplastic solitary kidney, or partial nephrectomy in the setting of a solitary kidney.
Because animal models and human congenital diseases of reduced nephron mass lead to hemodynamic maladaptation and morphologic evidence of FSGS, it is natural to speculate that a transplant donor would be at risk for this same pathophysiology. Fortunately, the development of hypertension or kidney damage in the remaining kidney in transplant donors is infrequent. This may reflect extensive screening of potential donors, resulting in a sufficiently healthy population with minimal vascular disease, such that the donor can readily compensate for a 50% reduction in kidney mass. Similar results are seen in experimental models where adult rats with unilateral nephrectomy rarely develop hypertension or kidney disease; however, when a single kidney is removed from immature rats, the glomerular lesion FSGS manifests in the remaining kidney. Therefore hemodynamic injury may be present or clinically apparent only when the kidney is undergoing normal growth. Another explanation of this benign clinical course in patients donating a kidney is that the development of clinical pathology is directly linked to the length of time and degree of reduction of nephron mass. Indeed, there are studies demonstrating an increased risk for hypertension, proteinuria, and progressive kidney disease in patients who have more than a 50% reduction in kidney mass, such as those with bilateral partial nephrectomy for carcinoma, and a greater likelihood of progressive kidney disease with a longer duration of nephron mass reduction.
Nonhemodynamic Injury
Besides the hemodynamic effects of systemic vasoconstriction, sodium retention, and efferent arteriolar vasoconstriction, activation of the RAAS leads to several nonhemodynamic maladaptive pathways (see Fig. 51.2 ), which in turn result in inflammation and fibrosis. AII has been demonstrated in high concentrations in virtually every compartment of the kidney in CKD, including the mesangial cells, endothelial cells, podocytes, the urinary space (Bowman capsule), and the tubulointerstitium.
Activation of the RAAS eventually results in fibrosis and a progressive decline in GFR. This fibrosis manifests with up regulation of several growth factors and their receptors, such as connective tissue growth factor (CTGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and monocyte chemotactic protein-1 (MCP-1). The activation of these factors by AII and aldosterone leads to cellular proliferation and hypertrophy of glomerular endothelial cells, mesangial cells, podocytes, tubulointerstitial cells, and fibroblasts. AII and TGF-β also upregulate other factors that lead to the overproduction of extracellular matrix, such as type 1 procollagen, plasminogen activator inhibitor 1, and fibronectin. In addition, excess adhesion molecules, such as integrins or vascular cellular adhesion molecule 1, allow the increased extracellular matrix and hypercellularity to accumulate and persist. This leads to cell proliferation, extracellular matrix accumulation, adhesion of these cells, and functional changes with eventual fibrosis ( Fig. 51.5 ).
Inflammation is also a key component in the progression of kidney disease (see Fig. 51.2 ). This may seem obvious in diseases in which inflammation is the primary insult, such as postinfectious glomerulonephritis or severe lupus nephritis, because it is apparent by light microscopy of kidney biopsy specimens. However, inflammation is an important factor in the progression of almost all types of kidney diseases and is mediated in part by the RAAS. AII recruits T cells and macrophages by stimulating endothelin-1 (ET-1) and increases production of nuclear factor κ–light-chain enhancer of activated B cells (NF-κB); these molecules release cytokines, creating more inflammation. Increased expression of TGF-β also induces cellular recruitment. Finally, free radical oxygen species lead to additional injury, which enables further inflammation and fibrosis.
Experimental evidence also supports the idea that proteinuria itself contributes to progressive nephrosclerosis. Through hyperfiltration, the increased glomerular permeability to albumin allows reabsorption of more albuminuria by the proximal tubular cells. Experimental models show that when this protein becomes prevalent in the interstitium, macrophages and inflammatory mediators, such as ET-1, MCP-1, and other chemokines, are upregulated, which eventually leads to inflammation and subsequent tubulointerstitial and glomerular fibrosis.
Through primary stimulation of the RAAS, predominantly through TGF-β, a cascade of events occurs that begins with inflammation, is perpetuated by accumulation of cells and matrix, is exacerbated by adhesion and persistence of these cells and matrix, and ends with injury, glomerulosclerosis, and tubulointerstitial fibrosis (see Fig. 51.2 ). This creates a progressive course of CKD, proteinuria, GFR loss, and a vicious cycle of continuous RAAS activation.
Risk Factors for Progression
Risk factors for progression include nonmodifiable characteristics such as older age, male sex, and black race. One study of younger patients with CKD estimated the lifetime risk for ESRD for a 20-year-old person to be 7.8% for black women, 7.3% for black men, 1.8% for white women, and 2.5% for white men. Conversely, other risk factors such as hypertension, proteinuria, and recurrent acute kidney injury (AKI) are all potentially modifiable and deserve attention ( Box 51.2 ).
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