Secondary factors and progression of chronic kidney disease

INTRODUCTION — A variety of chronic kidney diseases (CKDs) progress to end-stage kidney disease (ESKD), including chronic glomerulonephritis, diabetic nephropathy, and polycystic kidney disease. Although the underlying problem often cannot be treated, extensive studies in experimental animals and humans suggest that progressive CKD may be largely due to secondary factors that are sometimes unrelated to the activity of the initial disease. These include systemic and intraglomerular hypertension, glomerular hypertrophy, the intrarenal precipitation of calcium phosphate, hyperlipidemia, and altered prostanoid metabolism (table 1) [1-5].

The major histologic manifestation of these secondary causes of kidney injury is focal segmental glomerulosclerosis, which is called secondary FSGS [2]. Thus, glomerular damage and albuminuria typically occur with progressive kidney failure, even in primary tubulointerstitial diseases such as chronic pyelonephritis due to reflux nephropathy. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

The use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptors blockers to treat some of these secondary mechanisms and slow disease progression are discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

CLINICAL PREDICTORS OF ACCELERATED PROGRESSION — Clinical characteristics that are associated with accelerated loss of kidney function have been extensively described.

Major factors include increased albuminuria, uncontrolled hypertension, and hyperglycemia. (See "Overview of the management of chronic kidney disease in adults" and "Definition and staging of chronic kidney disease in adults" and "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Epidemiology and risk factors'.)

Many other risk factors have been identified including environmental exposures such as lead, smoking, diabetes, abnormal glucose concentration, metabolic syndrome, possibly some analgesic agents, obesity, and other factors [5-15]. Alcohol use, however, may not be associated with an increased risk [11,16].

Some of the clinical factors associated with increased progression of CKD are discussed below.

INTRAGLOMERULAR HYPERTENSION AND GLOMERULAR HYPERTROPHY — Intraglomerular hypertension, resulting from the transmission of systemic pressures or via glomerular-specific processes, may be deleterious over the long term. A dramatic illustration of the importance of kidney perfusion pressure comes from observations of patients with glomerular disease (eg, poststreptococcal glomerulonephritis or diabetic nephropathy) who have concurrent unilateral renal artery stenosis. These patients can develop unilateral glomerular disease as the hypoperfused kidney is relatively protected (picture 1) [17,18].

An increase in intraglomerular pressure has been demonstrated in many animal models of progressive kidney failure in association with a compensatory increase in filtration in the preserved nephrons (called glomerular hyperfiltration); indirect studies suggest that a similar response occurs in humans [19]. At least three factors contribute to these changes in renal hemodynamics [2,20]:

●A compensatory response to nephron loss in an attempt to maintain the total glomerular filtration rate (GFR). The risk of unilateral nephrectomy, as with kidney transplant donation, is also discussed elsewhere. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

●Primary renal vasodilation as occurs in diabetes mellitus and other disorders. (See "Mechanisms of glomerular hyperfiltration in diabetes mellitus".)

●A compensatory adaptation to a reduction in the permeability of the glomerular capillary wall to small solutes and water [21]. The fall in GFR is minimized in this by raising the intraglomerular pressure, a response that may be mediated by reduced flow to the macula densa and subsequent activation of tubuloglomerular feedback (figure 1) [22-24].

A compensatory increase in glomerular size also may occur in these settings [25]. This change can contribute to glomerular injury by further increasing wall stress.

The mechanisms by which glomerular hypertension and hypertrophy induce glomerular injury are incompletely understood as multiple factors may be involved [2,26]:

●Direct endothelial cell damage, similar to that induced by systemic hypertension.

●The increased wall stress and increased glomerular diameter may cause detachment of the glomerular epithelial cells from the glomerular capillary wall [2,4,27]. These focal areas of denudation permit increased flux of water and solutes; however, very large circulating macromolecules (such as immunoglobulin M [IgM] and fibrinogen and complement metabolites) cannot cross the glomerular basement membrane and are trapped in the subendothelial space [27]. The characteristic accumulation of these "hyaline" deposits can progressively narrow the capillary lumens, thereby decreasing glomerular perfusion and filtration.

●Increased strain on the mesangial cells can stimulate them to produce cytokines and more extracellular matrix [26,28,29]. The ensuing mesangial expansion can further encroach on the capillary surface area. The release of cytokines such as transforming growth factor-beta (TGF-beta) and isoforms of platelet-derived growth factor may also contribute to the glomerular injury, in part by mediating the rise in matrix synthesis [28,30,31].

Experimental studies suggest that TGF-beta may contribute to matrix production and the development of glomerulosclerosis in a variety of kidney diseases. As demonstrated in an animal model, lowering the glomerular pressure with an angiotensin-converting enzyme (ACE) inhibitor prevents the increase in cytokine gene expression and may result in regression of glomerulosclerosis if less than 50 percent of the glomeruli are affected [25,28,32]. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS' and "Antihypertensive therapy and progression of chronic kidney disease: Experimental studies", section on 'Other actions of ACE inhibitors'.)

In addition to processes affecting the glomeruli, secondary tubulointerstitial disease also is commonly seen. This change is often underappreciated, but long-term prognosis is more closely related to the degree of tubulointerstitial, rather than glomerular, injury. (See 'Tubulointerstitial fibrosis' below.)

OTHER SECONDARY FACTORS — Confirming a pathogenic role for these secondary factors is potentially important because some can be treated, possibly improving prognosis. Dietary protein restriction and the use of antihypertensive agents (particularly blockers of the renin angiotensin system [ie, angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) have been most widely studied and are discussed separately. (See "Dietary recommendations for patients with nondialysis chronic kidney disease" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

In addition to the potential importance of intraglomerular hypertension and glomerular hypertrophy, the following factors also may contribute to secondary kidney injury [1].

Albuminuria — Presence of albuminuria alone may contribute to disease progression [33-37]. Proposed mechanisms include mesangial toxicity, tubular overload and hyperplasia, toxicity from specific filtered compounds such as transferrin/iron and albumin-bound fatty acids, and induction of proinflammatory molecules such as monocyte chemoattractant protein-1 (MCP) and inflammatory cytokines [33,38-42]. (See 'Tubulointerstitial fibrosis' below.)

There are various strategies to reduce albuminuria, and albuminuria reduction in patients with CKD is associated with a slower progression of kidney function loss [43]. Some strategies that reduce albuminuria have been shown to slow progression, such as ACE inhibitors and ARBs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone [44-46], and glucagon-like peptide 1 (GLP-1) receptor agonists [47,48]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of diabetic kidney disease".)

Other treatments that can reduce albuminuria have not been shown to slow progression. These include pentoxifylline, a phosphodiesterase inhibitor with antiinflammatory and immunomodulatory properties [49,50], and thiazolidinediones [51,52].

Although the use of nondihydropyridine calcium antagonists in hypertensive patients can lower albuminuria and reduce blood pressure, they do not have any additional benefit on kidney outcomes beyond reduction of the blood pressure [53].

Podocyte injury or loss — Alterations in podocyte function may be associated with albuminuria. Furthermore, podocyte loss via apoptosis may be important in the development of glomerulosclerosis, both in primary and secondary focal segmental glomerulosclerosis (FSGS) [54-59].

Tubulointerstitial fibrosis — All forms of chronic kidney disease are associated with marked tubulointerstitial injury (tubular dilatation, interstitial fibrosis), even if the primary process is a glomerulopathy [60,61]. Furthermore, the degree of tubulointerstitial disease is a better predictor of the glomerular filtration rate (GFR) and long-term prognosis than is the severity of glomerular damage in almost all chronic progressive glomerular diseases, including IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and lupus nephritis [61-66]. It is possible in these settings that tubulointerstitial disease causes tubular atrophy and/or obstruction, eventually leading to nephron loss.

The mechanism by which tubulointerstitial fibrosis develops is incompletely understood. It may involve rarefaction of peritubular vessels induced by hypoxia or other antiangiogenic stimuli, plus the production of proinflammatory cytokines by tubular epithelial cells [67]. These cytokines promote kidney accumulation of inflammatory cells and fibroblasts [67]. Infiltration of the kidney by macrophage and T lymphocytes (and perhaps bone marrow-derived fibroblast-like cells) [3,68-75] and the G2/M phase cell cycle arrest of proximal tubular epithelial cells [76] may upregulate transforming growth factor-beta (TGF-beta) and other profibrotic cytokines that are central to the development of this process.

Other possible contributors include calcium-phosphate deposition and metabolic acidosis with secondary interstitial ammonia accumulation [3,77]. (See 'Hyperphosphatemia' below and 'Metabolic acidosis and increased ammonium production' below.)

Angiotensin II — Nonhemodynamic effects of angiotensin II also appear to contribute to the development of tubulointerstitial fibrosis, mediated via one of the angiotensin II type 1 receptors that are present in the glomerulus [78]. Animal studies have suggested that activation of angiotensin II receptor type 1B, which is largely limited to the glomerulus, but not type 1A, may accelerate kidney injury [79]. This effect is likely due to the generation of profibrotic factors such as TGF-beta, connective tissue growth factor, epidermal growth factor (EGF), and other chemokines [80]. Further support for this role is provided by the finding that the expression of angiotensin II type 1 receptors in podocytes is associated with FSGS [81]. It also appears that renin may lead to a receptor-mediated increase in TGF-beta that is independent of angiotensin II [82].

Actions of angiotensin II may also be mediated via EGF receptors, which are present throughout the nephron and, when stimulated, promote cell proliferation and collagen production via TGF-alpha, EGF, and other growth factors [83,84]. In experimental models, infusion of angiotensin II induces glomerulosclerosis and tubular atrophy. This effect is not seen in mice lacking EGF receptors or TGF-alpha, and pharmacologic inhibition of angiotensin II prevented these kidney lesions.

Angiotensin II also participates in cytokine- and chemokine-mediated recruitment of inflammatory cells into the kidney [78].

Immunologic processes — There is also evidence that an active immunologic process is involved in the glomerulonephritides, beginning early in the course of the disease and, in some cases, being an extension of the inflammation in the glomeruli [61,68,69,85-87]. As an example, the release of cytokines induced by immune activation results in the upregulation of intercellular adhesion molecule-1 (ICAM-1) on the capillary endothelial cells; ICAM-1 can then bind to lymphocyte function-associated antigen-1 (LFA-1), a receptor on activated T cells, leading to T-cell adhesion and subsequent migration into the interstitium [88]. In some experimental models of kidney disease, corticosteroid or other immunosuppressive therapy can ameliorate the tubulointerstitial damage (without effect on the glomerular injury) [89-92]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

The trafficking and deposition of excess filtered protein may be one link between initial glomerular injury and the development of immunologic tubulointerstitial disease. The correlation between these pathologic findings was examined in different animal models of kidney disease, including the remnant kidney and passive Heymann nephritis [93]. Soon after the onset of kidney injury in rats with both disorders, collections of protein (consisting of albumin and immunoglobulin) accumulated at specific sites in the proximal tubule; subsequently, infiltrates were only detected at or around the tubules containing these proteins. Although the interstitial inflammation became more irregularly distributed over time, the early relationship between inflammatory foci and proximal tubule protein deposition persisted to some extent. Enhanced levels of osteopontin (a hematopoietic cell chemoattractant expressed by affected tubule cells), chemokines, and platelet-derived growth factor may be some of the mediators underlying the inflammatory lesions [94].

In the remnant kidney model, administration of an ACE inhibitor prevents protein deposition in the renal tubules; this limits the tubular accumulation of complement components and immunoglobulin G (IgG), thereby ameliorating interstitial inflammation [95]. Multiple additional animal models further support a connection between albuminuria and complement-mediated inflammation and damage [96,97]. The addition of an immunosuppressive agent, mycophenolate mofetil, to the ACE inhibitor (or an angiotensin II receptor antagonist) further lowers overall hematopoietic cell infiltration and albuminuria [98-100].

Ongoing inflammatory disease may be suggested by increased levels of markers of inflammation, which may be associated with progression of kidney disease. Among nearly 600 older patients, for example, higher levels of C-reactive protein, factor VII, fibrinogen, and other markers were associated with a rise in the serum creatinine concentration and decrease in the estimated GFR (eGFR) over a follow-up period of seven years [101]. There is no consensus approach to assess the degree of severity of inflammation in individuals with kidney disease. (See "Acute phase reactants".)

Effective therapy of the ongoing kidney inflammation may not prevent progressive scarring if significant injury has already occurred. In this setting, healing may be associated with interstitial fibrosis, mediated in part by the release of cytokines and/or glomerular ultrafiltration of growth factors, particularly increased TGF-beta and monocyte chemotactic protein-1 levels, or the decreased expression of the bone morphogenic protein (BMP)/GDP family of proteins [61,102-109]. BMP interferes with profibrogenic processes in tubular epithelial cells (eg, decreasing proinflammatory cytokines, growth factor secretion, and TGF-beta secretion) and reduces epithelial to mesenchyma transformation, which contributes to the accumulation of fibroblasts and fibrosis [109-111].

Actions of the BMP family are facilitated by a newly discovered kielin/chordin-like protein (KCP), which acts as a ligand-trap protein to enhance the binding of BMP-7 to its receptor. The absence of KCP is associated with markedly increased kidney interstitial fibrosis in murine models of kidney disease [112].

Metabolic acidosis and increased ammonium production — As the number of functioning nephrons declines, each remaining nephron excretes more acid (primarily as ammonium). The local accumulation of ammonia can directly activate complement, leading to secondary tubulointerstitial damage (at least in experimental animals) [77]. On the other hand, buffering the acid with alkali therapy prevents the increase in ammonium production and minimizes the kidney injury [77].

The possible kidney protective effect of alkali therapy in patients with CKD is presented elsewhere. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease", section on 'Slowing of CKD progression'.)

Sodium bicarbonate is usually preferred to sodium citrate in CKD since citrate leads to a marked increase in intestinal aluminum absorption, possibly promoting the development of aluminum toxicity [113]. This may be less of a current concern since long-term administration of aluminum-containing antacids to bind dietary phosphate is uncommon. The effect of citrate may be mediated both by keeping aluminum soluble (via the formation of aluminum citrate) and by binding of calcium in the intestinal lumen; the ensuing fall in free calcium then may lead to increased permeability of the tight junctions between the cells and a rise in passive aluminum absorption [114]. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease".)

Altered prostanoid metabolism — Glomerular prostaglandin production tends to be increased in glomerular disease [115]. This response may represent an appropriate intranephronal adaptation since the ensuing renal vasodilatation helps to maintain the GFR in the presence of an often marked reduction in glomerular capillary permeability, induced by the underlying disease [21]. This adaptation is reversed by a nonsteroidal antiinflammatory drug (NSAID), leading to renal vasoconstriction and a subsequent fall in intraglomerular pressure [115]. These changes with NSAIDs are manifested clinically by reductions in GFR (usually by approximately 20 percent) and protein excretion (often by more than 50 percent) in many patients with chronic glomerular disease [116-118]. However, use of NSAIDs may result in hyperkalemia and marked reduction in GFR among patients with CKD.

Anemia — Progressive anemia, due largely to erythropoietin deficiency, is a common complication of advanced kidney disease. The relationship between correction of anemia with erythropoietin and its effects upon progression of kidney failure are presented separately. (See "Treatment of anemia in nondialysis chronic kidney disease".)

Putative endogenous and exogenous nephrotoxins — A variety of endogenous and exogenous compounds have been implicated as factors that may accelerate the progression of CKD.

Uremic toxins — Dialysis of nonuremic animals with glomerulosclerosis preserves the GFR and slows the rate of further glomerular damage [119]. This observation suggests that retention of ultrafiltrable toxins during the course of progressive kidney disease contributes to secondary glomerular injury. How this might occur is not clear. (See "Uremic toxins".)

Aldosterone — Aldosterone, whether of local or systemic origin, may contribute to progressive kidney injury as a result of excess mineralocorticoid receptor stimulation [120]. In animal models of kidney disease, stimulation of the mineralocorticoid receptor results in vascular remodeling and kidney fibrosis. In addition, aldosterone contributes to glomerular hyperfiltration by activating mineralocorticoid receptors in the macula densa, which then inhibits tubuloglomerular feedback [121]. ACE inhibition or angiotensin II receptor blockade fail to provide optimal kidney protection from this direct mineralocorticoid effect. (See 'Intraglomerular hypertension and glomerular hypertrophy' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Nonsteroidal MRAs such as finerenone slow the progression of diabetic nephropathy [122,123]. A few studies suggest that steroidal MRAs also may offer protection against progressive kidney failure [120,124-126].  

Hyperkalemia in the setting of CKD, in particular among patients with diabetic nephropathy, may limit the use of MRAs. However, the risk of hyperkalemia is less with finerenone than with steroidal MRAs such as spironolactone [127]. Furthermore, some gastrointestinal cation exchangers, such as patiromer and zirconium cyclosilicate, are well tolerated and may mitigate the MRA-mediated rise in serum potassium [128]. The use of MRAs in diabetic kidney disease and the management and prevention of hyperkalemia are discussed in detail elsewhere. (See "Treatment of diabetic kidney disease" and "Treatment and prevention of hyperkalemia in adults", section on 'Gastrointestinal cation exchangers'.)

Hyperlipidemia — Hyperlipidemia is common in patients with CKD, particularly those with the nephrotic syndrome. (See "Lipid abnormalities in nephrotic syndrome".)

In addition to accelerating the development of systemic atherosclerosis, experimental studies suggest that high lipid levels also may promote progression of the kidney disease.

Hyperphosphatemia — A tendency to phosphate retention is an early problem in kidney disease, beginning as soon as the GFR starts to fall. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

In addition to promoting bone disease, the excess phosphate also may contribute to progression of CKD [3,129,130]. Higher serum phosphorus concentrations have been associated with a greater risk of progression. In an observational study of 985 patients followed for a median of two years, the adjusted hazard ratio for doubling of the serum creatinine was 1.3 for every 1.0 mg/dL (0.33 micromol/L) increase in serum phosphorus [129]. A similar relationship was noted for the calcium-phosphorus product.

A potential causative mechanism could be calcium phosphate precipitation in the kidney interstitium [131], which might initiate an inflammatory reaction, resulting in interstitial fibrosis and tubular atrophy [3].

These observations do not prove a cause-and-effect relationship, and there are no data addressing the possible role of improved calcium and phosphorus control in slowing the progression of CKD. However, there are other reasons for controlling serum phosphorus in patients with CKD. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

Hyperuricemia — Hyperuricemia can develop in patients with CKD due to decreased urinary excretion of uric acid. It has been proposed that hyperuricemia may contribute to progression, in part by decreasing kidney perfusion via stimulation of afferent arteriolar vascular smooth muscle cell proliferation [132-135]. However, most data support the concept that uric acid does not have a causal role in kidney and cardiovascular diseases, but rather is a risk marker, suggesting higher risk if elevated [136].

Multiple observational studies reported that higher plasma or serum uric acid levels are associated with an increased risk for the development of CKD (among those without CKD at baseline) and for a faster rate of kidney function decline (among those with preexisting CKD) [135,137-141].

However, higher-quality data suggest that this association is not causal, and urate-lowering therapy is not a clearly effective strategy to prevent CKD or slow its progression [142-147]:

●In a 2020 meta-analysis of 28 trials and 6458 individuals, urate-lowering therapy had no significant effect on doubling of serum creatinine, kidney failure, or death [142].

●In a large randomized trial, 530 adults with type 1 diabetes and diabetic kidney disease were randomly assigned to allopurinol or placebo; the mean age of the population was 51 years, the mean baseline measured GFR (with iohexol) was 68 mL/min/1.73 m², and most patients had moderately increased albuminuria [144]. Uric acid levels decreased from 6.1 to 3.9 mg/dL (from 363 to 232 micromol/L) with allopurinol treatment and did not change with placebo. At three years, allopurinol had no effect on the change in measured GFR, but produced a 40 percent increase in urine albumin excretion and nonsignificantly increased the rate of fatal or nonfatal cardiovascular events (5.6 versus 2.4 percent).

●In a subsequent trial, 363 adults with more advanced CKD (mean eGFR 32 mL/min/1.73 m², mean urine albumin-to-creatinine ratio 717 mg/g) were randomly assigned to allopurinol or placebo and followed for two years [145]. Uric acid levels decreased from 8.2 to 5.1 mg/dL (488 to 303 micromol/L) in the allopurinol group and remained unchanged in the placebo group. Allopurinol did not slow the progression of eGFR decline (which decreased by 3 mL/min/1.73 m² annually in each group); the composite outcome of a 40 percent decline in eGFR, ESKD, or death occurred more frequently in the allopurinol group (35 versus 28 percent), but this was not statistically significant.

●A large Mendelian randomization study of nearly 800,000 individuals found that genetic determinants of higher serum uric acid levels were not associated with the development of CKD [146].

Organic solvents — Exposure to organic solvents may enhance the progression of glomerulonephritis [148]. The mechanism of pathogenic effect is unknown.

Lead-related nephrotoxicity — Lead-related nephrotoxicity refers to lead exposure as a modifiable risk factor for the progression of CKD and occurs at low levels of chronic exposure. Lead-related nephrotoxicity is distinct from lead nephropathy, a type of CKD caused by high levels of long-term lead exposure. (See "Lead nephropathy and lead-related nephrotoxicity".)

Iron toxicity — Increased glomerular permeability can result in the filtration of the normally nonfiltered iron-transferrin complex. Dissociation of this complex in the tubular lumen leads to the release of free iron, which can promote tubular injury by promoting the formation of hydroxyl radicals [149].

GENETIC FACTORS — A number of genetic factors (eg, single nucleotide polymorphisms and modifier genes) may influence the immune response, inflammation, fibrosis, and atherosclerosis, possibly contributing to accelerated progression of CKD [150,151]. Indirect evidence in support of such factors can be found in familial clustering of all-cause end-stage kidney disease (ESKD), with approximately one-quarter of dialysis patients having relatives with ESKD [152]. In addition, genome-wide association studies have identified a variety of genetic loci associated with CKD, CKD progression, and/or the development of ESKD [153-155]. These data are consistent with the hypothesis that common kidney diseases and progression to ESKD are influenced by the inheritance of specific genes.

The apolipoprotein L1 (APOL1) gene appears to play an important role in the progression of CKD. High risk APOL1 mutations, which are found exclusively among individuals of African descent, predict earlier development of CKD [156]. APOL1 is discussed in detail elsewhere. (See "Gene test interpretation: APOL1 (chronic kidney disease gene)" and "Epidemiology of chronic kidney disease", section on 'Apolipoprotein L1 in African Americans' and "Focal segmental glomerulosclerosis: Genetic causes", section on 'APOL1'.)

In the future, genetic testing and molecular analysis of kidney biopsy specimens (and/or urine) may provide useful prognostic information.

SUMMARY

●Secondary factors and progression of CKD – The progression of chronic kidney disease (CKD) to end-stage kidney disease (ESKD) may be largely due to secondary factors that are unrelated to the initial disease. These include systemic and intraglomerular hypertension, glomerular hypertrophy, the intrarenal precipitation of calcium phosphate, hyperlipidemia, and altered prostanoid metabolism. The major histologic manifestation of these secondary causes of kidney injury is focal segmental glomerulosclerosis, which is called secondary FSGS. (See 'Introduction' above.)

●Clinical predictors – Clinical characteristics that predict a faster decline in glomerular filtration rate (GFR) include greater albuminuria, higher blood pressure, lower serum high-density lipoprotein (HDL) cholesterol, and lower levels of serum transferrin. (See 'Clinical predictors of accelerated progression' above.)

●Intraglomerular hypertension and glomerular hypertrophy – Factors that contribute to intraglomerular hypertension include a compensatory response to nephron loss in an attempt to maintain the total GFR, a compensatory adaptation to a reduction in the permeability of the glomerular capillary wall to small solutes and water, and a compensatory increase in glomerular size. (See 'Intraglomerular hypertension and glomerular hypertrophy' above and "Dietary recommendations for patients with nondialysis chronic kidney disease" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

●Other secondary factors – In addition to intraglomerular hypertension and glomerular hypertrophy, factors that may contribute to secondary kidney injury include albuminuria, podocyte loss via apoptosis, tubular atrophy and/or obstruction, calcium phosphate deposition, metabolic acidosis, high lipid levels, hyperuricemia, and altered prostanoid metabolism. (See 'Other secondary factors' above.)

●Renin-angiotensin system – Nonhemodynamic effects of angiotensin II may contribute to the development of tubulointerstitial fibrosis. This is likely due to the generation of profibrotic factors and other chemokines. Aldosterone, whether of local or systemic origin, may contribute to progressive kidney injury as a result of excess mineralocorticoid receptor stimulation. (See 'Angiotensin II' above and 'Aldosterone' above.)

●Genetic factors – Genetic factors may contribute to accelerated progression of CKD. (See 'Genetic factors' above.)