ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Secondary factors and progression of chronic kidney disease

Secondary factors and progression of chronic kidney disease
Literature review current through: Jan 2024.
This topic last updated: Aug 08, 2023.

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 (>300 mg/day) alone may contribute to disease progression [33-36]. 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 [33,37-41]. (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 [42]. 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 [43,44], and glucagon-like peptide 1 (GLP-1) receptor agonists [45,46]. (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 [47,48], and thiazolidinediones [49,50].

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 [51].

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) [52-57].

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 [58,59]. 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 [59-64]. 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 [65]. These cytokines promote kidney accumulation of inflammatory cells and fibroblasts [65]. Infiltration of the kidney by macrophage and T lymphocytes (and perhaps bone marrow-derived fibroblast-like cells) [3,66-73] and the G2/M phase cell cycle arrest of proximal tubular epithelial cells [74] 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 [3,75]. (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 [76]. 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 [77]. 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 [78]. 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 [79]. It also appears that renin may lead to a receptor-mediated increase in TGF-beta that is independent of angiotensin II [80].

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 [81,82]. 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 [76].

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 [59,66,67,83-85]. 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 [86]. In some experimental models of kidney disease, corticosteroid or other immunosuppressive therapy can ameliorate the tubulointerstitial damage (without effect on the glomerular injury) [87-90]. (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 [91]. 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 [92].

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 [93]. Multiple additional animal models further support a connection between albuminuria and complement-mediated inflammation and damage [94,95]. 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 [96-98].

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 [99]. 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 [59,100-107]. 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 [107-109].

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 [110].

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) [75]. On the other hand, buffering the acid with alkali therapy prevents the increase in ammonium production and minimizes the kidney injury [75].

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 [111]. 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 [112]. (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 [113]. 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 [113]. 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 [114-116]. 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 [117]. 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 [118]. 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 [119]. 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 [120,121]. A few studies suggest that steroidal MRAs also may offer protection against progressive kidney failure [118,122-124].  

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 [125]. Furthermore, some gastrointestinal cation exchangers, such as patiromer and zirconium cyclosilicate, are well tolerated and may mitigate the MRA-mediated rise in serum potassium [126]. 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 [3,127,128]. 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 [127]. A similar relationship was noted for the calcium-phosphorus product.

A potential causative mechanism could be calcium phosphate precipitation in the kidney interstitium [129], 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 [130-133]. 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 [134].

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) [133,135-139].

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 [140-144]:

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 [140].

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 [142]. 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 [143]. 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 [144].

Organic solvents — Exposure to organic solvents may enhance the progression of glomerulonephritis [145]. 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 [146].

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 [147,148]. 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 [149]. In addition, genome-wide association studies have identified a variety of genetic loci associated with CKD, CKD progression, and/or the development of ESKD [150-152]. 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 [153]. 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.)

  1. Jacobson HR. Chronic renal failure: pathophysiology. Lancet 1991; 338:419.
  2. Rennke HG, Anderson S, Brenner BM. Structural and functional correlations in the progression of renal disease. In: Renal Pathology, Tisher CC, Brenner BM (Eds), Lippincott, Philadelphia 1989. p.43.
  3. Loghman-Adham M. Role of phosphate retention in the progression of renal failure. J Lab Clin Med 1993; 122:16.
  4. Nagata M, Kriz W. Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocytes as a pathway to sclerosis. Kidney Int 1992; 42:148.
  5. Yu HT. Progression of chronic renal failure. Arch Intern Med 2003; 163:1417.
  6. Hebert LA, Greene T, Levey A, et al. High urine volume and low urine osmolality are risk factors for faster progression of renal disease. Am J Kidney Dis 2003; 41:962.
  7. Morales E, Valero MA, León M, et al. Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies. Am J Kidney Dis 2003; 41:319.
  8. Stengel B, Tarver-Carr ME, Powe NR, et al. Lifestyle factors, obesity and the risk of chronic kidney disease. Epidemiology 2003; 14:479.
  9. Haroun MK, Jaar BG, Hoffman SC, et al. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol 2003; 14:2934.
  10. Ejerblad E, Fored CM, Lindblad P, et al. Association between smoking and chronic renal failure in a nationwide population-based case-control study. J Am Soc Nephrol 2004; 15:2178.
  11. Halbesma N, Brantsma AH, Bakker SJ, et al. Gender differences in predictors of the decline of renal function in the general population. Kidney Int 2008; 74:505.
  12. Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol 2005; 16:2134.
  13. Hallan S, de Mutsert R, Carlsen S, et al. Obesity, smoking, and physical inactivity as risk factors for CKD: are men more vulnerable? Am J Kidney Dis 2006; 47:396.
  14. Brantsma AH, Atthobari J, Bakker SJ, et al. What predicts progression and regression of urinary albumin excretion in the nondiabetic population? J Am Soc Nephrol 2007; 18:637.
  15. Chang AR, Grams ME, Ballew SH, et al. Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium. BMJ 2019; 364:k5301.
  16. Schaeffner ES, Kurth T, de Jong PE, et al. Alcohol consumption and the risk of renal dysfunction in apparently healthy men. Arch Intern Med 2005; 165:1048.
  17. Dikman SH, Strauss L, Berman LJ, et al. Unilateral glomerulonephritis. Arch Pathol Lab Med 1976; 100:480.
  18. Berkman J, Rifkin H. Unilateral nodular diabetic glomerulosclerosis (Kimmelstiel-Wilson): report of a case. Metabolism 1973; 22:715.
  19. Denic A, Glassock RJ, Rule AD. Single-Nephron Glomerular Filtration Rate in Healthy Adults. N Engl J Med 2017; 377:1203.
  20. Schieppati A, Remuzzi G. The June 2003 Barry M. Brenner Comgan lecture. The future of renoprotection: frustration and promises. Kidney Int 2003; 64:1947.
  21. Ting RH, Kristal B, Myers BD. The biophysical basis of hypofiltration in nephrotic humans with membranous nephropathy. Kidney Int 1994; 45:390.
  22. Blantz RC, Pelayo JC. A functional role for the tubuloglomerular feedback mechanism. Kidney Int 1984; 25:739.
  23. Briggs JP, Schnermann J. The tubuloglomerular feedback mechanism: Functional and biochemical aspects. Ann Rev Physiol 1987; 49:251.
  24. Schnermann J, Traynor T, Yang T, et al. Tubuloglomerular feedback: new concepts and developments. Kidney Int Suppl 1998; 67:S40.
  25. Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med 2004; 116:263.
  26. Cortes P, Riser BL, Yee J, Narins RG. Mechanical strain of glomerular mesangial cells in the pathogenesis of glomerulosclerosis: clinical implications. Nephrol Dial Transplant 1999; 14:1351.
  27. Rennke HG. How does glomerular epithelial cell injury contribute to progressive glomerular damage? Kidney Int Suppl 1994; 45:S58.
  28. Shankland SJ, Ly H, Thai K, Scholey JW. Increased glomerular capillary pressure alters glomerular cytokine expression. Circ Res 1994; 75:844.
  29. Yasuda T, Kondo S, Homma T, Harris RC. Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells. J Clin Invest 1996; 98:1991.
  30. Gaedeke J, Noble NA, Border WA. Curcumin blocks multiple sites of the TGF-beta signaling cascade in renal cells. Kidney Int 2004; 66:112.
  31. Eitner F, Bücher E, van Roeyen C, et al. PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. J Am Soc Nephrol 2008; 19:281.
  32. Fogo AB. Progression versus regression of chronic kidney disease. Nephrol Dial Transplant 2006; 21:281.
  33. Burton C, Harris KP. The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis 1996; 27:765.
  34. Eddy AA, McCulloch L, Liu E, Adams J. A relationship between proteinuria and acute tubulointerstitial disease in rats with experimental nephrotic syndrome. Am J Pathol 1991; 138:1111.
  35. Benigni A, Corna D, Zoja C, et al. Targeted deletion of angiotensin II type 1A receptor does not protect mice from progressive nephropathy of overload proteinuria. J Am Soc Nephrol 2004; 15:2666.
  36. Hirschberg R, Wang S. Proteinuria and growth factors in the development of tubulointerstitial injury and scarring in kidney disease. Curr Opin Nephrol Hypertens 2005; 14:43.
  37. Wang Y, Chen J, Chen L, et al. Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol 1997; 8:1537.
  38. Hebert LA, Agarwal G, Sedmak DD, et al. Proximal tubular epithelial hyperplasia in patients with chronic glomerular proteinuria. Kidney Int 2000; 57:1962.
  39. Birn H, Fyfe JC, Jacobsen C, et al. Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 2000; 105:1353.
  40. Arici M, Chana R, Lewington A, et al. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol 2003; 14:17.
  41. Eardley KS, Zehnder D, Quinkler M, et al. The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int 2006; 69:1189.
  42. Coresh J, Heerspink HJL, Sang Y, et al. Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies. Lancet Diabetes Endocrinol 2019; 7:115.
  43. Bakris GL, Ruilope LM, Anker SD, et al. A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes. Kidney Int 2023; 103:196.
  44. Filippatos G, Anker SD, Pitt B, et al. Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes. JACC Heart Fail 2022; 10:860.
  45. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6:605.
  46. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019; 394:131.
  47. Chen YM, Lin SL, Chiang WC, et al. Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int 2006; 69:1410.
  48. Lin SL, Chen YM, Chiang WC, et al. Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12-month randomized trial. Am J Kidney Dis 2008; 52:464.
  49. Sarafidis PA, Lasaridis AN, Nilsson PM, et al. The effect of rosiglitazone on urine albumin excretion in patients with type 2 diabetes mellitus and hypertension. Am J Hypertens 2005; 18:227.
  50. Kincaid-Smith P, Fairley KF, Farish S, et al. Reduction of proteinuria by rosiglitazone in non-diabetic renal disease. Nephrology (Carlton) 2008; 13:58.
  51. Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int 2004; 65:1991.
  52. Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 1998; 54:687.
  53. Ding G, Reddy K, Kapasi AA, et al. Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am J Physiol Renal Physiol 2002; 283:F173.
  54. Durvasula RV, Petermann AT, Hiromura K, et al. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 2004; 65:30.
  55. Pagtalunan ME, Miller PL, Jumping-Eagle S, et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997; 99:342.
  56. Meyer TW, Bennett PH, Nelson RG. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 1999; 42:1341.
  57. Lemley KV, Lafayette RA, Safai M, et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int 2002; 61:1475.
  58. Ong AC, Fine LG. Loss of glomerular function and tubulointerstitial fibrosis: cause or effect? Kidney Int 1994; 45:345.
  59. Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 1992; 20:1.
  60. D'Amico G. Influence of clinical and histological features on actuarial renal survival in adult patients with idiopathic IgA nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis: survey of the recent literature. Am J Kidney Dis 1992; 20:315.
  61. Alexopoulos E, Seron D, Hartley RB, Cameron JS. Lupus nephritis: correlation of interstitial cells with glomerular function. Kidney Int 1990; 37:100.
  62. Bajema IM, Hagen EC, Hermans J, et al. Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis. Kidney Int 1999; 56:1751.
  63. Bazzi C, Petrini C, Rizza V, et al. Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis. Nephrol Dial Transplant 2002; 17:1890.
  64. Meyer TW. Tubular injury in glomerular disease. Kidney Int 2003; 63:774.
  65. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010; 21:1819.
  66. Lan HY, Paterson DJ, Atkins RC. Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis. Kidney Int 1991; 40:425.
  67. Eddy AA. Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions. J Am Soc Nephrol 1994; 5:1273.
  68. Nath KA. The tubulointerstitium in progressive renal disease. Kidney Int 1998; 54:992.
  69. Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006; 69:213.
  70. Mahajan D, Wang Y, Qin X, et al. CD4+CD25+ regulatory T cells protect against injury in an innate murine model of chronic kidney disease. J Am Soc Nephrol 2006; 17:2731.
  71. Sakai N, Wada T, Yokoyama H, et al. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci U S A 2006; 103:14098.
  72. Wada T, Sakai N, Matsushima K, Kaneko S. Fibrocytes: a new insight into kidney fibrosis. Kidney Int 2007; 72:269.
  73. Kie JH, Kapturczak MH, Traylor A, et al. Heme oxygenase-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis. J Am Soc Nephrol 2008; 19:1681.
  74. Yang L, Besschetnova TY, Brooks CR, et al. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 2010; 16:535.
  75. Nath KA, Hostetter MK, Hostetter TH. Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3. J Clin Invest 1985; 76:667.
  76. Ruiz-Ortega M, Rupérez M, Esteban V, et al. Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases. Nephrol Dial Transplant 2006; 21:16.
  77. Crowley SD, Vasievich MP, Ruiz P, et al. Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis. J Clin Invest 2009; 119:943.
  78. Aros C, Remuzzi G. The renin-angiotensin system in progression, remission and regression of chronic nephropathies. J Hypertens Suppl 2002; 20:S45.
  79. Hoffmann S, Podlich D, Hähnel B, et al. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol 2004; 15:1475.
  80. Huang Y, Wongamorntham S, Kasting J, et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 2006; 69:105.
  81. Lautrette A, Li S, Alili R, et al. Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nat Med 2005; 11:867.
  82. Chen J, Chen JK, Neilson EG, Harris RC. Role of EGF receptor activation in angiotensin II-induced renal epithelial cell hypertrophy. J Am Soc Nephrol 2006; 17:1615.
  83. Okada H, Moriwaki K, Kalluri R, et al. Inhibition of monocyte chemoattractant protein-1 expression in tubular epithelium attenuates tubulointerstitial alteration in rat Goodpasture syndrome. Kidney Int 2000; 57:927.
  84. Zatz R, Noronha IL, Fujihara CK. Experimental and clinical rationale for use of MMF in nontransplant progressive nephropathies. Am J Physiol Renal Physiol 2002; 283:F1167.
  85. Anders HJ, Vielhauer V, Schlöndorff D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int 2003; 63:401.
  86. Hill PA, Lan HY, Nikolic-Paterson DJ, Atkins RC. ICAM-1 directs migration and localization of interstitial leukocytes in experimental glomerulonephritis. Kidney Int 1994; 45:32.
  87. Saito T, Atkins RC. Contribution of mononuclear leucocytes to the progression of experimental focal glomerular sclerosis. Kidney Int 1990; 37:1076.
  88. Romero F, Rodríguez-Iturbe B, Parra G, et al. Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int 1999; 55:945.
  89. Oldroyd SD, Thomas GL, Gabbiani G, El Nahas AM. Interferon-gamma inhibits experimental renal fibrosis. Kidney Int 1999; 56:2116.
  90. Noronha IL, Fujihara CK, Zatz R. The inflammatory component in progressive renal disease--are interventions possible? Nephrol Dial Transplant 2002; 17:363.
  91. Abbate M, Zoja C, Corna D, et al. In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. J Am Soc Nephrol 1998; 9:1213.
  92. Burton CJ, Combe C, Walls J, Harris KP. Secretion of chemokines and cytokines by human tubular epithelial cells in response to proteins. Nephrol Dial Transplant 1999; 14:2628.
  93. Abbate M, Zoja C, Rottoli D, et al. Antiproteinuric therapy while preventing the abnormal protein traffic in proximal tubule abrogates protein- and complement-dependent interstitial inflammation in experimental renal disease. J Am Soc Nephrol 1999; 10:804.
  94. Hsu SI, Couser WG. Chronic progression of tubulointerstitial damage in proteinuric renal disease is mediated by complement activation: a therapeutic role for complement inhibitors? J Am Soc Nephrol 2003; 14:S186.
  95. Nangaku M, Pippin J, Couser WG. C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys. J Am Soc Nephrol 2002; 13:928.
  96. Remuzzi G, Zoja C, Gagliardini E, et al. Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals. J Am Soc Nephrol 1999; 10:1542.
  97. Fujihara CK, Noronha IL, Malheiros, et al. Combined mycophenolate mofetil and losartan therapy arrests established injury in the remnant kidney. J Am Soc Nephrol 2000; 11:283.
  98. Suzuki Y, Ruiz-Ortega M, Gomez-Guerrero C, et al. Angiotensin II, the immune system and renal diseases: another road for RAS? Nephrol Dial Transplant 2003; 18:1423.
  99. Fried L, Solomon C, Shlipak M, et al. Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. J Am Soc Nephrol 2004; 15:3184.
  100. Kuncio GS, Neilson EG, Haverty T. Mechanisms of tubulointerstitial fibrosis. Kidney Int 1991; 39:550.
  101. Wang SN, Hirschberg R. Tubular epithelial cell activation and interstitial fibrosis. The role of glomerular ultrafiltration of growth factors in the nephrotic syndrome and diabetic nephropathy. Nephrol Dial Transplant 1999; 14:2072.
  102. Ledbetter S, Kurtzberg L, Doyle S, Pratt BM. Renal fibrosis in mice treated with human recombinant transforming growth factor-beta2. Kidney Int 2000; 58:2367.
  103. Yang J, Dai C, Liu Y. Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. J Am Soc Nephrol 2002; 13:2464.
  104. Böttinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol 2002; 13:2600.
  105. Peters H, Eisenberg R, Daig U, et al. Platelet inhibition limits TGF-beta overexpression and matrix expansion after induction of anti-thy1 glomerulonephritis. Kidney Int 2004; 65:2238.
  106. Neilson EG. Setting a trap for tissue fibrosis. Nat Med 2005; 11:373.
  107. Zhang XL, Selbi W, de la Motte C, et al. Bone morphogenic protein-7 inhibits monocyte-stimulated TGF-beta1 generation in renal proximal tubular epithelial cells. J Am Soc Nephrol 2005; 16:79.
  108. Gould SE, Day M, Jones SS, Dorai H. BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells. Kidney Int 2002; 61:51.
  109. Zeisberg M. Bone morphogenic protein-7 and the kidney: current concepts and open questions. Nephrol Dial Transplant 2006; 21:568.
  110. Lin J, Patel SR, Cheng X, et al. Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease. Nat Med 2005; 11:387.
  111. Molitoris BA, Froment DH, Mackenzie TA, et al. Citrate: a major factor in the toxicity of orally administered aluminum compounds. Kidney Int 1989; 36:949.
  112. Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia--a determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int Suppl 1994; 45:S125.
  113. Takahashi K, Schreiner GF, Yamashita K, et al. Predominant functional roles for thromboxane A2 and prostaglandin E2 during late nephrotoxic serum glomerulonephritis in the rat. J Clin Invest 1990; 85:1974.
  114. Shemesh O, Ross JC, Deen WM, et al. Nature of the glomerular capillary injury in human membranous glomerulopathy. J Clin Invest 1986; 77:868.
  115. Heeg JE, de Jong PE, de Zeeuw D. Additive antiproteinuric effect of angiotensin-converting enzyme inhibition and non-steroidal anti-inflammatory drug therapy: a clue to the mechanism of action. Clin Sci (Lond) 1991; 81:367.
  116. Vriesendorp R, Donker AJ, de Zeeuw D, et al. Effects of nonsteroidal anti-inflammatory drugs on proteinuria. Am J Med 1986; 81:84.
  117. Motojima M, Nishijima F, Ikoma M, et al. Role for "uremic toxin" in the progressive loss of intact nephrons in chronic renal failure. Kidney Int 1991; 40:461.
  118. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 2004; 66:1.
  119. Fu Y, Hall JE, Lu D, et al. Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors. Hypertension 2012; 59:599.
  120. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022; 43:474.
  121. Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med 2020; 383:2219.
  122. Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis 2005; 46:45.
  123. Rossing K, Schjoedt KJ, Smidt UM, et al. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005; 28:2106.
  124. Yang CT, Kor CT, Hsieh YP. Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia-Associated Hospitalization in Patients with Chronic Kidney Disease. J Clin Med 2018; 7.
  125. Agarwal R, Pitt B, Palmer BF, et al. A comparative post hoc analysis of finerenone and spironolactone in resistant hypertension in moderate-to-advanced chronic kidney disease. Clin Kidney J 2023; 16:293.
  126. Pitt B, Bakris GL. New potassium binders for the treatment of hyperkalemia: current data and opportunities for the future. Hypertension 2015; 66:731.
  127. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol 2006; 1:825.
  128. Chue CD, Edwards NC, Davis LJ, et al. Serum phosphate but not pulse wave velocity predicts decline in renal function in patients with early chronic kidney disease. Nephrol Dial Transplant 2011; 26:2576.
  129. Gimenez LF, Solez K, Walker WG. Relation between renal calcium content and renal impairment in 246 human renal biopsies. Kidney Int 1987; 31:93.
  130. Ohno I, Hosoya T, Gomi H, et al. Serum uric acid and renal prognosis in patients with IgA nephropathy. Nephron 2001; 87:333.
  131. Iseki K, Ikemiya Y, Inoue T, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004; 44:642.
  132. Sánchez-Lozada LG, Tapia E, Santamaría J, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int 2005; 67:237.
  133. Bellomo G, Venanzi S, Verdura C, et al. Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis 2010; 56:264.
  134. Johnson RJ, Bakris GL, Borghi C, et al. Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation. Am J Kidney Dis 2018; 71:851.
  135. Chonchol M, Shlipak MG, Katz R, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis 2007; 50:239.
  136. Weiner DE, Tighiouart H, Elsayed EF, et al. Uric acid and incident kidney disease in the community. J Am Soc Nephrol 2008; 19:1204.
  137. Obermayr RP, Temml C, Gutjahr G, et al. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol 2008; 19:2407.
  138. Bartáková V, Kuricová K, Pácal L, et al. Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus. J Diabetes Complications 2016; 30:1300.
  139. Chang YH, Lei CC, Lin KC, et al. Serum uric acid level as an indicator for CKD regression and progression in patients with type 2 diabetes mellitus-a 4.6-year cohort study. Diabetes Metab Res Rev 2016; 32:557.
  140. Chen Q, Wang Z, Zhou J, et al. Effect of Urate-Lowering Therapy on Cardiovascular and Kidney Outcomes: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol 2020; 15:1576.
  141. Sampson AL, Singer RF, Walters GD. Uric acid lowering therapies for preventing or delaying the progression of chronic kidney disease. Cochrane Database Syst Rev 2017; 10:CD009460.
  142. Doria A, Galecki AT, Spino C, et al. Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes. N Engl J Med 2020; 382:2493.
  143. Badve SV, Pascoe EM, Tiku A, et al. Effects of Allopurinol on the Progression of Chronic Kidney Disease. N Engl J Med 2020; 382:2504.
  144. Jordan DM, Choi HK, Verbanck M, et al. No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study. PLoS Med 2019; 16:e1002725.
  145. Jacob S, Héry M, Protois JC, et al. Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study. J Am Soc Nephrol 2007; 18:274.
  146. Alfrey AC, Froment DH, Hammond WS. Role of iron in the tubulo-interstitial injury in nephrotoxic serum nephritis. Kidney Int 1989; 36:753.
  147. Nordfors L, Lindholm B, Stenvinkel P. End-stage renal disease--not an equal opportunity disease: the role of genetic polymorphisms. J Intern Med 2005; 258:1.
  148. Hsu CC, Bray MS, Kao WH, et al. Genetic variation of the renin-angiotensin system and chronic kidney disease progression in black individuals in the atherosclerosis risk in communities study. J Am Soc Nephrol 2006; 17:504.
  149. Freedman BI, Volkova NV, Satko SG, et al. Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol 2005; 25:529.
  150. Parsa A, Kanetsky PA, Xiao R, et al. Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study. J Am Soc Nephrol 2017; 28:923.
  151. Böger CA, Gorski M, Li M, et al. Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. PLoS Genet 2011; 7:e1002292.
  152. Köttgen A, Glazer NL, Dehghan A, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009; 41:712.
  153. Parsa A, Kao WH, Xie D, et al. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183.
Topic 7181 Version 39.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟