Menoufia Medical Journal

: 2015  |  Volume : 28  |  Issue : 2  |  Page : 540--546

Renal fibrosis

Hassan Abd Elhady Ahmed1, Yassein SalahYassein Mohamed1, Ahmed Ragheb Tawfek1, Marwa Said Abd Elsaed Foda2,  
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Hurghada General Hospital, Hurghada, Egypt

Correspondence Address:
Marwa Said Abd Elsaed Foda
El Madares Street, Sakala Square, Hurghada, Red Sea 84511


Objective This mini-review attempted to highlight the recent progress in understanding of the cellular and molecular pathways leading to renal fibrosis and discussed the challenges and opportunities in developing therapeutic strategies. Background Renal fibrosis, characterized by tubulointerstitial fibrosis and glomerulosclerosis, is the final manifestation of chronic kidney disease. Renal fibrosis is characterized by an excessive accumulation and deposition of extracellular matrix components. There are many causes of tubulointerstitial fibrosis ranging from the effects of hypertension, glomerulonephritides, and pyelonephritis to conditions causing heavy proteinuria and any process that incites glomeruli or proximal tubules to produce proinflammatory mediators as occurs in acute or chronic allograft rejection. Epithelial to mesenchymal transition (EMT) of tubular epithelial cells that are transformed to mesenchymal fibroblasts migrating to adjacent interstitial parenchyma constitutes principal mechanism of renal fibrosis along with local and circulating cells. Proteinuria as well as hypoxia are included among the main mechanisms of EMT stimulation. Transforming growth factor-β1 through the SMAD pathway is considered as the main modulator regulating the EMT molecular mechanism, probably in cooperation with hypoxia-inducible factors. Hepatocyte growth factor and bone morphogenetic factor-7 are inhibitory to EMT molecules, which could prevent at experimental and clinical level the catastrophic process of interstitial fibrosis. Interesting data emerge indicating that hepatocyte growth factor and bone morphogenetic factor-7 administration prevents the peritoneal fibrosis of mesothelial cells. Many promising targets for the treatment of renal fibrosis have been validated in various animal models, and even more new targets have been identified. Angiotensin-converting enzyme inhibitors and angiotensin II receptor type 1 blockers are undisputedly the first-line drugs in combating renal fibrosis. These drugs, however, are not able to halt the progression completely. Methods Data about the patient are collected from different sources that deal with renal fibrosis, including references text books, pictures and presentations, medical journals, and concerned web sites. Conclusion Renal fibrosis characterized as a progressive detrimental connective tissue deposition on the kidney parenchyma appears as a harmful process leading inevitably to renal function deterioration.

How to cite this article:
Ahmed HA, Mohamed YS, Tawfek AR, Foda MA. Renal fibrosis.Menoufia Med J 2015;28:540-546

How to cite this URL:
Ahmed HA, Mohamed YS, Tawfek AR, Foda MA. Renal fibrosis. Menoufia Med J [serial online] 2015 [cited 2021 May 12 ];28:540-546
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Full Text


Renal fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease (CKD) [1],[2] .

 Causes of renal fibrosis

Informed consent was taken from the patients and the study was approved by the ethical committee. As renal fibrosis appears irrespective of the underlying disease (hypertension, diabetes, infection, inflammation of renal blood vessels and glomeruli, kidney stones, and cysts), some causes of renal fibrosis are as follows:

Glomerular diseases

Glomerulopathies presented with nephrotic syndrome

Minimal change disease: It is primary idiopathic or secondary due to neoplasia (e.g. Hodgkin's and non-Hodgkin's lymphomas), drugs (e.g. gold, antimicrobial, NSAIDs), infection (e.g. syphilis, HIV), atopy, superimposed on another renal disease, and miscellaneous (e.g. sclerosing cholangitis, renal artery stenosis, vasculitis, sarcoidosis) [3] .Membranous glomerulonephritis: It is primary or secondary due to infections (e.g. hepatitis B and C, syphilis), neoplasia (e.g. carcinomas, leukemia), autoimmune [e.g. systemic lupus erythematosus (SLE), thyroiditis, rheumatoid arthritis], drugs (e.g. NSAIDs), and others (e.g. de-novo renal transplant, sickle-cell disease, Guillain-Barre syndrome) [4] .Focal and segmental glomerulosclerosis: It is primary or secondary due to drugs (e.g. adriamycin, heroin), infection (e.g. HIV, malarial nephropathy), and malignancies and nephron loss (e.g. reflux nephropathy, surgical ablation, and low birth weight) [5] .Amyloidosis kidney: It is caused by rheumatoid disease, suppurative lung syndrome, familial Mediterranean fever, multiple myeloma, and non-Hodgkin's lymphoma.Diabetic nephropathy: It is due to advanced glycation end-products, which plays a critical role in diabetic nephropathy by stimulating extracellular matrix synthesis [6] .Glomerulopathies presented with nephritic syndrome

Diffuse proliferative glomerulonephritis : It is caused by postinfections (Streptococcal and non-Streptococcal, for example, Staphylococcus, P neumococcus, and viral, for example, mumps, hepatitis), SLE, Henoch-Schonlein purpura, and shunt nephritis (infected ventriculoatrial shunts).

Rapidly progressive glomerulonephritis (crescentic glomerulonephritis): It is caused by infectious diseases (e.g. post-Streptococcal glomerulonephritis and infective endocarditis), multisystem diseases (e.g. SLE, Henoch-Schonlein purpura), drugs (e.g. hydralazine, penicillamine, allopurinol, and rifampicin), and primary glomerular diseases.

Group of glomerulonephritis presented with nephrotic syndrome, nephritic syndrome, or mixed nephrotic/nephritic

Membranoproliferative or mesangiocapillary: It is caused by primary disease [type 1, type 2 (dense deposit disease and C3 nephritic factor), and type 3], genetic forms (factor H defects and C4 deficiency), and secondary causes are infections (e.g. Lyme disease, hepatitis B and C), chronic liver disease, and collagen vascular disease [7] .Mesangioproliferative glomerulonephritis: It is caused by idiopathic, bilharziasis, SLE, and IgA nephropathy (Berger's disease).Tubulointerstitial diseases

Tubulointerstitial diseases include the following:

Acute interstitial nephritis (drug-induced hypersensitivity nephritis) [8] .Chronic interstitial nephritis, which is primary or idiopathic and secondary [9] .Urinary tract infection

The urinary tract infection is acute and chronic [10] .

Urinary tract obstruction

The urinary tract obstruction may be congenital as fetal partial bladder outlet obstruction induces renal interstitial fibrosis as early as 2 weeks after obstruction or it may be due to renal stones [11],[12] .

Renal vascular diseases

Renal vascular diseases include renal artery stenosis.

Hypertension and atrophy of the affected kidney may result from renal artery stenosis, ultimately leading to renal fibrosis and finally renal failure if not treated [13] .

 Pathogenesis of renal fibrosis

Cellular events in renal fibrogenesis.

The pathologic findings of renal fibrosis are often described as glomerulosclerosis, tubulointerstitial fibrosis, inflammatory infiltration, and loss of renal parenchyma characterized by tubular atrophy, capillary loss, and podocyte depletion. The underlying cellular events leading to these histologic presentations are even more complicated; they include mesangial and fibroblast activation, tubular epithelial to mesenchymal transition (EMT), monocyte/macrophage and T-cell infiltration, and cell apoptosis [14] .

The hallmarks of mesangial and fibroblast activation, as well as tubular EMT, are de-novo expression of α-smooth muscle actin, a contractile protein normally restricted to perivascular smooth muscle cells in vivo, and overproduction of the interstitial matrix components such as type I and type III collagen and fibronectin [15] .

EMT has become widely accepted as a mechanism by which injured renal tubular cells transform into mesenchymal cells that contribute to the development of fibrosis in chronic renal failure.

 Key molecular pathway in renal fibrogenesis: it is the SMAD world

One of the central issues in renal fibrosis is to identify the key molecular pathway leading to fibrogenic cell activation. Although more than a dozen different fibrogenic factors have been documented, including various cytokines and hormonal, metabolic, and hemodynamic factors, it is widely accepted that transforming growth factor-b (TGF-b) and its downstream SMAD signaling play an essential role. Through intensive investigations over the last decade, much has been learned about the importance of TGF-b in tissue fibrosis in general and renal fibrosis in particular [16],[17] .

Upregulation of TGF-b is a universal finding in virtually every type of CKD.

 Matrix-degrading enzymes in renal fibrogenesis

Matrix homeostasis in normal tissues is a balance between matrix production and its degradation. It is generally believed that the excessive matrix accumulation seen in fibrotic kidney results from both overproduction of matrix components and defects in its degradation. This notion is supported by many observations that plasminogen activator inhibitor-1 and tissue inhibitor of matrix metalloproteinase-1 are often upregulated in a diseased kidney [18] .

 Endogenous antifibrotic factors and fibrosis therapy: it is all about the balances

The presence of fibrogenic factors almost certainly predicts that there have to be some antagonists that counteract their action. Indeed, recent studies have identified endogenous antifibrotic factors, particularly hepatocyte growth factor (HGF) and bone morphogenetic protein-7, which can precisely antagonize the fibrogenic action of TGF-β. Therefore, restoration of the balance between profibrotic and antifibrotic signaling could serve as a guiding principle for designing rational therapeutic strategies.

Hypoxia and fibrosis

Recent evidence revealed that hypoxia is a significant factor involved in interstitial fibrosis in chronic renal disease progression [19],[20] .

Diagnosis of renal fibrosis

Interstitial fibrosis does not show any visible symptoms at the very start, and hence it is very hard to detect. However, certain people are considered at high risk for interstitial fibrosis on account of their family history of the disease [21] .


The basic symptoms of renal or kidney interstitial fibrosis are the same as those of advancing kidney disease. They include changes in urination pattern with trouble urinating, swelling in the limbs, acute hair fall, extreme lethargy and fatigue, skin rash, taste changes including metallic taste in the mouth, severe nausea, dizziness, and leg pain. These symptoms are not comprehensive, and there might be other symptoms depending on the stage of the condition and patient physiology [22] .

Laboratory tests for detecting kidney fibrosis

Noninvasive detection of diseases, on the basis of urinary proteomics, is becoming an increasingly important area of research, especially in the area of CKD. Different platforms have been used in independent studies, mostly capillary-electrophoresis coupled ESI-MS (CE-MS), liquid chromatography coupled mass spectrometry, and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) [23] .

Cystatin C

Cystatin C acts as a new endogenous marker for detecting kidney function. Compared with blood urea nitrogen, serum creatinine, and creatinine clearance rate, cystatin C is much more favorable in laboratory tests. This kind of substance has a high sensitivity [24] .

β2 -Microglobulin

One's kidney function affects concentration of β2 -microglobulin in blood; it is one sensitive index indicating the kidney impairment in the very early stage [25] .

Urinary N-acetyl-B-d-glucosaminidase

The elevated N-acetyl-B-d-glucosaminidase occurs earlier than microalbuminuria in patients with diabetic nephropathy. N-acetyl-B-d-glucosaminidase is used to monitor hypertensive nephropathy and rejection after kidney transplant [26] .

Urine g-glutamyl transferase

The increase of g-glutamyl transferase in urine can be seen in patients with acute nephritis, nephritic syndrome, acute renal ischemia, and acute renal failure. In patients with SLE, their g-glutamyl transferase in urine is often regarded as one indicator of kidney impairment [26] .

 Evaluation of renal fibrosis by ultrasound imaging of blood flow by Targestar P ultrasound

Targestar P ultrasound perfusion agent is comprised of gas-encapsulated microspheres that can be used for noninvasive monitoring of blood flow with ultrasound imaging. It is distributed in the vasculature similar to erythrocytes, and therefore can be used as a marker of blood flow. Its use as a contrast agent boosts the sensitivity of ultrasound imaging to allow quantification of true microvascular flow in the assessment of disease and corresponding drug treatment [27] .

Ordinary ultrasound

It is used as a routine investigation in all kidney diseases with respect to the kidney size (which is almost shrunken in most of causes of renal fibrosis); in addition, it can detect renal stones, tumors, cysts, dilated pelvicalyceal system, echogenicity (which starts as poor differentiation between cortex and medulla and ends by loss of demarcation between cortex and medulla as the renal fibrosis goes on). In addition, it can detect parenchymal thickness (which is decreased and then lost in renal fibrosis) [28] .

Computed tomography in renal fibrosis

It can be useful in detecting the cause of renal fibrosis and the state of the cortex and the medulla [27] .

Renal biopsy

It is the only method by which we reach sure diagnosis of renal fibrosis [27] .

Treatment of renal fibrosis

Renal antifibrotic agents

A number of different strategies are being used to ameliorate, and hopefully even abrogate, progression. Therapies that reduce hypertension, proteinuria, hyperlipidemia, and hyperglycemia may potentially slow progression by improving the operating environment of the kidney [28],[29] .

Renin-angiotensin-aldosterone and kallikrein-kinin system

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor type 1 blockers are undisputedly the first-line drugs in combating renal fibrosis. These drugs, however, are not able to halt the progression completely and in some conditions, combination therapy of ACEI and angiotensin II receptor type 1 blockers [30] or high-dosage of ACEI [31] show potential in experimental studies to arrest or even regress renal fibrosis, at least in the early stages.Aldosterone inhibition, for example, with mineralocorticoid receptor blockers (spironolactone, eplerenone), also shows beneficial effects in experimental as well as in clinical studies [32] .Renin inhibitors (aliskiren, enalkiren, zalkiren) are promising drugs for combating renal fibrosis as shown in severely hypertensive transgenic rats (dTGR) harboring the human renin and angiotensinogen gene [33] .Endothelin, sympathetic nerve system

Endothelin, acting through its receptors ETA and ETB, is a potent vasoconstrictor and mediator of fibrotic response. Although the dual inhibitor of ETA and ETB bosentan is in clinical use, its benefits versus side effects (mainly hepatotoxicity and fluid retention) in CKD patients remain largely to be evaluated [34],[35] .

Immunosuppressive agents

Mycophenolate mofetil ameliorated fibrosis in various experimental models [36] . These effects were comparable, but not additive, with those of enalapril or lisinopril [37] . Confirmatory data in transplanted patients have recently emerged [38] .

Turnover and composition of the extracellular matrix

In renal fibrosis, local delivery of MMP-1 reduced collagen content in streptozotocin-induced diabetic nephropathy in rats [39] . In contrast, tubular MMP-2 overexpression in mice-induced renal fibrosis [40] and selective pharmacological MMP-2 inhibition increased fibrosis in UUO [41] .

Complement system

The terminal complex of complement, C5b-9 (or membrane attack complex), is formed at sites of tubulointerstitial injury; its depletion in experimental nephropathy reduces proteinuria, and inhibition of membrane attack complex formation in proteinuric animal models ameliorated tubulointerstitial injury [42] .


Few data are available on the role of interleukins in renal fibrosis. One exception is interleukin-1β, whose profibrotic properties in experimental renal disease have been established [42] .


Several chemokines and their receptors were shown to act in a profibrotic manner, mainly through recruitment of inflammatory cells into the tubulointerstitium [43] . These profibrotic molecules include monocyte chemoattractant protein-1 (CCL2) and its receptor CCR2, RANTES (CCL5) and its receptor CCR1 (but not CCR5) [44] , macrophage-colony stimulating factor, osteopontin [45] , and fractalkine receptor 1 (CX3CR1) [46] . The secondary lymphoid tissue chemokine (CCL21) and its receptor CCR7 have been implicated in the regulation of fibrocyte infiltration of the renal interstitium and promotion of fibrosis [47] .

TGF-β, TGF-β signaling molecules, p38 MAPK, bone morphogenetic protein-7

TGF-β, a central mediator of fibrosis, exerts its biological, in particular immunological, functions by the complex signaling pathways [48] . In view of its potent action as an endogenous immunosuppressant, complete blockade of TGF-β signaling could have serious adverse consequences.

HGF and connective tissue growth factor (CCN2)

HGF was shown to have antifibrotic properties in different animal models through inhibitory effects on SMAD2/3 and activation of SnoN, which binds and inactivates SMAD2 [49] .


Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, which is also involved in fibrosis [50] . In rats with 5/6-nephrectomy, cyclosporine nephropathy, and thrombotic microangiopathy, administration of VEGF121 reduced fibrosis and renal damage [51] .

Platelet-derived growth factor

Treatment with platelet-derived growth factor-D-neutralizing antibody ameliorated the early glomerular damage and the subsequent tubulointerstitial fibrosis [50] .

Other growth factors

The role of basic fibroblast growth factor-2 in renal fibrosis is well established, at least in vitro. Fibroblast growth factor-1 and its receptor were also identified in human interstitial fibrotic lesions [52] .

Nitric oxide, nuclear factor-kB, and Rho/Rho kinase

Enhanced production of nitric oxide following l-arginine administration prevented progression of renal fibrosis in several models [53] .

Stem cells

Stem cells hold great promise in acute renal failure and possibly even in chronic, fibrosing renal failure. Indeed, three recent studies showed a beneficial effect of bone marrow-derived cells in a mice model of Alport syndrome [54] .


Renal fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix that occurs in virtually every type of CKD.

The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. In a simplistic view, renal fibrosis represents a failed wound-healing process of the kidney tissue after chronic, sustained injury. Several cellular pathways, including mesangial and fibroblast activation as well as tubular EMT, have been identified as the major avenues for the generation of the matrix-producing cells in diseased conditions.

Among the many fibrogenic factors that regulate renal fibrotic process, TGF-β is one that plays a central role. Although defective matrix degradation may contribute to tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes in the injured kidney have become increasingly complicated.

Recent discoveries on endogenous antifibrotic factors have evolved novel strategies aimed at antagonizing the fibrogenic action of TGF-β/SMAD signaling. Many therapeutic interventions appear effective in animal models; however, translation of these promising results into humans in the clinical setting remains a daunting task. The process of renal fibrosis, in which multiple cellular events and molecular mediators participate and interact in concert, is enormously complicated.


Renal fibrosis characterized as a progressive detrimental connective tissue deposition on the kidney parenchyma appears as a harmful process leading inevitably to renal function deterioration, independently of the primary renal disease, which causes the original kidney injury. EMT of tubular epithelial cells that are transformed to mesenchymal fibroblasts migrating to adjacent interstitial parenchyma constitutes the principal mechanism of renal fibrosis along with local and circulating cells. Proteinuria as well as hypoxia are included among the main mechanisms of EMT stimulation. TGF-β1 through the SMAD pathway is considered as the main modulator regulating the EMT molecular mechanism, probably in cooperation with hypoxia-inducible factors. HGF and bone morphogenetic factor-7 are inhibitory to EMT molecules, which could prevent at experimental and clinical levels the catastrophic process of interstitial fibrosis.

It is recommended to find new biomarkers and advancing ultrasound or magnetic resonance-based or molecular-imaging techniques for early detection of renal fibrosis and monitoring of the disease process. Finding new therapeutic strategies and new renal antifibrotic drugs are also recommended.


Conflicts of interest

There are no conflicts of interest.


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