Principal functional and structural tubular biomarkers overexpressed in the urine and explored in clinical background of diabetic nephropathy [65, 66, 67].
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"},{slug:"suf-and-intechopen-announce-collaboration-20200331",title:"SUF and IntechOpen Announce Collaboration"}]},book:{item:{type:"book",id:"71",leadTitle:null,fullTitle:"Image Fusion",title:"Image Fusion",subtitle:null,reviewType:"peer-reviewed",abstract:"Image fusion technology has successfully contributed to various fields such as medical diagnosis and navigation, surveillance systems, remote sensing, digital cameras, military applications, computer vision, etc. Image fusion aims to generate a fused single image which contains more precise reliable visualization of the objects than any source image of them. This book presents various recent advances in research and development in the field of image fusion. 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Diabetes is often accompanied by chronic kidney disease (CKD) and accounts for more than half of the cause of end-stage renal disease (ESRD) and dialysis [1]. With the increasing prevalence of diabetes and high morbidity and mortality, its complications such as diabetic nephropathy impose great burden on individuals with diabetes and their society as well [2]. It is unclear whether the glomerulus or tubules are more important in the development and progression of diabetic nephropathy. The phenomenon of glomerulosclerosis led to an interest in the glomerulus as the primary site of injury in diabetic nephropathy. Indeed, changes in glomerular structure, such as glomerular basement membrane thickening, mesangial expansion, and nodular/global glomerulosclerosis, are key findings for the diagnosis of diabetic nephropathy and other forms of glomerulonephropathy [3]. Although changes in the glomerulus in diabetic neuropathy undoubtedly occur, there is growing evidence to suggest a prominent role for the proximal tubules as triggers or drivers of diabetic nephropathy. Indeed, this evidence provides a new perspective on the natural course and pathophysiology of diabetic nephropathy. These novel insights also provide new opportunities for diagnostic and therapeutic progress through targeting the proximal tubules in diabetic nephropathy. This review provides an outline of diabetic nephropathy, from the underlying pathophysiological mechanism to diagnostic and therapeutic approaches, based on a tubulocentric perspective.
It is very important to understand the natural course of disease to ensure that technical advances are fully exploited. However, the natural course of diabetic nephropathy is complex and depends on several factors, such as the clinical treatments used, and the race, type of diabetes, and comorbidities of the patient. Therefore, it is difficult to treat and prevent diabetic nephropathy. Current treatments include renin-angiotensin system (RAS) blockade, antihypertensives, glycemic control, and correction of dyslipidemia for the management of diabetic complications. Diabetes mellitus (DM) has a long history and was first described in 1552 BC; it has long been recognized as a socioeconomic burden [4]. Diabetes is regarded as a metabolic derangement and is closely related to renal dysfunction, as a microvascular complication [5]. Classically, diabetic nephropathy has a five-stage natural history: hyperfiltration, silent nephropathy, incipient nephropathy (microalbuminuric stage), overt nephropathy (macroalbuminuric stage), and ESRD [6, 7]. These five stages are almost exclusively applied to discussions of type 1 diabetes since the precise onset of disease in type 2 diabetes is not known. This natural course of diabetic nephropathy has served as a basis for clinical practice, and there are ongoing efforts to reduce albuminuria in patients with type 2 diabetes and renal dysfunction. Most adult cases of diabetes are type 2, and it is critical to delineate the progress of this disease. Type 2 diabetes differs from type 1 diabetes in several aspects. First, it is impossible to determine disease onset in type 2 diabetes. Second, in many cases, hypertension and albuminuria commonly accompany type 2 diabetes. Third, microalbuminuria has a lower predictive value for renal dysfunction because of the high mortality rate caused by cardiovascular disease [7, 8]. Recently, a new paradigm was suggested for exploring the natural course of diabetic nephropathy in the context of microalbuminuria and the nonclassical form of the disease.
Microalbuminuria is a robust indicator of the onset and progression of diabetic nephropathy, and it is assessed by reference to serum creatinine levels or the estimated glomerular filtration rate (eGFR). However, microalbuminuria has some major limitations as a predictor of renal dysfunction [9]. Albuminuria measurements can be imprecise and vary widely according to the assay method used, the time of urine collection, and the presence of clinical conditions such as fever, urinary tract infection, and congestive heart failure, as well as by exercise status [10]. Microalbuminuria was originally considered a subcategory denoted by an albuminuria level of 30–299 mg/day in a 24-h urine sample or 30–299 mg/g creatinine in a spot urine sample. Recently, normoalbuminuria and microalbuminuria were replaced by “normal to mildly increased albuminuria” and “moderately increased albuminuria,” respectively, because albuminuria is directly related to all-cause mortality, cardiovascular mortality, and renal dysfunction, even in patients with normoalbuminuria and microalbuminuria [11, 12] Furthermore, microalbuminuria shows dynamic characteristics (Figure 1), being a transient state that can progress to macroalbuminuria or regress to normoalbuminuria [13, 14]. A 7-year prospective study performed by the EURODIAB IDDM Complications Study Group in 352 type 1 diabetic patients showed that ~14% progressed to macroalbuminuria, 35% remained in a microalbuminuric state, and 51% regressed to normoalbuminuria [13]. The Joslin study reported that 58% of 386 type 1 diabetic patients with persistent microalbuminuria regressed to normoalbuminuria [14]. A better glycemic control contributes to the regression of microalbuminuria, and almost half of patients with microalbuminuria can regress to normoalbuminuria, as evidenced by the above two large studies. Although microalbuminuria is caused by glomerular injury, recent research has focused on the role of tubular dysfunction in albuminuria in type 1 diabetes. The Second Joslin Kidney Study reported that kidney injury molecule-1 (KIM-1) and N-acetyl-β-D-glucosaminidase (NAG) levels were important for predicting the regression of microalbuminuria [15]. This finding supports the theory that tubular injury plays a significant role in the progression of renal complications in type 1 diabetes. This pattern of microalbuminuria regression could also be applicable to type 2 diabetes, although no concrete evidence for this has been reported.
A triangle concept toward kidney function. eGFR, estimated glomerular filtration rate.
In 216 Japanese patients with type 2 diabetes and microalbuminuria, the regression rate to a normoalbuminuric state was ~50%, where regression was associated with a RAS-blocking agent, a better glycemic control, and a tight control of blood pressure [9]. However, none of 60 patients with type 2 microalbuminuric diabetic nephropathy regressed to normoalbuminuria in an African-American population [16]. This suggests that there are racial differences in changes in microalbuminuria status in type 2 diabetes, and further studies are needed to explore the role of genetic predisposition and race. A recent study suggested that macroalbuminuria and microalbuminuria can regress to microalbuminuria or normoalbuminuria, respectively [17]. In the FinnDiane study, 23.4% of 475 type 1 diabetic patients with macroalbuminuria regressed to a lower categorical albuminuric state and 2.5% regressed to normoalbuminuria, although the statistical power was low [17]. Such regression would improve the cardiovascular prognosis and all-cause mortality. Previous studies proposed that the regression of microalbuminuria contributes to a reduction in renal or cardiovascular risk in type 2 diabetic and hypertensive patients [18, 19]. These data suggest that it is necessary to treat diabetic patients with some degree of albuminuria to regress the albuminuria.
Protein in urine comprises albumin (40%) and nonalbumin proteins (NAPs; 60%). A third of NAPs are low-molecular weight proteins (LMWP), such as light-chain immunoglobulins (20%), and two-thirds are Tamm-Horsfall mucoproteins produced by the distal tubules [20, 21]. The proportional contribution of albumin attributes to be largely more variable at lower levels of proteinuria, and NAPs are important when assessing proteinuria as a biomarker of renal tubular damage [22]. Nonalbumin proteinuria can be defined as an albumin excretion rate (AER) of < 30 mg/24 h with a protein excretion rate (PER) of >149 mg/24 h. Nonalbumin proteinuria can be quantified in random spot urine samples using the following formula: NAP-to-creatinine ratio (NAPCR) = protein creatinine ratio (PCR) − albumin creatinine ratio (ACR). Because albuminuria tests could miss up to 40% of females and 30.8% of males in the general population with gross proteinuria, NAP levels should be checked to accurately assess renal damage [21]. Our laboratory reported that urinary NAPCR had a significant association with the decline in eGFR of 237 type 2 diabetic patients with preserved kidney function and normoalbuminuria [23]. In addition, NAP was related to tubular biomarkers such as KIM-1, neutrophil gelatinase-associated lipocalin (NGAL), and liver-type fatty acid-binding protein (L-FABP) in early type 2 diabetic nephropathy patients with preserved kidney function (eGFR ≥60 mL/min/1.73 m2) [24]. Moreover, NAPCR could serve a simpler and a more practical marker for assessing the progression of renal dysfunction compared with laboratory urinary biomarkers, such as KIM-1, NGAL, and L-FABP [25]. In the future, it will be necessary to study NAP in diabetic nephropathy to discover novel processes in and investigate the course of the disease.
In general clinical practice, the eGFR should be calculated at least once a year to properly manage diabetic patients. Like albuminuria, eGFR has some major limitations for predicting renal dysfunction, because serum creatinine and cystatin C levels cannot be measured precisely and do not reflect early changes in the kidney. However, currently, there are no available tools that are more powerful for assessing kidney function. Although the classic course of diabetic nephropathy involves sequential dysfunction of the kidney following albuminuria, recent epidemiologic data suggested the presence of normoalbuminuric diabetic nephropathy in some patients [26]. There is a close relationship between albuminuria and progressive dysfunction of the diabetic kidney. A recent Japanese study showed that a rapid decline in kidney function occurred in subjects with higher levels of ACR of ≥3000 mg/g creatinine in urine. In addition, the rate of annual decline in eGFR was doubled in macroalbuminuric versus normoalbuminuric diabetics for 9.2 years [11]. However, the focus should be on NARD with respect to early intervention strategies, because dipstick tests cannot reveal low levels of albuminuria or NAP. The UK Prospective Diabetes Study (UKPDS) reported that, among the patients who developed renal impairment during the study, 61% did not have albuminuria beforehand and 39% never developed albuminuria [27]. This suggests that distinct pathobiological mechanisms may underlie NARD and albuminuric renal decline. The prevalence of NARD was not low (20.5–63%) in several clinical trials performed in type 2 diabetic patients [26]. Interestingly, in another study, the prevalence of retinopathy was lower in the NARD group than in the albuminuric group, and patients with NARD had a shorter duration of diabetes [28]. This finding gives rise to a new hypothesis, in which NARD is not to be related to microangiopathy and instead shows a greater association with tubulointerstitial damage or macroangiopathy (i.e., arteriosclerosis).
Most diabetic patients with albuminuria show typical renal pathological changes, whereas typical diabetic glomerular changes are observed less frequently. In addition, atypical histologic changes suggestive of a severe interstitial or a tubular damage, or varying degrees of arteriosclerosis, were seen in patients with NARD [29]. Intrarenal arteriosclerosis is related to aging and hypertension. Furthermore, a recent study suggested that acute kidney injury (AKI) is a major component of CKD in patients with diabetes [30]. Both clinically evident and subclinical AKI can damage proximal tubular cells, podocytes, and endothelial cells, and such insults can create an apoptotic and inflammatory environment within the kidneys. Atubular glomeruli and glomerulotubular junction abnormalities in diabetes are also related to AKI and can lead to NARD [31].
Diabetic nephropathy has several phenotypes according to clinical and laboratory data; among them, PRD is the most serious. Generally, PRD is defined as a >3.5 mL/min/year loss in the eGFR in type 1 diabetes and PRD reasonably included NARD. Krolewski reported that the prevalence of PRD was 10, 32, and 50% in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively [32]. The recent Scottish Go-DARTS study identified biomarkers for PRD: 154 patients with type 2 diabetes and CKD showed a >40% decline in eGFR during the 3.5-year study period [33]. In the second Joslin Kidney Study, in which PRD was defined as a decrease in eGFR >30% from baseline during ≤5 years of follow-up, an early decline in renal function developed in 6 and 18% of patients with normoalbuminuric and microalbuminuric diabetes, respectively [34]. Although the mechanism underlying such a decline is unclear, more intensive and personalized treatments are needed to prevent progression to ESRD.
The clinical course of diabetic nephropathy varies such that physicians should treat diabetic patients using tailored approaches; the term “natural course” may no longer be applicable in this era of active interventions. In future, more phenotype-specific approaches informed by gene- and proteome-based analyses are needed to improve patient prognosis.
Glomerular dysfunction has long been considered a major driver of diabetic nephropathy. Kimmelstiel-Wilson nodules, which are characterized by the formation of diffuse nodular lesions of a pink hyaline material in glomerular capillary loops in the glomerulus [35], have contributed greatly to the identification of the glomerulus as the main culprit in the development of diabetic nephropathy. Diabetes-induced glomerulopathy can be caused by interactions among glomerular endothelial cells, mesangial cells, and podocytes via metabolic and hemodynamic perturbations [36]. However, glomerulopathy in diabetes is still not fully understood because various cells resident within the glomeruli have different roles in the disease process. Furthermore, recent studies revealed that glomerulopathy is preceded by tubular dysfunction during the development and progression of diabetic nephropathy [37]. These tubulocentric concept addressed in this chapter is summarized in Figure 2.
Tubulocentric concept for diabetic nephropathy. (1) Tubulointerstitial damage can cause a disconnect between glomerulus and tubule, (2) atubular glomerulus, (3) retrograde trafficking with NMN releasing by proximal tubule can contribute glomerulopathy, (4) proximal tubules are vulnerable to hypoxic injury, which can lead to fibrosis and apoptosis, (5) reduced retrieval of albumin by impaired tubule resorption is responsible for albuminuria in diabetic nephropathy.
Pathological changes in the tubulointerstitium that have been linked to diabetic nephropathy include the thickening of the tubular basement membrane (TBM), tubular atrophy, interstitial fibrosis, and arteriosclerosis, which are closely correlated with the magnitude of renal dysfunction and albuminuria [38]. Furthermore, such tubulointerstitial damage can cause a disconnect between the glomerulus and the proximal tubule, the so-called atubular glomerulus, which is an important and a common cause of irreversible CKD progression [39, 40]. These glomerulotubular junction abnormalities accompanied by atubular glomerulus have been linked to the development and progression of diabetic nephropathy in both type 1 and 2 diabetes [31, 41]. Recent studies suggest that the glomerular dysfunction triggered by proximal tubules, the so-called retrograde trafficking might be important in diabetic nephropathy [42, 43]. Proximal tubules communicate with podocytes by releasing nicotinamide mononucleotide (NMN), and proximal tubule-specific Sirt1 protects against diabetic kidney disease by maintaining glomerular NMN concentrations and preserving podocyte function [42]. Furthermore, injured proximal tubule epithelium can trigger an inflammatory response, and repeated injury results in maladaptive repair. This in turn leads to tubulointerstitial fibrosis, tubular atrophy, and, potentially, secondary glomerulosclerosis, which is pathologically similar to classic diabetic nephropathy [44]. Albuminuria, which has been primarily considered as a glomerular damage marker, is a sensitive marker, reflecting the functional impairment in tubule, alone or in combination with glomerular origin in animal nephrotoxicity study [45]. Finally, a substantial evidence from human urinary biomarker data supports that proximal tubule damage might have an important role in the development of early diabetic nephropathy as a primary cause, not a secondary phenomenon [46].
In diabetic kidney, proximal tubules are vulnerable to hypoxic injury because of an increased oxygen consumption, an impaired oxygen utilization, and a reduced oxygen delivery. Sodium reabsorption and gluconeogenesis processes occurring at the proximal tubules consume oxygen. The proximal tubule can be subdivided into three distinct segments (S1, S2, and S3) and is adapted for reabsorption. Transport across the tubular epithelium occurs via two routes: transcellular transport across luminal and basolateral membranes via Na+, K+ −adenosine triphosphatase (ATPase), and paracellular transport through tight junctions and the intercellular space. Glucose enters cells in the proximal tubule via the sodium-glucose cotransporter (SGLT), and is extruded from cells by GLUT1 and GLUT2 [47]. High Na+, K+-ATPase activity and oxygen consumption levels are needed to reabsorb glucose under high glucose conditions. A recent study showed that SGLT2 inhibitors downregulate Na+ and K+-ATPase activity and eventually reduce energy or oxygen requirements [48]. Similar to hepatocytes, epithelial cells in proximal tubules perform gluconeogenesis and export glucose into the circulation via oxygen- and energy-based processes. In diabetes, renal gluconeogenesis is particularly increased in the postprandial or fasting state [49]. Hypoxia induces apoptosis by upregulating Fas expression [50, 51]. Hypoxia stimulates extracellular matrix (ECM) expansion via transforming growth factor-β (TGF-β)-dependent and -independent pathways, such as an increased collagen production, a decreased matrix metalloproteinase-2 (MMP-2) activity, and an increased tissue inhibitor of metalloproteinase-1 (TIMP-1) expression [52, 53].
Recently, our laboratory studied the role of MMP-2 in diabetic nephropathy. Hyperglycemia-induced oxidative stress is a major driver of diabetic nephropathy, and high glucose levels stimulated the induction of intracellular MMP-2 in HK2 cells; this expression was blocked by the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) [54]. Intracellular MMP-2 exacerbates oxidative stress by inducing the mitochondrial permeability transition, which results in tubular epithelial cell-regulated necrosis [55]. Therefore, intracellular MMP-2 is related to oxidative stress, and proximal tubular cells are susceptible to hypoxic stress. This may be important in the pathogenesis of CKD in DM. The resultant may lead to glomerular change as well as tubulointerstitial hypoxia and finally loss of kidney function.
Unlike healthy individuals, patients with diabetes are persistently exposed to various metabolic and hemodynamic factors that sustain the disease state [56]. In addition, AKI frequently occurs after various nephrotoxic insults, such as ischemia during cardiac surgery and those associated with the administration of contrast media. The proximal tubule is particularly vulnerable to the ischemia and toxin-mediated injury that lead to AKI. In a mouse model of induced proximal tubule injury, tubular regeneration after a single episode of renal epithelium injury was robust and efficient, leading to complete restoration of the kidney architecture [45]. However, repeated injury resulted in maladaptive repair, manifested as tubulointerstitial fibrosis and tubular atrophy, and with the potential for secondary glomerulosclerosis [45]. Thus, these data suggest that the cumulative effects of repeated episodes of subclinical AKI arising from injurious stimuli lead to the progressive tubulointerstitial fibrosis that is characteristic of CKD, including diabetic nephropathy. Epidemiological and clinical observations support a relationship between intermittent AKI and CKD progression in diabetic patients [57, 58]. AKI increased the risk of advanced CDK in diabetic patients independent of other major risk factors of kidney disease progression, and each episode of AKI showed a cumulative dose-response association, doubling the risk of stage 4 CKD [57]. In AKI, a low eGFR and/or an elevated albuminuria level are compelling biomarkers for major adverse outcomes and death in diabetes [58].
The role of proximal tubules in albuminuria in various renal disorders, including diabetic nephropathy, remains controversial. The glomerular filtration barrier has long been considered largely impermeable to albumin, but recent data suggest that it may not be especially important in this process [59]. According to the “retrieval hypothesis,” albuminuria likely has a tubular origin, because albumin can be filtered by normal glomeruli in the nephrotic range if tubular reabsorption is only partial [60, 61]. Russo et al. [60] reported that more albumin was filtered and underwent a rapid retrieval process via transcytosis in proximal tubule cells. Therefore, controversy remains regarding the extent of the glomerular filtration of albumin. A study of Fanconi syndrome patients with proteinuria reported a markedly impaired albumin filtration rate [62]. Collectively, these data suggest that an increased glomerular leakage and an impaired tubular reabsorption are not mutually incompatible, and both are accountable for albuminuria in the early diabetic nephropathy [61, 63].
Classification of diabetic nephropathy based on albuminuria and the eGFR provides prognostic information that is helpful to guide therapeutic decisions. Albuminuria serves as a marker of endothelial dysfunction, which is a prognostic factor for renal impairments and a high cardiovascular risk [64]. However, its progress is unpredictable, since microalbuminuria can regress toward normoalbuminuria, progress toward macroalbuminuria, or remain stable [65]. Moreover, diabetic nephropathy can develop in normoalbuminuric patients. In addition, structural changes in the glomerulus may appear before the onset of microalbuminuria, even though microalbuminuria is the established screening tool for diabetic nephropathy [66]. Therefore, an intensive search for new blood or urine biomarkers that could improve diagnostic and prognostic precision in diabetic nephropathy has recently been reported.
Because of emerging evidence supporting tubulocentric concepts in diabetic nephropathy, the focus has shifted from glomeruli to proximal tubules, which may contribute to the pathogenesis of diabetic nephropathy from an early stage. Both functional and structural markers can be used to detect proximal tubule dysfunction in diabetic nephropathy. One method is to detect filtered proteins due to the impaired reabsorption by the proximal tubules. The main site for reabsorbing filtered proteins is the proximal tubules and, assuming no secretion or degradation of these proteins through the glomerulus, the more proteins are filtered, the higher the urinary excretion rate will be when tubular reabsorption is destroyed. These functional tubular biomarkers are low-molecular weight proteins (LMWP) that are mostly reabsorbed by the proximal tubules. Another method is to detect proteins released into the urine by tubular injury. These urinary proteins are structural tubular biomarkers that come directly from tubular cells rather than from plasma. The principal tubular biomarkers in diabetic nephropathy are briefly described in Table 1.
Functional tubular biomarkers | ||
Albumin | 65 kDa | Normally filtered very little at the glomerulus. With glomerular barrier damage, filtration occurs and followed by tubular reabsorption. The resulting albuminuria reflects the combined contribution of these two processes. |
Cystatin C | 13 kDa | Filtered by the glomerulus and reabsorbed in the proximal tubule. No tubular secretion. |
Retinol-binding protein 4 | 21 kDa | |
α1-microglobulin | 26–31 kDa | |
β2-microglobulin | 11.8 kDa | Filtered by the glomerulus and degraded in the proximal tubule via a megalin-dependent pathway. Unstable in urine. |
Structural tubular biomarkers | ||
Neutrophil gelatinase-associated lipocalin (NGAL) | 25 kDa | Hyper-produced in the kidney tubules within a few hours after renal ischemia-reperfusion injury. It is freely filtered and reabsorbed in the proximal tubule. |
Kidney injury molecule-1 (KIM-1) | 70–80 kDa | Cleaved and released into the lumen of the tubule. It facilitates repair of the damage by removing cellular debris and apoptotic bodies from the injured tubulointerstitial compartment. |
N-acetyl-β-D glucosaminidase (NAG) | >130 kDa | Plasma NAG is not filtered through the glomeruli. It is released into the urine after renal tubule injury. |
Liver-type fatty acid-binding protein (L-FABP) | 14.2 kDa | Associated with structural and functional tubular damage. It is freely filtered and reabsorbed in the proximal tubule. |
Megalin and Cubilin | Megalin 600 kDa Cubilin 460 kDa | Most proteins filtered through glomeruli have been identified as ligands of megalin, cubilin, or both. The central mechanism for protein reabsorption in the proximal tubule. |
Alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) | ALP 70–120 kDa GGT 90 kDa | ALP originates from damaged renal tubules, and its levels are associated with the degree of damage. Increased GGT excretion in the urine reflects the damage of the brush-border membrane and the loss of microvilli. |
In tubular proteinuria, the endocytic function of proximal tubule is damaged and a large amount of LMWP is detected in the urine. For example, retinol-binding protein 4 is markedly elevated when endocytic function is completely eliminated [67]. The cause of an increased LMWP excretion in diabetes is usually explained by tubular disease. Animal models suggest the pathway that the filtered proteins compete with each other for reabsorption in proximal tubules [68]. Clinical studies have also shown that the same pathway leads to the reabsorption of albumin and LMWP through glomeruli [69]. The ability of protein reabsorption in proximal tubules is not known but competition for reabsorption between albumin and LMWP may occur. As a result, a slight increase in filtered albumin through glomeruli in the early stage of diabetic nephropathy will not cause albuminuria, but an increase in LMWP excretion may be detected indirectly. In other words, early glomerular injury in diabetes may not cause albuminuria if proximal tubules are functioning normally and can reabsorb the excess albumin filtered from glomerulus. Other clinical study has also suggested the dissociation between albuminuria and increased glomerular leakage of albumin [70].
Studies using tubular biomarkers showed conflicting results regarding their predictive value for GFR decline or the development of albuminuria. In a retrospective analysis, two tubular injury biomarkers, β2 microglobulin and N-acetyl-β-D glucosaminidase (NAG), did not show prognostic utility for detecting GFR decline in type 2 DM (T2DM). However, histologic findings of interstitial fibrosis and tubular atrophy (IFTA) did have prognostic benefit. Both β2 microglobulin and NAG showed a statistically significant correlation with IFTA scores, identified as an independent predictor of progression to diabetic nephropathy [71]. In a nested case-control study from the diabetes control and complications trial (DCCT), both the baseline NAG and increase NAG over time predicted albuminuria independently [72]. A 3-year prospective study found that type 1 DM (T1DM) patients with high levels of urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) had a rapid deterioration in GFR. This suggests that tubular injury is important for the progression of diabetic nephropathy [73]. Fu et al. [74] showed that NGAL increased significantly from healthy controls to normoalbuminuric, microalbuminuric, and macroalbuminuric patients with T2DM. Conway et al. [75] revealed that the uKIM-1/Cr ratio was elevated in T2DM patients with early-stage nephropathy, suggesting tubular injury. The uKIM-1/Cr ratio was correlated with a rapid decline in GFR and the severity of proteinuria. Soggiu et al. [76]showed that increased RBP4 and α1-microglobulin excretion could predict early-stage nephropathy in T1DM. In a retrospective cohort study of 1549 patients with T1DM, liver-type fatty acid-binding protein (L-FABP) was a valuable predictor of the progression of diabetic nephropathy, irrespective of disease stage [77]. Our laboratory reported that albuminuria is significantly correlated with three tubular biomarkers (KIM-1, NGAL, and L-FABP) during the early stage of diabetic nephropathy [78]. Our laboratory also reported results obtained from 237 patients with T2DM who were measured for NAP and cystatin C. Both biomarkers were significantly associated with the decline in eGFR after adjusting for clinical parameters [23]. Prospective studies are needed to confirm the clinical utility of tubular biomarkers in the early stage of diabetic nephropathy.
Recently, many researches using high-throughput proteomics and microRNA (miRNA) approaches have been introduced in the field of diabetic nephropathy. These two novel approaches for discovering biomarkers can be used to explore diabetic nephropathy through multiple pathophysiological processes that can reflect complexed structural and functional pathways. Proteomics might provide dynamic profiles, reflecting the complexed pathophysiological changes that occur at different stages of diabetic nephropathy. Proteomics could serve as early biomarkers (e.g., CKD273 classifier, a panel consisting of 273 urinary peptides [79]) with a good predictive value in the clinical environments [80]. However, proteomic and miRNA approaches have yet not been able to replace albuminuria as a marker of diabetic nephropathy. miRNAs, which are small noncoding RNAs, are found in extracellular environment including various body fluids and function in posttranscriptional regulation of gene expression. The majority of miRNAs are located within the cell and can serve as a potential biomarker. In the urine, miRNAs are more stable in degradation than proteins and are valuable for urinary biomarkers. If miRNAs are handled and stored carefully, it could promote the discovery of novel urinary biomarkers for diabetic nephropathy. However, they were differentially expressed in T1DM and T2DM, and differed according to miRNA sources. In addition, miRNAs were reported to show gender-specific differences in T1DM [81]. Therefore, further studies are needed to optimize the utility of miRNAs in clinical practice.
Chronic hyperglycemia is an essential component of diabetes and the principal risk factor for microvascular complications, including diabetic nephropathy [82]. Patients with diabetes also have other risk factors such as obesity, systemic hypertension, and dyslipidemia. Despite advances in pharmacologic interventions (e.g., RAS blockers) to control these risk factors, the prevalence of diabetic nephropathy continues to rise and remains the leading cause of ESRD worldwide [83]. Several novel therapeutic strategies, including dual/triple RAS blockade and sulodexide and bardoxolone therapy, have been sought to improve renal outcome in diabetes [83]. However, these approaches proved either ineffective or harmful, suggesting that other strategies should be sought [84]. The optimal prevention and treatment of CKD in patients with diabetes requires the implementation of therapies that specifically consider the role played by proximal tubules [85]. The dimension and function of proximal tubules increase in response to a higher glucose load. These changes have been linked to an increase in GFR, or the so-called diabetic hyperfiltration [85]. Thus, considering the importance of proximal tubules in diabetic nephropathy, the development of novel antidiabetic agents, such as SGLT 2 inhibitors, could yield new tools to prevent diabetic nephropathy.
The glomeruli of normoglycemic healthy individuals filter ~140–160 g of glucose each day. This would result in a urinary loss of energy substrate equal to ~30% of the daily energy expenditure if not reclaimed by the renal tubules. Two glucose transporters are responsible for renal glucose reabsorption, SGLT1 and SGLT2, which are secondary active co-transporters located on the apical membrane that couple glucose reabsorption to sodium reabsorption. SGLT2 is located in the early (S1) proximal tubule and accounts for 90% of glucose reabsorption, while SGLT1 is located in the more distal part of the proximal tubule (S2/S3) and accounts for the remaining 10% [86].
In diabetes, hyperglycemia is maintained by the alterations in kidney. Both renal gluconeogenesis and glucose reabsorption are increased in diabetic subjects [3]. Hyperglycemia increases the amount of glucose filtered through the kidney, and the maximum capacity of resorption for glucose is increased by ~30% to ~500–600 g/day in patients with type 2 diabetes [84]. If the filtered glucose load exceeds the threshold of proximal tubules in diabetes, glucosuria increases in a linear fashion. These latter changes occur in parallel with upregulated SGLT2 expression [87]. More specifically, an increased capacity for glucose transport may contribute to the enhanced renal glucose reabsorption seen in diabetes. Upregulated renal SGLT2 levels have been reported in both human cells and some animal models of type 1 and type 2 diabetes [88]. Proximal tubule growth (hypertrophy) is a key feature of early-stage diabetes, which may explain the increased capacity for renal glucose reabsorption [61]. However, it remains unclear whether SGLT2 upregulation is the result of proximal tubule hypertrophy in diabetes.
Based on the observation that SGLT2 has an important role in renal glucose reabsorption, the proximal tubules of the kidney have been targeted to control the blood glucose. SGLT2 inhibitors are a novel class of antidiabetic drugs that recently entered the market. These medications target the kidney proximal tubules to block glucose reabsorption, thereby inducing urinary glucose excretion and reducing circulating plasma glucose levels. Their mechanisms of action are independent of the action of insulin and beta-cell function.
Phlorizin promotes glucosuria and lowers serum glucose levels in diabetic patients, and completely inhibits renal glucose reabsorption in humans [89]. However, the clinical use of phlorizin was not pursued due to poor intestinal absorption, low bioavailability, and lack of selectivity for SGLT2. Additionally, phlorizin is hydrolyzed to phloretin in the gut, which inhibits multiple GLUTs [90]. Thus, the development of SGLT2-specific inhibitor was an important breakthrough for therapies targeting renal glucose transport for blood glucose management [91].
Currently, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved three oral SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) for patients with type 2 diabetes. The SGLT2 inhibitors reduced HbA1C by 0.5–0.7% [92]. Additional drugs within this class are under development (Table 2). The glucose-lowering effect of SGLT2 inhibitors is closely related to the amount of filtered glucose. Since SGLT2 is responsible for >90% of glucose reabsorption by the kidney, its inhibition would be expected to induce a urinary glucose loss close to the filtered load (160–180 g/day in normoglycemia). However, SGLT2 inhibitor-associated urinary glucose excretion is only ~40–80 g/day in healthy individuals and patients with type 2 diabetes, suggesting that SGLT1 has an important role in glucose reabsorption under SGLT2 inhibition [88]. SGLT2 inhibitor decreases insulin levels and increases glucagon levels. Thus, SGLT2 inhibitor enhances endogenous glucose production, thereby reducing the glucose-lowering efficacy [93].
Generic name (trade name) | Company | Dosing | SGLT2/SGLT1 selectivity |
---|---|---|---|
Dapagliflozin (Forxiga/Farxiga) | AstraZeneca | 5–10 mg QD | 1400 |
Canagliflozin (Invokana) | Janssen | 100–300 mg QD | 160 |
Empagliflozin (Jardiance) | Boehringer Ingelheim | 10–25 mg QD | 5000 |
Ipragliflozin (Suglat) | Astellas Pharma | 25–100 mg QD | 570 |
Tofogliflozin (Apleway/Deberza) | Sanofi/Kowa | 20 mg QD | 1875 |
Luseogliflozin (Lusefi) | Taisho Pharmaceutical | 2.5–5 mg QD | 1770 |
Ertugliflozin (Steglatro) | Merck/Pfizer | 1–25 mg QD | 2200 |
Sotagliflozina (N.A.) | Lexicon Pharmaceuticals | 400 mg QD | 20 |
Remogliflozin etabonate (N.A.) | BHV Pharma | 100–400 mg QD | 1100 |
Henagliflozin (N.A.) | Jiangsu HengRui Medicine | 2.5–200 mg QD | 1800 |
SGLT2 inhibitors currently approved or in development.
Dual SGLT1/2 inhibitor.
SGLT2/SGLT1, sodium-glucose cotransporter 2/sodium-glucose cotransporter 1; QD, once daily; N.A., not applicable.
The EMPA-REG OUTCOME and CANVAS trials investigated the effects of empagliflozin and canagliflozin on renal and cardiovascular outcomes in type 2 diabetes patient with high cardiovascular risk factors and an eGFR of ≥30 mL/min/1.73 m2. In the EMPA-REG OUTCOME trial, empagliflozin was associated with a relative risk reduction of 39% in incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine level, initiation of renal replacement therapy, or death from renal disease). Moreover, empagliflozin was associated with significant risk reductions of 44 and 55% in doubling serum creatinine and the initiation of renal replacement therapy, respectively [94]. Empagliflozin was also associated with relative risk reductions of 38, 35, and 32% in cardiovascular death, hospitalization for heart failure, and death from any cause, respectively. However, there was no risk reduction in nonfatal myocardial infarction or in nonfatal stroke [95]. In the CANVAS trial, canagliflozin was associated with relative risk reductions of 27 and 40% in the risk of albuminuria progression and composite renal outcome (40% reduction in eGFR, the need for renal replacement therapy, or death from renal cause), respectively [96]. Canagliflozin was also associated with a relative risk reduction of 14% in primary cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) [96].
The beneficial effects of SGLT2 inhibitors could be associated with a glucose-lowering effect. However, the small HbA1C reduction is unlikely to explain the rapid onset and effect size. Therefore, pleiotropic effects of SGLT2 inhibitor likely played a role (Figure 3). A meta-analysis of randomized controlled trial demonstrated that SGLT2 inhibitors decrease the systolic blood pressure by 3–6 mmHg in type 2 diabetes patients [92]. The blood pressure-lowering effect of SGLT2 inhibitors is partly associated with glycosuria-accompanied osmotic diuresis, which increases urine output by 200–600 mL/day. SGLT2 inhibitors also induce natriuresis by decreasing sodium reabsorption in the proximal tubules [84]. Additionally, a positive interaction between SGLTs and Na+/H+ exchanger-3 (NHE3), and the inhibition of NHE3 with phlorizin at sites associated with a reduced NHE3 activity have been described [97]. Since NHE3 in the early proximal tubule is responsible for up to 30% of fractional sodium reabsorption, its potentially downregulated activity on SGLT2 inhibition may contribute to natriuresis and subsequent GFR and blood pressure lowering; however, this hypothesis requires further study [98].
Pleiotropic effects of sodium-glucose cotransporter (SGLT2) inhibitor. SGLT2 inhibitor may have beneficial effects on kidney and heart via several pleiotropic mechanisms: (1) SGLT2 inhibitor blocks glucose hyper-reabsorption in the proximal tubule of the diabetic kidney, increasing the tubuloglomerular feedback signal at the macula densa ([Na+/Cl−/K+]MD) and hydrostatic pressure in Bowman’s space (PBOW).This reduces albuminuria and tubular transport work and, thus, renal oxygen consumption by decreasing glomerular hyperfiltration. (2) SGLT2 inhibition reduces insulin levels and increases insulin sensitivity and glucagon levels. As a consequence, lipolysis and hepatic gluconeogenesis are elevated. These metabolic adaptations reduce fat tissue and body weight. (3) SGLT2 inhibitors induce a modest osmotic diuresis, natriuresis, glucosuria, and uricosuria, which can reduce extracellular volume (ECV), blood pressure, serum uric acid levels, and body weight.
Clinical trials with SGLT2 inhibitors in patients with type 2 diabetes showed a significant weight reduction of ~1.7 kg or 2.4% compared with placebo [99]. While initial weight loss appears to result from SGLT2 inhibitor-associated osmotic diuresis, steady-state weight loss with SGLT2 inhibitor is thought to be associated with a reduction in body fat mass. In obese rat, SGLT2 inhibitor reduces fat mass with a steady calorie loss by increasing lipolysis and fatty acid oxidation. SGLT2 inhibitor-induced fat loss is also associated with the increased use of fatty acids instead of glucose as an energy source [100]. SGLT2 inhibitor has also been reported to reduce the body weight by reducing visceral and subcutaneous adipose tissue in type 2 diabetes patients [101].
Serum uric acid-lowering effect of SGLT2 inhibitor may be associated with the improved renal and cardiovascular outcome. SGLT2 inhibitor induces glycosuria, thereby facilitating intracellular uric acid exchange via GLUT9 isoform 2 at the proximal tubule, thereby enhancing urinary excretion of uric acid [102]. However, further study is mandatory to verify the precise mechanism of uricosuric effect of SGLT2 inhibitor.
Glomerular hyperfiltration is a detrimental process in diabetic nephropathy and increases intraglomerular pressure. The complicated interaction of hyperglycemia-induced structural and hemodynamic alterations causes the glomerular hyperfiltration [84]. By inducing barotrauma and shear stress, it exacerbates albuminuria and likely contributes to the development and progression of CKD [84]. SGLT2 inhibition attenuates primary tubule hyper-reabsorption in diabetes and thereby reduces glomerular hyperfiltration. Specifically, SGLT2 inhibitors increase sodium delivery at the macula densa and subsequently activate tubuloglomerular feedback, which induce afferent arteriolar vasoconstriction and then reduce intraglomerular pressure [84]. Recent studies have also confirmed that the SGLT2 inhibitors lower GFR. The empagliflozin decreased the eGFR by 19% in type 1 diabetes patients. The canagliflozin also initially decreased GFR in patients with type 2 diabetes [103]. After an initial decrease in eGFR, canagliflozin-treated group showed the slower decline of eGFR compared with glimepiride-treated group over 2 years independently of glycemic effects [104].
Nephrons that survive in the advanced stages of CKD are assumed to hyper-filter as a way of compensating for the loss of other nephrons. In the short term, SGLT2 inhibitors decreased the eGFR in patients with type 2 diabetes and stage 2 or 3 CKD [105, 106]. In the long term, the amelioration of glomerular hyperfiltration by SGLT2 inhibitor in CKD may preserve the integrity of the remaining nephrons. This concept has also been suggested for angiotensin II inhibition. Indeed, both SGLT2 and angiotensin II inhibition confer additional renoprotective effect in type 2 diabetes patients with basal eGFR of >30 mL/min/1.73 m2 [94].
The kidney and cardiovascular protection is likely to be attributed to the pleiotropic effects of SGLT2 (EMPA-REG OUTCOME and CANVAS trials). Future research is required to assess their ability to improve renal outcome in diabetic patients with more advanced CKD. The large trials with different SGLT2 inhibitors are ongoing to confirm whether their beneficial effects are drug-specific or represent a class effect. It is also important to investigate their effect in patients with nondiabetic kidney disease. In addition, dual SGLT1/2 inhibitors are under development to maximize the beneficial effect of SGLT2 inhibitors without causing side effects associated with SGLT1 inhibitors.
Although researchers are trying to determine the pathophysiology of diabetic nephropathy, our understanding remains incomplete. A recent paradigm shift to a tubulocentric concept for diabetic nephropathy implies that the proximal tubules have a central role in the disease process, rather than being secondarily affected by other components during the development of diabetic nephropathy. Representing a considerable step toward shifting the glomerulotubular balance, these new perspectives might lead to significant diagnostic and therapeutic advances in diabetic nephropathy.
This was supported by the Biomedical Research Institute Grant (Research Council, 2018; 2017B021 to J.H.K.) of the Pusan National University Hospital and the National Research Foundation of Korea (2018R1C1B6002854 to S.S.K., 2016R1A2B4008243 to S.H.S., 2017R1D1A1B03034926 to I.Y.K., and 2017R1C1B5016636 to S.M.L.).
The authors have nothing to disclose.
Leather manufacturing, which is an allied industry and subsector for textile, is the first making practice in primitive period of humankind. Different types of animal skin products were used throughout the first ages as parchment and vellum or by making the raw material resistant to putrefaction, heat, chemicals and environmental effects with smoke, potash alum and natural tannin extracts from different plant parts. Traditionally, these products obtained by modification of by-products of meat industry have all been classified as leather, which is a serviceable product. In this respect, the leather industry could have been distinguished as an environmental industry, since it processes waste products from meat production [1].
These natural products generally consist of long thick collagen fibers, fiber bundles and thin elastin fibers of interweaving in three-dimensional ways. Other features such as hairs and hair roots and also fat cells are present in three-dimensional woven structure that predominates and gives skin-based materials providing many of their unique physical and mechanical qualities [2].
The leather-making operation assists in converting the raw hide or skin, a highly putrescible material, into leather, a stable material, which can be used in manufacturing a wide range of products. These include shoes, clothing, leather goods, furniture, upholstery for car seats and interiors, boats and aircraft, and many other goods in daily use. The whole process involves a sequence of complex chemical reactions and mechanical processes [3].
The processing of leather involves four main stages: beamhouse, tanning, post-tanning and finishing. The first phase of the hide processing is called beamhouse operations and involves multiple mechanical, chemical and biological unit operations. Its objective is to remove dirt, hair, epidermis, noncollagenous proteins and grease from raw skin, and open up the collagen fibers to favor the subsequent tanning process [4]. The process is performed in a drum by mixing the raw hides with an alkaline solution containing lime and reducing agents, usually sulfide salts, the hair being chemically removed from the surface of the hide [5]. The beamhouse operations are the most water consuming and the effluents generated present very high organic load [6].
The tanning process is one of the oldest procedures in the world, and currently, these industrial activities are based on chemical processes involving several organic and inorganic compounds [7]. This step gives the leather stabilization against the wet and dry heat, bacterial growth, mechanical stress and enzymatic attack, among others, and forms the basis of leather production. This stabilization is attributed to the formation of new chemical cross-links in the matrix proteins [8]. The tanning stages are classified as mineral, vegetable and synthetic. When the skin stabilization is achieved by a suitable inorganic salt, the process is known as mineral tanning, and the most commonly used mineral tanning salt is the basic chromium sulfate (Cr(OH)SO4). If the leather is tanned with chromium salt, it is called as wet-blue leather. Chromium (III) salts are the most extensively used compounds due to the quality and high stabilization ability they impart to leather [9].
The third part in leather production is post-tanning process. The tanned leather is considered a commodity, that is, it may be used to produce several articles. Each post-tanning operation is directed to the article that will be produced, such as garment, shoe upper and upholstery [10]. The aim of the post-tanning processes is to enhance the aesthetic properties of leather by coloring it and changing some physical and mechanical properties of the material by retanning, dyeing and fatliquoring stages [10].
The finishing step complements the previous stage, tanning, and provides the leather with the required physical and mechanical properties, such as color, tensile strength, impermeability, softness, flexibility and elasticity with different kinds of binder, pigment, wax and oils [11]. This operation consists of coating and changing the surface of leather. It is related to the fashion appearance, but also to conferring properties such as abrasion resistance, gloss, handle, flex, adhesion and rub fastness as well as other properties as required for the end use including extensibility, light and perspiration fastness, water vapor permeability and water resistance [10].
Leather industry has been categorized as one of the highly polluting industries because large quantities of water and different chemicals have been used during tanning process and different solid, gaseous and liquid wastes are generated that have an adverse effect on the environment [12]. These wastes have different characteristics because different chemicals are applied to the raw hides in different ratios. Solid wastes generated in tanneries mainly include salts, raw trimmings, hair wastes, fleshings, splitting wastes, chrome shavings, buffing dusts, crust trimmings and finished trimmings. These solid wastes and by-products are not properly treated and disposed of, and they can cause environmental damages to soil and groundwater as well as release emissions of odor and poisonous greenhouse gases into the atmosphere by direct landfill or incineration, which is an unsustainable way [13].
Salt, which is used to preserve hides or skin thrown into open dumping areas or accumulated in piles outside the tanneries, is likely to create groundwater pollution when rain washes it away. Hair wastes and lime sludge discharged into the effluent can produce choking of treatment pipelines. Trimmings, fleshings and splitting wastes putrefy easily producing noxious odors [14]. Moreover, disposal of chromium-containing solid wastes into soil and water has potential effects on public health due to the possibility of oxidation of chromium (III) into hazardous chromium (VI) [15]. These tannery solid wastes have different characteristics that mainly constitute protein (collagen) as the main component [16].
Provisions for pollution control, waste minimization and disposal, the correct use of chemicals and accident prevention are essential for minimizing potential impact on air, water and soil from the processing of hides and skin.
Collagen derivatives are value-added products extracted from solid organic wastes and by-products, and they are utilized for several industrial applications such as preparation of technical-grade gelatin, protein hydrolysates, collagen peptides and subunits [17]. The processing of hides and skin also generates by-products, which find outlets in several industrial sectors such as pet and animal food production. They can be used in cosmetics, printing inks and photography, while the latter one is an ideal candidate for fertilizer or feeding additives due to their high nitrogen content [18].
The present chapter describes the leather solid wastes, general features of collagen peptides, and their preparation methods and applications in different industries.
The tanning industry worldwide produces a significant amount of solid wastes and effluents, environmental concerns about discharge and escalating landfill costs are becoming increasingly serious problems for the industry, and their management alternatives regarding overall consideration have been based on multispot [19]. Huge amounts of solid wastes are generated at different stages of leather processing and there is no actual adopted utilization method available for solid wastes; hence, handling is more difficult for tanners. Leather solid wastes generated in fleshing, trimming, splitting and shaving processes and also sludges discharged from the wastewater treatment plant both contribute to increase the volume of the wastes [20].
Generally, out of 1000 kg of rawhide, nearly 800 kg of solid wastes are generated in leather-manufacturing industries, and only 200 kg of the raw material is converted into a usable product. About 600,000 tons of solid wastes annually are generated worldwide by leather industries [21]. An example of the types and quantities of solid wastes generated in leather processing based on one ton of raw hides/skin is given in Table 1.
Solid wastes generated from processing of raw hides/skin (1000 kg) | Quantity (kg) |
---|---|
Conservation salts | 80 |
Hair | 100 |
Raw trimmings | 40 |
Lime sludges | 60 |
Fleshings | 120 |
Wet-blue trimmings | 30 |
Chrome splittings | 65 |
Chrome shavings | 95 |
Buffing dusts | 65 |
Crust trimmings | 35 |
Dry sludge from common effluent treatment plants (CETPs) | 125 |
Solid wastes from tannery [22].
The ways to disposals and valorizations for these wastes are defined by the chemical characteristics depending on the fact that the wastes are generated in either beamhouse or tanning and after tanning. This differentiation might be, namely, untanned wastes and tanned wastes accordingly.
Most of the solid wastes are generated in beamhouse, especially in fleshing operation. Fleshings are solid wastes generated during a mechanical process aiming at removing the flesh deposits or fats from the inner part of the skin [23]. Fleshings contain subcutaneous tissue, fat and flesh, which are composed of protein (5–7%), fat (4–18%), lime (2–6%), sulfide (2–4%), etc. [23].
Trimming is to cut out unwanted parts of processed hides/skin just after fleshing operation is completed. Trimmings are cut-outs from the operation and may be collected and shipped to glue manufactures or other by-product manufacturers or sent for disposal in a landfill [24].
Hides are generally subjected to mechanical operation called splitting to divide the hide into two or three layers horizontally. Splitting operation can also be applied at chromium tanning stage (wet-blue stage), which is called wet-blue splitting. Whether split is untanned and obtained after liming or tanned and obtained after tannage, it is a valuable part of a hide, which is a fibrous sheet, and hence it is in fact not a waste and more precisely it is a by-product.
The untanned solid wastes, mainly including leftovers from trimming of rawhide and surplus parts after liming and fleshing, are composed of large amount of collagen and grease. The chemical composition of these solid wastes varies depending on types and quality of the raw hides/skin and also process conditions. Fats and proteins are the main components of these wastes (10.5%). Moisture amounts might be up to 60%, meaning a high water content. The aforementioned solid wastes do not contain chromium compounds [25]. For sufficient usage of these protein-rich wastes, various kinds of methods and technologies have been proposed, focusing on the extraction of collagen/gelatin by using acid, alkali and enzyme hydrolysis and subsequent purification processes. Moreover, grease residue can also be used to extract oils and fats, which can be raw material for biofuel and leather fatliquor [26].
The chromium tanning is based on the cross-linkage of chromium ions with free carboxyl groups in the collagen. Chrome-tanned leather also called wet-blue leather are characterized by top handling quality, high hydrothermal stability, user-specific properties and versatility [27]. At the end of the chrome-tanning process, 60–75% of the chrome offer (Cr2O3) remains in the collagen structure. Additionally, small amounts of other chemicals and auxiliaries such as tensides, acids and bases (in the form of soluble “reaction salts”) remain in the wet-blue leathers. The main environmental impact of tannery solid wastes is the oxidation of trivalent chromium into the hexavalent form, which is highly toxic and has carcinogenic and mutagenic effect. Leakages from chromium-containing wastes when they come to the agricultural lands cause ground water pollution and soil contamination. Water pollution affects aquatic animals, which are common sources of food, and soil contamination poses health effects through food chain and also poses a health hazard through inhalation of toxic dust, which can be inhaled by both people and livestock [28].
The solid wastes containing chromium namely tanned wastes are wet-blue shavings, wet-blue trimmings, buffing dusts, finished leather trimmings and wastewater treatment sludge [29]. Their chemical composition consists of fats and oils (3–6%) and mineral matters (15%). As chromium has been already used worldwide, they normally contain 3.5–4.5% of chromium as Cr2O3. Sludge from effluent treatment plants contains mainly water (up to 65%), organic substances (30%) and chromium (III) (around 2.5%) [25, 30].
Chrome shaving wastes are generated during the machine process of thickness adjustment of wet-blue leathers based on the required thickness. Shavings are mainly the scraps from the flesh side of leather, which are carried out by cutting unusable parts of leather and rags created during shaving operation [31]. Utilization or safe disposal of shavings continues to pose a serious challenge in many countries and is more critical because of their compositions. While processing one ton of raw hide, approximately 95–100 kg of wet-blue shavings are produced [32, 33]. Currently, a part of the chrome shavings is used in the manufacture of different types of areas such as leather board, collagen peptides, gelatin, animal feed and fertilizers. Unused portion of shavings is dumped in open areas around tanneries posing a serious environmental hazard [34].
The tannery solid wastes can cause severe problems associated with its organic load, inorganic matter, chromium, suspended solids, total organic and ammoniacal nitrogen, sulfide, and chloride, among others, depending on the chemical and mechanical processes applied to the raw hides/skin. Accumulation of these wastes leads to sludge problem and choking of treatment pipes and finally results in the reduction in efficiency of the treatment plant [35].
Leather industry is facing a lot of solid waste problem and many tanneries are closed for not meeting biological oxygen demand (BOD) and total dissolved solids (TDS) norms [4]. It is very important to analyze the nature of these wastes in order to assure a safe disposal or application of them. Salt, which is used to preserve hides or skin, discharges huge amount of pollution load in terms of total dissolved solids and chlorides and creates groundwater pollution [36]. Hair waste and lime sludge if discharged along with the effluents are likely to choke the drains. Trimmings, raw fleshings, limed fleshings and splitting waste can putrefy easily by producing noxious smells. Some of the biodegradable tannery solid wastes cause volatile organic compound emissions and, moreover, are sources of pathogenic bacteria [37].
Shaving dust contains environmentally unfriendly chemical called chromium, and when it is dumped in the environment, it can easily enter into the surface and ground, and this heavy metal pollutes the surface water by erosion and the underground water by leaching and erosion, leading to serious health problems to aquatic life in nearby rivers. As a result of this, pollution of surface and ground water results in shortage of drinking water for human beings and animals living at the downstream of the rivers [38].
According to Mu et al. [39], about 25% of tannery solid waste ends up as chromium-containing solid waste, which is more dangerous than other tannery solid waste. The waste generated from chrome-tanned leather is not biodegradable and toxic due to the chromium content [40]. Chromium-containing leather waste has been classified as one of the dangerous and hazardous waste if discharged into the environment without any pretreatment. Increased risks for a number of cancers such as lung cancer, testicular cancer, soft tissue sarcoma, pancreatic cancer and bladder cancer have been reported [41]. Chromium waste can also cause respiratory problems, a lower ability to fight disease, birth defects, infertility and tumor formation [42]. Chromium-containing solid waste percolates to the ground and causes ground water pollution and soil contamination. Water pollution affects aquatic animals that are common sources of food, and contamination of soil poses health effects through food chain and also poses a health hazard through inhalation of toxic dust, which can be inhaled by both people and livestock. It can damage the gills of fish; it can alter genetic materials and cause cancer [43]. Moreover, thermal incineration of these wastes is associated with serious air pollution problems due to emission of toxic hexavalent chromium (Cr+6), halogenated organic compounds, aromatic hydrocarbons, etc. into the environment [42].
The word collagen is derived from the Greek word “kola,” which means gum, and “gen,” which means producing. It is a fibrous structural protein present in extracellular matrix and connective tissue of animals [44]. Collagen is the most prevalent protein comprising approximately 30% of the total protein of animal and human bodies and is found primarily in connective tissues including animal hairs, bones, cartilages, tendons and blood vessels [45, 46].
There are many types of collagens, which are from collagen I to collagen XIX. Animal skin or hide contains collagen type I, mostly with approximately 90% of its dry weight [47]. Collagen precursors are synthesized in the endoplasmic reticulum of cells and transported to the Golgi apparatus in order to secrete into the extracellular spaces, and maturation of collagen can occur [47, 48].
Collagen polypeptide chains and cross-linkages can be broken down by hydrolytic processes and decomposition yielding in different subunits and fragments [49]. In other words, gelatin is produced by partial denaturation of collagen in triple helical structure. Gelatin and collagen peptides are new forms yielded by hydrolysis of native collagen with lower molecular weight fragments than original structure and including a wide range of subcategories having differentiated functionalities [50]. Native collagen exhibits superior and distinct properties from collagen peptides such as higher enthalpy, greater network structure of fibrils, basic isoelectric point and high resistance to protease hydrolysis [51]. The native triple helices and fibril networks in the native collagen are more rigid and firmer than gelatin and collagen peptides [52].
All proteins are composed of linear chains of amino acids attached together by peptide bonds, thereby making oligomers, which are the primary structure of the protein. Being arranged into sequences of different amino acids gives way to fold up the chains into a functional protein. Intermolecular and intramolecular bonds in the structure can enhance the folding of the peptide chains. This folding induces the weak forces such as hydrogen bonds and electrostatic, hydrophobic and van der Waals interactions [53]. Considering the reactivity of collagen molecule, the peptide bond itself is prioritized, capable of participating in hydrogen bonds with both hydrogen-bond donor and acceptor groups. For example, a carbonyl group in any protein has two lone pairs of electrons having the capability of accepting hydrogen bonds. In addition, the electronegative nitrogen induces a partial positive charge on its attached hydrogen, allowing the hydrogen to function as a hydrogen-bond donor [54]. Hydrogen bonding between peptide bonds is the basis of protein secondary structural formation, namely, helices, yielding in pleats and turns in the structure [55]. The side chains of amino acids are capable of a variety of interactions including hydrogen bonds, ionic bonding, hydrophobic interactions, van der Waals interactions and disulfide bonds. These interactions and secondary structural elements are responsible for taking a shape of the tertiary structure of proteins, their actual three-dimensional shape [56]. Due to the interactions between side chains of various amino acids, the protein molecule will bend and twist so as to gain individual stability or lower energy state.
Proteins included in the number and arrangements of subunits to give functionality are referred to as quaternary structure. The proteins comprising individual subunits may be identical, or they may be different. Like the secondary and tertiary structures, the quaternary structure of a protein is determined by its primary structure [57].
Collagens are trimeric molecules made up of three polypeptide chains, which contain the sequence repeat of (Gly-X-Y)n, X being frequently proline and Y hydroxyproline. These repeats allow the formation of a triple helix based on three polypeptide chains bound to each other by hydrogen bonding, which is the characteristic feature of the collagen [58]. The side chains of each X and Y residue are at the surface of triple helix, giving the collagen molecule a significant capacity for lateral interactions with other molecules of extracellular matrix and resulting in the formation of various supramolecular assemblies [59, 60]. An interchain hydrogen bonding between glycine and amide group in an adjacent chain is a key factor in stabilizing the collagen triple helix [61].
Collagen protein is more hydrophilic than lyophilic moieties due to the chemical nature of numerous amino acids present in its structure [62]. It has a highly complex structure and interacts with each other at the molecular level to form broader systems with distinctive properties [63]. The chemical structure of collagen type I is shown in Figure 1.
Chemical structure of collagen type I. (a) Primary amino acid sequence, (b) secondary left-handed helix and tertiary right-handed triple-helix structure, and (c) staggered quaternary structure [63].
Basic properties create characteristic structure of collagen fibril helicoidal structure is; fibril diameters ranging from 10 to 500 nm [64], average molecular weight of 285,000 Da [65] and glycine ratio of 1/3 in the polypeptide chain consisting of 1400 amino acids [66].
Having been readily recognized in tissues with commonly white and opaque colors, collagen fibers area considered as viscoelastic materials having high tensile strength and low extensibility. The tensile strength of collagen depends on the formation of covalent intermolecular cross-links between the individual protein subunits [67].
The collagen family is highly complex and shows a remarkable diversity in molecular and supramolecular organization, tissue distribution and function. Collagen types are classified in several subfamilies according to sequence homologies, similarities in their structural organization and supramolecular assembly. The availability of 27 collagen types was reported and they are classified by their size, function and amino acid distribution that differ considerably in their molecular structure [68]. The individual members are numbered with roman numerals. The family is subdivided into different classes: the fibrillar collagens (types I, II, III, V, XI, XXIV and XXVII), basement membrane collagens (type IV), fibril-associated collagens with interrupted triple helices (FACIT collagens, types IX, XII, XIV, XVI, XIX, XX and XXI), short chain collagens (types VIII and X), anchoring fibril collagen (type VII), multiplexins (types XV and XVIII), membrane-associated collagens with interrupted triple helices (MACIT collagens, types XIII, XVII, XXIII and XXV) and collagen type VI. The types indicated by an asterisk are heterotrimers, consisting of two or three different polypeptide chains. Type IV collagens contain six different polypeptide chains that form at least three distinct molecules and type V collagens contain three polypeptide chains in probably three molecules [68].
Each collagen type has its own specific amino acid composition and performs a distinctive role in tissues. Types I, II and III are of the most abundant collagens, which are responsible for tissue strength, elasticity and water retention capacity [69]. Type I collagen is the main structural component of extracellular matrix. It consists of one α2 chain and two α1 chains, which are encoded on chromosome 7 and 17 in humans [70]. Generally, type 1 collagen is the most commonly used in industrial scale especially in tissue repair and replacement, and they are intensive in skin, tendon, bone, cornea, dentin, fibrocartilage, large vessels, intestine, uterus, dermis, cornea and connective tissue [71]. It has outstanding mechanical properties and is present in virtually every extracellular tissue with mechanical function. In tendons and ligaments, collagen transmits the force from muscles to bones and stores elastic energy. Smooth walking would not be possible without these properties. Collagen also represents most of the organic matrix of bones and tooth dentin and confers them their fracture resistance. It is a major constituent of skin and blood vessels and is even present in muscles, which could not function without a collagen-rich matrix around the contractile cells. A slightly different type of collagen type II is a critical component of a tissue as soft as articular cartilage. The function of collagen is not only mechanical. In the cornea of the eye, for example, the ordering of collagen fibrils confers transparency in addition to mechanical stability [69]. Type II collagen is prevalent in hyaline cartilage, vitreous, nucleus pulposus, notochord and intervertebral disc. It provides biomarkers for osteoarthritis. Type III collagen is present in fetal dermis and epidermis, veins, uterus, synovium, connective tissue around muscles and also in small quantities in areas where type I collagen is present. Type III collagen is functional of fibrillogenesis of collagen I and for normal cardiovascular development [72].
The major sources of collagen for fabrication are bovine and porcine species, where collagen was extracted from the hides and skin and also bones of pigs and cows. Bovine hides, a by-product of meat production, are one of the major industrial sources of collagen [49]. The bovine hide is composed of approximately 30% protein, and the inner corium layer of the hide is rich in collagen. This collagen has a high denaturation temperature in comparison to collagen from other sources. Bovine hide is practiced upon in different development stages such as bovine dermis used for tendon regeneration, and skin and wound healing (in the form of collagen matrix); neonatal bovine dermis is used for hernia repair, plastic and reconstructive surgery [73].
Starting from the 1930s, the most significant raw material for large-scale industrial gelatin production is porcine skin [74]. The skin and bones of pigs are utilized as a collagen sources due to some advantages. Since porcine collagen is almost similar to human collagen, it does not cause much allergic response when used in health applications. But just like the bovine source, the zoonotic diseases poses a risk of contamination and pigs are proscribed due to religious reasons [60]. Halal certification of collagen derivatives is considered to be of main importance because of beliefs and it depends on the origin of raw materials used in its manufacture and traceability from the sources until product chain. Muslims and Jew people demand Halal-certified products for their needs, which is not prohibited and obtained by entirely traceable product chains. Nonspecific collagen is highly suspected of containing porcine elements and very strongly discouraged for use by the Muslims [75]. Nonetheless, adult porcine dermis and small intestinal mucosa are used for tendon regeneration, hernia repair, skin and wound healing, and plastic and reconstructive surgery [76].
There are some other sources of gelatin, somehow industrially applicable or not. Throughout the decade, huge numbers of fish species were investigated as alternatives to the source of collagen. Bones, skin, fins and scales of fresh or salt water fishes are mainly used for collagen procurement and gelatin extraction having different chemical composition. This in turn helps to reduce environmental pollution as considerable amount of wastes occurs during fish processing [77]. Collagen studies from marine origin are carried by on marine vertebrates and invertebrates [78, 79]. Marine sources are from some marine species such as fishes, starfish, jellyfish, sponges, sea urchin, octopus, squid, cuttlefish, sea anemone and prawn [80, 81, 82]. Some of the raw material sources of collagen peptides are given in Figure 2.
Main raw material sources of collagen peptides. (A) Bovine split, (B) pig skin, and (C) fish skin.
Collagen peptides can also be produced for research purposes in small quantities from other animal body parts such as eggshells, rat-tail tendons, frog skin, kangaroo tails, chicken and duck feet, sheepskin, poultry animal skin, feet, bones and many more [46, 83, 84].
The collagenic substances, which are involved in multiple collagen units (not subunits) in the quaternary structure and arguably misdefine the tertiary structure also, are normally processable structures. As known very well, leather manufacturing can convert low-value raw materials, which unless untanned and disposed of have detrimental effect to the environment, into valuable final products, and collagen is one of the most substantial structural protein, economically and biologically renewable material for processing. The wastes and by-products of leather processing are discarded parts and effluents from many steps, which are still valuable due to their composition. Lime splits and scraps, as ideal substances, go for gelatin and collagen peptide production.
In the production of industrial-scale collagen peptides, different animal’s skin and bones that are easily available and contains collagen protein in high proportion are being used. Collagen peptide preparation steps are dependent on final products’ properties. For the first step in general practice, acid and alkali extraction methods are used to remove noncollagenous components [85].
Enzymatic and chemical hydrolysis can be used in the extraction of collagen. Being affordable, chemical hydrolysis is the most commonly used method in industrial practices. Enzymatic hydrolysis is fast and produce waste in minimal amounts, but they are more expensive to carry out [86].
Collagen peptides can be produced by sensitive enzymatic reactions according to the desired molecular weights from collagen-rich raw materials by using protease enzymes. Depending on enzyme types and hydrolyzation conditions, final products can further differ with regard to molecular weight distribution [87]. The production processes could be optimized to obtain different peptides with different functionalities. In the structural level, the cleavage of triple helix is emerged and the collagen molecule is partially broken up. Long chains are hydrolyzed to form shorter chains and further hydrolysis leads to short peptides, some of which are bioactive with body-stimulating functions [88].
Chemical methods of collagen hydrolysis are carried out by means of strong acidic and highly alkaline conditions. Acid and alkaline hydrolysis methods are cost-effective and operation is simple. They have short hydrolysis time and are applicable to industrial processes [89]. However, the uses of strong acids or strong alkaline chemicals make the hydrolysis process environmentally unacceptable [90]. During the acidic treatment, the raw material is exposed to acid for a certain period of time. As this process occurs at a controlled temperature, the structure of the skin swells to twice or thrice more than its initial volume. Both organic acids such as acetic and citric acids and inorganic acids such as hydrochloric acid can be used during acid treatment; however, organic acids are more efficient for the purpose. Acidic treatment results unraveled the structural unity and the cleavage of the noncovalent inter- and intramolecular bonds. Materials with less intertwined collagen fibers such as fish and porcine skin are the preferred choice for the acidic process [85]. For the alkaline process, the raw materials are treated in basic solutions for a duration of a few days to weeks. The most commonly used process is through aqueous sodium hydroxide and calcium hydroxide solutions. However, other basic solutions can also be used in this alkaline process. This process entails the treatment of hard or thick substance that needs very aggressive penetration by the basic solutions [91].
To meet the technical needs of the different sectors, purification stage ensures the removal of ionic and nonionic impurities resulting from the processing of raw materials. Different filtration and purification systems can be used at this stage depending on the final product needs [92]. The purified and demineralized gelatin solution consists of over 95% water. This water has to be almost completely removed. Only dried gelatin with its normal residual water content of 10–12% has an unlimited shelf life from the microbiological point of view. In addition, dilute gelatin solutions can neither be stored nor transported easily. In the next production step, the highly concentrated and filtered gelatin solutions are sterilized. For this step, both indirect sterilization via plate heat exchangers and direct steam sterilization are used. Both methods are microbiologically safe to a very high degree [93]. After sterilization, the prepared material needs to be dried to final form. There are different drying methods used in the production of collagen peptides. Spray drying is the most commonly used method and widely used in the production of small molecular weight peptides [94].
Collagen peptides have shown to be an important ingredient in the food and beverage industries worldwide [95]. It has been used for a long time in foods globally, such as in the United States, China, Japan and many countries in Europe. Approved as Generally Recognized As Safe (GRAS), the safety of collagen peptides has been affirmed by the Food and Drug Administration (FDA) and Center for Food Safety and Applied Nutrition (CFSAN) [96]. It has been applied as protein dietary supplements, carriers in the meat processing, edible film and coatings of products and food additive to improve product’s functionality [97]. In addition, collagen may boost the health and nutritional value of the products relying on its inimitable properties on human bodies [75].
The source of the raw material and the degree of processing determine the properties of the collagen peptides like gelatin, which have several different applications in the food industry [98]. The major quality parameters are their higher gel strength and suitable melting and gelling temperatures for the food industry that uses them as an additive. Due to the fact that porcine and bovine gelatins are less preferred due to religious preferences, safety concerns and economic considerations, using fish skin or bones to obtain gelatin has become popular in recent years [99]. Thanks to its many unique properties, the numerous applications of gelatin include its usage as a thickener, stabilizer, setting agent, clarifying agent, water-retaining agent and adhesive in a wide range of foods, pharmaceuticals and household products. In the food industry, gelatin can be utilized in a wide range of confectioneries, beverages, snacks, desserts and meat products [100]. Gelatin is used as an additive to improve elasticity, consistency and stability of foods like desserts, candies, bakery products, jellied meats, ice cream and dairy products. Gelatin is also used as stabilizer to modify the structure of the food products. It is added to yogurt to reduce syneresis and increase firmness [100]. In addition, type A gelatin that is isolated with acid treatment with gel strength as 70–90 g, which is relatively low, is used to fine wines and juices. Type B gelatin is processed with an alkali treatment with gel strength as 125–250 g and is used in confectionery products [101]. Collagen peptides have also been reported to have antioxidant and antimicrobial activity [102]. However, the relationship between peptide characteristics and antimicrobial activity has not been clearly demonstrated.
Collagen can be used in cosmetics due to its biodegradability, availability and biocompatibility properties for different purposes such as in dermal fillers, skin substitutes or scaffolding, wound repairs and facial products [103].
The formation of unwanted wrinkles in the body with aging is related to the damage of the fibers in the skin. In the researches about aging, it has been determined that collagen hydrolysates contribute greatly to the repair of these fibers [104]. The introduction of collagen hydrolysate into the body ensures the stimulation of collagen formation that enables the recovery and improved tissue appearance [105]. Hence, the cosmetic industry reclaims some functionalities of its products by incorporating this biomolecule.
Collagen peptide has been known to be used in cosmetic formulations for reasons such as protecting the structure and the function of the skin, enhancing its appearance and preventing premature aging [106].
Collagen peptide is prepared in the form of liquid ampoules, powder mixes or tablets in the food and cosmetic industries. It has a regenerative effect on skin wrinkles and other signs of skin aging: collagen helps the skin remain soft and pliant and improves the hydration of the epidermis [107]. Many studies have shown that collagen sleek thin lines and can prevent the development of deeper wrinkles and grooves. Collagen is not only effective for the skin on the face but also stimulates the fiber structure of the body to repair and reduce cellulite tissue [108].
Collagen hydrolysates have also shown bioactivities such as antioxidant properties, antihypertensive activity, lipid-lowering activity, as well as reparative properties in damaged skin [109]. Moreover, it has been also observed that collagen provides the building block for elastin and collagen formation and acts as ligands in fibroblast cells to stimulate hyaluronic acid [110].
Collagen is the most abundant and ubiquitous protein in the body regarded as one of the most useful biomaterials. The excellent biocompatibility and safety due to its biological characteristics made collagen the primary resource in medical applications. It has various applications in some departments such as cardiology (heart valve), dermatology (for skin replacement, augmentation of soft tissue, skin tissue engineering and artificial skin dermis), surgery (as hemostatic agent, wound repair and dressing, nerve repair and blood vessel prostheses), orthopedy (tendon, bone and ligament repair and cartilage reconstruction), ophthalmology (corneal grafts and contact lenses), urology (hemodialysis and sphincter repair) and vascular surgery (vascular graft and vessel replacement) [111].
Collagen type I is considered to be the most valuable material for tissue engineering due to its high biocompatibility and immunogenicity. It is used as the basic matrix for cell culture [73, 112]. Biomaterials based on collagen are widely used in tissue engineering such as injectable matrices and scaffolds intended for bone regeneration [73, 113]. Moreover, collagen-based eye implants are preferred for the treatment of ophthalmic disorders. Such type of collagen-based implant preparation has shown considerable applicability because it provides stable and reasonable control over the postoperative complications such as intraocular pressure [114]. Collagen-based matrices find their use as corneal transplant and as temporary patches to repair perforations in case of emergencies [115].
Collagen is used in pharmaceutical industries for different functionalities as hard and soft dry capsules, microparticles, injectable dispersions, shields in ophthalmology sponges and drug delivery system. Its application in the pharmaceutical as well as biomedical field is due to its characteristics such as weak antigenicity, immunogenicity, biodegradability and biocompatibility [116].
As a collagen peptide, gelatin is the most important material for the production of hard and soft capsules as well as film-coated and effervescent tablets. Manufacturers take into account its adhesive, gelling and film-building properties. Orally administered medicines and dietary supplements in particular are protected by gelatin-containing capsules or tablets from light, moisture and oxygen and given a long shelf life [107, 117, 118]. Gelatin is also used as a raw material in many field of health industry as is the case with the manufacture of blood substitute [119]. These products prevent hypovolemic shock by stopping bleeding in the wound-occurred area. As local hemostatic agents, collagen sponges and films have long been used in the surgical field (e.g., in oral cavity and ophthalmological surgery, urology or gynecology) and for the treatment of wounds in dental surgery. The structural composition of the collagen material enables the absorption of large amounts of blood and makes it possible for new tissue to grow into the sponges. Since it only takes a few days for the body to completely resorb the sponges or films, they can be left in the wound without any negative effects [107, 120, 121].
Collagen peptides are ideal supply due to their numerous beneficial health effects for modern sportsperson nutrition as high-energy supplement to maximize muscle protein anabolism [122]. They are neutral in flavor, which means that they do not leave a bitter aftertaste that has to be masked in the final product, that is, through sugar or artificial sweeteners, as is often the case with soy, whey or other protein [107, 123]. Collagen peptides have been scientifically tested and have no undesirable side effects, and there is no evidence to elicit allergic reactions. It emulsifies foams and improves the shelf life of products [107, 124].
The more protein a body expends through physical exertion, the greater its needs for an external source, for example in the form of special dietary supplements such as protein shakes, energy bars, protein snacks or sports drinks. Several studies in the past few decades have reported that protein hydrolysates from various food sources, in addition to their nutritional properties, exhibited various biological functions including hypotensive activity, anticoagulant, cholesterol-lowering ability and hypoglycemic effect [125]. Consumption of hydrolyzed collagen increases collagen synthesis and decreases knee pain while standing and walking [126]. Shaw et al. [127] tested the role of gelatin consumption in collagen synthesis. In the study, double-blinded, placebo-controlled and crossover-designed research, subjected to whom consumed 15 g of gelatin showed double-fold collagen synthesis, measured through serum propeptide levels. From the results, it was observed that consuming hydrolyzed collagen might increase collagen synthesis and potentially decrease injury rate in athletes. Studies have also shown that products fortified with collagen peptide can promote joint health, bone synthesis and antisport fatigue ability [128].
Leather processing wastes like shavings that cause environmental pollution are opulent sources of novel and valuable biomolecule “collagen” [129]. Industry has been generally oriented on the recovery of collagen from leather waste, but the remaining waste also can be used for agricultural purposes. Collagen-based fertilizer products highly are demanded in agriculture industry because of being high amino acid and organic carbon source and nitrogen content [130].
The collagen hydrolysates obtained from leather wastes are being utilized as biofertilizer. Several plants can also take up and absorb amino acids as an example of biostimulants; these amino acids are sometimes better nitrogen sources than ammonia or nitrates [131]. Collagen peptides are recovered and channeled as an organic nitrogenous fertilizer to increase the yield of the crop [132]. Both plants and animal organisms can more easily absorb microelements like iron, copper, zinc, calcium, magnesium and manganese chelated with hydrolyzed collagen. The use of collagen hydrolysates in combination with potassium polyphosphates increases agricultural production by increasing the absorption of phosphorus and potassium [133].
Collagen hydrolysates obtained by chemical and chemical-enzymatic processes under moderate reaction conditions were used in a study for preparation of foliar fertilizers [134]. Hydrolysates of chromium-tanned leather shavings were used in a study as nitrogen source for growth of common bean plants and banana cultivation [135]. De Oliveira et al. [136] have studied the use of leather wastes after extraction as a nitrogen source to elephant grass. The chrome shaving wastes can also be hydrolyzed in an autoclave (150°C). The obtained product contains moisture content (7–10%), total nitrogen (10–11%), organic carbon (40%) and chromium (III) (2.5–3%). By blending with other additive components, the product can be sold as a fertilizer [133].
Both gelatin and collagen hydrolysates have positive effect on the growth of plants when applied as fertilizer. The crop yield is comparable with those obtained by using inorganic fertilizers but with a significantly high value in view of the low nitrate content, which is 20 times less. Besides, organic fertilizer improves the soil quality unlike the inorganic ones [137].
Collagen peptide due to its organic compounds such as fats, proteins and minerals plays an important role in the preparation of highly valuable animal feed [84]. Fat, protein and mineral products are in especially high demand in the animal feed industry because pure fats are excellent sources of energy and collagen is of importance for the healthy growth of animals [138].
As a collagen peptide, which is recovered from leather solid wastes, gelatin is primarily added to animal feed based on its hydrophilic properties. Its jelly-like consistency holds feed together, making it transportable and extends its shelf life [107, 139]. When animal feed is enriched with vitamins, the gelatin coatings also protect these from light and oxygen. A positive side effect of adding gelatin to feed ensures that the fur of animal remains wonderfully glossy [107, 140].
There are also many fields for collagen peptides and gelatin usage. They can be used for photography and X-ray films and inkjet applications [141], industrial paper production [93], leather board [142], glue manufacture [143], feedstock for biodiesel production [144], leather tanning and retanning agent [145] and many more specific applications, etc.
The tanning industry is one of the oldest industries in the world and recently its pollution load onto environment has become seriously threatening for transferring the potential to next generations. It produces a significant amount of solid wastes and effluents. It is a well-known fact that removing undesired substances out of the structure in leather processing produces effluents; that is highlighted agenda which needs to be overcome and as per the composition those are able to handle for recover and reuse through the current technology.
Revaluation of leather solid wastes is one of the promising waste management strategies that provides raw materials to another industry such as food, agriculture, cosmetic, health, etc. This method may offer a solution for utilization of huge volume of leather solid wastes, which are often dumped in open landfills. Commercial benefits of the system should be linked with both the value of the products and the disposal cost of solid wastes. In the economical point of view, feasibility should be based on converting them into value-added products instead of making a deposit for disposal.
Collagen peptides obtained from hides and their by-products have been practiced as healthful stuffs in many areas of our modern life. As the awareness of their technological value increases as time passes, this value-added material is considered to have higher interest with the usage in various fields. Analogous to collagen peptides, collagen hydrolysates and gelatins, emerged from this precious protein are involved in either partly or total denaturation. It is the process defined by disintegration of intra- and intermolecular bonds that keeps together the chains composed of amino acids in the conformation; thereby, a typical protein is formed. The discovery of benefits of collagen derivatives for health and their usage as additives has a long history and is dated back to some 8000 years ago. Today, its usage enlarges over many industries and applications includes in food, health, chemical, body care and agricultural etc. According to the molecular weight and properties, the usage of collagen derivatives increases as a gel or colloidal solution, their benefits are multiplied and this bio-based material supplies many valorization possibilities. As per the source and properties, they are bioavailable products that are digested and absorbed by human and animal body quickly and even by plants and are also easy to use in any industrial applications and processes.
In spite of the tremendous development in technology and sciences, there are still challenges ahead to better understand the collagen types and sources, structure and properties, gelatin processes and product characteristics. It seems that in the future the researches on bio-based materials as well as the efforts for their commercialization will continue intensively in a wider range of products.
The authors declare that they have no conflict of interest.
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She performed research in perioperative autotransfusion and obtained the degree of PhD in 1993 publishing Peri-operative autotransfusion by means of a blood cell separator.\nBlood transfusion had her special interest being the president of the Haemovigilance Chamber TRIP and performing several tasks in local and national blood bank and anticoagulant-blood transfusion guidelines committees. Currently, she is working as an associate professor and up till recently was the dean at the Albert Schweitzer Hospital Dordrecht. She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n12-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n13-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n14- Abdel Karim M. El Hemaly. 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