The incidence of chronic kidney disease (CKD) is increasing worldwide and is becoming a major concern for the healthcare. Approximately 1.8 million people, worldwide, are currently treated with renal replacement therapy (RRT), which consists primarily of kidney transplantation, hemodialysis, and peritoneal dialysis. More than 90% of these individuals live in industrialized nations, while availability of RRT is scarce in developing countries. It is estimated that more than 150 per million develop end-stage renal disease (ESRD) per year in India. The vast majority of these patients cannot afford renal replacement therapy on reaching ESRD and hence ESRD is equivalent to death in them. Primary prevention programs are very few compared to the burden of CKD, hence it is imperative to retard progression of CKD.
Regardless of the underlying cause, CKD is characterized by relentless progression, which is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. This article discusses the mechanisms of progression, viz, hemodynamic factors, role of proteinuria, systemic hypertension and the role of various cytokines and growth factors with special emphasis on renin angiotension system and the evidence based interventions to retard it.
Unlocking Diabetic Nephropathy (DN) through its key pathological mechanisms - Oxidative Stress and Fibrosis
https://coboscientific.com/biomarkers/diabetic-nephropathy/
Shifting Paradigms: Examining Pro-Thrombotic Activity from a Safety PerspectiveCorDynamics
This research marks the evolution of anti-thrombosis discovery investigations into pro-thrombotic safety models. Clearly, pro-thrombotic activity is an undesirable property for drugs outside the cardiovascular arena. The ability to create a pro-thrombotic window provides safety intel on lead candidates.
VHIR Seminar led by Daniel De Backer, PhD., from the Dpt of Intensive Care Erasme University Hospital Brussels - Belgium.
Abstract: Multiple studies have shown that alterations in microcirculatory perfusion are frequently observed in patients with septic shock. These alterations are characterized by heterogeneity of perfusion with capillaries with stop flow in close vicinity to well perfused capillaries. What are the consequences of these alterations? The presence of stop flow capillaries favours development of zones of tissue hypoxia, even though total perfusion to the organ is preserved. In addition, the heterogeneity in perfusion is associated with inadequate matching of flow to metabolism and is hence less well tolerated by tissues than an homogeneous decrease in perfusion. In patients with septic shock, the severity of the microvascular alterations was associated with development of organ dysfunction and an increase risk of death.
Different mechanisms have been implicated in the development of these alterations including loss of communication between vascular segments, impaired endothelial reactivity, alterations in red and white blood cells rheology, alteration in endothelial glycocalyx, platelet aggregation and microthrombosis. In view of the various mechanisms implicated in the development of these alterations, it is unlikely that therapies used in usual hemodynamic resuscitation. Novel therapies should aim at improving the matching of perfusion to metabolism rather than further increasing flow in the already perfused vessels or non selectively dilating microvessels.
Role of Plasma Exchange in ABO-incompatible Kidney TransplantationApollo Hospitals
In the past, ABO incompatibility was an absolute contraindication for solid organ transplantation. However,
multiple recent trials have suggested strategies for overcoming the reactions between graft antigens and recipient antibodies that cause graft rejection.
HPV Vaccine: A Breakthrough In Prevention of Cervical CancerApollo Hospitals
Cervical cancer is one of the commonest cancers in women. As it affects young women it has grave
personal, social and economic consequences. It is unfortunate that despite cancer cervix being a preventable
disease, we have failed to reduce the number of deaths related to it. Recent developments in the understanding of the disease process and its link to the oncogenic strains of Human Papilloma Virus (HPV) has opened new avenues in
the way of prevention of cervical cancer.
Unlocking Diabetic Nephropathy (DN) through its key pathological mechanisms - Oxidative Stress and Fibrosis
https://coboscientific.com/biomarkers/diabetic-nephropathy/
Shifting Paradigms: Examining Pro-Thrombotic Activity from a Safety PerspectiveCorDynamics
This research marks the evolution of anti-thrombosis discovery investigations into pro-thrombotic safety models. Clearly, pro-thrombotic activity is an undesirable property for drugs outside the cardiovascular arena. The ability to create a pro-thrombotic window provides safety intel on lead candidates.
VHIR Seminar led by Daniel De Backer, PhD., from the Dpt of Intensive Care Erasme University Hospital Brussels - Belgium.
Abstract: Multiple studies have shown that alterations in microcirculatory perfusion are frequently observed in patients with septic shock. These alterations are characterized by heterogeneity of perfusion with capillaries with stop flow in close vicinity to well perfused capillaries. What are the consequences of these alterations? The presence of stop flow capillaries favours development of zones of tissue hypoxia, even though total perfusion to the organ is preserved. In addition, the heterogeneity in perfusion is associated with inadequate matching of flow to metabolism and is hence less well tolerated by tissues than an homogeneous decrease in perfusion. In patients with septic shock, the severity of the microvascular alterations was associated with development of organ dysfunction and an increase risk of death.
Different mechanisms have been implicated in the development of these alterations including loss of communication between vascular segments, impaired endothelial reactivity, alterations in red and white blood cells rheology, alteration in endothelial glycocalyx, platelet aggregation and microthrombosis. In view of the various mechanisms implicated in the development of these alterations, it is unlikely that therapies used in usual hemodynamic resuscitation. Novel therapies should aim at improving the matching of perfusion to metabolism rather than further increasing flow in the already perfused vessels or non selectively dilating microvessels.
Role of Plasma Exchange in ABO-incompatible Kidney TransplantationApollo Hospitals
In the past, ABO incompatibility was an absolute contraindication for solid organ transplantation. However,
multiple recent trials have suggested strategies for overcoming the reactions between graft antigens and recipient antibodies that cause graft rejection.
HPV Vaccine: A Breakthrough In Prevention of Cervical CancerApollo Hospitals
Cervical cancer is one of the commonest cancers in women. As it affects young women it has grave
personal, social and economic consequences. It is unfortunate that despite cancer cervix being a preventable
disease, we have failed to reduce the number of deaths related to it. Recent developments in the understanding of the disease process and its link to the oncogenic strains of Human Papilloma Virus (HPV) has opened new avenues in
the way of prevention of cervical cancer.
An update on the treatment of glomerulonephritisaApollo Hospitals
Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of these entities are responsive to immunosuppressive agents and other therapies. There have been recent advances in the treatment options, notably the benefit shown with the use of rituximab in some forms of GN. Moreover, the KDIGO guideline on the management of glomerulonephritis has recently been published which has consolidated the available evidence on the management of this heterogeneous group of disorders. Though there are significant risks and side-effects involved, the treatment of some of the forms of GN can be very gratifying while others progress relentlessly to ESRD. This review summarizes some of the key recommendations from the KDIGO guideline along with a brief discussion of the supporting evidence.
Role Of Integrated Pet-Ct In Cancer of Unknown PrimaryApollo Hospitals
Whilst earlier Whole body CT played an important role in detecting the primary site presently, Integrated Positron emission tomography (PET) and computed tomography (CT) can play an important role in patients with unknown primary as it combines the advantage of cross sectional imaging with the diagnostic advantages of PET.
Painless Mammography-A Causal Analysis based on Patients's Feed-backApollo Hospitals
In India here is no official screening program. All screening is opportunistic, self- initiated
and self-funded. Women in the higher socioeconomic group utilise private or corporate
Health-care providers. In this milieu patients do defer or delay coming for screening
mammography, more so if their prior experience has been painful.
Advanced mammographic systems (Full Field Digital with Tomosynthesis) come with a cost to the Health-Care provider and there is a need to justify of the same, if women have to participate in screening mammograms for early detection of breast cancer.
Megaprosthetic replacement of knee in a young boy of 14 yearsApollo Hospitals
Now a days, Total Knee Replacement (TKR) is a common for elderly patients but is an uncommon procedure in young individuals. Recently, limb conservation surgery for malignant bone tumours like osteosarcoma around the knee has become a common indication for TKR in young. We report, here a histologically confirmed osteosarcoma in right
proximal tibia of a 14-year-old boy who was managed successfully by limb salvage surgery using Global Modular Replacement System (GMRS, Stryker).
Diabetic ketoacidosis induced cerebral infarct - A missing link in pathogenes...Apollo Hospitals
Diabetic ketoacidosis (DKA) is a known complication of acute pancreatitis (AP). We report a case of DKA precipitated by AP. This patient developed watershed infarct in brain during her course of disease which was possibly attributed to hypercoagulability, stasis and endothelial injury triggered by ketosis.
Progression of Chronic Kidney Disease: Mechanisms and Interventions in Retard...Apollo Hospitals
The incidence ofchronickidneydisease (CKD) is increasingworldwideandisbecoming a major concern for the healthcare. Approximately 1.8 million people, worldwide, are currently treated with renal replacement therapy (RRT), which consists primarily of kidney transplantation,
hemodialysis, and peritoneal dialysis.
End-stage renal disease (ESRD) can result from a wide variety of different kidney diseases. Currently, 90% of patients reaching CKD have chronic diabetes mellitus, glomerulonephritis or hypertension. With CKD comes a myriad of problems related to the kidney's inability to excrete waste products leads to symptoms of uraemia. The treatments of CKD require dialysis or kidney transplantation. In this review, an attempt has been made to explain the nutritional management of CKD along with various dialysis treatment and the complications related to the dialysis method. It is important to maintain optimal nutritional status so that the patient will be a good candidate to respond to the treatment effectively.Kidney Patients necessitate following a blanced diet plan to retain normal protein stores and to avoid metabolic complications. This article deals with the therapeutic aspects of nutrition in CKD patients and will improve the quality of life Keywords: ESRD, CKD, Dialysis, Nutritional management.
Comparative Study of Hscrp in Chronic Kidney Diseaseiosrphr_editor
Chronic kidney disease (CKD) is a global threat to health mainly in developing countries because therapy is expensive and lifelong. over 1 million people worldwide are on dialysis or with a functioning graft. Early detection of Chronic kidney disease (CKD) and its consequent complications can prevent its grave complications . It causes not only significant morbidity but also it causes high mortality. Because of increase in incidence of Diabetes mellitus, hypertension, obesity and an aging population there is increase in progression of chronic kidney disease to end stage renal disease (ESRD). . Cardiovascular disease (CVD) is the major cause of mortality in haemodialysis patients and so it has become imperative to have a screening programme at all levels to detect CKD at an early stage and to initiate specific therapy to reduce the progression of renal disease and also the burden of ESRD (1). High sensitive C-Reactive protein (Hs CRP) assay is useful for sensitive detection of inflammatory state (2,3). This study aims at estimating Hs CRP as a marker of inflammation in CKD patients...
Malignant Mixed Mullerian Tumor – Case Reports and Review ArticleApollo Hospitals
Malignant mixed mullerian tumors are very rare genital tumors. They are biphasic neoplasms composed of an admixture of malignant epithelial and mesenchymal elements. In descending order of frequency they originate in the uterus, ovaries, fallopian tubes, cervix and vagina. Also they arise denovo from peritoneum. They are highly aggressive and tend to occur in postmenopausal low parity women. Because of rarity, there is as such no treatment guidelines available. Multimodality treatment in the form of radical surgery followed by adjuvant chemotherapy or radiotherapy or combined chemoradiation gives a better prognosis & outcome. Two case reports of such tumors, one from ovary and other from penitoneum are presented along with the review of literature.
Intra-Fetal Laser Ablation of Umbilical Vessels in Acardiac Twin with Success...Apollo Hospitals
To interrupt blood supply to the acardiac twin in a case of TRAP sequence of monochorionic diamniotic multiple pregnancy to allow for continuation of the normal twin.
Breast Cancer in Young Women and its Impact on Reproductive FunctionApollo Hospitals
Breast cancer is the most common cancer in women in developed countries. Chemotherapy for breast cancer is likely to negatively impact on reproductive function. We review current treatment; effects on reproductive function; breastfeeding and management of menopausal symptoms following breast cancer.
Turner syndrome (gonadal dysgenesis) is one of the most common chromosomal abnormalities occuring 1 in 2500 to 1 in 3000 live-born girls. It is an important cause of short stature in girls and primary amenorrhea in young women that is usually caused by loss of part or all of an X chromosome. This review briefly summarises the current knowledge about the syndrome and the management strategies.
Due to pregnancy thyroid economy is affected with changes in iodine metabolism, TBG and development of maternal goiter. The incidence of hypothyroidism in pregnancy is quite common with autoimmune hypothyroidism being the most important cause. Overt as well as subclinical hypothyroidism has a varied impact on maternal and neonatal outcome. After multiple studies also, routine screening in pregnancy for hypothyroidism can still not be recommended. Management mainly comprises of dosage adjustments as soon as pregnancy is diagnosed based on results of thyroid function tests. The aim should be to keep FT4 at the upper end of normal range.
Growth Hormone Deficiency (GHD) can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. Growth harmone (GH) therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks of GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.
Advances in the management of thalassemia have led to marked improvements in the life span and quality of life of children and young adults. This poses new challenges for the treating physicians. There is now increasing recognition that thalassemics have impaired bone health which is multifactorial in etiology. This paper aims to highlight the factors that predispose these patients to osteoporosis and suggests measures to minimise the impact on bone health.
Laparoscopic Excision of Foregut Duplication Cyst of StomachApollo Hospitals
Retroperitoneal gastric duplication cysts lined by ciliated columnar epithelium are extremely rare lesions and its presentation during adulthood is a diagnostic challenge for treating clinicians. This entity often resembles cystic pancreatic neoplasm, retroperitoneal cystic lesions and sometimes as an adrenal cystic neoplasm. Correct diagnosis on the basis of radiological investigation is difficult and histopathologic analysis. We report a case of gastric duplication cyst in a 16year old girl that mimicked as a retroperitoneal /pancreatic /adrenal cystic lesion and was successfully managed by laparoscopy.
Occupational Blood Borne Infections: Prevention is Better than CureApollo Hospitals
Viral infections like HIV, hepatitis Band C virus pose a big risk to the contacts of individuals with high risk behaviour as well as to the attending health care workers. Blood, semen, vaginal and other potentially infectious materials can transmit the infection to the susceptible contacts. Universal precautions should be strictly implemented during clinical examination, laboratory work and surgical procedures to prevent transmission to the health care providers. Health care workers should receive vaccination for hepatitis B infection. An inadvertent exposure should be managed with proper first aid and infectivity of the source and severity of exposure should be assessed. Severity of exposure is based on the nature and area of exposed surface, mode of injury and volume of infective material. Post-exposure prophylaxis (PEP) should be started as soon as possible after a proper counseling about the effectiveness of post-exposure prophylaxis, side effects and risk of carrying the infection to his familial contacts and its prevention.
Evaluation of Red Cell Hemolysis in Packed Red Cells During Processing and St...Apollo Hospitals
Storage of red cells causes a progressive increase in hemolysis. Inspite of the use of additive solutions for storage and filters for leucoreduction some amount of hemolysis is still inevitable. The extent of hemolysis however should not exceed the permissible threshold for hemolysis even on the 42nd day of storage.
Efficacy and safety of dexamethasone cyclophosphamide pulse therapy in the tr...Apollo Hospitals
Various drugs used to treat pemphigus can cause remission, but none can provide permanent remission as relapses are common. With the introduction of DCP in pemphigus in 1984, patients started being in prolonged/permanent remission. This study was done to compare the efficacy of DCP to oral corticosteroids and cyclophosphamide in combination.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)Apollo Hospitals
Severe skin adverse drug reactions can result in death. Toxic epidermal necrolysis (TEN) has the highest mortality (30–35%); Stevens-Johnson syndrome and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (5–15%). Hypersensitivity syndrome, sometimes called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), has a mortality rate evaluated at about 10%. It is characterised by fever, rash and internal organ involvement. Prompt diagnosis is vital, along with identification and early withdrawal of suspect medicines and avoidance of re-exposure to the responsible agent is essential. Cross-reactivity to structurally-related syndrome caused by Carbamazepine medicines is common, thus first-degree relatives may be predisposed to developing this syndrome. We report a case of DRESS secondary to use of Carbamazepine.
Difficult Laparoscopic Cholecystectomy-When and Where is the Need to Convert?Apollo Hospitals
Laparoscopic cholecystectomy has now become the treatment of choice for the gall bladder stone. With increasing experience, surgeon has started to take more difficult cases which were considered relative contra indications for laparoscopic removal of gall bladder few years back.
We conducted this study at our hospital and included all laparoscopic cholecystectomy done from May'08 to January'10. Total time taken in surgery, conversion rate and complication rate were analysed. Factors making laparoscopic cholecystectomy difficult were also analysed. We defined difficult laparoscopic cholecystectomy when we found -dense fibrotic adhesions in and around Callot's triangle, gangrenous gall bladder, empyma, large stone impacted at gall bladder neck, contracted gall bladder, Mirrizi's syndrome, h/o biliary pancreatitis, CBD stones, acute cholecystitis of <72 hrs duration.
Out of 206 cases done during above period, 56 cases were considered difficult. Only two cases were converted to open.
With growing experience and technical advancement surgery can be completed in most of the difficult cases. This is important because recently it is shown in literature that laparoscopic cholecystectomy is associated with less morbidity than open method irrespective of duration of the surgery.
Deep vein thrombosis prophylaxis in a tertiary care center: An observational ...Apollo Hospitals
Deep vein thrombosis (DVT) is a major health problem with substantial mortality and morbidity in medically ill patients. Prevention of DVT by risk factor stratification and subsequent antithrombotic prophylaxis in moderate- to severe-risk category patients is the most rational means of reducing morbidity and mortality.
The spread of dengue and dengue haemorrhagic fever is increasing, atypical manifestations are also on the rise, although they may be under reported because of lack of awareness. We report two such cases of dengue hemorrhagic fever with hepatitis, intraocular hemorrhage, ARDS and myocarditis.
A 71-year-old male presented in ENT department with dysphagia for last three weeks, more to solids than liquids. He had a hard bony bulge in the posterior pharyngeal wall on palpation and hence was referred for an Orthopaedic opinion. Lateral radiograph of the cervical spine revealed diffuse ossification of the anterior longitudinal ligament. This ossification was extending almost half the width of the cervical body from its anterior body at C1 and C2 vertebra level.
Pediatric Liver Transplant (LT) is now an established procedure for End Stage Liver Disease (ESLD) with biliary atresia being the commonest indication. Intensive pre-transplant evaluation, nutritional buildup and immunization are the fundamental pre-requisites of a successful LT. With improvement in surgical micro-anastomotic techniques and superior immunosuppressive regimens the success rate of pediatric LT is in excess of 90%. Most of the transplants in our country however are Living related, due to which a fairly large number of children expire awaiting a donor liver. There should be a concerted effort to evolve the cadaveric donation program, so that majority of the children are benefitted.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
2. Review Article
Progression of chronic kidney disease: Mechanisms
and interventions in retardation
S. Balasubramanian*
Department of Nephrology, Apollo Hospitals, Chennai 600006, India
a r t i c l e i n f o
Article history:
Received 6 January 2013
Accepted 15 January 2013
Available online 1 February 2013
Keywords:
Chronic kidney disease (CKD)
Retardation
Renin angiotensin aldosterone
blockade (RASB)
a b s t r a c t
Theincidenceofchronickidneydisease(CKD)isincreasingworldwideandisbecomingamajor
concern for the healthcare. Approximately 1.8 million people, worldwide, are currently treated
with renal replacement therapy (RRT), which consists primarily of kidney transplantation,
hemodialysis, and peritoneal dialysis.1,2
More than 90% of these individuals live in indus-
trialized nations, while availability of RRT is scarce in developing countries. It is estimated that
more than 150 per million develop end-stage renal disease (ESRD) per year in India.3,4
The vast
majority of these patients cannot afford renal replacement therapy on reaching ESRD and
hence ESRD is equivalent to death in them.3,5
Primary prevention programs are very few
compared to the burden of CKD,6,7
hence it is imperative to retard progression of CKD.
Regardless of the underlying cause, CKD is characterized by relentless progression, which is
postulatedto result from a self-perpetuatingvicious cycle of fibrosis activated afterinitial injury.
This article discusses the mechanisms of progression, viz, hemodynamic factors, role of pro-
teinuria,systemichypertensionandtheroleofvariouscytokinesandgrowthfactorswithspecial
emphasis on renin angiotension system and the evidence based interventions to retard it.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Mechanisms of progression of CKD
1.1. Long-term adverse consequences of (Mal)
adaptations to nephron loss
Nephron loss causes various functional and structural adapta-
tions, which are regarded as a beneficial response that mini-
mizes the resultant loss of total GFR. They ultimately produce
complex series of adverse effects that eventually leads to pro-
gressiverenalinjuryandaninexorabledeclineinrenalfunction.
In the 5/6 nephrectomy model that has been extensively
studied,the rats subjected to partial nephrectomy subse-
quently develop hypertension, albuminuria, and progressive
renal failure. Histopathological studies in rat remnant kidneys
after 5/6 nephrectomy revealed progressive mesangial accu-
mulation of hyaline material encroaching the capillary
lumina, obliterating Bowman’s space and finally causing
global sclerosis of the glomerulus. Similar finding of sclerosed
glomeruli in human CKD of diverse etiologies, led to the hy-
pothesis that glomerular hyperfiltration ultimately results in
damage to remaining glomeruli and contributes to a vicious
cycle of progressive nephron loss.8
1.2. Role of hemodynamic factors
Various animal models of CKD including the 5/6 nephrectomy
and diabetic nephropathy showed that renal mass ablation
produced glomerular hyperfiltration and glomerular capillary
* Tel.: þ91 9840534220.
E-mail address: nephbala@yahoo.com.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.01.009
3. hypertension. Brenner and colleagues proposed that the he-
modynamic adaptations following renal mass ablation initi-
ates various processes of glomerular injury that eventually
leads to glomerulosclerosis. This further would induce
hyperfiltration in remaining, less affected glomeruli, which
causes a vicious cycle of progressive nephron loss. This is
regarded as a common pathway for irreversible progression of
CKD, regardless of the cause of the initial renal injury9
Various
interventions in experimental animals like low protein diet,
transplantation with isogeneic kidney prevented the hemo-
dynamic changes, effectively reversed glomerular hyperten-
sion and hyperfiltration and minimize the structural lesions.9
Direct evidence for the importance of renal mass in
humans is further shown by an observational study of 749
patients who underwent either radical nephrectomy or
nephron-sparing surgery for removal of a renal mass. Those
who had nephron-sparing surgery evidenced a significantly
lower incidence of reduced GFR (16.0% vs. 44.7%) and pro-
teinuria (13.2% vs. 22.2%).10
The importance of glomerular hemodynamic factors in the
development of progressive renal injury was further demon-
strated by various experimental and clinical studies that
reported dramatic protective effects with RAAS blockade. with
either ACEI or AT1RA treatment.11e15
1.2.1. Effect of mechanical stress on various glomerular cells
Experiments in isolated perfused rat glomeruli showed that
increased perfusion pressures cause increases in wall tension
and glomerular volume which result in stretching of glomerular
cells.16
The cellular responses to mechanical stress leading to
glomerulosclerosis through various complex pathways causing
proinflammatory and profibrotic state have been studied.17
1.2.1.1. Endothelial cells. The vascular endothelium acts as
a dynamic barrier to leukocytes and plasma proteins, and se-
cretes various vasoactive factors (prostacyclin, nitric oxide,
and endothelin). They bear receptors which detect changes in
mechanical stress that result from glomerular hyperperfusion.
This may stimulate expression of genes involved in production
of proinflammatory cytokines18
cell cycle control, apoptosis,
thrombosis, oxidative stress conversion of angiotensin I to
angiotensin II, and expression of cell adhesion molecules19
After 5/6 nephrectomy, endothelial cells are activated or
injured, resulting in detachment and exposure of the basement
membrane which may induce platelet aggregation, deposition
of fibrin and intracapillary microthrombus formation.8
1.2.1.2. Mesangial cells. Various in vitro studies indicate that
subjecting mesangial cells to cyclical stretch or strain has
been shown to induce proliferation and synthesis of extrac-
ellular matrix constituents,21
and also activates the tran-
scription factor, nuclear factor k light-chain enhancer of
activated B cells (NF-kB),20
stimulates synthesis of inter-
cellular adhesion molecule-1 (ICAM-1), transforming growth
factor-b (TGF-b)22
connective tissue growth factor (CTGF) and
also activates the RAAS in cultured mesangial cells,23
and
angiotensin II, in turn, may induce TGF-b synthesis.
1.2.1.3. Podocytes. It is increasingly evident that podocyte
injury in a variety of renal diseases, causes CKD progression.24
In 5/6 nephrectomized rats the number of podocytes corre-
lated with the severity of proteinuria, as well as mean arterial
blood pressure, suggesting that podocyte loss may contribute
to CKD progression25
Detailed in vitro studies have shown
cyclical stretching of podocytes was associated with dis-
ruption of contractile apparatus, increased production of
angiotensin II and TGF-b as well as upregulation of angio-
tensin II type 1 (AT1) receptors resulting in increased angio-
tensin II-dependent apoptosis26
and also resulted in a 50%
reduction of nephrin (a key component of the slit diaphragm).
1.3. Role of nonhemodynamic factors
Many nonhemodynamic factors have been identified in recent
studies, which contribute to progressive glomerulosclerosis
and these may offer new therapeutic targets for future reno-
protective interventions.
1.3.1. Transforming growth factor-b
TGF-b is associated with chronic fibrotic states throughout the
body by overproduction of extracellular matrix, including
CKD.27
Its expression is increased in several experimental
models including 5/6 nephrectomized rat model, diabetic ne-
phropathy, anti-Thy-1 glomerulonephritis28
as well as in
human glomerulonephritis,29,30
HIV nephropathy,31
and dia-
betic nephropathy.32
Treatment with an ACE Inhibitor or an AT1R antagonist
resulted in substantial renal protection and prevented upre-
gulation of TGF-b and correlated closely with the extent of
glomerulosclerosis.
1.3.2. Angiotensin II
Angiotensin II is an important factor which plays a key role
in the glomerular hemodynamic adaptations observed after
renal mass ablation. Angiotensin II subtype 1 receptors are,
distributed on many cell types within the kidney including
mesangial, glomerular epithelial, endothelial, tubule epi-
thelial, and vascular smooth muscle cells suggesting multi-
ple potential actions of angiotensin II within the kidney.33
Experimental studies revealed several nonhemodynamic
effects of angiotensin II that may be important in CKD pro-
gression (Fig. 2). In isolated, perfused kidneys, infusion of
angiotensin II results in loss of glomerular size permse-
lectivity and proteinuria, an effect that has been attributed
to both hemodynamic effects of angiotensin II resulting in
elevations in glomerular hydraulic pressure, and a direct
effect of angiotensin II on glomerular permselectivity.34
and
podocyte injury.35
In vitro, angiotensin II has been shown to
stimulate mesangial cell proliferation and induce expression
of TGF-b, resulting in increased synthesis of extracellular
matrix (ECM). Angiotensin II also stimulates production of
PAI-1 by endothelial cells and vascular smooth muscle
cells36,37
and may therefore further increase accumulation
of ECM through inhibition of ECM breakdown by matrix
metalloproteinases. Other reports indicate that angiotensin
II may directly induce the transcription of a variety of cell
adhesion molecules and cytokines, activate the transcrip-
tion factor, NF-kB38
and directly stimulate monocyte acti-
vation. which causes interstitial inflammatory cell
infiltration.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 820
4. 1.3.3. Aldosterone
Mechanisms whereby aldosterone may contribute to renal
damage include hemodynamic effects; mesangial cell prolif-
eration, apoptosis, hypertrophy, and podocyte injury and
apoptosis associated with reduced expression of nephrin and
podocin resulting in proteinuria; and increased renal pro-
duction of reactive oxygen species, TGF-b, and CTGF. Exper-
imental use of, spironolactone alone or in combination with
AT1RA various studies found significant amelioration of glo-
merulosclerosis in various experimental animals.
1.3.4. Endothelins
Endothelins are potent vasoconstrictor peptides that act via
atleast two receptor subtypes, ETA and ETB. Renal production
of endothelins is increased after 5/6 nephrectomy which in
various animal models, showed greater increases in efferent
than afferent arteriolar resistance resulting in an increase in
glomerular hydraulic pressure. The ultrafiltration coefficient
(Kf) was significantly reduced and thus SNGFR was unchanged
or was decreased.
1.3.5. Atrial natriuretic peptide (ANP) and other structurally
related NP
They mediate tubular sodium excretion in 5/6 nephrectom-
ized rats and also cause increase in whole-kidney and single-
nephron GFR by approximately 20%, by a rise in glomerular
hydraulic pressure resulting from significant afferent arte-
riolar dilatation and efferent arteriolar constriction.
1.3.6. Eicosanoids
Different Eicosanoids exert opposite effects on the renal he-
modynamics, but glomerular hyperfiltration associated with
renal mass ablation seems to be effect of vasodilators out-
weighing the vasoconstrictors.
1.3.7. Oxidative stress
CKD is associated with increased oxidative stress that likely
contributes to the progression of renal damage and the patho-
genesis ofthe associated cardiovasculardisease.39
Following 5/6
nephrectomy significant upregulation of NADPH (enzyme for
production) and downregulation of Super oxide dismutase
Fig. 1 e Common pathway for hemodynamic and nonhemodynamic factors medicated progression of chronic kidney
disease.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 21
5. (enzyme for removal) were observed in the liver and kidneys
resulting in increase in superoxide.40
Adverse consequences of
oxidative stress that may contribute to CKD progression include
hypertension (caused by inactivation of nitric oxide and oxida-
tion of arachidonic acid to generate vasoconstrictive iso-
prostanes),43
inflammation (caused by activation of NF-kB),41
fibrosis and apoptosis,42
and glomerular filtration barrier dam-
age.44
Inflammation may in turn increase oxidative stress
because of ROS generation by activated leukocytes, thus estab-
lishing a vicious cycle of oxidative stress and inflammation.
1.3.8. Acidosis
Acidosis is present in most patients when GFR falls below
20%e25% of normal. Acidosis may contribute to renal damage
after nephron loss include activation of the alternative com-
plement pathway by increased ammoniagenesis and induc-
tion of endothelin and aldosterone production.
1.3.9. Anti fibrotic factors
1.3.9.1. Hepatocyte growth factor. Several studies have
investigated the role of HGF as a potential antifibrotic factor in
CKD which offers renoprotection. HGF is upregulated in the
remaining kidney after uninephrectomy and may contribute
to renoprotection by amelioration of podocyte injury, apop-
tosis, and proteinuria; decreased ECM accumulation in asso-
ciation with increased expression of matrix metalloproteinase
9 (MMP-9) and suppression of TGF-b
1.3.9.2. Bone morphogenetic protein-7. Bone morphogenetic
protein-7 (Bmp7), also termed osteogenic protein-1, is a bone
morphogen involved in embryonic development and tissue
repair. Preliminary evidence suggests that Bmp7 may also
play a role in renal repair by inhibition of proinflammatory
cytokines, antagonizing fibrogenic effects of TGF-b in
mesangial cells.
1.3.9.3. PPAR-g (peroxisome proliferator activator receptor).
PPAR-g modifies numerous cytokines and growth factors,
including PAI-1 and TGF-b. PPAR-g is a transcription factor
and a member of the steroid superfamily.45
On activation,
PPAR-g binds the retinoic acid X receptor, translocates to the
nucleus and binds to peroxisome proliferator activator
Fig. 2 e Mutiple actions of angiotensin II and its role in progression of CKD.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 822
6. response elements (PPREs) in selected target genes, reducing
their expression. PPAR agonists, like thiazolidinediones, have
been shown to have anti fibrotic effect in some experimental
studies in CKD.
1.4. Role of proteinuria
Proteinuria, which has been considered as a marker of glo-
merular injury, has also been implicated as an important
factor involved in renal disease progression, especially caus-
ing tubulointerstitial fibrosis. Proteinuria is the result of
altered permselectivity of the glomerular filtration barrier,
caused by hemodynamic and nonhemodynamic factors.
Sieving studies using dextrans and other macromolecules in
rats 7 or 14 days after 5/6 nephrectomy revealed loss of both
size and charge-selectivity of the glomerular filtration barrier.
This is believed to be the result of detachment of glomerular
endothelial cells and visceral epithelial cells from the glo-
merular basement membrane and appearance of protein
reabsorption droplets seen as blebs in podocytes, observed on
ultrastructural examination.46
Recent studies identified decreased nephrin expression in
podocytes as a further mechanism contributing to protein-
uria after 5/6 nephrectomy.47
Direct role for angiotensin II in
modulating glomerular capillary permselectivity is thought
to be mediated through its nonhemodynamic effect on the
cellular components of the glomerular filtration barrier,
resulting in the opening interendothelial junctions and epi-
thelial cell disruption and through its hemodynamic effect,
principally a reduction in renal perfusion and an increase in
filtration fraction. Furthermore, angiotensin II and aldoster-
one have been shown to reduce nephrin expression in
podocytes and may therefore directly affect glomerular
permselectivity.47
A causative association between excessive proteinuria and
glomerular and interstitial inflammation was suggested by
various in vitro studies. Cellular uptake of these proteins by
endocytosis was observed to increase secretion of endothelin-
1, interleukin-8 (IL-8), reactive oxygen species .The liberation
of these molecules predominantly from the basolateral aspect
of the cells contributes to the development of tubulointer-
stitial inflammation and fibrosis. The tubulointerstitial
inflammation is also thought to be due to misdirection of
protein rich glomerular filtrate into the interstitium due for-
mation of adhesion of tuft to the Bowman’s capsule.
Preliminary evidence suggests that exposure of tubule
cells to albumin may also induce apoptosis.48
Other experi-
ments found apoptosis in tubule cells exposed to high-
molecular-weight plasma proteins but not smaller proteins.
Albumin and transferrin exposure also induced complement
activation in tubule cells and reduced binding of factor H,
a natural inhibitor of the alternative complement pathway.49
Other filtered molecules like immunoglobulins, free fatty
acids bound to albumin, Insulin like growth factor-1(IGF-
1),lipoproteins especially LDL, are also believed to play an
important role in provoking proinflammatory response in
tubule cells.
The net effect of the above described hemodynamic and
nonhemodynamic factors cause interstitial inflammatory
cellular infiltration and tubulo interstitial fibrosis (Fig. 1).
2. Interventions to retard progression of
chronic kidney disease
1. Role of renin angiotensin aldosterone blockade
2. Reduction of proteinuria
3. Effect of hypertension control
4. Role of low protein diet
5. Correction of metabolic acidosis
6. Dyslipidemia management
7. Lifestyle modification,
8. Novel targets for interventions
3. Role of renin angiotensin aldosterone
blockade
There is enough evidence to show that renin angiotensin
system blockade (RASB) using angiotensin converting enzyme
inhibitors (ACEI) and/or angiotensin II receptor blockers (ARB)
is very effective in retarding progression of CKD87
in protei-
nuric diseases such as diabetic nephropathy50e52,84
and glo-
merulonephritis,51e58
even when the disease is advanced.64
In the Ramipril Efficacy in Nephropathy (REIN) study, 352
patients with nondiabetic renal disease, randomly assigned to
receive either ACE inhibitor or placebo, achieved similar con-
trol of blood pressure. Among patients with proteinuria of
atleast 3 gm/day at baseline, a significantly lower rate of decline
in GFR was seen after 2 years in patients receiving ramipril
(À0.44 vs. À0.81 ml/min/month with non-ACE conventional
therapy). In the extension phase of the study, patients who
received placebo were switched to ACE inhibitors, and those
already on ACE inhibitors continued the treatment. In 36e54
months of follow-up, no patients in the latter group reached the
ESRD, and a small number actually experienced a rise in GFR.
The Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT)51
evaluated the effects of the ARB, irbesartan l versus amlodi-
pine or placebo, in 1715 subjects. The primary composite end
point of the study was doubling of baseline serum creatinine,
ESRD or death from any cause. For subjects receiving irbe-
sartan, the adjusted relative risk of reaching the primary com-
posite end point was 20% lower than for those receiving placebo
and 23% lower than for those receiving amlodipine. There was
no significant difference between placebo and amlodipine for
the primary composite end point. The relative risk of ESRD in
the irbesartan group was 17% lower than that of placebo group
and 24% lower than that in the amlodipine group. Proteinuria
was reduced an average of 23% in the irbesartan arm, compared
with 6% and 10% in the amlodipine and placebo arms respec-
tively. The more favorable renal outcomes were in excess of
effects directly attributable to blood pressure control.
The reduction of end points in NIDDM with losartan
(RENAAL) study59
was undertaken to determine whether ARB,
losartan reduces the number of patients with type 2 diabetes
doubling in serum creatinine, ESRD or death, as compared
with placebo-treated subjects. The primary and secondary
end points of the study were similar to those of IDNT study but
treatment was of longer average duration in the RENAAL
study (3.6 vs. 2.6 years). Losartan lowered the risk of doubling
of serum creatinine by 25%, ESRD by 28% and death by 20%
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 23
7. when compared to placebo. Proteinuria declined by 35% in the
losartan arm and increased slightly in the placebo group.
Besides reno-protective effects of ACE inhibitor treatment,
the Heart Outcomes Prevention Evaluation (HOPE)60
and Los-
artan Intervention for End Point Reduction in Hypertension
Study (LIFE)61
trials reported substantial reduction in all cause
mortality cardiac and stroke events in patients receiving
ramipril or losartan respectively.
Study by Mani MK,62
from our unit showed that by
increasing the dose of angiotensin converting enzyme inhi-
bition to the maximum, the rate of decline of estimated glo-
merular filtration rate in diabetic nephropathy has decreased
from 16 mL/min/y in 1993 to 2.7 mL/min/y in 2008, and in
chronic glomerulonephritis from 28 to 2.8, respectively. In the
entire group of patients with renal failure of all causes, the
projected increase in time to reach the end stage from a glo-
merular filtration rate of 50 mL/min is 26 years, which is 17
years longer than the controls.
It is well-recognized that the efficacy of RASB varies in in-
dividual patients and race as well as gender have an influence
on their efficacy.65,66
The efficacy and safety of combination of
ARB and ACEI or supramaximal doses (doses above the max-
imum recommended for control of hypertension) remains
a subject of much debate. Supramaximal doses of ACEI or ARB
have an additive effect in reducing proteinuria and dual
blockade also has similar effect.67e70
The effect of combina-
tion therapy on progression of renal disease is conflicting. The
only major study (COOPERATE),71
which showed benefit with
combination therapy on renal outcome, has recently been
retracted by the publisher, due to irregularities found in the
conduct of the study. A recently published ONTARGET study72
reported that combination of ARB and ACEI caused more rapid
decline in glomerular filtration rate (GFR) in patients with high
cardiovascular risk compared to either of the agents used
alone, causing widespread concern over the use of combina-
tion therapy. However, the validity of the design and inter-
pretation of results of the ONTARGET study has been
questioned for several reasons.73
A recent meta-analysis
showed that combination therapy and monotherapy were
associated with a similar rate of decline in GFR.74
We studied the effect of increasing RASB to the maximum
tolerated using multiple agents in supramaximal doses and
showed that, with careful monitoring, it can be achieved
safely in the majority of CKD patients. Such an intervention
was associated with significantly better renoprotection in CKD
patients of diverse etiology including nonproteinuric diseases
and the effect appeared to be dose dependent.75
Several small clinical trials reported additional reduction of
proteinuria by 15%e54%, blood pressure by approximately 40%,
and GFR by approximately 25%, when aldosterone receptor
blockers were added to ACEI or AT1RA treatment, but large
randomized trials are required to fully assess the potential
benefits of these treatments in CKD, and their use in CKD is
currently limited by the associated risk of hyperkalemia.
4. Treatment of hypertension
Several population-based studies have shown an increased
risk of developing progressive renal failure with higher levels
of blood pressure,76e79
and is exemplified by findings from the
Multiple Risk Factor Intervention Trial (MRFIT).80
Even small
increases in blood pressure, below the threshold usually used
to define hypertension, are associated with an increased risk
of ESRD.76,78
The Modification of Diet in renal disease study supports the
concept that proteinuria is an independent risk factor for the
progression of renal disease. The authors suggested a target
blood pressure of less than 92 mm Hg (125/75 mm Hg) for
patients with proteinuria more than 1 g/day and mean pres-
sure of less than 98 mm Hg (about 130/80 mm Hg) for pro-
teinuria less than a gram per day.81
The KDIGO guidelines 2012, suggest reducing BP to less
than 140/90 in nonproteinuric CKD (not yet on dialysis) and
a target to less than 13080 mmHg for proteinuric CKD, of any
stage (not yet of dialysis) .A J-shaped relationship between
achieved BP and outcome has been observed in the elderly and
in patients with vascular disease.83
Several recent RCTs have not shown a benefit of lower BP
targets in patients without proteinuria. The African American
Study of Kidney Disease and Hypertension (AASK) random-
ized participants to treatment to a MAP of either 92 mm Hg or
102e107 mm Hg. During the long-term follow-up of partici-
pants, there was a benefit associated with the lower BP target
among patients with a urine protein/creatinine ratio (PCR) of
4220 mg/g (422 mg/mmol), but not among those with a PCR
220 mg/g (22 mg/mmol).
5. Reduction of proteinuria
Several clinical studies have provided evidence to show
cause-and-effect relation between proteinuria and renal
damage.82
A meta-analysis of 17 clinical studies of CKD
revealed a positive correlation between the severity of pro-
teinuria and the extent of biopsy-proven glomerulosclerosis.84
Observations from the Modification of Diet in Renal Disease
(MDRD) trial also suggest that proteinuria is an independent
determinant of CKD progression: Greater levels of baseline
proteinuria were strongly associated with more rapid declines
in GFR and reduction of proteinuria over 3 or 6 months, in-
dependent of reduction in blood pressure, was associated with
lesser rates of decline in GFR81
in randomized trials of ACEI or
AT1RA treatment in diabetic nephropathy85
and nondiabetic
CKD.86
A meta-analysis that included data from 1860 patients
with nondiabetic CKD confirmed these findings and showed
that during antihypertensive treatment, the current level of
proteinuria was a powerful predictor of the combined end-
point of doubling of baseline serum creatinine level or onset
of end-stage kidney disease (ESKD) (relative risk 5.56 for
each 1 g/day of proteinuria).86
The Renoprotection of Opti-
mal Antiproteinuric Doses (ROAD) study63
has provided the
most direct evidence of the clinical benefit of proteinuria
reduction to date. Subjects with proteinuric CKD were ran-
domized to standard therapy with an ACEI or AT1RA (sepa-
rate groups) or to ACEI or AT1RA therapy titrated to the
maximum antiproteinuric dose (two further groups).
Despite comparable blood pressure control, subjects in the
groups randomized to maximum antiproteinuric doses
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 824
8. evidenced 51% and 53% relative risk reductions in the
combined primary endpoint of creatinine level doubling,
ESRD or death.
The close association between the severity of proteinuria
and renal prognosis implies that reduction of proteinuria
should be regarded as an important independent therapeutic
goal in clinical strategies seeking to slow the rate of progres-
sion of CKD.
6. Dietary protein restriction
Though the benefits of dietary protein restriction on retarda-
tion of CKD has been clearly shown in experimental studies,
its confirmation in clinical trials has proved elusive. The large,
multicenter, randomized study, the MDRD study,85
was con-
ducted with 585 patients with moderate chronic renal failure
(GFR at 25e55 mL/min/1.73 m2
) were randomized to usual
(1.3 g/kg/day) or low (0.58 g/kg/day) protein diets (study 1), and
255 patients with severe chronic renal failure (GFR at
13e24 mL/min/1.73 m2
) were randomized to low (0.58 g/kg/
day) or very low (0.28 g/kg/day) protein diets. All causes of CKD
were included, but patients with diabetes mellitus requiring
insulin therapy were excluded. Patients were also assigned to
different levels of blood pressure control. After a mean of 2.2
years follow-up, the primary analysis revealed no difference
in the mean rate of GFR decline in study 1, and only a trend
toward a slower rate of decline in the very low protein group in
study 2. Long-term follow-up of 255 participants in study 2 of
the MDRD trial found no renoprotective benefit associated
with randomization to very low protein diet in the original
study but did report a higher risk of death in this group (HR,
1.92; CI, 1.15e3.20).88
Despite inconclusive findings in several of the individual
studies, three meta-analyses each concluded that dietary
protein restriction is associated with a reduced risk of ESKD
(odds ratio [OR] of 0.62 and 0.67, respectively),89,90
as well as
a modest reduction in the rate of estimated GFR decline
(0.53 mL/min/year).91
Though the renoprotective benefit of dietary protein re-
striction in humans appears modest, it is associated with
other benefits including improvement in acidosis and reduc-
tion in phosphorus and potassium load. Thus comprehensive
dietary intervention with a moderate restriction in dietary
protein intake should remain an important part of the man-
agement of patients with CKD.92
7. Management of hyperlipidemia
The benefits of lipid lowering in retarding progression of CKD
have been elusive. Though some studies showed reduction in
proteinuria and cardiovascular end points with statins, they
have not shown to retard progression.
8. Correction of metabolic acidosis
Observational clinical studies identified acidosis as an inde-
pendent risk factor for CKD progression,93,94
but to date only
small studies investigated the renoprotective potential of al-
kali supplementation in human subjects. In one randomized
study95
in adults with creatinine clearance 15e30 mL/min/
1.73 m2
, randomization to treatment of acidosis (serum bi-
carbonate 16e20 mmol/L) with sodium bicarbonate was
associated with less decline in creatinine clearance (1.88 vs.
5.93 mL/min/1.73 m2
) and lower incidence of end-stage kidney
disease (6.5% vs. 33%). In another randomized, placebo-
controlled trial in subjects with a mean estimated GFR of
75 mL/min/1.73 m2
, treatment with sodium bicarbonate for 5
years was associated with a slower reduction in estimated
GFR (derived from plasma cystatin C measurements) than
placebo or treatment with sodium chloride.96
Further large
randomized studies with more direct measures of GFR are
required to adequately evaluate the renoprotective potential
of alkali supplementation in human CKD.
9. Life style modifications
Cessation of smoking, and achieving ideal body mass index in
obese patients have shown to benefit the process of retarda-
tion of CKD progression.
10. Novel targets for intervention
The following interventions that inhibit the effects of TGF-b
have been shown to afford renoprotection in animal models of
renal disease: Transfection of the gene for decorin, a naturally
occurring inhibitor of TGF-b, into skeletal muscle limited the
progression of renal injury in anti-Thy-1 glomerulonephritis97
Administration of anti-TGF-b antibodies to salt-loaded Dahl-
salt sensitive rats ameliorated the hypertension, proteinuria,
glomerulosclerosis, and interstitial fibrosis typical of this
model. Treatment with tranilast (n-[3,4-dimethoxycin-
namoyl]anthranilic acid) an inhibitor of TGF-b-induced
extracellular matrix production, significantly reduced albu-
minuria, macrophage infiltration, glomerulosclerosis, and
interstitial fibrosis in 5/6 nephrectomized rats.98
Transfer of
an inducible gene for Smad 7, which blocks TGF-b signaling by
inhibiting Smad 2/3 activation, inhibited proteinuria, fibrosis,
and myofibroblast accumulation after 5/6 nephrectomy.
Epithelial Growth Factor receptor-tyrosine kinase in-
hibitors prevent inhibition of abnormal increase in collagen I
gene expression, decrease proteinuria and improvement in
GFR, and prevent the development of renal vascular and glo-
merular fibrosis.
Advanced glycation end product interacts with receptor,
causing intracellular signaling for increased production of TGF
b and CTGF production. Pimagedine, an inhibitor of AGE for-
mation showed reduction in decline of GFR over 36 months of
follow-up 9.8 vs 6.3 ml/min in diabetic nephropathy.99
Conflicts of interest
The author has none to declare.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 25
9. r e f e r e n c e s
1. Remuzzi G, Weening JJ. Albuminuria as a test for vascular
disease. Lancet. 2005 Feb 12e18;365(9459):556e557.
2. Xue JL, Ma JZ, Louis TA, Collins AJ. Forecast of the number of
patients with end-stage renal disease in the United States to
the year 2010. J Am Soc Nephrol. 2001 Dec;12(12):2753e2758.
3. Kher V. End-stage renal disease in developing countries.
Kidney Int. 2002;62:350e362.
4. Modi GK, Jha V. The incidence of end-stage renal disease in
India: a population-based study. Kidney Int. 2006;70:2131e2133.
5. Mani MK. Treating renal disease in India’s poor-the art of the
possible. Semin Nephrol. 2010;30:74e80.
6. Mani MK. Nephrologists sans frontiers: preventing CKD on
a shoestring. Kidney Int. 2006;70:821e823.
7. Mani MK. Experience with a programme for prevention of
chronic failure in India. Kidney Int Suppl. 2005;94:S75eS78.
8. Hostetter TH, Olson JL, Rennke HG, et al. Hyperfiltration in
remnant nephrons: a potentially adverse response to renal
ablation. J Am Soc Nephrol. 2001;12:1315e1325.
9. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake
and the progressive nature of kidney disease: the role of
hemodynamically mediated glomerular injury in the
pathogenesis of progressive glomerular sclerosis in aging,
renal ablation and intrinsic renal disease. N Engl J Med.
1982;307:652e659. 213.
10. Malcolm JB, Bagrodia A, Derweesh IH, et al. Comparison of
rates and risk factors for developing chronic renal
insufficiency, proteinuria and metabolic acidosis after radical
or partial nephrectomy. BJU Int. 2009;104:476e481.
11. Anderson S, Rennke HG, Brenner BM. Therapeutic advantage
of converting enzyme inhibitors in arresting progressive renal
disease associated with systemic hypertension in the rat. J
Clin Invest. 1986;77:1993e2000.
12. Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II
receptor blockade limits glomerular injury in rats with
reduced renal mass. J Clin Invest. 1992;90:766e771.
13. Taal MW, Chertow GM, Rennke HR, et al. Mechanisms
underlying renoprotection during renin-angiotensin system
blockade. Am J Phys. 2001;280:F343eF355.
14. Anderson S, Rennke HG, Garcia DL, et al. Short- and long-
term effects of antihypertensive therapy in the diabetic rat.
Kidney Int. 1989;36:526e536.
15. Fujihara CK, Padilha RM, Zatz R. Glomerular abnormalities in
long-term experimental diabetes. Role of hemodynamic and
nonhemodynamic factors and effects of antihypertensive
therapy. Diabetes. 1992;41:286e293.
16. Cortes P, Zhao X, Riser BL, et al. Regulation of glomerular
volume in normal and partially nephrectomized rats. Am J
Physiol. 1996;270:F356eF370.
17. Hostetter TH. Progression of renal disease and renal
hypertrophy. Annu Rev Physiol. 1995;57:263e278.
18. Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profiling
of vascular endothelial cells exposed to fluid mechanical
forces: relevance for focal susceptibility to atherosclerosis.
Endothelium. 2004;11:45e57. 241.
19. Nagel T, Resnick N, Atkinson WJ, et al. Shear stress selectively
upregulates intercellular adhesion molecule-1 expression in
cultured human vascular endothelial cells. J Clin Invest.
1994;94:885e891.
20. Ingram AJ, Ly H, Thai K, et al. Activation of mesangial cell
signaling cascades in response to mechanical strain. Kidney
Int. 1999;55:476e485.
21. Riser BL, Cortes P, Zhao X, et al. Intraglomerular pressure and
mesangial stretching stimulate extracellular matrix
formation in the rat. J Clin Invest. 1992;90:1932e1943.
22. RiserBL,CortesP,HeiligC,etal.Cyclicstretchingforceselectively
up-regulates transforming growth factor-beta isoforms in
cultured rat mesangial cells. Am J Pathol. 1996;148:1915e1923.
23. Becker BN, Yasuda T, Kondo S, et al. Mechanical stretch/
relaxation stimulates a cellular renin-angiotensin system in
cultured rat mesangial cells. Exp Nephrol. 1998;6:57e66.
24. Durvasula RV, Shankland SJ. Podocyte injury and targeting
therapy: an update. Curr Opin Nephrol Hypertens. 2006;15:1e7.
25. Yu D, Petermann A, Kunter U, et al. Urinary podocyte loss is
a more specific marker of ongoing glomerular damage than
proteinuria. J Am Soc Nephrol. 2005;16:1733e1741.
26. Durvasula RV, Petermann AT, Hiromura K, et al. Activation of
a local tissue angiotensin system in podocytes by mechanical
strain. Kidney Int. 2004;65:30e39.
27. Border WA, Noble NA. Fibrosis linked to TGF-beta in yet
another disease. J Clin Invest. 1995;96:655e656.
28. Ketteler M, Noble NA, Border WA. Transforming growth
factor-beta and angiotensin II: the missing link from
glomerular hyperfiltration to glomerulosclerosis? Annu Rev
Physiol. 1995;57:279e295.
29. Niemir ZI, Stein H, Noronha IL, et al. PDGF and TGF-beta
contribute to the natural course of human IgA
glomerulonephritis. Kidney Int. 1995;48:1530e1541.
30. Yamamoto T, Noble NA, Cohen AH, et al. Expression of
transforming growth factor-beta isoforms in human
glomerular diseases. Kidney Int. 1996;49:461e469.
31. Yamamoto T, Noble NA, Miller DE, et al. Increased levels of
transforming growth factor-beta in HIV-associated
nephropathy. Kidney Int. 1999;55:579e592.
32. Yamamoto T, Nakamura T, Noble NA, et al. Expression of
transforming growth factor beta is elevated in human and
experimental diabetic nephropathy. Proc Natl Acad Sci U S A.
1993;90:1814e1818.
33. Chan LY, Leung JC, Tang SC, et al. Tubular expression of
angiotensin II receptors and their regulation in IgA
nephropathy. J Am Soc Nephrol. 2005;16:2306e2317.
34. Lapinski R, Perico N, Remuzzi A, et al. Angiotensin II
modulates glomerular capillary permselectivity in rat isolated
perfused kidney. J Am Soc Nephrol. 1996;7:653e660.
35. Hoffmann S, Podlich D, Hahnel B, et al. Angiotensin II type 1
receptor overexpression in podocytes induces
glomerulosclerosis in transgenic rats. J Am Soc Nephrol.
2004;15:1475e1487.
36. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the
expression of plasminogen activator inhibitor-1 in cultured
endothelial cells. A potential link between the renin-
angiotensin system and thrombosis. J Clin Invest.
1995;95:995e1001.
37. Feener EP, Northrup JM, Aiello LP, et al. Angiotensin II induces
plasminogen activator inhibitor-1 and -2 expression in
vascular endothelial and smooth muscle cells. J Clin Invest.
1995;95:1353e1362.
38. Gomez-Garre D, Largo R, Tejera N, et al. Activation of NF-
kappaB in tubular epithelial cells of rats with intense
proteinuria: role of angiotensin II and endothelin-1.
Hypertension. 2001;37:1171e1178.
39. Himmelfarb J, Stenvinkel P, Ikizler TA, et al. The elephant in
uremia: oxidant stress as a unifying concept of cardiovascular
disease in uremia. Kidney Int. 2002;62:1524e1538.
40. Vaziri ND, Dicus M, Ho ND, et al. Oxidative stress and
dysregulation of superoxide dismutase and NADPH oxidase
in renal insufficiency. Kidney Int. 2003;63:179e185.
41. Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keap1
pathway to oxidative stress and inflammation in chronic
renal failure. Am J Physiol Renal Physiol. 2009;298:F662eF671.
42. Vaziri ND. Roles of oxidative stress and antioxidant therapy
in chronic kidney disease and hypertension. Curr Opin Nephrol
Hypertens. 2004;13:93e99.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 826
10. 43. Vaziri ND, Oveisi F, Ding Y. Role of increased oxygen free
radical activity in the pathogenesis of uremic hypertension.
Kidney Int. 1998;53:1748e1754.
44. Whaley-Connell AT, Chowdhury NA, Hayden MR, et al.
Oxidative stress and glomerular filtration barrier injury: role
of the renin-angiotensin system in the Ren2 transgenic rat.
Am J Physiol Renal Physiol. 2006;291:F1308eF1314.
45. Guan YouFei, Breyer Matthew D. Peroxisome proliferator-
activated receptors (PPARs): novel therapeutic targets in renal
disease. Kidney Int. 2001 Jul;60(1):14e30.
46. Guan Y, Breyer MD, Olson JL, et al. Altered glomerular
permselectivity and progressive sclerosis following extreme
ablation of renal mass. Kidney Int. 1982;22:112e126.
47. Miceli I, Burt D, Tarabra E, et al. Stretch reduces nephrin
expression via an angiotensin II-AT (1)-dependent
mechanism in human podocytes: effect of rosiglitazone. Am J
Physiol Renal Physiol. 2009;298:F381eF390.
48. Erkan E, De Leon M, Devarajan P. Albumin overload induces
apoptosis in LLC-PK (1) cells. Am J Physiol Renal Physiol.
2001;280:1107e1114.
49. Morais C, Westhuyzen J, Metharom P, et al. High molecular
weight plasma proteins induce apoptosis and Fas/FasL
expression in human proximal tubular cells. Nephrol Dial
Transplant. 2005;20:50e58.
50. Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effect
of ACE inhibitors in diabetic and nondiabetic chronic renal
disease: a systematic overview of randomized placebo-
controlled trials. Am J Kidney Dis. 2000;35:695e707.
51. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect
of the angiotensin-receptor antagonist irbesartan in patients
with nephropathy due to type 2 diabetes. N Engl J Med.
2001;345:851e860.
52. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan
on renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy. N Engl J Med. 2001;20(345):861e869.
53. Chiurchiu C, Remuzzi G, Ruggenenti P. Angiotensin-
converting enzyme inhibition and renal protection in
nondiabetic patients: the data of the meta-analyses. J Am Soc
Nephrol. 2005;16(suppl 1):S58eS63.
54. Schrier RW, Estacio RO. The effect of angiotensin-converting
enzyme inhibitors on the progression of nondiabetic renal
disease: a pooled analysis of individual-patient data from 11
randomized, controlled trials. Ann Intern Med.
2001;135:138e139.
55. Jafar TH, Stark PC, Schmid CH, , et al, AIPRD Study Group.
Progression of chronic kidney disease: the role of blood
pressure control, proteinuria, and angiotensin-converting
enzyme inhibition: a patient-level meta-analysis. Ann Intern
Med. 2003;39:244e252.
56. Ruggenenti P, Perna A, Remuzzi G, Gruppo Italiano di Studi
Epidemiologici in Nefrologia. ACE inhibitors to prevent end-
stage renal disease: when to start and why possibly never to
stop: a post hoc analysis of the REIN trial results. Ramipril
efficacy in nephropathy. J Am Soc Nephrol. 2001;12:2832e2837.
57. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in
Nefrologia). Randomized placebo-controlled trial of effect of
ramipril on decline in glomerular filtration rate and risk of
terminal renal failure in proteinuric, non-diabetic
nephropathy. Lancet. 1997;349:1857e1863.
58. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R,
Remuzzi G. Renal function and requirement for dialysis in
chronic nephropathy patients on long-term ramipril: REIN
follow-up trial. Gruppo Italiano di Studi Epidemiologici in
Nefrologia (GISEN). Ramipril efficacy in nephropathy. Lancet.
1998;352:1252e1256.
59. Brenner BM, Coffee ME, et al. Effects of Losartan on renal and
cardiovascular outcomes in patients with type2 diabetes and
nephropathy (RENAAL study). N Engl J Med. 2001;345:861e869.
60. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin
converting enzyme inhibitor, ramipril, on cardiovascularevents
in high risk patients. The Heart outcomes prevention Evaluation
study Investigators (HOPE). N Engl J Med. 2000;342:145e153.
61. Dahlof B, Devereux R, Siedldsen S, et al. Cardiovascular
morbidity and mortality in the Losartan intervention for
endpoint reduction in hypertension study ( LIFE ). A
randomized trial against atenolol. Lancet. 2002;359:995e1003.
62. Mani MK. Semin Nephrol. January 2010;30(1):74e80.
63. Hou FF, Xie D, Zhang X, et al. Renoprotection of optimal
antiproteinuric doses (ROAD) study: a randomized controlled
study of benazepril and losartan in chronic renal
insufficiency. J Am Soc Nephrol. 2007;18:1889e1898.
64. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of
benazepril for advanced chronic renal insufficiency. N Engl J
Med. 2006;354:131e140.
65. Ruggenenti P, Perna A, Zoccali C, et al. Chronic proteinuric
nephropathies. II. Outcomes and response to treatment in
a prospective cohort of 352 patients: differences between
women and men in relation to the ACE gene polymorphism.
Gruppo Italiano di Studi Epidemologici in Nefrologia (GISEN). J
Am Soc Nephrol. 2000;11:88e96.
66. Mitchell HC, Smith RD, Cutler RE, et al. Racial differences in
the renal response to blood pressure lowering during chronic
angiotensin-converting enzyme inhibition: a prospective
double-blind randomized comparison of fosinopril and
lisinopril in older hypertensive patients with chronic renal
insufficiency. Am J Kidney Dis. 1997;29:897e906.
67. Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximal
dose of candesartan in proteinuric renal disease. J Am Soc
Nephrol. 2009;20:893e900.
68. Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH.
Enhanced renoprotective effects of ultrahigh doses of
irbesartan in patients with type-2 diabetes and
microalbuminuria. Kidney Int. 2005;68:1190e1198.
69. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis:
effect of monotherapy and combination therapy with
inhibitors of the renin angiotensin system on proteinuria in
renal disease. Ann Intern Med. 2008;148:30e48.
70. Catapano F, Chiodini P, De Nicola L, et al. Antiproteinuric
response to dual blockade of the renin-angiotensin system in
primary glomerulonephritis: meta-analysis and metaregression.
Am J Kidney Dis. 2008;52:475e485 [PUBMED] [FULLTEXT].
71. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T,
Ideura T. Combination treatment of angiotensin-II receptor
blocker and angiotensin-converting-enzyme inhibitor in non-
diabetic renal disease (COOPERATE): a randomized controlled
trial. Lancet. 2003;361:117e124 [PUBMED] [FULLTEXT].
72. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes
with telmisartan, ramipril, or both, in people at high vascular
risk (the ONTARGET study): a multicentre, randomized,
double-blind, controlled trial. Lancet. 2008;372:547e553.
73. Lambers Heerspink HJ, de Zeeuw D. Dual RAS therapy not on
target, but fully alive. Nephron Clin Pract. 2010;116:c137ec142.
74. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J,
Clark HD. Combination therapy with an angiotensin receptor
blocker and an ACE inhibitor in proteinuric renal disease:
a systematic review of the efficacy and safety data. Am J
Kidney Dis. 2006;48:8e20.
75. Limesh M, Annigeri RA, Mani MK, et al. Retarding the
progression of chronic kidney disease with renin angiotensin
system blockade. Indian J Nephrol. 2012;22(2):108e115.
76. Iseki K, Iseki C, Ikemiya Y, et al. Risk of developing end-stage
renal disease in a cohort of mass screening. Kidney Int.
1996;49:800e805.
77. Perry Jr HM, Miller P, Fornoff JR, et al. Early predictors of 15-
year end-stage renal disease in hypertensive patients.
Hypertension. 1995;25(4 Pt 1):587e594.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 27
11. 78. Haroun MK, Jaar BG, Hoffman SC, et al. Risk factors for
chronic kidney disease: a prospective study of 23,534 men
and women in Washington County, Maryland. J Am Soc
Nephrol. 2003;14:2934e2941.
79. Fox CS, Larson MG, Leip EP, et al. Predictors of new-onset
kidney disease in a community-based population. JAMA.
2004;291:844e850.
80. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and
end-stage renal disease in men. N Engl J Med. 1996;334:13e18.
81. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control,
proteinuria, and the progression of renal disease. The
modification of diet in renal disease study. Ann Intern Med.
1995;123:754e762.
82. Perna A, Remuzzi G. Abnormal permeability to proteins and
glomerular lesions: a meta-analysis of experimental and
human studies. Am J Kidney Dis. 1996;27:34e41.
83. Kidney disease: improving global outcomes (KDIGO)
guidelines. Kidney Int Suppl. 2012;2(5).
84. Bjorck S, Mulec H, Johnsen SA, Norden G, Aurell M. Renal
protective effect of enalapril in diabetic nephropathy. BMJ.
1992;304:339.
85. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein
restriction and blood-pressure control on the progression of
chronic renal disease. Modification of Diet in Renal Disease
Study Group. N Engl J Med. 1994;330:877e884.
86. Jafar TH, Stark PC, Schmid CH, et al. Proteinuria as
a modifiable risk factor for the progression of non-diabetic
renal disease. Kidney Int. 2001;60:1131e1140.
87. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors
of the renin-angiotensin system and other antihypertensive
drugs on renal outcomes: systematic review and meta-
analysis. Lancet. 2005;366:2026e2033.
88. Menon V, Kopple JD, Wang X, et al. Effect of a very low-
protein diet on outcomes: long-term follow-up of the
Modification of Diet in Renal Disease (MDRD) Study. Am J
Kidney Dis. 2009;53:208e217.
89. Pedrini MT, Levey AS, Lau J, et al. The effect of dietary protein
restriction on the progression of diabetic and nondiabetic renal
diseases: a meta-analysis. Ann Intern Med. 1996;124:627e632.
90. Fouque D, Wang P, Laville M, et al. Low protein diets delay
end-stage renal disease in non-diabetic adults with chronic
renal failure. Nephrol Dial Transplant. 2000;15:1986e1992.
91. Kasiske BL, Lakatua JD, Ma JZ, et al. A meta-analysis of the
effects of dietary protein restriction on the rate of decline in
renal function. Am J Kidney Dis. 1998;31:954e961.
92. Mitch WE, Remuzzi G. Diets for patients with chronic kidney
disease, still worth prescribing. J Am Soc Nephrol.
2004;15:234e237.
93. Menon V, Tighiouart H, Vaughn NS, et al. Serum bicarbonate
and long-term outcomes in CKD. Am J Kidney Dis.
2010;56:907e914. Epub June 3, 2010.
94. Shah SN, Abramowitz M, Hostetter TH, et al. Serum
bicarbonate levels and the progression of kidney disease:
a cohort study. Am J Kidney Dis. 2009;54:270e277.
95. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al.
Bicarbonate supplementation slows progression of CKD and
improves nutritional status. J Am Soc Nephrol.
2009;20:2075e2084.
96. Mahajan A, Simoni J, Sheather SJ, et al. Daily oral sodium
bicarbonate preserves glomerular filtration rate by slowing its
decline in early hypertensive nephropathy. Kidney Int.
2010;78:303e309.
97. Dahly AJ, Hoagland KM, Flasch AK, et al. Antihypertensive
effects of chronic anti-TGF-beta antibody therapy in Dahl S
rats. Am J Physiol Regul Integr Comp Physiol. 2002;283:R757eR767.
98. Kelly DJ, Zhang Y, Gow R, et al. Tranilast attenuates structural
and functional aspects of renal injury in the remnant kidney
model.
99. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial
of an inhibitor of formation of advanced glycation end
products in diabetic nephropathy. J Am Soc Nephrol.
2004;15:2619e2629.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 828