Renal failure results from the slow progression of disorders which lead to kidney destruction. It affects more than 82,000 individuals in France, and requires treatment with dialysis or transplantation. In 50% of cases, chronic kidney disease which leads to renal failure is the consequence of diabetes or hypertension.
Dazzling progress has been made in the past 10 years in understanding the mechanisms involved in kidney destruction in the course of these disorders. The research carried out has been able to identify diagnostic and prognostic markers. It also enables more suitable treatments to be found for patients, and reduces recurrence.
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Understanding renal failure
Chronic renal failure (CRF) results from progressive and irreversible kidney destruction. It culminates in the patient's death if no treatment is provided.
Its causes are diverse and sometimes unknown, a combination of genetic, environmental and degenerative factors. The associated complications are due to the variety of functions performed by the kidneys. They are most widely known for their role in filtering blood to eliminate waste from the metabolism (urea, creatinine, uric acid, etc.). However, they also serve to maintain constant water levels in the body, and to balance the concentrations of mineral salts essential to the body, such as potassium, phosphorus and sodium. They also produce hormones, enzymes and vitamins vital to the production of red blood cells, blood pressure regulation and calcium binding.
What about acute renal failure?
Chronic renal failure corresponds to progressive and irreversible kidney destruction. Conversely, acute renal failure is used to describe transient and reversible dysfunction of these organs, caused by hemorrhage, generalized infection (septicemia), drug poisoning, or obstruction of the urinary tract (kidney stones, prostatic adenoma), for instance. Dialysis is then absolutely essential. It allows the patient to survive while the kidneys repair themselves once the patient's condition has stabilized. This process is now known to be incomplete, and complications can persist.
10% of the French population are said to be affected
The total number of patients with renal failure is difficult to evaluate as the disease only becomes apparent once it reaches a very advanced stage, sometimes after progressing silently for several decades. It is rarely evident before the age of 45, and its prevalence increases with age, particularly after the age of 65.
REIN (the French nephrology epidemiology and information network) records patients undergoing dialysis or transplantation. At the end of 2015, it listed 82,295 patients treated for end-stage chronic renal failure. The number of new cases is growing each year, and primarily concerns elderly patients over the age of 75, and diabetics.
According to current estimates, the number of individuals with asymptomatic kidney disease is said to represent approximately 10% of the French population, the invisible part of the iceberg. It ranks chronic renal failure in the "top list" of public health challenges: screening for the disease should be routinely performed in high-risk subjects (hypertension, diabetes) and in the population aged over 60, etc.
Causes of the disease
The current main causes of renal failure are diabetes and hypertension.
Diabetic hyperglycemia induces deterioration of the small vessels in the glomeruli, which ultimately causes renal dysfunction. This is called diabetic nephropathy. This is the leading cause of dialysis in developed countries, with a growing proportion and a declining age of onset. It represented 22% of new cases of end-stage chronic renal failure in 2015.
Hypertension is the other main cause of renal failure. It is associated with narrowing of the kidney's small arteries, which can become blocked, and with a reduction in vascularization which can lead to renal failure. Hypertensive nephropathy accounted for 25% of new cases of end-stage chronic renal failure in 2015, and is on the rise.
Other types of nephropathy may involve different mechanisms, of an inflammatory, degenerative or genetic nature. These are often detected following a blood or urine test (proteinuria, hematuria), or when measuring blood pressure for another reason.
Primary glomerulonephritis, which represented the majority of renal failure in the 1990s, now only affects 12% of patients; however, it must be accurately diagnosed as it often responds to specific treatment.
Pyelonephritis accounts for 4.3% of new cases of renal failure. It is caused by recurrent bacterial infections of the upper urinary tract, often due to E. coli, affecting one or both kidneys.
Renal failure may also be caused by a hereditary genetic disease affecting the kidneys. Polycystic kidney is the most commonly observed, affecting 1 in 1,000 people, representing 800,000 individuals in France and 5.4% of new cases recorded in 2015. This is evidenced by the progressive development of cysts along the tubule which collects waste filtered by the glomerulus. These cysts proliferate and grow, invading the kidneys and preventing them from functioning normally.
Slowing disease progression
Once kidney disease has been identified, the objective of treatment is to slow kidney destruction by reducing the problematic inflammation in glomerulonephritis and by prescribing "renoprotective" treatment. The objective is to delay the progression to end-stage renal failure by several months or years.
Both a cause and consequence of chronic renal failure, hypertension should be controlled by a low-sodium diet and blood pressure-lowering treatment. Other cardiovascular risk factors should also be reduced, and nephrotoxic medications should be avoided or their doses adjusted. Certain medications which promote erythropoiesis, reduce phosphorus absorption, and the elimination of excess water and sodium, restore the acid/base balance, and provide sufficient vitamin D and calcium are also sometimes prescribed.
Adopting a healthy lifestyle is also able to slow kidney destruction. Stopping smoking and eating a suitable diet are essential (reducing animal protein and phosphorus, sodium, potassium, and fat intake, and drinking plenty of water), along with daily physical exercise.
Compensating for functional renal failure
Five stages have been defined in the progression of kidney destruction observed in chronic renal failure. The final stage, known as end-stage disease, corresponds to the moment when both kidneys lose more than 85% of their function (glomerular filtration rate <15 ml/min).
Certain patients may remain stable in stage 5 for several years. However, renal function usually needs to be compensated by kidney transplantation or extracorporeal (hemodialysis) or peritoneal (peritoneal dialysis) blood purification method. These techniques have revolutionized the management of chronic kidney disease, which was once fatal.
Hemodialysis filters the blood through an artificial membrane for 4 hours, three times a week. This should be accompanied by prescription of erythropoietin and a suitable diet to compensate for metabolic abnormalities not corrected by this treatment, such as anemia and phosphorus-calcium mineral disorders.
Peritoneal dialysis, developed in the 1930s, uses the patient's peritoneum as the filter membrane. However, this treatment method is contraindicated in the presence of internal scars or adhesions, abdominal hernia or diverticular disease of the colon, or in the event of severe respiratory failure. The filtration capacity of the peritoneum decreases over time, which often limits its use to approximately 5 years. However, major advances have been made in the development of daily home dialysis techniques, improving patient quality of life.
Transplantation, the preferred treatment
Kidney transplantation is the preferred treatment as it improves patient quality of life and life expectancy: 70% of transplants are still functional after 10 years, 50% after 14 years. However, it requires daily administration of immunosuppressant treatments, which often cause complications (infections, susceptibility to certain types of cancer).
Despite efforts to promote donation, the need for kidney transplants is far from being met: in 2015, 3,488 transplants were performed in France, while the total number of candidates reached 16,529. This demonstrates the importance of developing live donor transplantation. In France, family members (parents, children, brothers, sisters, uncles, aunts, and first cousins), as well as any other person having been in a close, stable emotional relationship with the future recipient for at least 2 years, may donate a kidney. In spite of this, live donor transplantation is still in the minority in France, representing less than 20% of kidney transplants performed.
Challenges facing research
France is one of the world leaders in kidney research. Inserm teams have widely contributed to the vast developments in the therapeutic strategies observed in recent years. This progress is based on a better understanding of the mechanisms at play. Defining these mechanisms enables diagnostic and prognostic biomarkers to be identified with a view to adapting the therapeutic strategies. The management of certain forms of renal failure has thus been revolutionized, while others have benefited from more effective new drugs.
Research on the correction of failing genes (gene therapy) or on kidney regeneration (cell therapy) is still in its infancy. Reconstitution of the kidney (currently being studied in animals) is a real challenge: this organ is, in fact, made up of more than 30 different types of cells.
Understanding the mechanisms at play
Contributions from the study of renal physiology
The research conducted by Pascal Houillier (Inserm Unit 1138, Centre de recherche des Cordeliers, Paris) and Dominique Eladari (Inserm Unit 1188, La Réunion), studying the physiology of the renal tubule has shed light on the mechanisms behind the progression of kidney disease. They represent the French school of physiology and alone have access to the investigation techniques vital to this research.
Contributions from the study of genetic diseases
There have been outstanding advances in the understanding of genetic kidney disease. At the forefront in this domain, the team led by Corinne Antignac (Inserm Unit 1163, Imagine Institute, Paris) has found several causes of genetic diseases affecting the glomerulus in young children, but also in adolescents and young adults. In 2004, they notably identified a mutation inducing an anomaly in intracellular transport: the sequestration of podocin, a protein which plays a key role in controlling permeability to proteins by podocytes. This discovery has led to highly active research into chaperone proteins, molecules which assist others in their functions and which could, in this case, bind to podocin to direct it towards the membrane. This promising approach has already led to positive results in Fabry's disease a form of which stems from the sequestration of an enzyme, alpha-galactosidase A, in a cell organelle, the lysosome. Identification of a specific chaperone, the medicinal product Migalastat, has now enabled this transport to be restored.
Collagen gene mutations (COL4A1) in the basement membranes of the vessels have been identified by Emmanuelle Plaisier (Inserm Unit 1155, Hôpital Tenon, Paris). These mutations are the cause of cystic kidney disease associated with a vascular disorder. This new syndrome provides important information on the role of this collagen in the vascular disorder, thus illustrating how the discovery of a rare disease can offer new insight into common disorders such as hypertension.
Progress has also been made in understanding multigene kidney disorders, in certain cases revolutionizing patient management. For example, this is the case for extramembranous glomerulopathy, an autoimmune disease which, in 30% of cases, leads to renal failure requiring dialysis or transplantation. The study of the whole genome in 600 patients, conducted by a consortium of British, Dutch and French scientists, including the unit led by Pierre Ronco and Hanna Debiec (Inserm Unit 1155), made it possible to identify the predisposition genes for this disease. One codes for the antigen attacked by the immune system, PLA2R1, and the second for HLA molecules which present this antigen to the immune system.
The anti-PLA2R1 antibodies have since demonstrated their diagnostic and prognostic value, and have paved the way for therapeutic research (see below). This discovery is also proving to be essential to defining transplantation strategies. A very recent study by the same unit has, in fact, shown that the risk of recurrence on the transplant is associated with the presence of specific HLA variants in the donor. It will thus be possible to eliminate this risk by selecting the kidneys to be transplanted in these patients, based on this criterion.
Identification of podocyte destruction pathways
Numerous studies have, moreover, shed light on the mechanisms involved in the deterioration of podocytes, glomerular cells which control permeability to proteins. These cells are the first to be affected in glomerular disease. They are also affected whenever the number of functional nephrons decreases, and thus play a decisive role in the progression of kidney disease. Injury and death of these cells lead to the death of the glomeruli, and ultimately the kidney. Shedding light on the cascading process leading to the deterioration of podocytes may enable targets to be identified in order to slow this degradation.
This is how the team led by Fabiola Terzi (Inserm Unit 1151) identified an enzyme which plays a decisive role in the adaptation of nephrons to chronic kidney disease, AKT2. When activated, this enzyme protects the podocytes. For instance, this discovery made it possible to limit the prescription of an immunosuppressant widely used to prevent kidney transplant rejection (mTOR inhibitor) as this medicinal product prevents AKT2 activation.
The team led by Pierre-Louis Tharaux (Inserm Unit 970, PARCC, Paris) demonstrated the role of a growth factor (HB-EGF) which induces podocyte proliferation then death in response to glomerular inflammation. Administration of a pharmacological inhibitor of this growth factor in mice preserves renal function and improves survival. This inhibitor, developed for the treatment of certain types of cancer, could thus be an addition to the conventional immunosuppressant treatments if therapeutic trials confirm its benefit in humans.
Another novel mechanism by which the podocyte adapts to excessive targeting was updated by the team led by Nicolas Pallet (Inserm Unit 1147, Centre universitaire des Saints Pères, Paris). This corresponds to the autophagy process which enables cells to renew their constituents by a sort of recycling process, but leads to their destruction in the event of prolonged stress, whether of toxic, immunological, infectious, metabolic or ischemic origin. This discovery also paves the way for studies on the medicinal methods of controlling this stress to protect the cell, and on the identification of biomarkers to measure tissue distress.
Impact of diet on disorders associated with immune abnormalities
Another promising line of research aims to shed light on the possible role of the intestinal flora (microbiota) and the diet in certain forms of nephropathy associated with immune abnormalities, particularly in Berger disease, or IgA nephropathy. In this disease, the intestinal mucosa produced IgA antibodies with an abnormal structure in excessive quantities. These agglutinate and are deposited in the glomerulus, ultimately leading to renal failure in 20 to 30% of cases. Growing research now points to the contribution of certain gut bacteria in the hyperproduction of IgA. The role of molecules which also contribute to celiac disease, related to gluten ingestion, also suggests the influence of diet in susceptible subjects. The team led by Renato Monteiro (Inserm Unit 1149, Inflammation Research Center, Paris), for instance, demonstrated that this common approach improved the condition of the glomeruli by eliminating gluten in mice suffering from the disease.
Identifying markers to tailor treatment to the patient: a step towards personalized medicine
An active area of research focuses on identifying markers, i.e. molecules which, when detected in a patient, contribute to the diagnosis or prognosis, and thus guide treatment.
Taking extramembranous glomerulopathy as an example once again, the anti-PLA2R antibodies are a specific marker for the disease. A reliable diagnosis is thus possible thanks to a simple blood test, and, in the near future, perhaps using a urinary reagent strip. This type of marker can, at least in certain cases, eliminate the need for kidney biopsy, which until now has been necessary in order to reach a diagnosis. The PLA2R antigen also has prognostic value since persistent high levels can lead to chronic renal failure if appropriate immunosuppressant treatment is not introduced.
Other biomarkers have been identified by Inserm teams, including periostin, DDR1 (Christos Chatziantoniou, Inserm Unit 1155), phosphatase SHP-1 (Renato Monteiro and Sanae Ben Mkaddem), lipocalin (Fabiola Terzi) and the c-mip gene (Dil Sahali, Inserm Unit 955, Créteil) to mention but a few. The potential prognostic value of these biomarkers has been evidenced in animals or on small patient samples. They first need to be validated on large populations before being used more extensively. This is one of the objectives of patient cohorts such as CKD-Rein which comprises more than 3,000 patients with chronic kidney disease (Bénédicte Stengel and Ziad Massy, Inserm Units 1018 and 1088).
More generally, cohorts are necessary in order to understand social, cultural, environmental, family and genetic determinisms which would allow for personalized treatment, adapted to each patient profile.
Identifying new therapeutic strategies
Inserm has achieved renown in therapeutic research through numerous original studies which have on occasion given rise to treatments for diseases which previously had none. Hemolytic uremic syndrome (HUS) is a particularly fine example of this. A very rare form of this disease is caused by an innate immunity abnormality affecting a complement pathway. This abnormality leads to destruction of the kidney and then the transplanted organ, after transplantation. A French team led by Christophe Legendre (Inserm Unit 1151, Hôpital Necker, Paris) has demonstrated the efficacy of a treatment targeting complement component C5, including in the prevention of recurrence after transplantation.
Likewise, identification by the team led by Guillaume Canaud (Inserm Unit 1151) of the AKT/mTORC signaling pathway, involved in the mechanisms leading to thickening of the vessel wall and destruction of the kidneys and transplanted organs in phospholipid syndrome, has made it possible to avoid the recurrence of vascular lesions and improve the survival of the transplanted organ by using an inhibitor of this pathway, sirolimus. Furthermore, Sophie Brouard and her team (Inserm Unit 1064, Nantes) demonstrated that T-lymphocytes in the blood of transplant patients have a particular profile, which could enable early diagnosis of graft tolerance or rejection and thus allow immunosuppressant treatment to be adapted accordingly.
In patients suffering from extramembranous glomerulopathy, further to research on the PLA2R1 antigen, the teams led by Pierre Ronco and Tabassome Simon (Hôpital Saint-Antoine, Paris) tested rituximab, an antibody directed against immune cells responsible for this toxic effect, in 80 patients, from 2012 to 2014. This molecule has proven to be more effective than the anti-proteinuric treatments conventionally prescribed, with immunological remission (disappearance of antibodies) in 50% of patients from the third month (versus 12%) and clinical remission in 64% of patients (versus 34%) at the end of follow-up.
The research conducted by the team led by Fabiola Terzi on lipocalin 2 (LCN2), involved in several signaling pathways leading to deterioration of the nephrons, has also allowed researchers to envisage new treatment approaches with a view to slowing the progression of chronic kidney disease. This team was able to demonstrate that phenylbutyric acid (PBA), a medicinal product used to treat genetic urea metabolism disorders, inhibits LCN2 secretion and could thus slow the kidney destruction process.
These few examples offer a mere glimpse of the different research fronts in which Inserm teams play a leading role, worldwide.