The Future of Chronic Kidney Disease Treatment Future directions in therapy for chronic kidney disease.

The Future of Chronic Kidney Disease Treatment Future directions in therapy for chronic kidney disease.

It is known that the prevalence of chronic kidney disease progressively increases, and all registries in all countries with data show a steady increase in the number of patients requiring renal replacement therapy. The consequences from socially and economically are very important and can not be very happy with morbidity and mortality in patients with end - stage renal disease which remains unacceptably high 1.2 . The reasons for this high mortality are very different, but a very important increase in the age of the patients receiving this treatment, a restoration with both hemodialysis and peritoneal dialysis of only 15 to 20 ml / min of renal function , And associated major comorbidity. Despite advances in hemodialysis (membrane biocompatibility, high-flow membranes, increased frequency of sessions, control of water quality, among others) and in peritoneal dialysis (decreased risk of Infections, introduction of the cycler, etc.) there has been no clear improvement in the evolution of patients.

So, if after so many years we have improved so little, what awaits us in the future for the replacement of renal function? This article intends to point out the future possibilities for dealing with renal insufficiency, both with substitution techniques and with hemodialysis, peritoneal dialysis or renal transplantation (or creation of new organs), such as the possibility of regression of chronic kidney disease Before the total loss of kidney function.

Hemodialysis: portable or implantable kidneys

As we have commented, the situation of patients on hemodialysis, in general, translates into a great sacrifice for patients and families, especially derived from poor quality of life and the need to travel to the dialysis centers three times Or more per week. In addition, high mortality (similar to that of metastatic breast carcinoma, colon carcinoma or prostate cancer) forces us to move towards different techniques.

Improvement with frequent and prolonged dialysis in both quality of life and control of anemia, tension control, hospitalizations, reduction of medications (such as antihypertensives or phosphorus chelators), improvement Of appetite, improvement in volume control, reduction of morbidity and mortality, etc., directs current research towards those types of techniques in which treatment is continued.

It is true that continuous ambulatory peritoneal dialysis could, in some way, approach, and in fact do, continuous treatment. Although in many centers it is a technique implanted already for many years, however, the percentage of patients is not higher than 10-15% of those who are on dialysis and, in addition, there is a tremendous drop with time due to the Loss of ultrafiltration or diffusion capacity of the peritoneum, which is often insufficient when residual renal function disappears.

The requirements of the new dialysis technologies, therefore, are based on the following objectives:

1. Continuous operation.

2. Removal of solutes of molecular weight as does the kidney.

3. Elimination of water and solutes according to the needs of the patient.

4. Biocompatible.

5. Portable or better implantable.

6. Low cost.

7. Insurance.

At present, within the perspective of the future, there are four possible models that could achieve these objectives: HNF (Human Nephron Filter), microfluidic techniques, WAK (Wereable Artificial Kidney) and RAD (Bioartificial Renal Assist Device).

Human Nephron Filter (HNF)

Nisenson et al. 3,4 have proposed this model as an innovation in the treatment of renal failure. The HNF consists of two membranes that work in series in a vessel. The first membrane is called the G-membrane and is similar to the glomerular membrane of the nephron. It uses convective transport to produce a plasma ultrafiltrate containing solutes that approach the molecular weight of albumin. The second membrane is called the T-membrane and reproduces the functions of the tubule. It is made by molecular engineering and consists of pores of different sizes and angulations; Each of said pores allows a solute-dependent selection, so that between solutes with the same molecular weight some are discarded and some are not. Pores with similar radius are designed to have different selective transport properties. The ultrafiltrate formed once the blood contacts the membrane G contains desirable and undesirable solutes. When it passes to the membrane T, it rejects the undesirable ones and lets pass the desirable solutes, since each of its pores discriminates, according to the design, between what has to be maintained and what has to be eliminated. Blood flows at a flow rate of 100 ml / min and no dialysate is used in this system. Between what has to be maintained and what has to be eliminated. Blood flows at a flow rate of 100 ml / min and no dialysate is used in this system. Between what has to be maintained and what has to be eliminated. Blood flows at a flow rate of 100 ml / min and no dialysate is used in this system.

There are important differences between the membranes constructed with molecular engineering and the usual polymer membranes. They have a predetermined number of pore sizes with specific interactions that allow selectivity in transport. In contrast, conventional polymer membranes are much thicker, produce non-selective solutes transport and have very different pore sizes.

The HNF can be portable, with the filter including the G and T membranes and also attaching to the belt a high capacity battery and a waste bag with a conventional vascular access or using the different varieties of percutaneous access.

Dialysis without membrane: microfluidic techniques

The microfluidic technology is based on the parallel flow of two currents in a single channel. Two liquids (eg, blood and a PBS solution) circulate in a laminar form, side by side without any turbulent mixing and without being physically separated by a membrane. Under such circumstances diffusion occurs, so that small particles (such as ions, small proteins and numerous molecules and many drugs) tend to diffuse rapidly from the side of greater concentration to that of lower concentration, whereas large molecules and particles, Like cells, tend to diffuse only minimally. Leonard et al. 5,6 have proposed that the microfluidic technique is a new science of possible application in the field of hemodialysis. At present, there are prototypes of H filters that allow, simply by gravity, to facilitate the diffusion of small molecules from the blood to the dialysis fluid and it is possible that in the future the construction of multiple microfluidic chambers may be of clinical application And that allow a miniaturization of the artificial kidney and the obtaining of a portable kidney. However, there is still considerable research time to solve problems such as ultrafiltration and albumin retention. The construction of multiple microfluidic chambers may be of clinical application and allow a miniaturization of the artificial kidney and the obtaining of a portable kidney. However, there is still considerable research time to solve problems such as ultrafiltration and albumin retention. The construction of multiple microfluidic chambers may be of clinical application and allow a miniaturization of the artificial kidney and the obtaining of a portable kidney. However, there is still considerable research time to solve problems such as ultrafiltration and albumin retention.

Wearable Artificial Kidney (WAK)

Gura et al. 7.8 developed a portable hemodialysis apparatus based on a high flow dialyzer of 0.6 m 2 of polysulfone. It consists of a circuit in which the blood compartment is located with the arterial line that sends the blood to the dialyzer and returns to the patient and the dialysate compartment where the dialysis liquid enters the dialyser and then circulates through a series of sorbents, Where it is regenerated and to which bicarbonate is added. There are also a number of miniature pumps that regulate anticoagulation and ultrafiltration.

Davenport et al. 9 studied 8 patients on hemodialysis, who placed that portable kidney for 4-8 hours. Patients received heparin for anticoagulation. There were no major cardiovascular changes or adverse effects. The mean blood flow was 58 ml / min, with a dialysate flow of 47 ml / min and an average creatinine clearance of 20.7 ml / min. In 2 cases there was a coagulation of the circuit by reducing the dose of heparin.

It is clear that the prototype is still very incipient, that more numerous and longer trials are needed to confirm the safety and efficacy of the treatment, but it has the potential to become a method to achieve a more frequent dialysis in the patients with insufficiency Renal disease.

Bioartificial Renal Assist Device (RAD)

Based on the fact that there are a number of progenitor cells that regenerate the tubular epithelium after tubular necrosis or acute renal failure of any etiology, Humes et al. 10 were able to select this type of cell population and in collagen gels form tubule-like elements with programmed growth factors. They introduced a fixation matrix into a polysulfone capillary, filling it with progenitor cells. In the extracapillary space they added culture media with growth factors that would facilitate the expansion and differentiation of the cells to form a layer that filled the inner surface of the capillary, so they actually made a bioartificial tubule.

Up to that point, renal function replacement therapy in acute renal failure only succeeded in replacing the removal of small molecular weight solutes and volume, but without restoring the metabolic properties and endocrine functions of the kidney, which reside in cellular elements of the same.

They developed an extracorporeal circulation device with a hemofiltration filter containing 0.5 A1 x 10 8 cells of the human renal tubule inside the capillary fibers. In preclinical studies, these cells retained the metabolic and endocrine transport properties in uremic animals 11 and also improved multiorgan dysfunction in septic shock by gram-negative in large series of animals 12,13 .

Tumlin et al. 14 have studied, within 72 hours, whether RAD treatment improves the survival of patients with acute renal failure when compared to continuous replacement therapy in a randomized controlled multicenter study involving 58 patients with renal failure Acute that required dialysis. Forty patients received venovenous hemofiltration associated with RAD and 18 only continuous replacement of renal function. The primary objective was mortality at 28 days and other objectives were mortality at 90 and 180 days, recovery time of renal function, length of hospital stay in the intensive care unit, total hospitalization time and safety. On the 28th, The mortality was 33% in the RAD group and 61% in the group that received continuous renal replacement therapy. They also found a better survival at day 180 in the RAD group with a 50% mortality risk compared to the continuous replacement group. Also, with RAD treatment there was a rapid recovery of renal function and was better tolerated.

At present this technological breakthrough is in the preparation of randomized multicenter phase 3 to evaluate its therapeutic effect in a more consistent way. There are multiple publications available to interested readers 15-19 .

Peritoneal dialysis: Viwak PD

The Vicenza Wearable Artificial Kidney for Peritoneal Dialysis (ViWAK PD) is an early prototype that seeks greater comfort for patients receiving peritoneal dialysis, a technique that, although it is the most important home technique, still has important barriers, such as daily time Of duration of the technique, with limitations for the normal life.

Ronco et al. 20 have developed the ViWAK PD system, which aims to perform continuous ambulatory peritoneal dialysis with some maneuvers only in the morning and in the afternoon, leaving the patient free during the day and at night. The method consists of: 1 ) a peritoneal double-lumen catheter; 2 ) a dialysate outlet line; 3 ) a small pump; 4 ) a circuit for the regeneration of the dialysate with four cartridges in parallel of a mixture of active carbon and resins; 5 ) a filter for microbiological protection; 6 ) a dialysis fluid inlet line, and 7 ) a very small computer as a remote control.

The system allows a weekly clearance of 100 to 110 liters and consists of filling the cavity with 2 liters of solution. At 2 hours there is an activation of recirculation of dialysis fluid at a rate of 20 ml / min for 10 hours. After stopping the recirculation, glucose is added if ultrafiltration is necessary and at 2 hours it is emptied and icodestrin is added overnight if necessary. This system may be a possible alternative to APD or CAPD by reducing the time spent on exchanges and improving the effectiveness of technique and patient rehabilitation.

In short, the techniques described above are based on the evolution of technology in recent years, which has made it possible to reduce the size and weight of the necessary instruments. We hope that in the future, miniaturization will improve the treatment of renal function replacement with dialysis, allowing a more continuous treatment and, consequently, more physiological treatment. There is, of course, a still very important step: the improvement of vascular access which, unfortunately, is still far from the preferred place of research that it should occupy at the present time.

Kidney transplant

In this context of the advances in the treatment of renal diseases, we will speak of xenotransplantation and regenerative medicine. The advances referred to the increase in the donor pool , the new immunosuppressants, the research on the dysfunction of the transplanted kidney, and especially the tolerance in the identification of biomarkers that can predict that a patient is or not in a state of tolerance, The development of therapeutic strategies to induce tolerance, will not be included.

Xenotransplantation

Xenotransplantation using pig kidneys could solve the problem of donor scarcity. In the last 20 years, there has been much progress in the immunological mechanisms of the non-human primate pig model and we are close to clinical trials.

The results of porcine kidney transplantation to non-human primates before 1998 produced a hyperacute rejection by the presence of preformed antibodies, preferably anti-GAL, an antigenic constituent of the pig's vascular wall, leading to complement activation and intravascular coagulation and Thrombosis 21 . In the year 2000 the Cambridge group achieved a survival of up to 78 days in cynomolgus monkeys 22 using transgenic pig kidneys for human complement regulatory proteins (hDAF). Therefore, it was possible to avoid hyperacute rejection, but, nevertheless, the graft was still lost due to the presence of acute humoral rejection. Apparently this was produced by the presence of non-anti-LAG antibodies 23 . Nevertheless,

At present, future directions for the study of xenograft can be summarized in the following 24 :

1. New immunosuppressive agents.

2. Identification of non-GAL antigens in the pig.

3. Study of coagulation dysregulation between pigs and primates.

4. Solve the problem of coagulation by acting on transgenic pigs with an anticoagulant or antithrombotic gene or by withdrawing procoagulant genes.

5. Development of donor-specific tolerance.

6. Improvement in the study of physiology for some type of organs.

7. Study of cross-species infection (xenozoonosis).

8. Minimize the risk of endogenous porcine retroviruses.

9. Consolidation and improvement of ethical and social regulations.

Regenerative medicine

The kidney has a potential for regeneration through tubular epithelial cells, which is what occurs in part in acute renal failure. However, in chronic kidney disease, the kidney does not possess the potential for self-regulation and complete kidney development is needed again.

To obtain a regenerated kidney, it is necessary that the techniques that are applied achieve a precise structure of the kidney, a kidney that produces urine, and that grows without necessity or with minimal immunosuppression.

We will discuss four possibilities for getting a kidney again:

1. Embryonic kidney (metanephros).

2. Embryonic stem cells.

3. Nuclear transplantation.

4. Xenogenic embryos.

Embryonic kidney (metanephros)

Metanephros is the renal precursor that originates during the fifth week of gestation in humans or towards day 12 in the embryonic development of the rat.

Rogers et al. 25 implanted metanephros of rats into the peritoneum of non-immunosuppressed rats. These metanephros of 15 days by 6 weeks after implantation had increased in size, had vascularized thanks to the supply of vessels by the recipient rat (absence of hyperacute rejection) and had formed mature tubules and glomeruli. A ureter junction of the metanephros was performed to a proper kidney that was excised and 4 weeks after the ureteroureterostomy, the contralateral kidney was removed. The transplanted kidney produced urine and the transplanted rats increased their half-life. These results make it reasonable to use metanephros from very early embryos as a potential source of kidney to be regenerated and to solve the problem of donor scarcity. Osafune et al.

Embryonic stem cell

These are undifferentiated pluripotent cells, isolated from the inner layer of the blastocyst, which have the ability to differentiate into different types of cells: mesodermal, endodermal and ectodermal, depending on the culture conditions. They are, therefore, cells that possess a potential possibility of tissue regeneration. There are no published data describing the formation of a complete kidney from embryonic stem cells, but several groups have shown that stem cells can differentiate into renal structures when injected into immunosuppressed rats.

We will simply give some examples. Thus, Vigneau et al. 27 , with a combination of different culture and selection conditions, and especially predifferentiating the embryonic stem cells in vitro to the desired line, were able to generate a pure population of proximal tubule progenitors capable of integrating into normal nephrons without producing teratoma (which is One of the main problems of these techniques). After 7 months they achieved, with a simple injection in kidneys of newborn rats, that integration, although not in glomeruli. However, all that type of cells can provoke an immune response. Kunter et al.

Nuclear transplantation

It involves introducing a nucleus of a donor cell into a nucleus-free oocyte to generate an embryo with a genetic map similar to that of the donor.

Lanza et al. 29 attempted to create a unit that would eliminate the problem of the immune response. They generated a histocompatible kidney for organ transplantation. They used the nuclear transplant technique, in which dermal fibroblasts isolated from an adult cow were transferred to enucleated bovine oocytes and implanted into recipients. A renal device filled with cloned metanemal cells was transplanted into the cow from which the fibroblasts were extracted. Surprisingly, it produced urine, which points to the possibility that a nuclear transplant can be done for renal regeneration without the risk of long-term immunosuppression.

We are, therefore, close to achieving these ideal facts of an artificially regenerated kidney: precise renal structure, urine production and growth without immunosuppression.

Xenogenic embryos as an organ factory

During development of metanephros, a glial cell derived neurotrophic factor (GDNF) is expressed to initiate development, so that mesenchymal stem cells expressing GDNF are likely to differentiate into renal structures if they are placed in the right place.

Yokoo et al. 30,31 injected human mesenchymal stem cells at the site of metanephros formation and, after culturing the embryo, the metanephros that were subsequently cultured were dissected. They then verified that if what they injected were mesenchymal cells expressing GDNF could generate complete nephrons. However, to achieve a functional nephron it was necessary to have a vascular integration and for this they transplanted metanephros into the peritoneum of rats, getting them to increase in size and develop a renal structure similar to what was previously expressed in the works of Roger 25 . They collected urine in the ureters and also observed the production of erythropoietin 32 .

Chronic Kidney Disease

Personally I think that one of the great advances that we will find in the future, besides what has already been commented, is how we will face chronic kidney disease. And here are three concepts whose discussion is important: Brake to progression, regression of sclerosis and, finally, humanization and reduction of social cost of chronic kidney disease.

Brake to progression

Today, in the daily clinic, when we are facing a patient with chronic kidney disease, the main objective is to slow down their progression. There are numerous publications on each of the steps that must be controlled in patients to achieve this goal and, logically, in this article on the future we will not refer to them, but to summarize how the existence of a brake on The progression 33 , with the following measures: control of blood pressure, control of proteinuria, control of diabetes, blockade of the renin-angiotensin system double or triple, inhibition of renin, restriction of dietary proteins (doubtful) , Use of statins (to be confirmed), use of paricalcitol (also to be confirmed), control of anemia (not yet clearly demonstrated),

Regression

The question of whether a chronic kidney disease can regress is enormously complex. Numerous studies have been carried out in humans in which a slowdown in the rate of renal function decline has been observed at best 34-37 . There are, however, experimental studies in which a regression seems to be achieved, which probably means that the pathogenic mechanisms are different between animal and man.

In the progression of kidney disease the following factors stand out:

1. Paracrine factors: angiotensin 2, endothelin, growth factors.

2. Metabolic factors: proteinuria, hyperglycemia, dyslipidemia, oxidative stress, hypoxia.

3. Genetic factors.

4. Hemodynamic factors: arterial hypertension, glomerular hypertension, shear stress .

5. Cellular factors: transition epiteliomesenquimal, myofibroblasts.

6. Inflammatory factors: cytokines, chemokines, Toll like receptors .

Of all of them, angiotensin 2 is the target element, the most important to achieve a regression of renal fibrosis, but in humans this is just not enough.

There are many experimental data that have been successful in reversing chronic kidney disease by suppressing the renin-angiotensin system (RAS). Irrespective of whether renal failure has occurred with a model of aging or inhibition of nitric oxide, or with nephrectomy, or through the induction of diabetes, the fact is that, in most studies, regression was obtained by Mechanism of the RAS block 38 .

Thus, the regression of experimental chronic kidney disease achieved in rodents has not been replicated in humans. In this case it is true that angiotensin 2 plays a very important role in the development of kidney disease, due to its multiple actions, regardless of the development of hypertension and sodium balance. Angiotensin 2 participates in almost everything that has to do with vascular disease and many other actions that are being demonstrated every day. This blockage is therefore necessary, but the clinical data point, as we have said, that is not enough. It is necessary to continue to identify additional target elements and to act on them.

1. Anti-inflammatory agents including TAK 603, rapamycin or (NF) kappa beta inhibitor. It appears that the inhibition of inflammation can be beneficial if it is performed very early in the development of chronic kidney disease, but in the long run its effect is limited.

2. Beta-TGF antagonists: this is a factor considered to be the major activator of extracellular matrix synthesis and hence the production of fibrosis. Among the agents proposed to block the fibrogenic action of TGF beta are bone morphogenic protein (BMP7) or hepatocyte growth factor (HGF). Other antifibrotic drugs that inhibit TGF beta are IN1130 or Tranilast, which inhibits the release of TGF beta from inside cells such as fibroblasts and macrophages.

3. Inhibitors of tyrosine kinase growth factor receptors.

4. Intracellular signal inhibitors, such as the p38MAPK inhibitor, a protein kinase that has been studied in chronic kidney graft nephropathy, or inhibition of protein kinase C, which has so far yielded no measurable results.

5. Antagonism of aldosterone. It is an important prophylactic agent in myocardial fibrosis, less known in the progression of renal disease, although the data at the moment do not confirm this possibility 39 .

6. Activation of kinin receptors and, consequently, inhibition of the angiotensin converting enzyme.

7. Statins: in action independent of cholesterol reduction. Its beneficial action has been shown in some animals; Treatment with rosuvastatin has a renoprotective effect on morphology and inflammation, with reduction in matrix metalloproteinase activity independently of blood pressure 40 .

8. Inhibitors of collagen receptors.

9. Agents that degrade the extracellular matrix. There are laboratory data indicating that the activation of matrix metalloproteinase plays a beneficial role against the development of renal fibrosis induced by nitric oxide deficiency 41 .

In conclusion, regarding regression of chronic renal disease in most studies, this was obtained by blocking or antagonizing the action of RAS. A list of mediators of this progestogenic action of angiotensin 2 will surely appear in the future, but in any case what seems clear is that if someday some beneficial effect is achieved in humans it will be with the establishment of a very early treatment , Before the point of no return of renal failure is reached.

Preservation of endothelial integrity

The kidney has a very important endothelial surface and has recently been given much importance to vascular damage that causes renal tissue ischemia and progression of chronic kidney disease. Therefore, preservation of vascular and endothelial wall integrity not only prevents cardiovascular events associated with chronic kidney disease, but is also a very important aspect in stopping the progression of renal disease. Endothelial cells in the vascular tree respond to signals such as endocrine or paracrine hormones, cytokines and growth factors, exogenous and endogenous toxins, including traditional and non-traditional vascular risk factors. On the other hand, the endothelium also responds to rheological and hemodynamic changes. However, of all of them,

Although it was traditionally thought that damaged endothelial cells were replaced by neighboring cells that were introduced into the injured endothelial area, we now know that there are cells called endothelial progenitor cells (EPCs) that come from hematopoietic stem cells and contribute to vascular repair And even vascular regeneration. It is known, with experimental data, that the infusion or injection of these stem progenitor cells improve cardiac function after myocardial infarction and promote blood flow in peripheral ischemia models 42 . Theoretically, these endothelial progenitor cells would favor reendothelialization and neovascularization,

Different studies of endothelial progenitor cells in chronic kidney disease have shown that there are abnormalities in number and function in these patients, that the in vivo reendotelization capacity of these progenitor cells is affected in patients with type 2 diabetes and That this reduction in the function of these cells in chronic kidney disease is improved by dialysis or renal transplantation 43-45 . There are also pharmacological pathways to improve the regenerative capacity of CHD in chronic kidney disease. Thus, there has been an improvement in the number and functional capacity of CLD with rosiglitazone in diabetics 46 , erythropoietin 47 ,

Thus, the endothelial damage that associates the progression of chronic renal disease with cardiovascular disease can be attempted to be controlled through repair-regeneration through two possibilities: pharmacological treatment to improve DPC dysregulation and cell therapy. However, in this field the physiological significance and long-term risks, namely poor differentiation or inadequate transformation, are not clear at this time.

Humanization and reduction of the social cost of chronic kidney disease

In 2008, about 45,000 people in Spain, or around 1,000 per million population, were in renal replacement therapy, a figure that is estimated to almost double in the next 10 years due to the progressive aging of the population and Increased prevalence of other chronic processes such as diabetes mellitus. The same is true in the developed world, where, despite the fact that the incidence is stabilizing, the prevalence of patients receiving renal replacement therapy, either with renal dialysis or renal transplantation, continues to increase considerably, reaching figures Of 2,200 cases per million population in 2008 in Taiwan and 1,900 in Japan or 1,650 in the United States. 1 . This growth in prevalence is alarming,

As in the rest of the developed countries, in Spain the population that starts dialysis is aging in an amazing way. Thus, according to the Spanish Registry of Renal Patients of 2007, with an incident population of 125 / million on average, the number of patients over 75 years old is 405 cases per million population 51 . Many of these cases older than 75 years present three or more comorbidities and have very scarce life expectancies. The ethical question must be posed with courage: dialysis for the whole world?

Developed countries, at present, have no limitations on the application of renal replacement therapy. This situation often does not adequately assess the appropriateness of the treatment in each individual patient, and yet it is evident that not all patients benefit equally from this treatment. We have very important ethical reflections with our patients and their relatives, who fortunately in Spain are already in our magazine NEFROLOGÍA 52-54 . Some studies that retrospectively analyze the survival of patients older than 75 years in clinical predialysis chronic kidney disease stage 5 found that the advantage of dialysis is substantially reduced by comorbidity and ischemic heart disease in particular 55 . A really practical approach to this topic is that carried out by Couchoud et al. 56 who, with a simple graduation of comorbidities, predict the short-term prognosis in patients older than 75 years who initiate dialysis. This can help make a rational clinical decision in the discussion with patients and family members. With a simple graduation of comorbidities, predict short-term prognosis in patients older than 75 years who initiate dialysis. This can help make a rational clinical decision in the discussion with patients and family members. With a simple graduation of comorbidities, predict short-term prognosis in patients older than 75 years who initiate dialysis. This can help make a rational clinical decision in the discussion with patients and family members.