Anemia is constant during chronic renal failure (CRF), with the exception of polycystic disease.
It worsens along with the decrease in glomerular filtration. The main cause is bone marrow hypoplasia, a consequence of renal hyposecretion of erythropoietin (EPO); the other mechanisms are accessory: various deficiencies, chronic hemolysis, plasma inhibitors of erythropoiesis, medullary fibrosis in large secondary hyperparathyroidies. In particular, the consequences of a slowed erythropoiesis may be increased by deficiency factors: folate deficiency and / or vitamin B 12 , especially almost constant iron deficiency at an advanced stage of CKD. It may be due to occult digestive bleeding or, in women, to frequent menometrorrhagia, but often reflects inadequate dietary intake and intestinal absorption of iron. A haemolytic mechanism may also contribute to worsening anemia. It is a chronic extracorporeal hemolysis related to the accumulation in the plasma of medium molecules some of which have been identified. Finally, certain “uremic toxins” are inhibitors of erythropoiesis: various average molecules as well as spermine and PTH have been incriminated.
In the absence or after correction of any associated deficiencies, anemia of CKD is therefore normochromic, normocytic, normosideremic and poorly regenerative. The marrow is poor, reflecting the deficit in EPO. The appearance of recombinant human EPO (rHu-EPO) confirmed the central role of EPO: indeed, anemia of CKD can still be corrected by this treatment, provided that the ferric stocks are correct. and that there is no intercurrent inflammatory pathology or aluminum overload, which may interfere with iron metabolism.
EPO is a glycoprotein hormone belonging to colony stimulating factors (CSF) or hematopoietic growth factors. It is synthesized by the liver during fetal life, the kidney taking over from birth. The exact site of secretion has recently been the subject of controversy since with comparable in situ hybridization techniques, the origin of EPO has been localized sometimes in the endothelium of the tubular capillaries, sometimes in the interstitial tissue. The cystic or cancerous epithelium is also capable of synthesizing it. There is a basal production of EPO by the kidney, but this secretion is modulated by hypoxia without knowing the exact location of the system of measurement of tissue oxygen.
In contrast to other hematopoietic factors, EPO is specific for the differentiation of erythroid precursors and has little effect on other lineages, except on the megakaryocytic line (it potentiates the in vitro growth of CFU-mega [colony forming unit] colonies). During the differentiation of the erythroblastic lineage, the BFU-E primitive cells (burst forming unit erythroid) are not very sensitive to EPO; it is in the next stage of CFU-E that EPO plays a critical role, since in the absence of a hormone, CFU-E are unable to differentiate into erythroblasts and die by apoptosis. Receptors were identified on the surface of erythroblastic and megakaryocytic cells by binding of the labeled hormone. The EPO molecule was purified by Miyake in 1977 from urine of anemic patients.
Subsequently, the gene could be cloned; it is localized in humans on chromosome 7. The initial protein of 193 amino acids loses a signal peptide of 27 amino acids during the secretion of the hormone, which therefore comprises 166 amino acids.
Native EPO is highly glycosylated, which prevents it from being rapidly catabolized by the liver; therefore, the recombinant protein is still produced in mammalian cell systems.
Treatment with rHu-EPO has transformed the life of the renal failure. It removes the functional signs of anemia, transforms the nutritional status of frequently anorexic patients, improves sleep disorders and the depressive tendency of some patients and increases libido. The effect is particularly beneficial on the cardiovascular level, even in the absence of coronary artery disease, since there is a slowing of the heart rate and especially a regression of the cardiomegaly with, in echography, decrease of the endocavitary diameters and improvement of the contractile parameters.
This treatment, however, is not devoid of side effects, first and foremost aggravation or reappearance of arterial hypertension whose origin is multifactorial: the increase in plasma viscosity increases vascular resistance; the adaptation of the frequency and cardiac output to the elevation of the oxygen content would be deficient; EPO would exert a vasoconstrictor effect both indirectly, by increasing sympathetic tone and interfering with secretion
endothelial of various vasomotor factors such as nitric oxide, and direct by elevation of the calcium content of smooth muscle cells. To this may be added, for dialysis patients, the increase in interdialytic weight gain related to the recovery of appetite, causing less control of hydration.
An increased frequency of thrombosis of the vascular approach was observed in hemodialysis patients in some studies. These data are discussed. These thromboses are mainly due to the rapid increase in blood viscosity.However, changes in plasma coagulation proteins have been reported: it appears that the free fraction of protein S transiently drops during the first weeks of treatment. Finally, the role of endothelial stimulator of EPO, still poorly known, is indisputable; in particular, it promotes the synthesis of thromboxane A 2 by the endothelial cell. Apart from arteriovenous fistulas, no thrombogenic effect of EPO has been reported. Cases of critical ischemia of the lower limbs have been observed in arteritic patients, especially diabetic patients with distal non-bridging arterial lesions (personal observations). Nevertheless, the improvement of tissue oxygenation could compensate for and even preempt the slowing of blood flow and the increase in peripheral vascular resistance.
In hemodialysis patients, fears about lower quality of treatment due to increased viscosity and reduced plasma volume were excessive and the introduction of EPO did not significantly alter treatment strategies. Although an increase in azotemia, serum potassium and phosphoremia can be observed initially, it is due to the recovery of the appetite in asthenic and malnourished patients. In non-dialysis patients, initiation of treatment does not result in deterioration of clearance.
EPO was initially administered intravenously at three injections per week at the end of the hemodialysis sessions. In the early years of use, various studies have shown that subcutaneous administration is more cost-effective, resulting in lower doses due to a spread of serum concentrations. The treatment involves an attack phase of 6 to 8 weeks, after which the initial dose, generally of the order of 50 units / kg, is gradually decreased as soon as the hemoglobin reaches 10 to 11 g / l. The level of hemoglobin sought varies according to the field (existence or not of angina, age, physical activity … etc), but in recent years, the tendency has been rather to the elevation of this plateau, the functional benefit and cardiovascular appearing significantly more important with hemoglobin figures of the order of 12 g.
Leukocytes and platelets. The leukocyte lineage is much less affected by CKD. Although the leucocyte count is frequently at the lower limit of normal, frank leukopenia is exceptional outside of certain pathologies.
On the other hand, the leucocyte functions are modified (see below).
For platelets, there is no thrombocytopenia but the numbers are in the lower parts of the normal range. There are, as we shall see, abnormalities of platelet functions.
Hemostasis disorders:
The haemorrhagic tendency of the renal insufficiency is known for a long time and before the appearance of the means of dialysis, it was part of the procession of clinical manifestations marking the entry of the patient in the terminal phase of the IRC. In addition to their prognostic significance, haemorrhages, in particular digestive haemorrhages, were frequently the cause of death. Thanks to a sufficiently early dialysis treatment, hemorrhagic manifestations have become rare and much less spectacular. The hemorrhagic risk has not disappeared, however, as can be seen from biopsies or surgical procedures.
The anomalies are complex. They mainly concern primary haemostasis, so the normality of the plasma clotting tests usually observed does not exclude a haemorrhagic risk that can only be detected by the measurement of bleeding time (TS). It is frequently lengthened in very anemic patients, the decrease in blood viscosity and the acceleration of the circulatory speed hindering the formation of the haemostatic nail; correction of anemia by transfusion or with EPO is usually sufficient to correct this anomaly.
Platelet functions are disrupted. There is a decrease in adhesion, aggregation and platelet factor III production.Multiple studies have shown a decrease in aggregability in the presence of ADP (adenosine diphosphoric acid), collagen and ristocetin, while von Willebrand factor receptors have been found intact. The inhibitory effect of uremic plasma was obviously attributed to “uremic toxins”, but also to PTH whose inhibitory effect on aggregation was demonstrated in vitro, and which is responsible for an increase in platelet ion content. Ca 2+ which would be corrected by the administration of 1,25 (OH) 2 D 3 ; other explanations call for an imbalance of secretion of arachidonic acid derivatives, thromboxane A 2 and prostacyclin.
Plasma proteins of coagulation have been widely studied, first of all the von Willebrand factor whose concentration would be lowered within the platelets, but normal and even high in the plasma. On the other hand, the molecule would have functional anomalies linked to structural modifications with the absence of certain multimers. Other “classical” plasma factors of coagulation are usually considered normal. In particular, there is no abnormality of fibrinogen or its receptor, the platelet GP IIb-IIIa complex. Data on fibrinolytic activity are contradictory; perhaps it is slightly increased despite normal antigenic levels of activators.
Physiological inhibitors of coagulation have been widely studied in recent years. Very discordant results have been reported concerning antithrombin III as well as protein S. These discrepancies can be explained by the different methods used, antigen assay or determination of its biological activity, and secondly by possible binding defects to the carrier protein, only the free fraction being active. If, however, there are anomalies in this system, they can not play a prohemorrhagic role; on the contrary, a decrease in the biological activity of this procoagulant system could be at the origin of some unexplained thrombotic episodes, a paradoxical situation that is not exceptional in CKD.
Recent work has emphasized the importance of the vascular wall. Some studies have shown a secretory imbalance with excessive prostacyclin formation which seems to play an ancillary role, more recent work having shown instead a hyperproduction of thromboxane B 2 and endothelin I. Plasma plasminogen activator tissue inhibitor and tissue plasminogen activator would be normal.
The clinical consequences of these abnormalities of hemostasis are most often summarized by an increased hemorrhagic tendency during surgical procedures. Anticoagulants are not contraindicated, especially during hemodialysis sessions, but also in the long term if necessary. When there is a significant lengthening of the TS or a haemorrhagic complication, the first step to take is the correction of the anemia by the EPO, or in case of urgency by transfusion.
In the rare cases where the prolongation of TS persists, by analogy with Willebrand disease have been proposed estrogen, the administration of cryoprecipitates now abandoned, finally the dDAVP (1-desamino-8-D-arginine vasopressin) which is capable of releasing the von Willebrand factor polymers from their endocellular storage sites.The dDAVP, effective in a few hours, is for this reason preferred to estrogens whose time of action is several days;however, the exhaustion of its effect during iterative administration must make it reserved for the supervision of invasive procedures.
Immune deficiency of chronic renal failure:
It constitutes a state of moderate immunodeficiency.
Infections are indisputably more common. Currently supplanted by cardiovascular complications, they once represented the leading cause of death in hemodialysis patients. Susceptibility to bacterial infections is the consequence of alterations in leukocyte function.
Neutrophil polynuclear cells have increased free radical production; oxidative activity, glucose consumption, chemotaxis, adhesion and phagocytosis abilities are lowered. Various compounds present in uremic plasma have been incriminated: chloramines, free radicals, p-cresol.
Recently several polypeptides capable of inhibiting leukocyte functions have been isolated from uremic plasma ultrafiltrate: the granulocyte inhibitory protein or GIP I and II, and the polymorphonuclear leukocyte degranulation inhibitory protein or DIP. GIP I has similarities with light immunoglobulin chains, GIP II with beta-2 microglobulin and DIP with angiotensin. Mono- and dimers of light kappa and lambda chains extracted from the plasma of dialysis patients would have an inhibitory effect on various leukocyte functions. The monocytic functions, antigen presentation and phagocytic activity, are reached as well as the production of cytokines. The proportion of T lymphocytes is normal in CKD, despite sometimes moderate lymphopenia, and the distribution of T lymphocyte subpopulations is normal.However, disturbances of cellular immunity have been known for a long time, for example the prolongation of the survival of experimental cutaneous homografts or, clinically, a better allograft tolerance and the frequent cutaneous anergy to different antigens. These immune disturbances can be aggravated by undernutrition, improved by dialysis.They correspond to abnormalities of the T cell functions that are reproduced in vitro when the lymphocytes are brought into contact with the uremic plasma, although the latter is not cytotoxic with respect to the lymphocytes.
Overactive suppressive T cells have been suggested. It has been shown more recently that patients with renal insufficiency have an interleukin-2 secretion deficiency (IL2) due to preactivation of T cells resulting in excessive adsorption of IL2 molecules on an abnormally high number of receptors. Humoral immunity is inconsistently and less profoundly depressed than cellular immunity. The number of B cells and the number of different subpopulations is decreased; serum immunoglobulin levels are normal but the antibody response has sometimes been found to be diminished.
Iron overload associated with CKD appears to be a major factor of infection.
Hemosiderosis mainly affects hemodialysis patients, although the frequency has decreased significantly since the onset of EPO. However, there are still many patients who are polytransfused and / or subjected to excessive parenteral iron administration.
The incidence of bacteremia is three times higher in patients with ferritin greater than 1000 mg / L. These patients have an insufficient granulocyte response that can normalize after reduction of iron overload under the effect of EPO and possibly bleeding. The decrease in plasma ferritin is accompanied by an improvement in phagocytosis. The correction of anemia by itself directly improves the granulocytic functions, as well as other immune functions: distribution of lymphocyte subpopulations, production of cytokines, humoral response especially after vaccination.Other mechanisms contribute to the immune depression, in particular the accumulation of elements such as cadmium, mercury and copper, but especially the depletion of zinc and the deficit of 1,25 (OH) 2 D 3 , which has receptors on monocytes and T and B lymphocytes and behaves like a cytokine against monocytes and macrophages. Finally, malnutrition is common in the hemodialysis population and significant hypoalbuminemia appears correlated with a high risk of infection.
In patients treated with hemodialysis or peritoneal dialysis, bacterial infections are very often staphylococcal. Nasal carriage of Staphylococcus aureus is more common in these patients than in the rest of the population. Local long-term prophylaxis appears to reduce the risk of staphylococcal infections of the vascular approach in hemodialysis, or peritonitis in peritoneal dialysis patients.
The vaccine response is usually decreased during advanced CKD. The response to vaccination against hepatitis B has been particularly studied: even using currently available recombinant vaccines, the percentage of responding patients in CKD is lower than in a reference population, the peak obtained is lower and the rates are lower. Antibody protectors persist for a shorter time. This defective response is due to functional deficiency T and insufficiency of IL2 secretion.
The intensification of vaccine protocols in terms of unit dose and / or duration seems capable of improving the vaccine response. By analogy with zinc deficiency, responsible for abnormalities of lymphocyte and granulocyte functions, some authors have administered zinc which seems capable of increasing the number of T lymphocytes as well as the granulocyte response and chemotactic activity. The addition of IL2 increases the response rate in hemodialysis patients to 70%.
The weakening of immunovigilance vis-à-vis neoplastic cells remains a highly debated point. Several studies have reported a high incidence of cancer in dialysis CKDs. The duration of evolution of CKD and the existence of smoking would be significant risk factors; a selenium deficiency has been incriminated. However, some cohorts included patients who had received prolonged immunosuppressive medications. Some nephropathies are associated with a high risk of cancer, such as interstitial nephropathies toxic to phenacetin, responsible for urothelial cancers and especially polycystic disease that can be complicated by adenocarcinoma.
In addition, patients who have undergone dialysis treatment for years may develop, irrespective of their original nephropathy, renal cysts which may also be at the origin of adenocarcinomas, which may be favored by the existence of genomic abnormalities. . The incidence of other cancers hardly seems to be increased by CKD; an increase in the risk of prostate cancer in men, endometrium in women, has nonetheless been reported. The duration of evolution of CKD and the existence of smoking would be significant risk factors. The diagnostic problems of neoplasia in patients with renal failure are complicated by the fact that most tumor markers are elevated during renal failure.
DIGESTIVE COMPLICATIONS:
Digestive disorders are more and more frequent as the CRI progresses. In the pre-terminal stage, anorexia is almost constant with predominance for protein foods. Nausea, or even vomiting, is a component of the endemic uremic syndrome and prompts to start dialysis; however, they may be hyponatraemia which must be corrected. Structural and / or functional abnormalities affect the entire digestive tract.
Oral lesions:
They are observed nowadays exceptionally when the dialysis is not begun within the usual delays. These are stomatitis with painful ulcerations and parotitis triggered by increased urea concentration in salivary secretions.Changes in the lingual mucosa may produce a metallic taste in the mouth. The ammoniated smell of the breath reflects a very high azotemia.
Esophageal lesions:
At the oesophageal level, focal hemorrhagic lesions may be observed which are favored by the diffusion of plasma urea, converted in situ by urease to NH 3 .
Especially, gastroesophageal reflux is very common, especially in dialysis patients (about 20%) and especially in patients treated with peritoneal dialysis that increases the intra-abdominal pressure.
Gastroduodenal lesions:
They reported a few years ago still 5% of deaths. Although digestive hemorrhages and ulcerative perforations have become rare, their prognosis remains severe. In a recent study of 92 hemodialysis patients compared to 100 dyspeptic controls, 77% of dialysis patients complained of gastrointestinal symptoms, and the frequency of hiatal hernia but also duodenal ulcer was significantly higher as well as histological abnormalities. superficial gastritis and mucosal atrophy.The presence of Helicobacter pylori was less frequent among dialyzed patients than in controls. Erosive and / or petechial haemorrhagic gastritis accounts for almost one-third of all CKD regardless of whether patients are receiving dialysis or not; the incidence of these lesions does not increase after transplantation, unlike true ulcerous lesions.
The pathophysiology is complex. Toxic mucosal drugs and haemostasis disorders may play a role. Gastrin secretion increases in patients with serum creatinine greater than 300 μmol / L; this hypergastrinemia is not corrected by hemodialysis but normalizes after transplantation. However, it is associated, according to the studies, sometimes with hyperchlorhydria, sometimes with achlorhydria, finally sometimes with a strictly normal acid secretion; it therefore seems meaningless. In addition, the most recent studies have shown that although some fragments such as G 34 did indeed see their increased plasma concentration, moreover unrelated to acid secretion, the shorter and more active fragments (G 17, little gastrin), are normal. The cholecystokinin level is multiplied by 5 as soon as serum creatinine exceeds 300 μmol / L. That of pepsinogen I, a marker of G cell activity, multiplied by 4, is not decreased by dialysis and there is a hyperplasia of G cells. Finally, the secretion of gastrointestinal peptide is increased by CRI but decreased by dialysis; this inhibitor decreases H + secretion.
In the small intestine:
Structural changes have been described: decreased length of villi and structural abnormalities of enterocyte microvilli, a consequence of vitamin D deficiency in some cases. From the functional point of view, contradictory experimental results have been reported; it seems that changes in the hormonal environment are responsible for changes in the absorption of carbohydrates and amino acids. In humans, the D-xylose test is normal. A crucial point in these anemic patients, the intestinal absorption of iron was found sometimes low sometimes normal; these contradictions are explained by the administration of different forms of iron, iron in ferric form being very sensitive to duodenal pH.
Vascular pathology:
Mesenteric vessels are frequently the site of atheromatous lesions, but the clinical symptomatology of abdominal angina is rare and is observed almost exclusively during hemodialysis sessions.
Mesenteric infarction is a rare and serious complication of hemodialysis that may occur in an inaugural manner with excessive hypovolemia.
The increased incidence of gastrointestinal bleeding in CKD is currently most likely due to the presence of angiodysplasia lesions, which are found in a quarter of CKDs and would, once in two, cause bleeding. They are recurrent and difficult to treat because of their diffusion.
Colonic pathology:
With the exception of angiodysplasia, it has no particularity, except an increased incidence of diverticulosis associated with polycystic kidney disease. These patients aside, the frequency of diverticula is estimated at 50%, not different from the normal population.
Constipation is a common complaint, due to decreased physical activity and multiple drug intake.
Pancreatic pathology:
The frequency of pancreatic abnormalities was revealed by an autopsy series showing the existence in 60% of CKD of pancreatic ectasia with interstitial inflammation, fibrosis, proliferation and metaplasia of acini. Although the largest lesions have been reported in patients with high levels of PTH, the large secondary hyperparathyroidism observed in hemodialysis patients
do not complicate acute pancreatitis. Overall, however, an increased incidence of acute pancreatitis has been reported, particularly in patients treated with peritoneal dialysis, with a mortality of 20 to 30%. The occurrence of acute pancreatitis is unrelated to the frequent but moderate hyperamylasemia that reflects the decrease in renal excretion of the enzyme. Although amylase and lipase levels are difficult to interpret, amylasemia at 3 times normal may be considered pathological.
Essential ascites of hemodialysis:
These are patients who are free from any other form of hyperhydration, heart failure or liver disease. This isolated ascites is exceptional today, while abdominal ultrasound has become a routine examination in hemodialysis patients. It is due to an increase in capillary permeability and disappears only after transplantation.
Hepatopathies:
The most common cause of hepatomegaly in CKD is definitely right or global heart failure. Hemochromatosis following polytransfusion and / or iatrogenic martial overload was already rare before the appearance of EPO. Polycystic liver disease, associated in 20% of cases with polycystic kidney disease, never leads to liver failure but, rarely, mechanical disorders: heaviness of the right hypochondrium, jaundice by compression of bile ducts or localized pain linked to intracystic haemorrhage.
Thanks to vaccination, hepatitis B has become exceptional in hemodialysis patients.
Acute hepatitis is most often anicteric with delayed seroconversion and evolves in 30% of cases towards chronic carriage; in this case the HBs antigen may sometimes disappear, only remaining positive anti-HBe antibodies while the search for DNA (deoxyribonucleic acid) viral plasma can be negative, reflecting the absence of viral multiplication. The cirrhogenic evolution is exceptional. CKDs are poor responders to vaccination, however the multiplication of injections or the doubling of doses makes it possible to obtain a response rate reaching 80% or more if the vaccination was started at the stage of moderate CKD (see above).
In the absence of vaccination, hepatitis C has become a much more worrying problem as the progression to chronic hepatitis is frequent. The infectiousness is however much inferior to that of the hepatitis B, there is not properly an epidemic in the centers of dialysis and the risk of contamination for the personnel is practically nonexistent.
The overall prevalence among hemodialysis patients currently varies from 5 to 30%, or more, depending on the hygiene precautions and the duration of treatment. Transfusion transmission has been well documented, but it has decreased considerably as a result of routine donor screening and transfusion depletion. The mode of nosocomial transmission remains poorly understood, but it is indisputable. Strict hygiene precautions seem to limit new cases of seroconversion. An enzyme-linked immunosorbent assay (Elisa) test is not sufficient to assert the carriage of the virus C and must be followed by a RIBA-3 (recombinant immunoblot assay), then in case of a positive search for RNA ( ribonucleic acid) by PCR (polymerase chain reaction). The combination of a positive PCR and even transient cytolysis justifies a liver biopsy (always performed transjugularly because of haemostasis disorders), especially in patients awaiting renal transplantation. Under immunosuppressive therapy, the worsening or recurrence of cytolysis is frequent and hepatic lesions may worsen.
Interferon, effective in the short term in two thirds of patients but with 50% recurrence, must be administered before the transplant. This treatment is much more consistently effective in chronic hepatitis B who may also benefit from other antiviral treatments.
NEUROLOGICAL COMPLICATIONS:
Formerly constant at the end stage of CKD, neurological complications have become rare since patients benefit from early dialysis care, while a new iatrogenic pathology appears.
Central nervous system (CNS) lesions Uremic encephalopathy:
The term “endemic encephalopathy” refers to central disorders occurring at the end stage of CKD in the absence of any other cause of encephalopathy such as drug poisoning, vitamin B 1 deficiency, hyponatremia, hypercalcemia or hypophosphoremia. major, malignant hypertension or subdural hematoma. The signs are different from one patient to another and fluctuating. Some may be considered psychogenic: permanent fatigue, sleep disorders, decreased libido, emotional lability, decreased emotional investments, memory disorders.
The picture is sometimes psychiatric: paranoid manifestations and hallucinations. Objective anomalies, however, are noted: impaired short-term memory, rhythm and fluidity of speech, slow decision-making, inability to fix attention, reason in the abstract, or manipulate symbols. In severe forms can appear asterixis, ataxia, aphasia, nystagmus and vertigo, aphasia.
The evolution was formerly towards a confusional state then towards the coma with myoclonus and convulsions preceding the death. The electroencephalogram (EEG) is similar to other metabolic encephalopathies: generally slowed down with diffuse slow waves; the frequency of the elements below 7 Hz is correlated with the creatinine level.
After treatment in hemodialysis, there may be a dissociation between the clinical improvement (sometimes incomplete) and the aggravation of the EEG which can continue to deteriorate during the first 6 months, then normalize gradually.In some cases, only transplantation was able to eliminate clinical and electroencephalographic abnormalities.
Anatomical lesions have no specificity. An autopsy study of 400 patients showed no cerebral edema but diffuse neuronal degeneration of varying intensity. The only biochemical abnormalities found experimentally were the increase in the calcium content and the amount of cerebral osmoles, half of which was due to urea and half to the appearance of “idiogenic” osmoles. Oxygen consumption is decreased and the study of subcellular structures has shown the existence of a generalized dysfunction of Ca pumps dependent on cerebral synaptosomes, in particular Na-K-ATPase.The decrease in uptake of sodium by uremic rat synaptosomes persists in a non-uremic environment whereas, conversely, an uremic environment is sufficient to reveal this anomaly. Of the uremic toxins studied, none could be satisfactorily related to clinical or electroencephalographic manifestations, except for PTH.
The increase in cerebral calcium content and the appearance of electroencephalographic abnormalities in the uremic dog would be prevented by parathyroidectomy (PTX) and reproduced by the injection of PTH, even in the absence of an increase in the phosphocalcic product. PX-enhanced neuropsychic symptoms and EEG abnormalities have been reported in primary hyperparathyroidism.
In CRI, PTX improves cognitive testing and EEG. PTH facilitates the entry of calcium into different types of cells and could be the cause of increased brain calcium content. It would be able, by ways independent of cAMP (cyclic monophosphoric acid), to inhibit the activity of these pumps. A mechanism of direct toxicity has also been invoked.
Uremic encephalopathy may be difficult to differentiate from other metabolic encephalopathies, particularly hepatic encephalopathy. However, patients with both cirrhosis and CKD have increased production of ammonia secondary to increased urea concentration in the colonic mucosa and an increased risk of hepatic encephalopathy. In addition, the diagnosis of uremic encephalopathy should not be made lightly by disregarding an intercurrent disease or especially a drug toxicity, common in CKD.
Central disorders due to hemodialysis:
Imbalance syndrome, once a frequent complication of early dialysis sessions, is now exceptional. Headache, nausea, visual disturbances and hypotension precede the onset of disorientation, tremor and clonic
finally convulsions and a coma always reversible within hours of stopping the session. The EEG is normal. This syndrome, which particularly affects children or patients of low weight, still complicates a too fast purification in patients starting late dialysis with very high numbers of urea and creatinine. The mechanism initially invoked, that of a cerebral edema due to a slower purification of urea in the cerebrospinal fluid than in the blood, from which entry of water into the brain cells, does not seem anymore relevant. Cerebral edema is a consequence of a decrease in the intracellular pH of the cerebral cortex associated with increased production of organic acids.
Alumic encephalopathy has been described exclusively in hemodialysis patients. This encephalopathy has been observed either sporadically or as epidemics in some areas depending on the aluminum content of the city water. It has completely disappeared thanks to advances in water treatment techniques. This “dialysis dementia” began with the appearance of dysarthria and dysmetria with, in particular, micrography, associated with tremor, or even myoclonus, and with memory and mood disorders.
She progressed to a pseudopsychiatric state with hallucinations, then within a few months to a dementia leading to death in a coma and convulsions. The EEG was characterized by the existence of diffuse bursts of slow theta and delta waves. The demonstration of the aluminum responsibility allowed the stabilization and the regression of the symptoms when the patients were removed from the contaminated water and treated by desferrioxamine (DFO), chelator of the iron but also of the aluminum, which had to be continued for 6 to 18 months. DFO was used as a diagnostic test, the increment of aluminemia after injection of a dose being more valuable than the plasma aluminum assay, uncorrelated with tissue overload.
Cerebral atrophy:
Cerebral atrophy has been demonstrated by computed tomography and / or nuclear magnetic resonance in uremic patients, even those without dialysis. Lesions can be cortical or subcortical with only ventricular dilatation. They are roughly correlated with the duration of uremia. Computed tomographic abnormalities would be of interest to more than half of patients; in addition, 10% of the patients studied had areas of hypodensity, sequelae of cerebral ischemia.
Subdural hematoma:
Subdural hematoma is a classic complication of hemodialysis due to rapid dehydration and the administration of anticoagulants. Cerebromeningeal haemorrhages, promoted by anticoagulants but especially hypertensive attacks, have become rare (including rupture of aneurysms associated with polycystic disease).
Polyneuropathy:
“Uremic polyneuritis”, which is exceptional when glomerular filtration is greater than 10 mL / min, is observed today only in certain dialysis patients, and most often moderate forms are found, resulting in a decrease in the rate of nerve conduction. (VCN) sensory and motor. There is no specific character to differentiate it from other alcoholic, diabetic or carential metabolic polyneuropathies. The earliest sign is the “restless legs” syndrome, which occurs most often in the evening. Later signs of muscle dysfunction appear: general fatigue, cramps and amyotrophy. In severe forms, motor impairment may result in stepping. The examination revealed a symmetrical and bilateral mixed polyneuropathy chart characterized, like all distal axonopathies, by an insidious onset, predominance in the lower limbs, anesthesia in “socks” and the early loss of the Achilles reflex. Motor PNT is moderately slow due to the persistence of intact motor fibers. This measure is crude because spontaneous cyclic variations of the order of 20% can be observed from one day to another in the same individuals; the sensitive VCN is more reliable.
The study of evoked potentials is certainly the most sensitive examination.
The lesions of distal degeneration are due to the existence of neurotoxic compounds inhibiting certain enzymatic processes and depleting the axons of their energy reserves with an insufficient recharge from the soma, which blocks the axonal transport and distal degeneration. Segmental distal demyelination, exceptionally diffuse in severe forms, is sometimes associated; some patients even have predominant demyelinating neuropathy.
Different neurotoxins have been implicated (urea, creatinine, myo-inositol, methylguanidine, various medium-sized molecules) and a transketolase deficiency. In fact, no experimental argument has actually demonstrated the involvement of either toxin, although the role of molecules from 500 to 2500 Da has been particularly studied. The role of PTH remains hypothetical: the effects observed in dogs do not correspond to the evolution of axonal neuropathy and in hyperparathyroidism without CKD, no peripheral toxicity has been demonstrated in humans. Moreover, improvement after treatment in hemodialysis is observed even in patients whose PTH levels are very high. There is probably a combination of multiple toxic agents leading to anatomical damage that takes place over months or even years.
Axonal neuropathy is usually progressive but there are acute forms without any particular risk factors being identified.Dialysis recovery is very slow and sometimes incomplete. After transplantation, healing is observed in 6 to 12 months with a rapid initial phase followed by a slower recovery.
Achievement of cranial nerves:
Exceptional nowadays, it would most often interest VIII in the form of hypoacusis with or without vertigo. Other manifestations have been described: VII involvement with facial asymmetry, oculomotor paralysis responsible for nystagmus, miosis and heterophoria.
Dysautonomy:
It remains relatively common in dialysis-treated CKD patients, but it is often unknown because it is most often moderate forms detected by tests not usually performed routinely. Abnormalities mainly concern cardiovascular dysregulation, which can be associated with hyposudation, very common, more rarely impotence. The occurrence of hypotensive episodes laryngotics is not sufficient to assert the existence of a dysautonomia but the involvement of the autonomic nervous system (ANS) represents an indisputable predisposition. In addition, dysautonomia is a risk factor for anesthesia.
Different segments of the reflex arc are reached.
Baroreceptor dysfunction is evidenced by a decreased bradycardic response to norepinephrine (NA) or angiotensin II.
Achievement of the parasympathetic efferent pathway is responsible for the decrease in amplitude of the inspiratory variations of the heart rate.
The efferent sympathetic path seems less affected and a sympathetic hyperactivity has even been reported. It is true that the tests used only indirectly measure the sympathetic activity. The cold blood pressure response is usually normal, unlike the hand grip test, which causes an abnormal response to heart rate and blood pressure; these discrepancies have not yet been clearly elucidated. Concentrations of catecholamines are usually normal in patients with moderate CKD, but elevated to the end stage. The results for hemodialysis patients are discordant, rather high, which is not synonymous with sympathetic hyperactivity since plasma levels do not reflect more than 10% of catecholamine metabolism. In addition, a decrease in tyrosine hydroxylase activity was demonstrated in the uremic rat myocardium and the dopamine beta-hydroxylase activity was decreased in hemodialysis patients, suggesting a decrease in sympathetic activity. .
Some of the manifestations of autonomic dysfunction may be due in part to an alteration of the vascular response to agonists. The response to NA is decreased in non-dialyzed CKD more than in hemodialysis. This anomaly appears to be due to a downregulation of alpha-1 adrenergic receptors, demonstrated on the isolated uremic rat mesenteric artery; elevation of THP rates may be partially responsible. PTX normalizes the pressor response to NA in uremic rats.There is a correlation between the degree of impairment of this response and the levels of PTH.
Parasympathetic dysfunction is present in 65% of uremic patients, associated with sympathetic abnormalities in only 24% of them; the profile usually evidenced is that of an alteration of baroreceptors that would interest 50% of patients.In peritoneal dialysis, repletion of the abdominal cavity does not affect test results. The anomalies appear to be changing in dialysis. In diabetic patients, the anomalies are earlier and more severe; they continue to worsen on dialysis. For some, postdialytic hypotension is thought to be associated with transient acute worsening, which only affects baroreceptor or parasympathetic patients, without affecting the efferent sympathetic pathway. Some studies have found no improvement in either short-term or long-term dialysis but only after transplantation, which is not compatible with the effect of uremic toxins.
PULMONARY COMPLICATIONS:
Pulmonary edema, pleural effusions but also bronchial and pulmonary infections are common in CKD.
Bacterial pneumopathies are part of the increased sensitivity of uremics to infection (see above). In patients with severe CKD or dialysis, episodes of pulmonary edema such as chronic overload with or without pleural effusion are most commonly seen in left ventricular failure or extracellular hyperhydration. The “uremic lung”, radiologically characterized by the traditional image of “butterfly wings”, is not, however, limited to pulmonary arterial hypertension, to which would be added, at least in some cases, an increase in vascular permeability.
Some unexplained chronic pleural effusions are immediately serosanguinolent, even frankly hemorrhagic and correspond to inflammatory necrosis phenomena whose pathophysiology remains mysterious.
The evolution alternates spontaneous remissions and relapses, with long-term risk of progression to fibrosis responsible for a restrictive syndrome that sometimes requires decortication.
In asymptomatic CKD, whose chest radiograph was normal, it was possible to demonstrate functional alterations: restrictive syndrome, decrease of the DLCO (pulmonary diffusion capacity for carbon dioxide). The respiratory functional tests performed at the end of the hemodialysis sessions give abnormal results, attributed to the dehydration of the pulmonary parenchyma.
Pulmonary metastatic calcifications were found in microscopic form in asymptomatic CKD, even in the absence of radiological opacity. Consequences of secondary hyperparathyroidism and perhaps local phenomena of complementary activation, they sit in the alveolar septa and provoke in the long time thickening then fibrosis, which are then accompanied by a decrease of the DLCO and the vital capacity . Before this stage, transplantation can cause them to regress.
Hemodialysis may be accompanied by hypoxemia, which has been widely studied. The hypothesis of fibrinoleucoplaquettaires microemboli was eliminated, as well as that of an increase in the affinity of hemoglobin for oxygen related to alkalinization. It has long been thought that the metabolism of the acetate ion, formerly used as a buffer in dialysis baths, was responsible for hypoventilation by increasing oxygen uptake and decreasing CO 2production; it was finally proven that it was the loss of CO 2 through the dialysis membrane that was the cause of acetate-induced hypoventilation. Finally, in the era of dialysis on bath bicarbonate, currently widespread, it persists a certain degree of hypoxia linked to the very complex phenomena of “bio-incompatibility”, the complement activation by the membranes being at the origin of sequestration of activated leukocytes in the pulmonary microcirculation; isotopic studies have shown the existence of a contemporary vascular hyperpermeability of maximal leukopenia and hypoxia.
The peritoneal dialysis technique may be responsible for pleural effusions, more frequent on the right, and basal atelectases.
MEASURING DISTURBANCES:
Intolerance to carbohydrates:
During the course of CKD, the half-life of insulin is prolonged, resulting from a decrease in renal degradation but also in metabolic, hepatic and muscular clearance; the latter is improved by dialysis. Rates of C-peptide and pro-insulin, exclusively renal excretion, are even higher. In non-diabetic CKD, fasting blood glucose is normal, contrasting with mild hyperinsulinemia. During a glucose load, the early response is variable but, at the end of the test, persistent hyperinsulinemia is constant; insulin resistance is confirmed by clamp tests showing a decrease in tissue uptake that improves on dialysis; muscle uptake is decreased while production of lactates, a control of intracellular metabolism, is normal. The anomaly is distal and not at the level of the receptors. In some patients, secretory abnormalities of beta cells are added. Finally,
the antagonistic hormonal mechanisms also play a role. There is indeed hyperglucagonemia, a consequence of the reduction of renal degradation, not corrected by dialysis but normalized by transplantation. However, secretion is normal, either in the basal state, after stimulation with insulin or amino acids or braking with glucose or somatostatin.In contrast, the tissue sensitivity is decreased as shown by the insufficient decrease in triglycerides after administration of exogenous glucagon; this is also a cellular resistance since the number of receptor sites has been found paradoxically high on the uremic rat hepatocytes.
Hypoglycaemia is not unusual in diabetics due to decreased renal degradation of insulin in non-diabetic but malnourished CKD due to decreased gluconeogenesis, part of which is normally done by the kidney. Malnutrition, which reduces hepatic glycogen stores, as well as prescriptions for beta-blockers that inhibit hepatic glycogenolysis, are contributing factors.
Dyslipidemia:
From the early stage of IRC, the composition of apolipoproteins is modified. Apart from diabetes and glomerulopathies responsible for nephrotic syndrome, hyperlipidemia is observed only below 30 mL / min glomerular filtration, mainly in the form of moderate hypertriglyceridemia, the prevalence of which increases with progression of the CKD, up to 50 to 75% of hemodialysis; it is a type IV hyperlipemia with increased VLDL (very low density lipoproteins) and IDL (intermediate density lipoproteins) which may be associated with a decrease in HDL (high density lipoproteins) cholesterol, and sometimes presence of apoproteins atypical presumably corresponding to the accumulation of lipoprotein remunants rich in triglycerides. The increase of LDL (low density lipoproteins) -triglycerides and the decrease of HDL-cholesterol can be observed before the appearance of hypertriglyceridemia. Whatever the cause of CKD, the same pattern is found for apolipoproteins: decreased apo AI and A II, apo B normal or slightly elevated, apo E normal or decreased, but the most characteristic feature is the increase free from apo C III and to a lesser extent apo CI and C II. As a result, the apo AI / apo C III and apo AI / apo B contributions are decreased while the apo C III / apo E ratio is increased. The proportion of apo B, C and E is tripled in the VLDL, and two in the IDL, while the amounts of apo C, E, AI and A II are decreased in the HDL.
Triglyceride production has sometimes been increased by the addition of fatty acid precursors that stimulate hepatic synthesis of VLDL: Patients treated with peritoneal dialysis with transperitoneal glucoside overload have triglyceride apo AI and apo B higher, and an apo AI / apo B ratio lower than hemodialysis patients. However, catabolism of triglycerides and VLDL is slowed as a result of decreased hepatic triglyceride lipase and lipoprotein lipase (LPL) activity, resulting in the accumulation of IDL and chylomicron remnant. The lipolytic activity of postheaparin, which indirectly measures LPL activity, is diminished, possibly because of apo C II deficiency, a cofactor of LPL activation but especially of insulin resistance. Hyperparathyroidism would depress LPL activity, and in some studies there is a positive correlation between PTH and triglyceride levels. Lecithin Cholesterol Acyltransferase (LCAT), an enzyme associated with HDL particles
and activated by apo AI, which catalyzes the esterification of free cholesterol released by the degradation of triglyceride-rich lipoproteins and plays an important role in the retrotransport of cholesterol, has a reduced activity, perhaps due to the decrease in apo A I.
Hypercholesterolemia is rare. Total cholesterol may be low, especially at the expense of HDL-cholesterol with usually a lowered HDL-C / LDL-C ratio. The decrease relates to both the HDL 2 and HDL 3 fraction, the decrease in HDL 2 having been found to correlate with an increased incidence of cardiovascular mortality in US white hemodialysis patients.
Lipid abnormalities may be reduced by a state of malnutrition. Dialysis has a positive correlation between albumin on the one hand, triglycerides and apo B on the other, and patients with the lowest cholesterol, triglyceride and apo B higher.
After renal transplantation, there is no normalization but a change in lipid profile, hypercholesterolemia becoming the most common abnormality, while triglycerides decline. The hypercholesterolemia mainly concerns LDL cholesterol; it is due to both corticosteroids and ciclosporin.
Lipoprotein (a), an independent risk factor for atherosclerosis in the general population, was found to be elevated during CKD. In dialysis patients, this anomaly is found in hemodialysis but not in patients treated by peritoneal dialysis, and it would represent for the former a predictor of cardiovascular morbidity.
Undernutrition:
Extremely restrictive diets in proteins previously prescribed were responsible for severe malnutrition. With access to dialysis methods, the IRC regime has expanded considerably without eliminating the problem of malnutrition.
Caloricoprotid malnutrition is attributable to both the catabolic effect of CKD and anorexia. Moreover, during hemodialysis sessions, bioincompatibility phenomena stimulate muscle catabolism; during hemodialysis sessions, the addition of glucose to the dialysate can limit the loss of amino acids. Peritoneal dialysis is accompanied by a loss of albumin and amino acids in the dialysate which has to be compensated for by a high protein diet, while peritoneal glucose intake helps to depress appetite. Evidence of a strong correlation between malnutrition and mortality, especially infectious, in dialysis patients has been the cause of increasing attention to the nutritional problem. One in three hemodialysis patients would be malnourished but the diagnosis of minor undernutrition is difficult.
The dietary survey carried out by a dietician is often sufficient to highlight the insufficiency of caloric intake, particularly protein. Weight monitoring is extremely unreliable in CKD because of the interference of hydration problems and the possibility of relative fat retention, which may mask significant muscle wasting when insufficient protein intake is compensated by glucidolipidic ingestats providing a caloric ration approximately normal.
Anthropometric measurements can be used to assess lean body mass but unreliable. The assessment of body composition may involve heavier methods: measurements of dilute water sectors such as the potassium pool are of little value here; On the other hand, CT, magnetic resonance imaging, two-photon absorptiometry and impedance measurement seem to be able to provide interesting results. None of these methods has been validated in the IRC.
Before the dialysis stage, daily nitrogen excretion is a good indicator of protein intake. Low cholesterol (less than 1.50 g) is certainly indicative of severe malnutrition and is associated with a poor prognosis. Albumin is not very sensitive because of a long half-life and its metabolism is modified in uremic by non-nutritional factors. Transferrin has a shorter half-life but can be modified by changes in the ferric pool and inflammatory phenomena; however, a transferrin of less than 2 g / L may be considered an index of malnutrition. Prealbumin or transthyretin is increased by IRC even in case of malnutrition, due to the increase of its carrier protein, retinol binding protein (RBP); its half-life is short but it can be lowered by many pathological states; however, in hemodialysis patients, a rate of less than 0.30 g / L would indicate malnutrition. IGF I (insulin-like growth factor I), a growth hormone mediator (GH), is currently considered an excellent index of protein malnutrition.
The currently recommended intakes are 35 to 40 cal / kg, 1 to 1.2 g / kg of protein in hemodialysis and 1.3 g in peritoneal dialysis patients. Fats must not represent more than 30% of caloric intake and the existence of hypertriglyceridemia must limit short sugars. In case of hypertriglyceridemia very important, omega III fatty acids may be prescribed; the provision of L-carnitine by the general route or in the dialysate has been proposed. Inhibitors of HMG Co-A reductase (hydroxy-3-methylglutaryl coenzyme A reductase) are effective on hypercholesterolemia. Oral nutritional supplements are widely used but they have the disadvantage of bringing potassium, increase the interdialytic weight gain and can maintain anorexia. Discontinuous parenteral nutrition during hemodialysis sessions is more and more frequently prescribed in malnourished patients, particularly elderly patients. Recombinant growth hormone has recently been proposed in adult CKD. It is positive nitrogen balance provided that the dietary contributions are adequate. Its association with parenteral parenteral nutrition seems interesting.
ENDOCRINE ANOMALIES (OUTSIDE EPO AND VITAMIN D):
Gonadal functions :
In men, the libido is often diminished and erectile dysfunction is common. There may be abnormalities of spermatogenesis in late hormone-dependent stages. Total or free plasma testosterone is moderately lowered despite a normal level of thyroxin binding globulin (TBG). The follicle stimulating hormone (FSH) is usually normal but the plasma levels of luteinizing hormone (LH) slightly increased.
The testosterone response to hCG (human chorionic gonadotropin) is damped. Testicular abnormalities are considered to reflect direct toxicity of uremia, but other factors may be involved: secondary hemochromatosis in polytransfused patients, zinc deficiency. In addition to this peripheral dysfunction, there are hypothalamic disturbances with a decrease in frequency of pulsatile secretion of LH and a decrease in secretion by 24 hours, masked by the prolongation of the half-life, which explains the abnormally high plasma concentration. Moderate hyperprolactinemia is observed in about one-third of hemodialysis men. In addition to slowing catabolism, there is hypersecretion due to a weakening of the dopaminergic inhibitory tone. This hyperprolactinemia, an inhibitor of gonadotropin secretion, aggravates hypogonadism and the administration of bromocriptine is sometimes effective. Correction of anemia with EPO reduces hyperprolactinemia.
In women, hypothalamic disturbances play a major role and ovarian dysfunction seems to be directly involved only in infertility. In the advanced stage of CKD, the cycles are rarely strictly normal, but amenorrhea can occur as well as menometrorrhagia. The cycles are anovulatory in the majority of the patients. Estradiol and plasma progesterone are normal in the first part of the cycle, then almost all women on dialysis have luteal insufficiency.
The secretion of LH and FSH is very disturbed with, throughout the cycle, oscillations without individualized peak; it is this disappearance of the cyclic component of the secretion of gonadotropins, the basal tonic secretion being intact, which is at the origin of the anomalies of the cycle. The abnormalities are hypothalamic and not pituitary, as shown by the efficacy of Clomid ® or the administration of gonadotrophin releasing hormone (GnRH). After menopause, LH and FSH levels rise normally, showing the integrity of the pituitary response to changes in circulating peripheral hormones.
The disappearance of ovulation leads to a hormonal imbalance responsible for frequent menometrorrhagia and sometimes polycystic ovaries. Progestogen treatment is doubly justified by the need to avoid menometrorrhagia that may aggravate anemia and that of effective contraception excluding synthetic estrogen-progestin. Indeed, if the fertility of women with severe CKD is generally low, pregnancy can occur even in an amenorrheic woman. In the case of moderate CKD, pregnancy can be terminated at the cost of frequent hypotrophy and near-constant prematurity, with significant maternal risk associated with worsening arterial hypertension and high blood pressure. IRC. In dialysis, pregnancy is rare and the fetal prognosis is poor. Transplantation normalizes gonadal function, at least when renal function is normal, and if transplant patients are usually advised to wait 1 to 2 years before starting a pregnancy so that the renal function is perfectly stabilized, the prognosis both fetal and maternal is excellent.
Women with CKD have moderate hyperprolactinemia, which only rarely results in galactorrhea, but appears to participate in hypothalamohypophyseal functional disturbances. In some cases, treatment with EPO may improve libido and return to regular cycles by reducing hyperprolactinemia.
Thyroid function:
It has been widely studied in uremic. During advanced CKD, the diagnosis of hypothyroidism can be frequently discussed clinically, especially in elderly or very anemic patients. However, there is no hypothyroidism related to uremia but a particular hormonal profile. The “low T 4 , low T 3 ” syndrome previously described was based on dosages of total hormones that are effectively lowered; the decrease in T 4 would be related to the presence in the plasma of inhibitors of its binding to the carrier protein TBG whose concentration is normal. On the other hand, the free fractions of T 4 and T 3 are in the ranges of normal, even if the values found in CKD are on average lower than those of a reference population and increase under EPO or after transplantation. These rates of free T 3 at the limit
lower than normal correspond to a decrease in the peripheral conversion of T 4 while the tissue degradation of T 3remains normal. However, it is not the usual syndrome of “low T 3 ” encountered in multiple pathologies, because rT 3is not increased; Nutritional abnormalities of CKD are therefore not the only cause.
In patients treated with peritoneal dialysis, the passage of a certain amount of TBG-bearing proteins into the dialysate does not seem to play a significant role. The thyroid stimulating hormone (TSH) levels are often at the upper limit of normal; the nycthemeral cycle of secretion is altered with disappearance of the nocturnal peak. The response to thyrotropin releasing hormone (TRH) is delayed and amortized; but
CKD patients who develop true hypothyroidism are able to have greatly increased TSH counts and an exaggerated response to the HRT test. It is possible that these hypothalamohypophyseal disturbances are associated with abnormalities of the target tissues; Ultrasound studies have reported a higher than normal thyroid volume in dialysis patients.
Relatively low levels of T 3 in CKD could have a protective effect on exaggerated protein catabolism of urea as thyroid hormone administration to increase circulating levels of T 3 results by a negative nitrogen balance. For this reason, hormonal supplementation should be strictly reserved for patients with intrinsic hypothyroidism.
Growth hormone:
It has long been believed that there is hypersecretion of GH during CKD due to the presence of immunoreactive oligomers and degradation products. Thanks to the current techniques of dosing and calculation of the integrated secretion over 24 hours, complex disturbances have been demonstrated. While normally daytime secretion is negligible, CKDs have detectable levels throughout the nycthemeron, resulting in an increase in secreted mass as a consequence of inhibition of somatostatin secretion and / or hypersecretion of GH- RH (growth hormonereleasing hormone); hypothalamohypophyseal feedback is inhibited as a result of abnormal binding of IGF I to its carrier proteins. The binding of GH to its receptors is diminished by the IRC. The level of IGF I, the primary mediator of GH tissue action, is normal in undrained CKD; uremic children have values comparable to those of normal children for age.
These children have a growth deficit in which the size is more affected than the bone age. Administration of recombinant human frowth hormone (rhGH) is consistently effective on protein growth and anabolism, without accelerating bone maturation. This treatment could be proposed in adults as anabolic (see above), but the current experience is insufficient and the side effects to evaluate.
Adrenal hormones:
The half-life of cortisol is prolonged and its binding to CBG decreased. Cortisol retrocontrol explains the absence of clinical abnormality in the presence of slightly increased concentrations of free cortisol in plasma. Catecholamines are generally elevated because of the slowing down of the degradation linked to reduced cathecol-omethyltransferase (COMT) activity (see above). Normal, high or low values of plasma renin activity and aldosterone have been reported in hemodialysis patients. The response of aldosterone to volume stimulus, orthostatism, ACTH and angiotensin is decreased; in terminal IRC, serum potassium is the major secretory stimulus.
OTHER COMPLICATIONS:
Skin abnormalities:
Patients at advanced stages of CKD often complain of pruritus, which in hemodialysis reaches approximately 50% of patients. This symptom is never observed during acute renal failure, suggesting accumulation of a toxicant;nevertheless it disappears immediately after transplantation. The causes of pruritus are multiple: atrophy of the sweat and sebaceous glands responsible for xerosis hypercalcemia and / or hyperphosphatemia; cutaneous accumulation of mast cells, possibly responsible for high levels of histamine. The exacerbation during hemodialysis sessions is frequent, which can be attributed to both an immunological mechanism, increased calcium levels, dialysate heat, or even stress.
The phenomena of biocompatibility do not seem to play an important role, insofar as it has not been shown a significant difference as a function of the dialysis membranes; in addition, patients on peritoneal dialysis are as concerned as hemodialysis. On the other hand, pruritus seems quite parallel to the efficiency of the treatment.
Systemic cutaneous biopsies have demonstrated in patients with end-stage CKD a microangiopathy of dermal capillaries with basal thickening, signs of endothelial activation and infiltration by inflammatory cells with high mastocyte involvement. These findings, unrelated to any associated vascular pathologies, are correlated with the duration of hemodialysis and are attributed to either uremic toxins or bio-incompatibility phenomena.
Cutaneous calcifications are seen in patients with severe hyperparathyroidism or adynamic osteopathy. During the great hyperparathyroidism can also be observed the exceptional phenomenon of “calciphylaxis”, calcification embolism from calcifications of the media of the small peripheral arteries, at the origin of a livedo reticularis which can precede a digital gangrene of poor prognosis . Finally, hemodialysis patients may have a dermatitis bullosa called “cutaneous pseudoporphyrism of late hemodialysis” whose pathogenesis involves genetic predisposition and iron overload.
Ophthalmological complications:
Corneal and conjunctival calcifications directly related to an excessive phosphocalcic product are usually asymptomatic but may in some cases cause irritation. They are easily detected by slit lamp examination and regress after PTX or transplantation. The involvement of the posterior segment of the eye is not the consequence of the uremia but of the arterial hypertension or the diabetes. Heparin given during hemodialysis sessions has been made responsible for worsening cases of diabetic retinopathy. Finally, the intraocular pressure rises during hemodialysis sessions because of the osmotic imbalance associated with a slower purification of urea in the aqueous humor; this phenomenon has only a problem in patients with a history of glaucoma.
Otolaryngological Sphere:
Transient dysphonia and hypoacusis due to hypovolemia may be seen at the end of hemodialysis sessions.Permanent hypoacusis has been mentioned in neurological complications involving cranial nerves.