Cerebral imaging changes in patients with chronic renal failure treated conservatively or in hemodialysis.

BACKGROUND: Nonuremic patients with apparently normal memory and behavior, studied by means of cerebral computed tomography and found to have cerebral atrophy (CA), evidenced functional intellectual deficits when they underwent psychometric testing. The finding of CA has been repeatedly reported in limited case groups of uremic patients who also demonstrated functional intellectual deficits on the basis of the same tests. This retrospective study considered all diagnostic cerebral computed tomography scans done in our department between 1981 and 1998. Fifty-five uremic patients in conservative treatment (CT) and 111 patients in hemodialysis treatment (HT) were selected on the basis of the following two criteria: primary nephropathy as the cause of uremia and an age < or =55 years to exclude involutive brain changes occurring with age. AIMS: The aims of the study were to determine the percent of uremic patients with CA, the characteristics of their CA (cortical or subcortical), and eventual associated morphological lesions. RESULTS: CA was detected in 50.9% (cortical atrophy in 47.3% and subcortical atrophy in 3.6%) of the uremic patients in CT and in 77.5% of those in HT (cortical atrophy in 65.7% and subcortical atrophy in 7.7%). The average degree of CA was 0.872 in the patients in CT and 1.765 in the patients in HT. Thirty-four of the patients in the CT group and 46 in the HT group were hypertensive: these patients had a more severe degree of CA than the nonhypertensive subjects. In the CT group, the degree of CA in the hypertensive patients was 1.205 versus 0.428 for the nonhypertensive subjects. In the HT group, the degree of CA was 2.087 for the hypertensive patients versus 1.538 for the nonhypertensive patients. Of the overall population, 7.8% had ischemic lesions, 9.6% had endocranial calcifications, and 5.4% evidenced periventricular white matter hyperintensities. CONCLUSIONS: The high percent of CA found in young uremic patients increased in subjects in HT and, even more so in hypertensive patients. Vascular calcifications, focal ischemia and leukoaraiosis, well-known expressions of a chronic state of cerebrovascular insufficiency, were also found in HT patients; hypertension alone is a recognized accelerator of vascular damage. Thus, early and severe atherosclerosis and related hypoperfusion can be considered as the paramount causes of parenchymal cerebral damage in uremia.

[Antiphospholipid antibody syndrome]. / Sindrome da anticorpi antifosfolipidi.

Antiphospholipid antibodies (aPL) are an eterogeneous group of immunoglobulins, that include lupus anticoagulant and anticardiolipin antibodies. Patients with aPL are at high risk of venous and arterial thrombosis, thrombocytopenia and recurrent fetal loss. Antiphospholipid antibodies should be suspected in case of unexplained thrombophilia and prolongation of coagulation assays (aPTT); infact although such antibodies present an anticoagulant effect in vitro, in vivo the interfere with physiological anticoagulant reactions and may have a procoagulant effect. This paper deals with a case report characterized by a poor sintomatology, a short bleeding, but a spread of abnormal laboratoristic findings that give us the opportunity to investigate an uncommon syndrome.

[Amyloidosis and renal failure]. / Amiloidosi ed insufficienza renale.

A heterogeneous group of disorders associated with abnormal extracellular deposition of fibrillar proteins is defined amyloidosis. The renal involvement may occur in the absence of a recognized underlying disease or the kidney is affected as a result of systemic amyloidosis. Even if the diagnosis can only be confirmed by demonstrating the presence of amyloid deposits in the tissues, the development of a radiolabelled serum amyloid P component as a diagnostic nuclear tracer and the reduced urinary excretion of glycosaminoglycans as a decrease in the synthesis of functioning glomeruli and trapping by amyloid fibrils allow new diagnostic insight for the future. Patients maintained on haemodialysis or continuous ambulatory peritoneal dialysis for long develop amyloid deposits composed of beta 2 microglobulin that are predominantly osteoarticular, associated with carpal tunnel syndrome, large-joint pain, stiffness and pathological fractures. Systemic amyloidosis and some local forms are progressive and no treatment specifically resolves the amyloid deposits but therapy may reduce amyloid precursor proteins and improve survival.

Hypertension as an etiopathological factor in the development of cerebral atrophy in hemodialyzed patients.

Twenty-five patients on long-term regular hemodialysis treatment (RDT) at our dialysis unit who underwent diagnostic cerebral computed tomography (CCT) participated in a study aimed at clarifying the pathogenesis of cerebral atrophy occasionally found at their original scan. The upper age limit was 55 years to exclude the physiological involutive brain changes occurring with age. Cerebral atrophy (CA), as defined morphologically (enlargement of cerebral sulci or an increased Evan's Index), was detected in all cases. Seventeen patients underwent magnetic resonance imaging (MRI) to define possible white matter changes more accurately. No significant correlation was found between the degree of atrophy and the following uremia-altered hematoseric parameters: creatinine, hematocrit, cholesterol, triglyceridemia, albumin, PTH, calcium, inorganic phosphate. There was no correlation between degree of atrophy and number of months the patients had been on RDT or time that passed between the finding of a creatinine clearance <30 ml/min and the start of RDT. Very high correlations were found between the degree of CA and predialytic blood pressure values, and between CA and the duration of hypertension (n = 13, r = 0.66, p < 0.013). Thus, hypertension seems to be an early cause of cerebral parenchymal damage in RDT patients, and should be promptly corrected.

[Treatment of arterial hypertension in diabetic nephropathy. Certainties and hypotheses]. / Le traitement de l'hypertension artérielle dans la néphropathie diabétique. Certitudes et hypothèses.

Clinical observation has long emphasized the importance of arterial hypertension in the course of diabetic nephropathy and recent studies suggest that hypertension might play a decisive pathogenetic role in the course of the disease, hence the necessity of correcting the hypertension of diabetic patients has by now been universally accepted. There is, however, still some uncertainty concerning the usefulness of acting preventively on so-called microhypertension; in other words, whether early antihypertensive drug treatment can prevent diabetic nephropathy. This paper discusses the criteria to be followed in the choice of antihypertensive medication during diabetic nephropathy giving special attention to pathophysiological considerations. Moreover, it also discusses the effects of antihypertensive drugs currently regarded as first-choice agents, i.e. calcium antagonists and the angiotensin converting enzyme inhibitors, on intrarenal hemodynamics.

[The feasibility and current limits in the prevention of diabetic nephropathy]. / Fattibilità e limiti attuali nella prevenzione della nefropatia diabetica.

Diabetic nephropathy is the leading cause of uremia in Italy and other industrialized countries: once diabetic nephropathy commences, it advances slowly but inexorably to uremia. Prevention begins with strict control of blood sugar to inhibit or normalize glomerular hyperfiltration, and control of blood pressure to prevent glomerular hypertension and decrease microalbuminuria. Pharmacological measures include ACE-inhibitors and calcium channel blockers, alone or in combination, to reduce proteinuria and preserve renal function. It is believed that some classes of anti-hypertensive drugs have a direct pharmacological depressive effect on cell growth factors that lead to mesangial sclerosis: ACE-inhibitors would thus depress angiotensin II, and the calcium channel blockers would inhibit the increase in intracellular calcium of the mesangial cells which increases gene expression of early growth. Dietary sodium restriction seems to correct the expansion of the sodium pool and related volemic expansion hypertension. A protein-poor diet limits the precapillary glomerular vasodilatation resulting from protein-induced hyperaminoacidemia. The earlier dietetic and pharmacological measures are taken, the more effective they become: while they cannot arrest diabetic nephropathy once it has commenced, they are able to delay evolution of the disease to uremia.

Progression of cerebral atrophy in patients on regular hemodialysis treatment: long-term follow-up with cerebral computed tomography.

Fifteen patients (10 males, 5 females) on regular hemodialysis treatment (average age 43.6 +/- 4.0 years, average time on dialysis 100.7 +/- 62.8 months) underwent cerebral computed tomography between 1981 and 1984. Ten patients showed mild cerebral atrophy (CA) on the basis of cortical sulci exceeding 3 mm in breadth and an Evans ratio exceeding 0.31, for a total of 14 degrees of CA (mean 0.9 +/- 1). The same 15 patients underwent a second cerebral computed tomography during 1991/92 (101 +/- 23.7 months later). At that time, the patients exhibited a degree of CA of 2.6 +/- 1.4, for a total of 39 degrees with an overall increase of 25 degrees. Since CA is not detected before the age of 55 years in the normal population, we conclude that the CA in this patient group can only be attributed to uremia-related pathology and that it tends to worsen as regular hemodialysis treatment continues. Nevertheless, no evident cognitive, affective, or behavioural changes were verified in these patients. To our knowledge, this is the first presentation of radiologically documented progression of CA in the same patient population over time.

A diffusion immunogold procedure for accurate ultrastructural investigation of renal cell membrane epitopes.

A role for renal antigenic targets has been supposed and sometimes convincingly demonstrated in the development of various types of experimental glomerulonephritides. In this report we describe a reliable protocol for accurate ultrastructural investigation of antigens on the renal cell surface by means of a pre-embedding technique associated with colloidal gold staining. Sprague-Dawley rats were injected with a monoclonal antibody specific for a 90-kD cell membrane glycoprotein and killed 12 or 48 h later; after prefixation, renal fragments were cryoprotected and snap-frozen. Cryostat sections were incubated with a 5-nm colloidal gold-goat antimouse antibody, postfixed in osmium tetroxide reduced with potassium ferrocyanide and embedded in Durcupan ACM. At the glomerular level, gold granules were localized on the endothelial cell surface. In the proximal tubules uniform labelling was noticed on the brush border microvilli, followed by later marking of the basolateral membranes. By this pre-embedding immunogold method we obtained suitable histological preservation and fine resolution of the cell membrane immunoreactive sites. This procedure represents a useful tool for ultrastructural studies on the interaction of circulating antibodies with renal cell surface antigens.

[Diabetic nephropathy and arterial hypertension: the physiopathological aspects and antihypertensive treatment]. / Nefropatia diabetica ed ipertensione arteriosa: aspetti fisiopatologici e trattamento antiipertensivo.

The purpose of our review is to delineate the pathogenic steps linking arterial hypertension in diabetes to diabetic nephropathy. The results of recent studies suggest that arterial hypertension in diabetes might lay a decisive pathogenetic role in the evolution of diabetic nephropathy: the existence of a higher ratio of erythrocytic Na/Li counter-transport in nephropathic diabetics as well as higher pressure values in the parents of diabetics who develop nephropathy indicates that hypertension may be casually related to renal complications. Diabetes-associated hypertension involves the modification of two important pressure- regulation factors: 1. an alteration in extracellular volume and increased renal absorption of sodium which leads to an expanded pool; 2. increased cardiovascular reactivity to norepinephrine and angiotensin II, an effect which might be related to increased intracellular calcium. Hyperfiltration seems to be present at the onset of diabetes, and arterial hypertension increases the transglomerular pressure gradient which is thought to play an important role in the pathogenesis of kidney damage. Antihypertensive drugs such as ACE-inhibitors and calcium channel blockers tend to protect the regulation of renal function. This could be explained by the fact that ACE-inhibitors suppress the trophic effects of angiotensin II on the nephron, while calcium channel blockers might interfere with intracellular processes involved in cell hypertrophy that require the interaction of calcium ions. In the management of diabetes prevention of diabetic nephropathy requires early and careful correction of diabetes-associated hypertension. We discuss the major groups of antihypertensive drugs, their metabolic side-effects and intrarenal induced hemodynamic changes.

[The pathogenesis of arterial hypertension in diabetes mellitus and its role in nephropathy]. / Patogenesi dell'ipertensione arteriosa nel diabete mellito e suo ruolo nella nefropatia.

This paper synthesizes the pathogenic steps of arterial hypertension in diabetes mellitus: hyperosmolarity due to the hyperglycemia and increased sodic tubular reabsorption accounting for the expansion of the extracellular volume with hypervolemia; abnormalities of the ionic membrane pumps leading to abnormal intracellular calcium distribution, thereby inducing an increased vascular tone; atypical vasomotor reactivity to cathecolamines; modifications of the renin-angiotension-aldosterone system. The pathophysiological derangements by which hypertension could induce nephropathy are examined: the vasodilatation which can be detected from the onset of diabetes, may be a determinant in the transmission of systemic hypertension to the glomerular microcirculation with resulting enhancement of the hydrostatic transglomerular pressure gradient (i.c. the major factor producing glomerular injury), glomerular plasmatic flow and filtration rate. The nephron hyperfiltration increases the movement of plasmatic proteins across the glomerular capillary wall with subsequent mesangial hyperactivity and sclerosis. Antihypertensive treatment in diabetes follows general guidelines and it should be instituted even in the case of microhypertension being facilitated in this setting the appearance of microalbuminuria i.e. the starting point of nephropathy. Even if experimental studies are to favor ACE inhibitors as the first-line drugs for abating glomerular hypertension by mitigation of the direct effect of angiotensin II on the efferent arteriolar tone, clinical observations suggest that, regardless of type of treatment, the normalization of systemic arterial pressure, by reversing glomerular hypertension may be effective in preventing diabetic nephropathy.

[Current approach in the prevention and treatment of diabetic nephropathy]. / Attuali orientamenti di prevenzione e trattamento della nefropatia diabetica.

Diabetic renal microangiopathy accounts for enormous morbidity and mortality, particularly in patients who develop diabetes in childhood or early youth; in the last few years its pathogenesis has been therefore extensively studied, aiming to prevent renal complications or at least of slowing down its progression toward uremia. Though not always in accordance with theoretical expectations, the results of clinical trials have nevertheless widened our therapeutic possibilities; in fact, besides the attainment of an optimal metabolic control, other possible interventions include a careful correction of albeit minimal elevations in arterial pressure; the interference with intrarenal hemodynamic parameters; the correction of insulin-independent metabolic pathways, abnormally activated in the diabetic, such as non enzymatic glycation and polyol pathway; the treatment of endothelial and platelet alterations; the improvement of the rheologic properties of blood.

[The physiopathologic bases of the neurotoxicity of phosphorus chelating agents containing soluble aluminum salts in patients with renal insufficiency]. / Le basi fisiopatologiche della neurotossicità dei chelanti del fosforo contenenti sali solubili di alluminio nel paziente con insufficienza renale.

To what extent can damage to the central and peripheral nervous systems be ascribed to chronic aluminum (Al) intoxication taken as a chelating agent for phosphorus, to limit hyperphosphatemia in uremic patients? Since Al is normally eliminated by the renal route, its accumulation in uremia has to be ascribed to a reduced or abolished renal clearance of the metal, which results in preferential toxicity for certain tissues, especially nervous tissue, which shows difficulty in eliminating Al, even after intake has been stopped. This review discusses, on the basis of toxicologic, experimental and clinical data, the possible pathogenic steps of Al neurotoxicity in uremia, considering: the damage to axonal transport in which Al intoxication tends to affect the components of the cytoskeleton, the polymerization phase of the alpha and beta tubulin constituents of neurotubules, and the normal translocation of neurofilaments from the perikaryon to more distal positions of the axon; the abnormalities in the brain pool of adrenergic, cholinergic and GABA neurotransmitters; the increase in permeability and changes in perm-selectivity of the blood-brain-barrier, with further loss of neurotransmitters and with acquisition, from the systemic circulation, of neurotransmitter-like substances such as hormones, monoamines and peptides, which may adversely modulate synaptic and membrane functions; the cerebral energy metabolism and particularly the hexokinase reaction, by Al replacement of the Mg-ion in the Mg-ATP complex, so that phosphorylation of glucose to G6P is blocked; the interaction of Al with calmodulin by displacement of the Ca-ion and subsequent formation of a stable Al-calmodulin complex with a cytotoxic effect due to the increase in the intracellular calcium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis of cerebral atrophy in uraemia. State of the art.

This paper discusses the possible pathogenesis of the cerebral atrophy (CA) observed in a large percentage of uraemic patients, taking the form of prevalently cortical damage (cortical atrophy) and/or subcortical enlargement of ventricular cavities (subcortical atrophy). This central nervous system pathology seems to share very little either with the better known 'dialysis encephalopathy' or with the 'acute encephalopathy syndrome', even though sporadic cases of both these forms have shown concomitant CA. Histopathologically it offers the picture of loss of neurons and nerve fibres and can thus be compared with uraemic peripheral nervous system damage. CA is unquestionably important because of its implications in terms of impairment of superior cortical functions, just as in CA of non-uraemic aetiology. A first aetiopathogenic hypothesis might include endogenous uraemic intoxication to the nerve tissue, believed responsible for peripheral uraemic neuropathy, but other possibilities merit consideration: vascular calcification secondary to hyperparathyroidism, blood lipid disorders, and systemic hypertension--factors that contribute to impairing the brain vasculature, with cascade effects on brain tissue oxygenation, neuronal metabolism, and energy exchanges. Tissue oxygenation is already jeopardized in the uraemic patient by the concomitant chronic anaemia and by cardiac insufficiency in cases with hypertensive heart disease. In dialysis patients with volume-dependent hypertension the brain may be further damaged by abrupt pressure changes produced by dialytic ultrafiltration; these constitute a severe challenge to cerebral blood flow autoregulation. Cyclic variations of brain tissue hydration connected with regular dialysis treatment may have adverse effects on neurotransmitter functions, particularly those mediated by neuropeptidergic systems. Chronic intoxication may result from oral Al(OH)3 of phosphorus-chelating agents: in animal studies and clinical observations in non-uraemic populations the neurotoxic potential of Al is indicated by a significant correlation between histological neuronal damage, impaired function, and Al concentration in brain tissues. In addition, a concausal role of malnutrition in central nervous system damage in the uraemic patient cannot be overlooked, since malnutrition is known to give rise to functional and structural alterations in non-uraemic human pathology. In the light of these clinical observations and experimental findings, it would appear that the prevention of CA in uraemia is today feasible.

Physiopathology and clinical aspects of diabetic nephropathy.

End-stage renal failure is a severe and relatively frequent complication of insulin-dependent diabetes, also representing the only growing cause of uremia requiring replacement therapy in Western countries. Five principal pathogenic factors are to be considered: genetic, immunologic, hemorheologic, biochemic, and hemodynamic; of these, nonenzymatic glycosylation of proteins and glomerular hyperfiltration appear to be most important. In the last few years, a better understanding of the natural history of type I diabetes has been gained, with particular significance attributed to the stage of the disease defined as incipient diabetic nephropathy which is characterized by microalbuminuria. However, advances in pathophysiologic notions have not always been followed by corresponding results in the prevention and therapy of diabetic nephropathy; possible reasons for this are briefly discussed. In spite of these uncertainties, the importance of achieving the best possible correction of glycemic homeostasis and of albeit initial elevations in the arterial pressure appears to be well established.