[C-reactive protein in the assessment of iron status in patients on hemodialysis]. / La proteina C-reattiva nella valutazione del bilancio del ferro dei pazienti in emodialisi.

Iron availability is a prerequisite for an efficient hematopoietic response to erythropoietin. Dynamic evaluation of iron status is difficult in hemodialysis patients and can be further complicated by the presence of an inflammatory state. Several cytokines, in particular interleukin 6 (IL-6), stimulate the production of hepcidin in the liver. This hormone is the main regulator of the extracellular iron concentration through its effect on the iron channel ferroportin, present in several cell types. IL-6 is also the major stimulus for the production of C-reactive protein (CRP), a nonspecific but sensitive marker of inflammation. Measurement of hepcidin is technically difficult and has so far been limited to research. On the other hand, measurement of CRP, which is both sensitive and easily measurable with automated techniques, might possibly be used as a surrogate measure of iron status in hemodialysis patients. Several studies have suggested the value of CRP in this context, but they dealt with small patient groups and single-time-point measurements. Even the definition of normal values of CRP in dialysis patients is uncertain. During the period between 2003 and 2007, we performed 8322 measurements of CRP in 401 hemodialysis patients followed for 3-60 months. All parameters of iron balance (serum iron, TSAT, percent hypochromic RBC and Hgb concentration in reticulocytes) were clearly affected by the presence of an inflammatory state. We believe that measurement of CRP must be part of the routine hematological assessment of hemodialyzed patients to allow the correct interpretation of data in anemia treatment.

[New therapies for ADPKD]. / Nuove prospettive terapeutiche nel rene policistico.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common causes of chronic renal failure. Currently, there are no established specific treatments to prevent or slow down the progression of the disease. The last decade, however, has witnessed a significant effort to improve the prognosis of patients with ADPKD. Patients with chronic renal failure are now offered different therapies such as a low-protein diet, angiotensin II converting enzyme inhibitors or receptor blockers, and statins. In addition, a number of important breakthroughs have greatly advanced our understanding of the pathogenesis of ADPKD. These have led to several novel therapeutic approaches directed either at inhibiting the proliferation of cyst epithelium (antisense C-myc oligonucleotides, EGFR tyrosine kinase inhibitors, caspase inhibitors, paclitaxel, rapamycin, CDK inhibitors) or at decreasing cyst fluid secretion (Na transport inhibition, vasopressin V2 receptor antagonists, somatostatin). Some of these novel approaches have not yet been tested in the clinical setting, others are the object of ongoing studies. It seems likely that in the next few years treatment of patients with ADPKD will radically change from one of passive follow-up to one of active treatment, probably with protocols combining different drugs targeting the different pathogenetic mechanisms of the disease.

Is anemia of chronic renal failure related to secondary hyperparathyroidism?

A pathogenetic role of secondary hyperparathyroidism in the anemia of chronic renal failure has been suggested. To investigate this relationship, the biochemical factors of secondary hyperparathyroidism (calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone) were correlated with hematocrit levels in 96 long-term hemodialysis patients. We also compared hematocrit values before and after parathyroidectomy in 18 patients. No correlation between hematocrit level and biochemical indices of secondary hyperparathyroidism could be found. However, in 44% of the patients with parathyroidectomies, the hematocrit reading increased after surgery. The importance and possible cause of this improvement of anemia in this group is discussed.

Pregnancy-induced hypertension in rats with adriamycin nephropathy is associated with an inadequate production of nitric oxide.

Hypertensive complications are relatively common in pregnancy, particularly in the presence of preexisting renal disease. Although the pathogenesis of such complications is still unknown, recent animal studies have suggested that it may be related to impaired synthesis of nitric oxide (NO). Rats with adriamycin nephropathy develop a "preeclamptic-type" pregnant state characterized by elevated blood pressure, lack of hyperfiltration, and enhanced proteinuria. Preliminary studies with this model have implicated inadequate NO synthesis in the development of preeclamptic-like pregnancy. The aim of the present study was to confirm this hypothesis. Pregnant rats, both normal (PREG) and those with adriamycin nephropathy (AN-PREG), received 100 mg/L N omega-nitro-L-arginine methyl ester PO from the middle of gestation to term (day 11, term approximately 22 days). One group of AN-PREG rats received either L-arginine or D-arginine (2 g/L) from midpregnancy. At term, systolic pressure, mean arterial pressure, urinary metabolites of NO, creatinine clearance, and urinary protein were assessed. At term, compared with virgin rats with adriamycin nephropathy, untreated AN-PREG rats had increased systolic pressure, mean arterial pressure, and proteinuria (mean arterial pressure, 124 +/- 2.5 versus 99.7 +/- 1.6 mm Hg [P < .05]; proteinuria, 434 +/- 58 versus 216 +/- 63 mg/d [P < .05]). Creatinine clearance did not change (1.68 +/- 0.23 versus 1.35 +/- 0.09 mL/min, P = NS). In PREG rats, urinary metabolites of NO increased approximately threefold at term pregnancy compared with control. By contrast, in AN-PREG rats, excretion of urinary metabolites of NO increased only by approximately 1.7-fold (P < .01) versus PREG rats. With the exception of AN-PREG rats, inhibition of NO synthesis with N omega-nitro-L-arginine methyl ester enhanced blood pressure and decreased creatinine clearance but did not influence proteinuria. Excretion of urinary metabolites of NO was similarly inhibited in all rats. In AN-PREG rats, L-arginine normalized blood pressure (91 +/- 2.15 mm Hg) and lowered proteinuria partially but significantly. D-Arginine had no effect. In summary, AN-PREG rats are unable to adequately increase NO synthesis when physiologically required. Correction of this deficit by L-arginine treatment induced a significant clinical improvement.

Minimal-change nephropathy and malignant thymoma.

A 56-year-old man had fever, precordial pain, and a mediastinal mass. The mass disappeared two months later and the patient remained asymptomatic for 2 1/2 years. At that time a full-blown nephrotic syndrome developed, with minimal-change glomerulopathy. The chest x-ray film showed the reappearance of a giant mediastinal mass. On biopsy of the mass, malignant thymoma was diagnosed. Association between minimal-change disease and Hodgkin's disease is well known, while the association with malignant thymoma has not been previously reported. The relationship between malignant thymoma and minimal-change disease is discussed, and a possible pathogenic mechanism involving cell-mediated immunity is proposed.

Effect of the prostacyclin analogue iloprost in sodium-depleted rats pretreated with captopril.

Previous studies have shown that administration of captopril to sodium-depleted rats decreases the glomerular filtration rate (GFR) and blunts the increase in glomerular prostacyclin synthesis normally occurring in response to sodium depletion. To clarify the relationship between these two responses, iloprost, a stable analogue of prostacyclin, was administered to Na-depleted, captopril-treated (LNC) rats. At a dosage not affecting systemic blood pressure (12.5 ng/kg/min), iloprost increased GFR in LNC rats by 25% (from 0.26 +/- 0.03 to 0.35 +/- 0.03 ml/min/100 g body wt, P less than 0.01), without significant effects on renal plasma flow. No effect was observed in control rats. The results suggest that altered prostacyclin synthesis could contribute to the decrease of GFR in this model.

Effect of sodium and chloride depletion on urinary prostaglandin F2 alpha excretion in potassium loaded rats.

Previous studies have shown that the urinary excretion of prostaglandin (PG) F2 alpha is stimulated by potassium (K) loading. Because changes of sodium chloride (NaCl) intake also affect renal PG production, in this study we investigated the interaction between the effect of K and that of concomitant reduction of Na and Cl intake. The urinary excretion of PGF2 alpha and PGE2 was measured in 12 groups of female rats on normal, high or low K intake. Na and Cl intake were adjusted so that rats had normal intake (controls, C), were selectively Cl depleted (CD), selectively Na depleted (ND) or Na and Cl depleted (NCD). In rats with normal K intake, urinary PGF2 alpha was not modified by changes of Na or Cl intake, whereas PGE2 was increased in by Cl depletion (in both NCD or CD groups). Potassium chloride loading increased urinary PGF2 alpha and selective Na depletion (ND group) induced a further increase. On the other hand, PGF2 alpha was not stimulated when K load was associated with Cl depletion. Urine PGF2 alpha was directly correlated with plasma aldosterone and urinary kallikrein. Urinary PGE2 did not change with K-loading. The results suggest that PGF2 alpha participates in the renal adaptation to KCl-loading but not when K is accompanied by non-Cl anions.

Sodium loading and renal prostaglandins in old rats.

1. Previous studies have shown that altered synthesis of prostaglandins (PGs) in the kidney of ageing rats contributes to impaired Na conservation during sodium deprivation. In the present study, we wished to assess whether the disturbance of prostaglandin synthesis also affects the response to sodium loading in old rats. 2. We measured the urinary excretion of thromboxane B2 (TXB2), 6-keto PGF1 alpha (6KPGF1 alpha) and PGE2 in young (3-4 months) and old (20-21 months) rats after 24, 48 and 72 h of Na loading. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na loading. 3. Young and old rats excreted similarly the Na load. The urinary excretion (U) of TXB2 and 6KPGF1 alpha were unchanged during Na load in young rats. U6KPGF1 alpha, which was significantly higher in old rats and UTXB2 which also tended to be elevated, decreased in old rats with Na loading. Sodium loading was associated with a transient increase of UPGE2 in young, but not in old rats. 4. TXB2 synthesis was increased in all portions of the kidneys of old rats. 6KPGF1 alpha production was elevated in glomeruli and cortex and that of PGE2 in cortex. In medulla and papilla only TXB2 synthesis was enhanced. 5. Sodium loading did not significantly change prostanoid synthesis in the kidneys of young rats. In old rats, glomerular and cortical TXB2 decreased whereas medullary and papillary 6KPGF1 alpha increased.(ABSTRACT TRUNCATED AT 250 WORDS)

NADH-dependent prostaglandin E2-9-ketoreductase activity and prostaglandin synthesis in the Brattleboro rat kidney: effects of the antidiuretic hormone.

The activity of prostaglandin (PG)E2-9-ketoreductase (9KR), an enzyme catalyzing the conversion of PGE2 to PGF2 alpha, was significantly increased in glomerular and cortical homogenates of diabetes insipidus (DI) rats, as compared to normal Long Evans (LE) rats, and did not change with ADH treatment. Medullary 9KR was similar in the three groups and papillary 9KR was increased, but not significantly, in both groups of DI rats. Km values for PGE2 and NADH were compared in the various compartments of the kidney. Levels of 9KR were not correlated with the PGE/PGF ratio in urine or supernatants. The synthesis of PGE2 and PGF2 alpha by isolated glomeruli was increased in DI rats. This was not reversed by ADH treatment, PGE2 synthesis increasing even further, especially in the presence of arachidonic acid. In contrast, medullary slices produced significantly less PGs in DI than in LE rats and returned to normal with ADH treatment. Papillary slices produced similar quantities of prostaglandins in all groups. The results do not support the concept that the alterations in PG synthesis observed in DI rat are related only to changes in 9KR activity, but do not exclude the possibility that the enzyme participates in the regulation of PG biosynthesis.

Endogenous digoxin-like factor raises blood pressure and protects against digitalis toxicity.

Digoxin-like immunoreactive factor (DLIF) is an endogenous natriuretic material which causes diuresis and natriuresis after salt or fluid loading and which may play a pathogenetic role in various hypertensive states. In order to study the cardiovascular effects of DLIF, we administered partially purified material (500 ng/kg) iv to normal rats. DLIF administration caused a significant rise in blood pressure, induced a brisk diuresis, and slowed the heart rate. In addition, DLIF protected against digitalis toxicity. While iv digoxin, 1 mg/kg, uniformly produced lethal arrhythmias, administration of DLIF 15 min prior to digoxin infusion consistently protected against arrhythmias. These findings support the theory that DLIF may play a role in hypertension. In addition, DLIF may compete with digoxin for cardiac receptors.

Atrial natriuretic peptide administration to normal and salt depleted rats--effects on digoxin-like immunoreactive factor, aldosterone, ACTH, and renal function.

In view of the known interrelationships between renin, aldosterone, and atrial natriuretic peptide (ANP), we sought to examine whether there also exists an interaction between ANP and digoxin-like immunoreactive factor (DLIF). We therefore studied the effects of ANP administration on normal and salt-depleted rats, and measured the effects on blood pressure, urine output, glomerular filtration rate, sodium excretion, aldosterone, ACTH, and DLIF levels. ANP administration resulted in a significant elevation of sodium excretion and glomerular filtration rate and a fall in blood pressure. DLIF concentrations in plasma rose significantly, as did urinary DLIF excretion. ANP administration resulted in a fall in aldosterone as well as ACTH. These observations suggest that ANP has a direct inhibitory effect on ACTH secretion. Our findings support the concept of an interrelationship between ANP and DLIF.

Diminished chemokine and cytokine-induced adhesion of CD4+ T cells to extracellular matrix ligands in patients with end-stage renal failure.

BACKGROUND: Cell-mediated immunity is impaired in uremia. Cell-matrix interactions of immune cells such as CD4+ T lymphocytes with extracellular matrix are an important requirement for an intact immune response. The adherence of CD4+ T cells of healthy subjects (normal T cells) to ECM components is inhibited in the presence of uremic serum. Such decreased adhesive capacity is also found in T cells of dialysis patients. Various chemokines and cytokines affect the attachment of CD4+ T cells to ECM. OBJECTIVE: To evaluate chemokine (MIP-1 beta and RANTES) and tumor necrosis factor-alpha-induced adhesion of CD4+ T cells to ECM in a uremic milieu. METHODS: We examined adhesion of normal CD4+ T cells (resting and activated) to intact ECM in response to soluble or bound chemokines (MIP-1 beta and RANTES) and to TNF-alpha following incubation in uremic versus normal serum. Thereafter, we evaluated the adhesion of resting CD4+ T cells from dialysis patients in a similar fashion and compared it to that obtained from a healthy control group. RESULTS: Addition of uremic serum diminished soluble and anchored chemokine-induced attachment of normal resting and activated CD4+ T cells to ECM compared to a normal milieu (a peak response of 10-11% vs. 24-29% for soluble chemokines, P < 0.001; 12-13% vs. 37-39% for bound chemokines on resting cells, P < 0.01; and 18-20% vs. 45-47% for bound chemokines on activated cells, P < 0.02). The same pattern of response was noted following stimulation with immobilized TNF-alpha (7 vs. 12% for resting cells, P < 0.05; 17 vs. 51% for activated cells, P < 0.01). Adherence of dialysis patients' cells to ECM following stimulation with both bound chemokines was reduced compared to control T cells (15-17% vs. 25-32%, P < 0.0000). In contrast, adherence following stimulation by TNF-alpha was of equal magnitude. CONCLUSIONS: Abnormal adhesive capacity of T lymphocytes to ECM in uremia may, in part, be related to a diminished response to MIP-1 beta, RANTES and TNF-alpha. However, whereas reduced adhesion to chemokines was present in both normal CD4+ T cells in a uremic environment and in dialysis patients' T cells, TNF-alpha-induced adhesion was found to be inhibited only in normal cells in a uremic milieu.

Effect of propranolol treatment on the urinary excretion of prostaglandins E2 and F2 alpha in patients with essential hypertension.

The 24-h urinary excretion of prostaglandins (PG) E2 and F2 alpha, which reflects the renal synthesis of these substances, was measured by radioimmunoassay in 10 patients with essential hypertension before and after treatment with propranolol. In addition, changes in the urinary excretion of PGE2 and PGF2 alpha after furosemide injection were also studied before and after propranolol treatment. The urinary excretion of PGE2 was significantly increased after propranolol treatment, whereas that of PGF2 alpha did not change. An enhanced response in PGE2 excretion after furosemide injection was observed after propranolol treatment. In contrast PGF2 alpha increased in response to furosemide before, but not after, propranolol treatment. Changes in renal hemodynamics induced by propranolol seem to be the main factor in PGE2 alpha increase. However, an indirect effect of beta-blockade or a direct effect on the enzymes governing renal PG synthesis cannot be ruled out.