Mauro Rathaus

Monoclonal lymphocyte proliferation and bcl-2 rearrangement in essential mixed cryoglobulinaemia

Abstract. A patient with essential mixed cryoglobulinaemia (EMC) type II and hepatitis C virus (HCV) infection, in whom immunophenotypic and genotypic studies demonstrated a clonal proliferation of B lymphocytes, is described. Fluorescent in situ hybridization with probes to Ig heavy chain gene and to the oncogene bcl‐2 demonstrated a translocation of bcl‐2 to the immunoglobulin heavy chain locus on chromosome 14. A sharp rise in the level of the monoclonal IgM was associated with a second genetic aberration [t(8:22) (q24:q11)]. No other clinical evidence of disease progression could be demonstrated. Low grade lymphoproliferative disorder with typical cyto‐genetic abnormalities developed on the background of EMC and HCV. Clinical progression was associated with a second genetic abnormality involving the myc oncogene. It is possible that HCV chronic infection may indirectly influence oncogenes associated with lymphoma.

Effect of Tetrahydrobiopterin on Blood Pressure in Rats after Subtotal Nephrectomy

Background: Previous studies have shown that endothelial dysfunction after 5/6 nephrectomy (5/6 Nx) in rats is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. Blood pressure is significantly increased by day 10 after surgery. Tetrahydrobiopterin (BH4) is a key cofactor of NO synthase. Suboptimal levels of BH4 result in uncoupling of NO synthase, low NO synthesis and augmented production of superoxide anions. The aim of this study was to evaluate whether BH4 supplementation may improve NO production and prevent the increase of blood pressure after 5/6 Nx. Methods: Three groups were evaluated: 5/6 Nx (untreated rats), BH4 (5/6 Nx rats treated with BH4, 10 mg/day i.p. for 10 days) and L-ARG (5/6 Nx rats treated with L-arginine, 260 mg/kg BW, p.o for 10 days). Systolic blood pressure (SBP), urinary nitrate excretion (UNO3) and creatinine clearance (CCR) were measured before surgery and on days 3 and 10 after surgery. Endothelial NO synthase (eNOS) protein content of mesenteric resistance vessels was measured at the end of the study. Results: SBP increased from 107 ± 2 to 127 ± 4 mm Hg in untreated 5/6 Nx rats (p < 0.01). By contrast, rats treated with BH4 or L-ARG remained normotensive. Ten days after 5/6 Nx, creatinine clearance decreased similarly in all groups. Both BH4 and L-ARG supplementation markedly increased UNO3 excretion. The mesenteric vascular expression of eNOs protein was significantly higher in BH4 but not in L-ARG, compared with Nx rats. Conclusions: BH4 supplementation prevents the earlier increase in blood pressure observed in rats after 5/6 Nx, possibly by upregulating eNOS in resistance vessels.

Captopril, but not diltiazem, favorably affects the course of early chronic renal disease in rats

The concepts that increased intracellular Ca2+ content and increased glomerular capillary pressure play an important role in the progression of chronic renal diseases has led to the suggestion that treatment with calcium-blocking agents (diltiazem; CBB) or converting enzyme inhibitors (captopril; CEI) may be indicated to prevent renal failure. We studied the effects of CCB and CEI on the early course of adriamycin (ADR) nephropathy, where glomerular pressure has been shown to be unchanged, blood pressure was only mildly elevated and renal failure incipient. Animals were studied 2, 7, 12, 16 and 20 weeks after the second injection of ADR, 2 mg/kg. In treated rats, blood pressure remained normal. At the end of the study, proteinuria and serum creatine were lower in ADR-CEI than in ADR rats (149 +/- 42 vs. 616 +/- 90 mg/day, p less than 0.01 and 0.36 +/- 0.04 vs. 0.58 +/- 0.02 mg%, p less than 0.01, respectively). ADR-CCB had values similar to those of untreated ADR rats. Mesangial expansion and focal glomerulosclerosis were present only in ADR and ADR-CCB rats, whereas in ADR-CEI rats the glomeruli were virtually normal. Glomerular 45Ca uptake was increased in ADR, decreased in ADR-CCB rats, and normal in ADR-CEI. Glomerular 6-keto PGF1 alpha and TxB2 were significantly increased in ADR rats, and both treatments decreased TxB2. The results suggest that endogenous angiotensin II is important for the early progression of glomerular injury toward renal insufficiency, while tissue Ca2+ accumulation may play an important role in more advanced phases.

Increased Renal Prostaglandins in Normal Pregnancy and in Pregnancy with Hypertension

The 24-hour urinary excretion of prostaglandins (PGs) E2 and F2 alpha (which reflects the renal synthesis of these substances) was measured by radioimmunoassay in normal nonpregnant women (NW, n = 23), nonpregnant women suffering from essential hypertension (HW, n = 23), normal pregnant women (NP, n = 24) and women with hypertension in pregnancy (HP, n = 14). All pregnant women were in the third trimester of their pregnancy (week 24-40). The excretion of both PGE2 and PGF2 alpha was increased in NP as compared to NW. PGF2 alpha was relatively more elevated, leading to a decreased PGE2/PGF2 alpha ratio. In HP, PGE2 and PGF2 alpha excretions were even greater, and the PGE2/PGF2 alpha ratio was even lower than in NP. This contrasted with the lowered PGE2 excretion in HW. The increased renal PGs synthesis in normal pregnancy could be related to the effects on the kidney of several hormonal changes peculiar to pregnancy. In addition, the lowered PGE2/PGF2 alpha ratio suggests the possibility of an increased activity of the PGE2-9-ketoreductase, which could be related to the changes in renal sodium handling observed in pregnancy. The pattern of PGE2 excretion in HP is opposite to that observed in HW (i.e. increase rather than decrease). However, both groups share the lowered PGE2/PGF2 alpha ratio with respect to the normotensive counterparts. The causes of altered PG synthesis in pregnant women with hypertension are presently unclear.

Urinary Kallikrein in Normal Pregnancy, Pregnancy with Hypertension, and Toxemia

The 24-hour urinary excretion of kallikrein (K) and prostaglandin E2 (PGE2), which reflects their intrarenal synthesis, was measured in 7 normal women (NW), 10 women with essential hypertension (EH), 26 normal pregnant women (NP), 12 women with hypertension in pregnancy (HP), and 4 women with toxemia. All pregnant women were in the last trimester of their pregnancy (week 24-40). K was raised in NP (99.6 +/- 8.1 KU/24 h) and HP (106.5 +/- 8 KU/24 h) compared to NW (57 +/- 8.23 KU/24 h) (p less than 0.05). PGE2 excretion was decreased in EH (403.25 +/- 90.6 ng/24 h) compared to NW (508.6 +/- 80.26 ng/24 h). During pregnancy PGE2 was increased to 1,088 +/- 93.2 ng/24 h in NP and significantly more in HP, 1,885 +/- 40 ng/24 h (p less than 0.002). In this regard it differed from K. These data may suggest that, in addition to K, other factors (as angiotensin II and/or antidiuretic hormone) possibly activate renal PGE2 production in HP. In toxemia, K (23 +/- 6.1 KU/24 h) and PGE2 (583 +/- 172.83 ng/24 h) were markedly decreased. The above results suggest that the renal kallikrein-kinin and prostaglandin systems may play a role in sodium homeostasis during pregnancy. Their exact influence on the pathogenesis of hypertension in nonpregnant, pregnant, and toxemic subjects awaits further investigation.

Uremic Optic Neuropathy

A 41-year-old male patient in end-stage renal failure presented on two occasions, over an 18-month period, with painless unilateral visual deterioration and optic disc edema. Clinical findings were compatible with a diagnosis of uremic optic neuropathy. On his initial presentation, the patient refused the onset of dialysis, resulting in a permanent visual deficit of the left eye. On his subsequent admission with a similar clinical picture, this time of the right eye, dialysis combined with corticosteroid therapy was promptly instituted. This led to a rapid improvement of the visual acuity and visual field defects of the right eye concomitant with subsidence of the edema of the optic nerve head.

Early endothelial dysfunction following renal mass reduction in rats

Background Endothelial dysfunction has been previously described in severely hypertensive rats with renal mass reduction (RMR) receiving large dietary Na loads. Because hypertension and Na loading reduce endothelium‐dependent vasodilation, the effect of renal failure per se is unclear.

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)

Renal prostaglandins E2 and F2α throughout normal human pregnancy

Abstract. Twenty‐five normal pregnant women were studied sequentially at 4‐week intervals, beginning from weeks 8–16 until delivery. In eighteen women the study was repeated 6 weeks after delivery. The 24‐h urinary excretion of PGE2 and PGF2α plasma renin activity (PRA), plasma aldosterone and fractional excretion of sodium (FENa) were measured at each visit. PGE2 and PGF2α, increased progressively throughout pregnancy (867 ± 81 and 1048 ± 94 ng 24 h‐1 respectively, before week 15 and 1581 ± 175 and 2625 ± 305 ng 24 h‐1, respectively, after week 35) and returned to normal values 6 weeks after delivery (748 ± 107 and 1503 ± 165 ng 24 h‐1, respectively). PRA and aldosterone increased in a similar fashion, but values of prostaglandins did not correlate with those of PRA or aldosterone. PGE2 correlated directly with FENa but this correlation was weak. These results may suggest that tubulo‐interstitial prostaglandins play a role in the regulation of sodium homeostasis during pregnancy.

The urinary excretion of prostaglandins E2 and F2α in essential hypertension

Abstract. The 24 h urinary excretions of prostaglandins E2 (E2/d) and F2α (F2α/d) were measured in twenty‐five normal subjects and in thirty‐five patients with essential hypertension [seventeen with low renin (LRH) and eighteen with normal renin (NRH) hypertension].