Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts.

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

Effects of dietary salt on intrarenal angiotensin system, NAD(P)H oxidase, COX-2, MCP-1 and PAI-1 expressions and NF-kappaB activity in salt-sensitive and -resistant rat kidneys.

BACKGROUND: Chronic consumption of a high-salt diet causes hypertension (HTN) and renal injury in Dahl salt-sensitive (SSR) but not salt-resistant rats (SRR). These events are, in part, mediated by oxidative stress and inflammation in the kidney and vascular tissues. Activation of the angiotensin II type 1 (AT(1)) receptor plays an important role in the pathogenesis of oxidative stress and inflammation in many hypertensive disorders. However, the systemic renin-angiotensin system (RAS) is typically suppressed in salt-sensitive HTN. This study was designed to test the hypothesis that differential response to a high-salt diet in SSR versus SRR may be related to upregulation of tissue RAS and pathways involved in inflammation and reactive oxygen species (ROS) production. METHODS AND RESULTS: SSR and SRR were studied 3 weeks after consumption of high- (8%) or low-salt (0.07%) diets. The SSR consuming a low-salt diet exhibited significant increases in AT(1) receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-I kappaB in the kidney as compared to those found in SRR. The high-salt diet resulted in severe HTN and proteinuria (in SSR but not SRR) and marked elevations of renal tissue monocyte chemoattractant protein 1, p22(phox), NADPH oxidase subunit 4, angiotensin-II-positive cell count, infiltrating T cells and macrophages and further increases in AT(1) receptor, COX-2, PAI-1 and phospho-I kappaB in the SSR group. The high-salt diet significantly lowered plasma renin activity (PRA) in SRR but not in the SSR. COX-1 abundance was similar on the low-salt diet and rose equally with the high-salt diet in both groups. Among subgroups of animals fed the low-salt diet, kidney glutathione peroxidase (GPX) abundance was significantly lower in the SSR than SRR. The high-salt diet raised GPX and mitochondrial superoxide dismutase (SOD) abundance in the SRR kidneys but failed to do so in SSR. Cu/Zn-SOD abundance was similar in the subgroups of SSR and SRR fed the low-salt diet. The high-salt diet resulted in downregulation of Cu/Zn-SOD in SSR but not SRR. CONCLUSIONS: Salt sensitivity in the SSR is associated with upregulations of the intrarenal angiotensin system, ROS-generating and proinflammatory/profibrotic proteins and an inability to raise antioxidant enzymes and maximally suppress PRA in response to high salt intake. These events can contribute to renal injury with high salt intake in SSR.

Heat shock proteins and cardiovascular disease.

The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension.

Mycophenolate mofetil treatment reduces cholesterol-induced atherosclerosis in the rabbit.

Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the development of atherosclerosis. We tested the effect of mycophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n=10 each) of New Zealand White (NZW) rabbits were fed a 1% cholesterol diet for 12 weeks. One group received MMF (CHOL+MMF group) by gastric gavage (30 mg/kg daily) and the other group (CHOL) received the same volume of saline by the same route. There were no differences in the serum cholesterol (mean values > or =30 mmol/l in both groups after 2 weeks) or in the triglyceride, blood sugar, total protein, and albumin serum levels and weight gain in both groups of animals. The cholesterol-fed untreated rabbits had atherosclerotic plaques covering 43.9.1+/-SD 16.40% of their thoracic aorta and 41.9+/-22. 59% of their abdominal aorta, while the MMF treated group had 18. 5+/-7.17% and 17.7+/-9.71%, respectively (P<0.01). The cholesterol content of the aorta (mg/g) in the cholesterol-fed untreated group was 4.61+/-SD 1.21 in the thoracic aorta and 4.54+/-2.07 in the abdominal aorta, whereas the MMF treated group had and 2.83+/-0.84 and 2.77+/-1.44, respectively (P<0.01). Infiltrating macrophages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta were 58.4+/-SD26.16 in the CHOL group and 8.5+/-5.51 in the CHOL+MMF group: (P<0.001). CD18 positive cells/100 nuclei were 27.4+/-17.6 in the CHOL group and 5.3+/-3.82 in the CHOL+MMF group (P<0.01), and the intima/media ratio was 0.66+/-0.11 in the CHOL group and 0. 30+/-0.09 in the MMF treated rabbits (P<0.001). MMF also reduced proliferating smooth muscle cells (HHF35 positive) infiltrating between the macrophages. These results indicate that MMF ameliorates importantly the atherogenic potential of a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinely in various clinical conditions with relatively minor side effects, consideration may be given to its use as adjuvant therapy in atherosclerotic cardiovascular disease.

Family studies of the HLA system in acute post-streptococcal glomerulonephritis.

Eighteen families (67 siblings) of index cases with acute post-streptococcal glomerulonephritis (APSGN) were typed for HLA-A,B,C,DR antigens. Twenty cases of clinical nephritis and 10 cases of asymptomatic disease with detected among the sibships. In eight families with more than one affected individual comprising 18 sib pairs random segregation of paternal and maternal HLA haplotypes was found (0.5 less than p less than 0.06), but some antigens (CW1, DR3) showed deviation from the expected 1:1 ratio in affected and nonaffected siblings in backcross families. We had previously noticed the existence of Mendelian recessive ratios in APSGN but in the absence of clear evidence for a dominant or recessive mode of inheritance for a putative APSGN susceptibility gene(s), pedigree data were analyzed twice for linkage with HLA using the two genetic models. The data obtained, although not sufficient to reject the hypothesis of linkage, provide no support for it. Comparison of the frequency of 61 HLA antigens among 42 unrelated APSGN patients and 109 controls, showed that HLA-DRW4 is more frequent among the former (pc = 0.0500).

Melatonin prevents oxidative stress resulting from iron and erythropoietin administration.

Intravenous iron (Fe) and recombinant human erythropoietin (rHuEPO) are routine treatments in the management of anemia in patients with chronic renal failure. We investigated the oxidative stress acutely induced by these therapies and whether pretreatment with oral melatonin (MEL) would have a beneficial effect. Nine patients (four women) were studied within 1 month of entering a chronic hemodialysis program in the interdialytic period. Plasma malondialdehyde (MDA), red blood cell glutathione (GSH), and catalase (CAT) activity were measured in blood samples obtained before (baseline) and 1, 3, and 24 hours after the administration of Fe (100 mg of Fe saccharate intravenously over 1 hour) or rHuEPO (4,000 U intravenously). One hour before these treatments, patients were administered a single oral dose of MEL (0.3 mg/kg) or placebo. Each patient was studied on four occasions, corresponding to studies performed using either placebo or MEL in association with intravenous Fe and rHuEPO administration. Baseline data showed increased oxidative stress in patients with end-stage renal failure. Increments in oxidative stress induced by Fe were more pronounced at the end of the administration: MDA, baseline, 0.74 +/- 0.09 nmol/mL; 1 hour, 1.50 +/- 0.28 nmol/mL (P: < 0.001); GSH, baseline, 2.51 +/- 0.34 nmol/mg of hemoglobin (Hb); 1 hour, 1.66 +/- 0.01 nmol/mg Hb (P: < 0.001); and CAT activity, baseline, 27.0 +/- 5.7 kappa/mg Hb; 1 hour, 23.3 +/- 4.2 kappa/mg Hb (P: < 0.001). rHuEPO-induced increments in oxidative stress were more pronounced (P: < 0.001) at 3 hours (MDA, 1.24 +/- 0.34 nmol/mL; GSH, 1.52 +/- 0.23 nmol/mg Hb; CAT activity, 18.0 +/- 3.1 kappa/mg Hb). MEL administration prevented the changes induced by Fe and rHuEPO and had no adverse side effects. These studies show that intravenous Fe and rHuEPO in doses commonly used to treat anemia in chronic hemodialysis patients acutely generate significant oxidative stress. Oral MEL prevents such oxidative stress and may be of clinical use.

Adult respiratory distress secondary to strongyloidiasis.

A patient with a renal transplant who was receiving immunosuppressive therapy developed the adult respiratory distress syndrome (ARDS). Numerous filariform larvae of Strongyloides stercoralis were seen in the bronchial lavage. The patient died despite intensive treatment, and the postmortem examination revealed abundant larvae of the parasite in the lungs. There were no other factors that could explain the ARDS.

Skin window immune response to normal human IgG in patients with rheumatoid arthritis and acute poststreptococcal glomerulonephritis.

The skin window technic was utilized to determine the reactivity of patients with rheumatoid arthritis (RA) and acute poststreptococcal glomerulonephritis (APSGN) to human IgG (H-IgG). The response to H-IgG was compared in nine patients with RA, 20 patients with APSGN, and 10 normal individuals. All subjects were tested concomitantly with the saline solution used as solvent for H-IgG. The normal controls and five patients were challenged, in addition, with diphtheria-tetanus-pertussis antigen (DPT) to which they had previous prophylactic exposure. The following results were obtained: 1) Four patients with RA and nine patients with APSGN responded with increased lymphocyte migration (more than 2 SD above the normal mean level) at nine and 12 hours. 2) The mean estimated immunogenic lymphocytosis (calculated subtracting the lymphocyte counts of the saline skin windows) of both patient groups was significantly higher than that of controls at the same time intervals. 3) The response of normal individuals and patients to DPT was comparable in time of appearance and intensity to the response of patients to H-IgG. Our studies that patients with RA and APSGN respond to H-IgG in a manner comparable to that observed with a known antigenic stimulus and support a clinical role for antiglobulin reactivity.

The influence of the blood levels of lead, aluminum and vanadium upon the arterial hypertension.

The present study describes the relationship between the whole blood Pb, plasma Al and plasma V levels and the arterial hypertension, for four groups of individuals: 20 normotensive azotemic patients in periodic hemodialysis (CRF), 20 hypertensive azotemic patients in periodic hemodialysis (CRF-AHT), 20 individuals with severe essential hypertension and normal renal function (AHT) and 20 individuals with normal renal function and normal blood pressure (controls) evaluated during a period of 1 year. The renal population's blood Pb was comparable with that found in the non-renal groups. Blood Pb in the essential AHT was higher than in controls (P < 0.05). CRF and CRF-AHT showed higher Al levels than those individuals with normal renal function (P < 0.01). In CRF, plasma Al did not correlate with the arterial hypertension. Plasma Al was increased in the AHT individuals (P < 0.05) with respect to the control group, suggesting the possible influence of this metal in the appearance of the arterial hypertension. In this study, the CRF-AHT patients had plasma V statistically higher (P < 0.005) than controls. However, no differences were found between plasma V of CRF and CRF-AHT groups or between AHT and controls. These results suggest that V in AHT is of doubtful significance, except maybe when the renal failure and the arterial hypertension appear together. In summary, high levels of blood Pb and plasma Al are associated with arterial hypertension in individuals without renal disease. Higher plasma V levels were not found in hypertensives with normal renal function with respect to controls.

Bone metal content in patients with chronic renal failure.

Bone accumulation of metals, other than aluminum (Al), in patients with chronic renal failure (CRF) has rarely been studied. We report the bone and blood levels of iron (Fe), vanadium (V), lead (Pb), Al and calcium (Ca) in 18 CRF patients on long-term hemodialysis and in 14 controls (C). Significant increments in mean blood Al (1,300%), V (160%) and Fe (60%) and decrease in blood Pb (-50%) were found in the patients with CRF. Renal subjects had higher bone concentrations (mean +/- S.E.M.; microgram/g of bone) of Al (CRF = 129.1 +/- 16.9; C = 12.6 +/- 2.9; P < 0.0001), Fe (CRF = 940.4 +/- 133.4; C = 263.4 +/- 49.0; P < 0.0001) and V (CRF = 2.55 +/- 0.43; C = 1.39 +/- 0.36; P = 0.0308) and lower Ca (CRF = 268.2 +/- 11.1 mg/g; C = 377.2 +/- 28.1; P = 0.0017). A positive correlation was found between bone Al and V (r = 0.355, P < 0.05). Results indicated that a significant bone accumulation of Al, Fe and V, but not Pb, occurred in the hemodialyzed azotemic individuals.

Glomerular binding sites for peanut agglutinin in acute poststreptococcal glomerulonephritis.

Streptococcal neuraminidase may be responsible for the development of auto-immune reactivity in acute poststreptococcal glomerulonephritis (APSGN). Neuraminidase may react with immunoglobulins in the circulation and with sialic acid-rich sites in the endothelial and epithelial glomerular capillary, therefore, extrinsic or intrinsic sialic acid-depleted substrate may be localized in the glomeruli. We studied renal biopsies from 17 patients with APSGN, 48 patients with other renal pathologies and 2 normal kidneys for the capacity to bind fluorescein-labelled peanut agglutinin (PNA) lectin. PNA has specificity for galactosyl radicals which are exposed after sialic acid removal. We similarly studied the kidneys of rats at intervals ranging from hours to 32 days after an intravenous injection of 0.02 units of neuraminidase per g of body weight. Five biopsies of APSGN patients and 2 biopsies from patients with renal pathologies different from APSGN showed glomerular PNA binding. Of APSGN patients, 4 corresponded to the 5 patients biopsied within 30 days of the beginning of the disease and only 1 biopsy was positive in the 12 patients who were biopsied later. The PNA binding predominated in the mesangium and the pattern was irregular and speckled. These findings suggest that sialic-acid depleted material is present in the glomeruli, early in the course of APSGN.

Extracellular neuraminidase production of streptococci associated with acute nephritis.

The possibility that streptococcal neuraminidase has a pathogenic role in acute poststreptococcal glomerulonephritis is reviewed. Experimental and clinical evidence suggesting autologous immune phenomena and anti-Ig reactivity in this disease is discussed. Neuraminidase may also induce sialic acid depletion that would be expected to result in changes of the electrical charge in the immune complex as well as in the glomerular polyanion filtration barrier. The nature of these changes will facilitate penetrability of material with nephritogenic potential. Neuraminidase production was detected in the majority of streptococcal isolates obtained from patients with glomerulonephritis and the best substrate for screening purposes appears to be bovine submaxillary gland mucin. On the basis of available evidence, it is suggested that the development of glomerulonephritis after streptococcal infection probably does not depend on neuraminidase production by the bacteria; however, this enzyme may be responsible for the anti-Ig reactivity demonstrated in some patients and thereby influence the course of the disease.

Long-term prognosis of epidemic poststreptococcal glomerulonephritis in Maracaibo: follow-up studies 11-12 years after the acute episode.

In 1968 there was an epidemic outbreak of acute poststreptococcal glomerulonephritis in Maracaibo during which 384 cases were hospitalized. Of these cases, 120 were recalled in 1974 and the results of their investigations were reported. The present work concerns 71 patients from this group followed for 11-12 years and studied with measurement of creatinine clearance (CCr), protein excretion and urine sediment analyses. Measurements of serum immunoglobulins, cryoglobulins, C3 levels and rheumatoid factor titers were also made. One patient developed uremia and is in chronic dialysis. Persistent abnormalities were detected in 21.1% of the patients. Depressed creatinine clearance was found in 12.6% of the patients and proteinuria (0.5-2.0 g/day) in 11.2%. Microscopic hematuria occurred in 4.1%. Only 2 patients wer hypertensive. Transient serological abnormalities were seen in 36 patients: elevated IgG levels in 27, serum cryoglobulins in 17 and a low C3 level in 1 patient. Cryoglobulins were found in 50% of the patients with abnormal renal findings and in 22.9% of the patients with normal renal function and urine sediment. Children (at the time of the epidemic) had urinary abnormalities less frequently (16.1%) than did adults (55.5%). Of 9 patients who had been found abnormal five years before, 3 were improved or normal, 3 were stable and 3 showed progressive disease. our studies indicate that uremia is rare in the first decade after epidemic poststeptococcal glomerulonephritis. Nevertheless, the increasing incidence of depressed renal function dictates the need for continued follow-up of this group of patients.

Histological evidence of neuraminidase involvement in acute nephritis: desialized leukocytes infiltrate the kidney in acute post-streptococcal glomerulonephritis.

Serum neuraminidase (NA, sialidase) activity has been demonstrated in acute poststreptococcal glomerulonephritis (APSGN) and implicated in the pathogenesis of the disease. Recent investigations show that neuraminidase-treated leukocytes accumulate preferentially in kidneys; therefore, we were interested in knowing if desialized cells infiltrate the kidney in APSGN. We first tested the capacity of peanut agglutinin lectin (PNA) to detect injected NA-treated leukocytes in the kidney of rats. NA-treated leukocytes were transfused and desialized cells were identified with fluorescein-conjugated peanut lectin (FITC-PNA) in renal tissue. PNA positive cells were identified in rat kidneys 3 hours after injection (glomeruli: 1.67 +/- 0.19 cells/g.c.s.; interstitium: 0.50 +/- 0.12 cells/int). Sections from available renal biopsy material of APSGN (n = 11), other glomerulonephritis (n = 28) and normal kidneys (n = 5) were double-stained with FITC-PNA and with monoclonal antibody to the CD11b molecule, which is expressed on polymorphonuclear and monocytes the main types of infiltrating cells during APSGN. Desialized (FITC-PNA positive) cells were found in the glomeruli (2.17 +/- SEM 0.22 cells per glomerular cross section, g.c.s.) and interstitium (0.61 +/- 0.15 cells per 0.0625 mm2, int) in all biopsies of APSGN. Only in 2 of 28 other glomerulonephritis showed desialized cells. More than 80% of the PNA positive cells in APSGN expressed the CD11b molecule and the infiltration was more intense in early biopsies. In conclusion, desialized leukocytes represent a significant part of the inflammatory infiltrate in APSGN. This finding gives support for a role of NA in the disease and provides clinical validation for a mechanism of renal cellular infiltration suggested by experimental observations.

Short-term treatment with captopril in hypertension due to acute glomerulonephritis.

We report that the inhibition of the angiotensin converting enzyme is an effective short-term treatment of low-renin hypertension in acute glomerulonephritis (AGN). We treated 9 patients who had AGN with moderate to severe hypertension and suppressed plasma renin activity with 25-50 mg of captopril per os every 6-8 hours. Control of blood pressure was achieved in 1-2 hours and maintained thereafter. Captopril therapy was associated with an increase in plasma renin activity, a decrease in plasma aldosterone and an increase in the urinary excretion of prostaglandin E2 and kallikrein, independent of changes in urine output. Creatinine clearance increased 39.6 +/- SE 15.2% with captopril and decreased in the postcaptopril period, suggesting that captopril exerted a reversible effect on glomerular filtration rate, possibly modifying intrarenal vasoconstriction. Our study shows that rapid control of hypertension in AGN may be obtained with oral inhibition of the angiotension converting enzyme. Stimulation of PGE2 and kinins, as well as angiotensin II blockade appear to contribute to the hypotensive effect of the drug; by inference, the suppressed activity of vasodilator systems seems to play a significant role in the hypertension of AGN.

Effect of prostaglandin synthesis inhibition on glomerular filtration rate in renal transplant recipients.

To determine the influence of prostaglandin (PG) synthesis inhibition on the renal function in renal transplant recipients, we carried out a crossover, double-blind, placebo controlled study of 18 ambulatory patients. Glomerular filtration rate (GFR) was measured using 51-Cr EDTA, before and after indomethacin (50 mgr. three times a day for three days), and placebo. Overnight urinary PGE excretion decreased 88.9 +/- SEM 4.81% after indomethacin, but remained unchanged following placebo. GFR decreased 15.3 +/- SEM 3.94% (p = 0.0139) after indomethacin. There was no correlation between PGE urinary excretion and GFR changes. Pre-existing renal functional impairment was not a significant risk factor. Caution should be exercised when using non-steroidal anti-inflammatory drugs in renal transplant patients.

Cationic antigens in poststreptococcal glomerulonephritis.

Antigen charge is an important factor in the pathogenesis of experimental immune complex glomerulonephritis. Its potential role in man was investigated in post-streptococcal glomerulonephritis, a disease where the causative agent is known. Cationic, extracellular streptococcal antigens were detected in 8 of 18 renal biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). The antigen was found mainly in earlier biopsies in which both IgG and IgM were present. Patients' sera taken at the time of biopsy contained antibody to cationic, streptococcal antigens. Cationic moieties are known to have affinity for the glomerular basement membrane and it is possible that the type of antigen described here initiates APSGN via in situ immune complex formation.

Removal of trace metals by continuous ambulatory peritoneal dialysis after desferrioxamine B chelation therapy.

We studied the removal of aluminum (Al), iron (Fe), copper (Cu), lead (Pb) and zinc (Zn) with continuous ambulatory peritoneal dialysis, before and after desferrioxamine B (DFO) administration (2 g intravenously) in two patients with chronic renal failure and Al-related osteopathy. Both patients had 4 peritoneal dialysis exchanges (2 liters each) per day. Blood concentrations of Al increased 413% (patient A) and 190% (patient B) after DFO. Patient B had a 15% increase in Fe; other metals remained unchanged. Dialysate efflux Al concentrations had peak post-DFO increments of 761% and 840% in patients 1 and 2, respectively. Peak post-DFO increments in Fe dialysate concentration were 342% and 89.5% in the respective patients. Dialysate/plasma (D/P) concentration ratios of Al increased from pre-DFO levels (mean +/- SEM) of 0.370 +/- 0.048 to 0.523 +/- 0.061 after DFO; similarly, Fe D/P ratios increased from 0.259 +/- 0.053 to 0.446 +/- 0.075 with DFO therapy. These results indicate an increase in the ultrafiltrable proportion of Al and Fe in plasma after DFO administration. During 3 days after DFO, patient 1 had a total removal of Al and Fe of 2.9 mg and 4.9 mg, respectively. Metal removal in patient 2 was 7.6 mg of Al and 2.7 mg of Fe. Peritoneal extraction of other trace metals was minor.

Urinary prostaglandin E and kallikrein activity in glomerular hyperfiltration induced by a meat meal in man.

Because renal vasodilator systems may be involved in the physiologic response to a protein meal, we studied the relationship of prostaglandin E (PGE) and kallikrein (KE) activity to the renal hemodynamic changes induced by a meat meal. Ten normal subjects on a maintenance diet providing 1 g protein per kg and 100 mmol Na daily were studied before and after a meal of 86 g of meat protein, once without medication, and again after treatment with indomethacin (150 mg daily for 3 days before and 50 mg the morning of the test). A carbohydrate meal of similar caloric, Na and K content was used in control studies. Glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, para-aminohippurate [PAH] clearance), PGE and kallikrein urinary excretion were determined. All studies were performed during water diuresis to avoid bladder catheterization. The protein load induced an increase in GFR (ml/min, mean +/- s.e.m.: baseline 107.2 +/- 6.05, peak postmeal 146.4 +/- 6.79, p less than 0.01) and RBF (baseline 529.7 +/- 42.9, postmeal 678.9 +/- 61.9, p less than 0.05). Renal hemodynamic changes were unrelated to changes in urinary PGE and KE excretion. Indomethacin treatment inhibited PGE excretion by 73% during the test meal but did not modify the protein-induced hyperfiltration. Our results suggest that these renal vasodilator systems are not primarily responsible for the hyperfiltration response. In addition, the data show that inhibition of prostaglandin synthesis is not a practical approach to prevent glomerular hyperfiltration in clinical practice.

Intrarenal manometry in the diagnosis of acute rejection superimposed on acute tubular necrosis in renal transplantation.

We used fine-needle intrarenal manometry as a guide for detection of acute rejection superimposed on protracted oliguric acute tubular necrosis occurring in the postoperative course of human renal transplantation. We followed intrarenal pressure (IRP) in 31 patients who received 32 renal transplants, 12 from living related donors and 20 from cadaveric donors. There were 19 rejection episodes and 10 episodes of transient cyclosporin A (CyA) nephrotoxicity. Nine patients had posttransplant acute renal failure. Levels of IRP (mmHg) in acute rejection were (mean +/- SD) 48.6 +/- 11.1, significantly higher (p less than 0.001) than the levels in CyA nephrotoxicity (28.2 +/- 5.21), acute tubular necrosis (24.5 +/- 5.5) and normal functioning grafts (26.4 +/- 6.63). Antirejection treatment was associated with return to normal of IRP after 10 days. Intrarenal manometry was performed routinely ever 2-3 days in patients who had postoperative acute renal failure. Increments in IRP were detected on the 7-10th postoperative day in 7 patients who had 10-25 days of post-transplant oliguria. Renal biopsy findings were compatible with acute rejection, and the patients responded to intravenous bolus of steroids. We suggest that fine-needle intrarenal manometry is a reliable test for the detection of acute rejection in circumstances when traditional parameters of altered renal function cannot be evaluated.