Permselectivity in thin membrane nephropathy.

The glomerular permselectivity to polydisperse neutral dextrans was compared in 6 patients with thin membrane nephropathy (TMN) and 10 healthy controls. Despite having normal renal hemodynamics and minimal proteinuria, the patients with TMN had significantly increased fractional clearance of neutral molecules with Stokes radius > 42 A. Conventional theories of glomerular barrier size selectivity cannot fully explain these data since they would predict that our patients would have had nephrotic range proteinuria.

Some properties of human blood monocyte cell lysate neutral proteinase(s).

The proteinase content of highly purified preparations of human peripheral blood monocytes was investigated. Monocyte cell lysates exhibited activity at neutral pH against azocasein, 3H-labelled elastin as well as several synthetic substrates used to detect serine proteinases (EC 3.4.21.-) of human polymorphonuclear leucocytes. The cell lysates also contain at least two acid proteinases. The levels of neutral proteinase activity in monocytes was considerably less than that found in polymorphonuclear leucocytes. The effect of inhibitors on the monocytes neutral proteinases showed them to be of the serine type. Monocytes also solubilized and degraded the type IV collagen found in human glomerular basement membrane at neutral and acid pH. The action of the monocyte proteinase on glomerular basement membrane indicated that their properties were similar but not identical to that of the polymorphonuclear leucocyte serine proteinases. Since monocytes infiltrate the glomerulus in certain forms of immunologically mediated glomerulonephritis, it may well be that monocyte serine proteinases make a contribution to the glomerular damage that occurs.

A sensitive chemiluminescence based immunoassay for antibody to staphylococcal peptidoglycan.

A sensitive chemiluminescence based immunoassay is described for measuring antibody to staphylococcal peptidoglycan in blood and dialysates from patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Peptidoglycan was isolated from a strain of S. epidermidis obtained from the dialysate of a CAPD patient with peritonitis and after sonication used to coat polystyrene beads. The coated beads were incubated with standard or sample and bound IgG was detected by the addition of affinity-purified goat anti-human IgG labelled with acridinium ester. After a wash stage 0.1 M nitric acid containing 0.1% hydrogen peroxide was added to the beads. Subsequently the chemiluminescence produced following the addition of 0.3 M sodium hydroxide was measured over a 2 s time interval with an automatic luminescence analyser. Using this technique the optimum dilution of serum for detecting antibodies to peptidoglycan was found to be 1/800 and for overnight effluent from CAPD patients the dilution was 1/8. Initial values of serum and dialysate antibody levels from 34 subjects are presented. This method has the advantage that it will detect concentrations of anti-peptidoglycan which are less than 1% of those in sera, the reagents remain stable for long periods and large numbers of samples can be processed on the same day.

Blood transfusions, suppressor T cells, and renal transplant survival.

Fifteen men undergoing chronic hemodialysis were transfused with 2 units of packed red cells, none of these patients having been previously transfused. They were studied before and after transfusion to determine suppressor T cell numbers and activity, and to monitor the appearance of cytotoxic antibodies. Although the number of suppressor T cells did not change, their function was significantly increased three weeks after the transfusion. This had largely returned to normal by 20 weeks. No cytotoxic antibodies were produced. Twelve of the patients subsequently received cadaveric renal transplants and nine of these kidneys are currently functioning more than a year after transplantation. Although the blood transfusions may have helped to produce these satisfactory results, it is accepted that the nonspecific increase in suppressor cell function may not have been the only mediator because this activity had returned to normal in most cases by the time the patients were transplanted.

The significance of monocytes in glomeruli of human renal transplants.

A total of 50 biopsies from 42 renal transplants obtained during a 30-month period were studied for the presence of monocytes in the glomeruli using the nonspecific esterase reaction. Eleven biopsies from ten grafts were positive. Immune deposition was light or absent. The prognosis for the grafts containing glomerular monocytes was significantly worse during the six months after the biopsy than for those without such cells present.

Clinical pharmacokinetics of epoetin (recombinant human erythropoietin).

Epoetin (recombinant human erythropoietin, EPO) is of proven benefit in the treatment of renal anaemia, and preliminary reports suggest that it may have a role in the management of other anaemic conditions. Pharmacokinetic and therapeutic studies have examined the use of epoetin administered intravenously, intraperitoneally and subcutaneously, and there is accumulating evidence that the last route has several advantages. After intravenous administration, epoetin is distributed in a volume comparable to the plasma volume, and plasma concentrations decay monoexponentially with a half-life of between 4 and 12 hours. Administration of epoetin in peritoneal dialysis fluid results in detectable concentrations in the bloodstream after 1 to 2 hours, and peak concentrations of the order of 2 to 4% of those obtained with the same intravenous dose are found after approximately 12 hours. The bioavailability of epoetin administered intraperitoneally in dialysis fluid is about 3 to 8%, but this may be increased by injecting the drug into a dry peritoneal cavity. Subcutaneous administration results in peak concentrations at about 18 hours which are 5 to 10% of those found after the same intravenous dose. The bioavailability of subcutaneous epoetin is about 20 to 30% and detectable serum concentrations are still present 4 days after administration, in contrast to intravenous administration after which concentrations have returned to baseline within 2 to 3 days. Remarkably little is known about the metabolic fate of either erythropoietin or epoetin. In addition, there is much controversy surrounding the relative roles of the kidney and liver in the catabolism of epoetin. About 3 to 10% of epoetin is excreted unchanged in the urine. In common with other glycoproteins, the carbohydrate residues which constitute 40% of its molecular size are essential for maintaining the stability of epoetin in circulation. Desialated epoetin, although biologically active in vitro, is cleared very rapidly from plasma with resultant loss of activity. Further work is required, however, in identifying the pathways of metabolism and elimination of this glycoprotein hormone.

Effects of a selective adenosine A1 receptor antagonist on the development of cyclosporin nephrotoxicity.

1. The clinical application of cyclosporin as an immunosuppressive agent is limited by its nephrotoxicity. 2. The effect of FK453, a selective A1-receptor antagonist, administered twice daily to rats at a dose of 100 mg kg-1 was assessed on the development of nephrotoxicity induced by cyclosporin (10 mg kg-1 i.p. daily) administered for 14 days. The effects of nifedipine administered twice daily (0.3 mg kg-1 s.c.) for 14 days, on cyclosporin nephrotoxicity were also studied. 3. Cyclosporin induced a 46.58% and 35.78% decline in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) respectively and a reduction of 16.69% in filtration fraction (FF). Co-administration of FK453 resulted in falls of 30.5%, 18.59% and 14.7% in GFR, ERPF and FF respectively, the former two significantly less than the falls seen with cyclosporin (CyA) alone (P < 0.05 vs CyA, ANOVA). 4. Nifedipine appeared to have a more pronounced protective effect resulting in a decline of only 20.91% in GFR, with no significant change in ERPF (increase of 0.93%) when co-administered with CyA. 5. These observations indicate adenosine plays a minor role in the pathophysiology of CyA nephrotoxicity.

In vivo exposure to bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improves ex vivo peritoneal macrophage function.

The impact on peritoneal macrophage (PMO) function of acidic lactate-buffered (Lac-PDF [PD4]; 40 mmol/L of lactate; pH 5.2) and neutral-pH, bicarbonate-buffered (TB; 38 mmol/L of bicarbonate; pH 7. 3) and bicarbonate/lactate-buffered (TBL; 25 mmol/L of bicarbonate/15 mmol/L of lactate; pH 7.3) peritoneal dialysis fluids (PDFs) was compared during a study of continuous therapy with PD4, TB, or TBL. During a run-in phase of 6 weeks when all patients (n = 15) were treated with their regular dialysis regimen with Lac-PDF, median PMO tumor necrosis factor alpha (TNFalpha) release values were 203.6, 89.9, and 115.5 pg TNFalpha/10(6) PMO in the patients subsequently randomized to the PD4, TB, and TBL treatment groups, respectively. Median stimulated TNFalpha values (serum-treated zymosan [STZ], 10 microgram/mL) were 1,894.6, 567.3, and 554.5 pg TNFalpha/10(6) PMO in the same groups, respectively. During the trial phase of 12 weeks, when the three groups of patients (n = 5 per group) were randomized to continuous treatment with PD4, TB, or TBL, median constitutive TNFalpha release values were 204.7, 131.4, and 155.4 pg TNFalpha/10(6) PMO, respectively. Stimulated TNFalpha values (STZ, 10 microgram/mL) were 1,911, 1,832, and 1,378 pg TNFalpha/10(6) PMO in the same groups, respectively. Repeated-measures analysis of variance comparing the run-in phase with the trial phase showed that PMO TNFalpha release was significantly elevated in patients treated with both TB (P = 0.040) and TBL (P = 0.014) but not in patients treated with Lac-PDF (P = 0. 795). These data suggest that patients continuously exposed to bicarbonate- and bicarbonate/lactate-buffered PDFs might have better preserved PMO function and thus improved host defense status.

Results of surgical treatment of renal hyperparathyroidism.

OBJECTIVE: To assess the outcome of parathyroidectomy for renal failure-related hyperparathyroidism. DESIGN: A retrospective analysis with a mean follow-up of 4.34 years of a case series of 67 consecutive patients with renal failure-associated hyperarathyroidism. SETTING: All patients were operated on at the University Hospital of Wales and Cardiff Royal Infirmary between October 1981 and December 1991. PATIENTS: Of the 67 consecutive patients, 35 were receiving hemodialysis and 32 had received a renal transplant. INTERVENTION: Total parathyroidectomy with autotransplantation was performed in 52 patients and subtotal parathyroidectomy was performed in 15. MAIN OUTCOME MEASURES: Symptomatic improvement after parathyroidectomy, the normalization of biochemical parameters, and the rate of recurrent hyperparathyroidism after parathyroidectomy. RESULTS: Symptomatic improvement after parathyroidectomy occurred in 81% of hemodialysis patients and in 72% of transplant patients. The best predictor for successful relief of skeletal pain after parathyroidectomy was an elevated preoperative alkaline phosphatase level. Recurrent hyperparathyroidism developed in four of 38 patients after total parathyroidectomy with autotransplantation and in one of 14 surviving patients after subtotal parathyroidectomy. All five patients with recurrent disease were hemodialysis patients (22%). CONCLUSIONS: Transplant patients usually present with less severe disease, have better normalization of biochemical parameters after parathyroidectomy, and rarely develop recurrent hyperparathyroidism compared with hemodialysis patients. Both total parathyroidectomy with autotransplantation and subtotal parathyroidectomy result in good control of renal hyperparathyroidism with excellent improvement of symptoms.

Familial interstitial nephritis.

We report a family in whom sixteen members in three consecutive generations have died or currently suffer from chronic renal failure. Histology revealed an interstitial nephritis. One patient also had medullary cysts. The condition appears to be similar to familial juvenile nephronophthisis.

Suppressor cell numbers and activity in non-transfused renal dialysis patients.

Suppressor cell activity was studied in 30-non-transfused renal dialysis patients using the Concanavalin A enhancement method. Suppressor cell numbers were estimated in 19 patients by the T suppressor (T gamma) rosette technique and in 15 patients using a monoclonal antibody (OKT8) specific for T suppressor cells. The role of prostaglandin secreting monocytes in the observed suppression was investigated in 6 patients using the prostaglandin secreting inhibitor flurbiprofen. Both suppressor cell numbers and activity were either normal or low compared with normal healthy controls. Flurbiprofen at concentrations of 10(-4) and 10(-6) M caused a decrease in activity in both patients and normal controls. The results indicate that the increased suppressor cell activity and number reported in dialysis patients may be due to the effect of blood transfusion previously administered to the patients.

The hematological response to continuous ambulatory peritoneal dialysis.

Over the first three months of continuous ambulatory peritoneal dialysis (CAPD) the level of hemoglobin (Hb) rises significantly in most patients. To elucidate this further we studied the hematological response over 3 months of 8, previously non-transfused new patients treated with CAPD. Mean Hb rose by +2.78 g/dl (P less than 0.02). Mean RCM rose by 284 ml (37.7%) (P less than 0.05) and 3.7 ml/kg (29.6%) (P less than 0.05). PV fell relative to BW only, by -8.6 ml/kg (P less than 0.05). There was no significant change in serum vitamin B12 or folate concentrations or evidence of hemolysis. Plasma ferritin fell in all patients, but hematological changes of iron deficiency appeared in only one. Bio-assayable erythropoietin (EPO) levels were generally in the normal range, but inappropriately low for the degree of anemia. EPO did not change significantly apart from in two patients, one with polycystic disease. These results indicate that over the initial 3 months of therapy the majority of CAPD patients have a rise in Hb, due mainly to a rise in RCM, unrelated to changes in serum EPO level.

The detection of monocytes in human renal biopsies: a prospective study.

A total of 52 non-transplant and 16 transplant renal biopsies were examined for the presence of monocytes in the glomeruli using the non-specific esterase reaction. Four of the non-transplant and 4 of the transplant group were positive. The 4 non-transplant samples all showed the presence of granular IgG and C3 together with electron dense deposits in the basement membrane. In contrast the positive transplant samples showed vascular rejection with little immune protein deposition and no deposits. One patient with focal glomerulosclerosis had large clumps of esterase positive material in the glomeruli in association with deposits of C3 and the presence of foam cells.

Acute renal failure associated with non-fulminant hepatitis A.

A 49-year-old man developed acute renal failure as a complication of non-fulminant hepatitis A. This is a rare association of uncertain etiology.

1,25-dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: effects of simultaneous protein and phosphorus restriction.

Vitamin D3 metabolites and immunoreactive parathyroid hormone (iPTH) were measured in sera obtained from subjects with advanced chronic renal failure (CRF) (creatinine clearance less than 10 ml/min) before and after 3 months on a diet very low in protein (less than 0.2 g/kg/day), phosphorus (less than 500 mg/day), and supplemented with a mixture of essential amino acids and ketoacid analogues of essential amino acids. iPTH and phosphate fell in all subjects (p less than 0.02). 1,25-dihydroxycholecalciferol (1,25[OH]2D3) fell in all but one of the subjects (p less than 0.02), while no significant change was seen in creatinine clearance or in serum 25-hydroxycholecalciferol (25[OH]D3) levels. A strongly positive correlation was found between initial serum levels of 25(OH)D3 and 1,25(OH)2D3 (r = 0.95, p less than 0.001). Thus in contrast with the reported effects of dietary phosphorus reduction in subjects with early and moderate CRF and in normal subjects, this regime was associated with decreased 1,25(OH)2D3 levels in subjects with advanced CRF.

Staphylococcus aureus infections during peritoneal dialysis.

Peritoneal dialysis is in widespread use for the treatment of chronic renal failure. Infection is still one of the major complications and can include peritonitis and pericannular problems. The rate of peritonitis is currently 0.5 episodes per patient year with disconnect systems, and there are about 0.4 exit-site infections (ESIs) per patient year. ESI is associated with a high rate of catheter removal and replacement. Staphylococcus aureus is a common cause of peritonitis and accounts for more than half of all ESIs. Nasal carriage of S. aureus is associated with a much higher rate of ESI. Treatment of ESIs is unsatisfactory. The type of exit-site care, however, does influence the rate of infection and prophylaxis with oral rifampicin and local or nasal mupirocin has been claimed to reduce ESIs. A large multicentre double-blind trial of nasal mupirocin has just been completed and preliminary results show a reduction in the incidence of S. aureus-induced ESI. The cost benefits of such a regimen are being evaluated.

Biocompatibility studies on peritoneal cells.

This review outlines the problems involved in assessing the biocompatibility of PD fluids. It has summarized the data available from conventional in vitro studies and highlights many of the inadequacies of this approach. In vivo data are lacking both on host defense and on the clinical effect of changing conventional PD fluids for a more "ideal" formulation. The best parameters for assessing biocompatibility need to be defined. Alternative formulation of fluids must be aimed towards (1) a system that interferes minimally with host defense, and (2) a system that maintains the integrity of the peritoneal membrane for ultrafiltration and clearance. Cell culture studies should be designed to model the in vivo situation. Ex vivo studies (cells exposed within the peritoneal cavity) should be used to support in vivo findings. Finally, in vitro results must be related to clinical significance, and changes in fluid composition should be followed by improvements in clinical outcome.

Synthesis of phospholipids by human peritoneal mesothelial cells.

OBJECTIVE: To assess the capacity of cultured human peritoneal mesothelial cells to synthesize choline-containing phospholipids. The study compares the phospholipids secreted from cultured cells with those which we, and others, have identified in the dialysate of patients treated by continuous ambulatory peritoneal dialysis (CAPD). PATIENTS: CAPD effluent was collected from 8 patients who had been receiving CAPD treatment for at least 11 months and who had normal ultrafiltration. CELL CULTURES: Using human omental tissue, homogeneous cultures of mesothelial cells were established. METHODS: Synthesis of phospholipids by mesothelial cells was assessed following incubation with [methyl-14C] choline chloride--a precursor capable of being incorporated into phosphatidylcholine (PtdCho) and sphingomyelin. Lipids from CAPD effluent, cultured cells, and cell medium were extracted in chloroform/methanol. Phospholipids were separated and identified by thin layer chromatography. Synthesis and secretion of PtdCho and other choline-containing lipids by the mesothelial cells were determined by beta scintillation counting of the appropriate bands, while the fatty acid composition of the phospholipids was ascertained by gas liquid chromatography. RESULTS: Synthesis and secretion of PtdCho by mesothelial cells were observed during a 96-hour period. When maintained in medium replete with essential fatty acids, the fatty acid composition of the PtdCho synthesized by cultured mesothelial cells closely resembled that isolated from the peritoneal cavity. CONCLUSION: The demonstration of phospholipid secretion from mesothelial cells, with a fatty acid composition similar to the phospholipids isolated from peritoneal dialysate, lends added support to the hypothesis that the mesothelial cells are the source of the peritoneal phospholipids. As such they offer a useful experimental system in which to study peritoneal phospholipid synthesis.

Can the risk of peritonitis be predicted for new continuous ambulatory peritoneal dialysis (CAPD) patients?

Serum and overnight dialysate samples were obtained from 36 adult uraemic patients at the end of their continuous ambulatory peritoneal dialysis (CAPD) training. The samples were analysed for albumin, IgG, C3, and antistaphylococcal peptidoglycan antibody. None of the dialysate measurements correlated with the risk of peritonitis during up to one year's CAPD treatment. Nineteen of the 36 patients were retested 6 to 20 months after starting CAPD. There were significant rises in serum C3 (p less than 0.02) and albumin (p less than 0.001) and a significant fall in dialysate IgG (p less than 0.02). Eight further patients were sampled at the end of training and three weeks later. They had a significant fall in dialysate IgG (p less than 0.05). During CAPD training peritoneal permeability appears to be transiently increased. Analysis of overnight dialysate samples during training does not allow prediction of those at risk of subsequent peritonitis.

Design and testing of the Baxter Integrated Disconnect Systems (IDS).

This paper describes the result of a miltidisciplinary approach to the design and evaluation of a new CAPD disconnect system: the Baxter Integrated Disconnect System (IDS). This system consists of a bag full of fresh Dianeal, an empty bag for the drainage of spent dialysate and tubings connecting the 2 in a Y fashion. With this system, the patient makes only one connection. The system is disposable. The major property that makes this unique is that all components are preassembled, and the whole system is steam-sterilized as 1 unit. In general, similar systems use different sterilization methods for the various components of the system. Those components are then assembled, under clean conditions by the manufacturer, without final sterilization of the unit. Assembly of the components is sometimes left to the patient. The concept of IDS, therefore, is unique and warrants lower rates of contamination. This system has been tested on patients for a total observation period of 765 patient months, and has proven to be simple, safe and effective. It yields a 63% probability of peritonitis-free patients at 24 months.