Cancer in patients receiving dialysis.

The incidence of cancer and related mortality was studied in 1651 patients from six dialysis centres in England over 10 years. The only type of cancer for which there was a significant excess was non-Hodgkin''s lymphoma (four cases observed against an expected incidence of 0.15 (p < 0.001); three deaths against an expected 0.1 (p < 0.001)). This excess could not be attributed to either subsequent transplantation or treatment with immunosuppressive drugs. Since immunodepression is a feature of chronic renal failure, these observations together with those on patints treated with immunosuppressive drugs suggest that immunosuppression favours the development of non-Hodgkin''s lymphoma. Studies in which it is concluded that patients receiving dialysis show an excess of other types of cancer have certain shortcomings; the unusual opportunities for detecting cancer in such patients may account for some of the reported excess.     

Antinuclear antibodies in patients receiving non-practolol beta-blockers.

Antinuclear antibodies (ANA) were found in 54 (7.0%) out of 767 treated hypertensive patients compared with 59 (2.4%) out of 2470 healthy controls. Inclusion of a non-practolol beta-blocker in the treatment regimen did not significantly affect the incidence of ANA. ANA was found in significantly more patients being treated with methyldopa (13.0%) than patients receiving other hypotensive agents (3.8%). Non-practolol beta-blockers in combination with methyldopa did not increase the incidence of ANA further.     

Adverse outcomes among Aboriginal patients receiving peritoneal dialysis

Background

The Aboriginal population in Canada experiences high rates of end-stage renal disease and need for dialytic therapies. Our objective was to examine rates of mortality, technique failure and peritonitis among adult aboriginal patients receiving peritoneal dialysis in the province of Manitoba. We also aimed to explore whether differences in these rates may be accounted for by location of residence (i.e., urban versus rural).

Methods

We included all adult patients residing in the province of Manitoba who received peritoneal dialysis during the period from 1997–2007 (n = 727). We extracted data from a local administrative database and from the Canadian Organ Replacement Registry and the Peritonitis Organism Exit-sites/Tunnel infections (POET) database. We used Cox and logistic regression models to determine the relationship between outcomes and Aboriginal ethnicity. We performed Kaplan–Meier analyses to examine the relationship between outcomes and urban (i.e., 50 km or less from the primary dialysis centre in Winnipeg) versus rural (i.e., more than 50 km from the centre) residency among patients who were aboriginal.

Results

One hundred sixty-one Aboriginal and 566 non-Aboriginal patients were included in the analyses. Adjusted hazard ratios for mortality (HR 1.476, CI 1.073–2.030) and adjusted time to peritonitis (HR 1.785, CI 1.352–2.357) were significantly higher among Aboriginal patients than among non-Aboriginal patients. We found no significant differences in mortality, technique failure or peritonitis between urban- or rural-residing Aboriginal patients.

Interpretation

Compared with non-Aboriginal patients receiving peritoneal dialysis, Aboriginal patients receiving peritoneal dialysis had higher mortality and faster time to peritonitis independent of comorbidities and demographic characteristics. This effect was not influenced by place of residence, whether rural or urban.The Canadian Aboriginal population suffers from a high burden of illness,^1,2 low socio-economic status and geographic isolation.³ A high prevalence of diabetes mellitus, obesity and hypertension in this population is resulting in rapid growth in rates of kidney disease and renal failure (i.e., end-stage renal disease).^4–6 The escalation in demand for dialytic services and care of patients with end-stage renal disease care will require appropriate planning and allocation of health care resources.Hemodialysis is resource-intensive and requires residence in proximity to a dialysis centre. In Canada, roughly 18% of all dialysis patients are receiving peritoneal dialysis.⁷ These patients are responsible for their own dialysis therapy and are seen periodically in an ambulatory clinic setting. No clear mortality-related benefit is associated with choice in modality of dialysis; each method has its own risks and benefits.^8–10 Complications of peritoneal dialysis include technique failure, which often requires conversion to hemodialysis and relocation of the patient, and peritonitis.Dosage of peritoneal dialysis is determined by the combined clearance of solutes from the peritoneum (termed the peritoneal Kt/V) and, if applicable, by residual renal function (termed renal Kt/V). The peritoneal equilibration test is a marker of the peritoneal membranes solute transport characteristics and high peritoneal equilibration test values have been associated with inflammation, volume overload, technique failure and mortality.¹¹Compared with non-Aboriginal patients who have end-stage renal disease, Aboriginal patients with end-stage renal disease are younger on average and more likely to reside in geographically remote locations.¹² Use of home-based dialysis modalities, such as peritoneal dialysis, would be well suited to this population because it allows patients to continue to live in their communities. However, residing far from a dialysis centre or a patient’s primary nephrologist is associated with increased mortality, poor compliance and impaired quality of life.^12,13 Previous studies have found that Aboriginal patients receiving peritoneal dialysis have similar mortality and rates of technique failure to patients of other ethnicities. But whether this is true in a contemporary cohort is not known.^14,15Our objective was to examine differences in mortality and in rates of technique failure and peritonitis among Aboriginal patients versus non-Aboriginal patients receiving peritoneal dialysis and to explore whether differences may be accounted for by urban versus rural residence.     

Raised serum human chorionic gonadotrophin concentrations in hyperemesis gravidarum.

Serum human chorionic gonadotrophin (HCG) concentrations were determined by radioimmunoassay with an antiserum specific to HCG beta-subunit in 42 patients with hyperemesis gravidarum and 115 women with normal pregnancies. Mean concentrations (+/- SE of mean) were higher in the women with hyperemesis gravidarum at 7-8 weeks (40.8 +/- 5.2 IU/ml v 22.1 +/- 1.4 IU/ml; P less than 0.001), 9-11 weeks (38.1 +/- 2.3 IU/ml v 27.1 +/- 2.1 IU/ml; P less than 0.0025), and 12-14 weeks of gestation (35.9 +/- 4.2 IU/ml v 25.1 +/- 1.7 IU/ml; P less than 0.005), but there was no difference between the two groups at 15-20 weeks of gestation. In the hyperemesis gravidarum group primigravid women had a higher (P less than 0.005) mean HCG concentration (41.8 +/- 4.0 IU/ml) than multigravid women (32.2 +/- 2.3 IU/ml). The results suggest a causal relation between a high serum HCG concentration and hyperemesis gravidarum.     

Raised plasma glutathione S-transferase values in hyperthyroidism and in hypothyroid patients receiving thyroxine replacement: evidence for hepatic damage.

Using plasma glutathione S-transferase measurements hepatocellular integrity was assessed in groups of hyperthyroid and hypothyroid patients before and after treatment. Ten of 14 hyperthyroid patients had clearly raised plasma glutathione S-transferase values at presentation and in each patient treatment with either iodine-131 or carbimazole resulted in a significant fall in glutathione S-transferase. The eight hypothyroid patients had normal glutathione S-transferase values at presentation and all showed a significant increase in these after thyroxine replacement therapy. In three of these patients in whom standard doses of replacement therapy were associated with a raised free thyroxine (T4) concentration but normal total and free triiodothyronine (T3) values glutathione S-transferase was increased. Similar though less consistent changes were seen in the results of standard chemical tests of liver function. It is concluded that hyperthyroidism may produce subclinical liver damage in a high proportion of patients and that this resolves with effective treatment. More important, the data suggest that hypothyroid patients receiving thyroxine replacement therapy may have similar subclinical liver damage. Patients receiving thyroxine should be monitored by the measurement of free, not total hormone concentrations, and in those in whom free T4 is raised the dose of thyroxine should be reduced. It would also be expedient to include periodic biochemical assessment of liver function in patients receiving thyroxine.     

Total and free thyroid hormone concentrations in patients receiving maintenance replacement treatment with thyroxine.

Total and free serum concentrations of thyroxine and triiodothyronine were measured in 122 subjects with hypothyroidism who were clinically well while receiving conventional replacement treatment with thyroxine. In a third of patients concentrations of total and free thyroxine were raised, often considerably; nevertheless concentrations of total and free triiodothyronine were usually normal. Though significant correlations were obtained between total triiodothyronine concentrations and total thyroxine concentrations (p less than 0.001) and between the triiodothyronine concentrations and free thyroxine concentrations (p less than 0.001) the slope of the line of the regression equation describing these correlations was small, hence large increases in both total and free thyroxine concentrations were accompanied by only modest increases in total and free triiodothyronine concentrations. The presence of total or free thyroxine concentrations above normal in patients taking thyroxine therefore are not necessarily of clinical consequence. In the assessment of adequacy of replacement treatment with thyroxine the most logical combination of in vitro thyroid function test results may be a normal thyrotrophin concentration and normal free triiodothyronine concentration.     

The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin

Previously we reported that the variable heavy chain region (V_H) of a human beta₂ glycoprotein I-dependent monoclonal antiphospholipid antibody (IS4) was dominant in conferring the ability to bind cardiolipin (CL). In contrast, the identity of the paired variable light chain region (V_L) determined the strength of CL binding. In the present study, we examine the importance of specific arginine residues in IS4V_H and paired V_L in CL binding. The distribution of arginine residues in complementarity determining regions (CDRs) of V_H and V_L sequences was altered by site-directed mutagenesis or by CDR exchange. Ten different 2a2 germline gene-derived V_L sequences were expressed with IS4V_H and the V_H of an anti-dsDNA antibody, B3. Six variants of IS4V_H, containing different patterns of arginine residues in CDR3, were paired with B3V_L and IS4V_L. The ability of the 32 expressed heavy chain/light chain combinations to bind CL was determined by ELISA. Of four arginine residues in IS4V_H CDR3 substituted to serines, two residues at positions 100 and 100 g had a major influence on the strength of CL binding while the two residues at positions 96 and 97 had no effect. In CDR exchange studies, V_L containing B3V_L CDR1 were associated with elevated CL binding, which was reduced significantly by substitution of a CDR1 arginine residue at position 27a with serine. In contrast, arginine residues in V_L CDR2 or V_L CDR3 did not enhance CL binding, and in one case may have contributed to inhibition of this binding. Subsets of arginine residues at specific locations in the CDRs of heavy chains and light chains of pathogenic antiphospholipid antibodies are important in determining their ability to bind CL.     

The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin

Previously we reported that the variable heavy chain region (VH) of a human beta2 glycoprotein I-dependent monoclonal antiphospholipid antibody (IS4) was dominant in conferring the ability to bind cardiolipin (CL). In contrast, the identity of the paired variable light chain region (VL) determined the strength of CL binding. In the present study, we examine the importance of specific arginine residues in IS4VH and paired VL in CL binding. The distribution of arginine residues in complementarity determining regions (CDRs) of VH and VL sequences was altered by site-directed mutagenesis or by CDR exchange. Ten different 2a2 germline gene-derived VL sequences were expressed with IS4VH and the VH of an anti-dsDNA antibody, B3. Six variants of IS4VH, containing different patterns of arginine residues in CDR3, were paired with B3VL and IS4VL. The ability of the 32 expressed heavy chain/light chain combinations to bind CL was determined by ELISA. Of four arginine residues in IS4VH CDR3 substituted to serines, two residues at positions 100 and 100 g had a major influence on the strength of CL binding while the two residues at positions 96 and 97 had no effect. In CDR exchange studies, VL containing B3VL CDR1 were associated with elevated CL binding, which was reduced significantly by substitution of a CDR1 arginine residue at position 27a with serine. In contrast, arginine residues in VL CDR2 or VL CDR3 did not enhance CL binding, and in one case may have contributed to inhibition of this binding. Subsets of arginine residues at specific locations in the CDRs of heavy chains and light chains of pathogenic antiphospholipid antibodies are important in determining their ability to bind CL.