New results from the Modification of Diet in Renal Disease study: the importance of clinical outcomes in test strategies for early chronic kidney disease.

A formula derived from the Modification of Diet in Renal Disease (MDRD) study in chronic renal disease is widely used to estimate glomerular filtration rate (GFR). Recently a ten-year follow-up of MDRD participants evaluated four tests of kidney function measured at baseline as predictors of important long-term clinical outcomes. Surprisingly, neither formula-estimated GFR nor reference method GFR showed a clear advantage over simple creatinine measurement whereas another test, cystatin C, looked more promising. This raises important points of principle in terms of how the usefulness of test strategies should be assessed. Data on clinical outcomes are an essential ingredient in this process.

A case of membranous glomerulonephritis presenting as pulmonary embolism and acute hyperlipidaemia.

This paper describes the case of a 48 year old man who presented with acute hyperlipidaemia following pulmonary embolism. Subsequent investigation revealed that the hyperlipidaemia was secondary to nephrotic syndrome of glomerulonephritis. The case illustrates the importance of investigating acute hyperlipidaemia for its underlying causes.

Simplified detection of a mutation causing familial hypercholesterolaemia throughout Britain: evidence for an origin in a common distant ancestor.

Familial hypercholesterolaemia (FH) is an inherited autosomal codominant disorder caused by many different mutations in the low-density lipoprotein receptor (LDLR) gene. The one described most frequently in patients with FH from England, arises from a G-->A transition at the first nucleotide of codon 80, resulting in the substitution of lysine for glutamic acid at residue 80 of the mature protein, FH E80K. We describe a simple method to detect this mutation in genomic DNA using the polymerase chain reaction (PCR). A 69 base pair (bp) fragment of exon 3 of the LDLR gene is amplified using a mutagenic upstream PCR primer. This substitutes a T for an A residue in the amplified product, 2 bp upstream from the mutant site, generating a restriction site for the endonuclease Taq I, in normal, but not in mutant DNA. Following digestion of amplified DNA with Taq I, normal but not mutant DNA is cut into two fragments of 29 and 40 bp, which are readily identified by polyacrylamide gel electrophoresis. Using this method, 410 patients with clinically diagnosed FH, attending lipid clinics in Edinburgh (72), Newport (158), Walsall (30) and Southampton (150), were screened for the mutation. Five individuals tested positive as heterozygotes, one from Edinburgh, three from Newport and one from Southampton. This finding was confirmed by DNA sequence analysis. We conclude that FH due to this mutation occurs in individuals throughout Great Britain and that it can be detected accurately using this simple technique. DNA from these and other individuals previously identified to be heterozygous for FH E80K, was then studied using PCR of highly informative microsatellite markers flanking the LDLR gene. Sixteen of 17 apparently unrelated individuals heterozygous for FH E80K also were heterozygous for an identical size (239 nucleotide) allele, of polymorphic microsatellite D19S394, located approximately 250 kb away from the LDLR gene. This supports the hypothesis that FH E80K in these 16 individuals arose from a single ancestor less than 1000 years ago.

The one-stop coronary cholesterol clinic: a multidisciplinary approach to implementing evidence-based treatment.

We describe a 'one-stop' cholesterol clinic implementing a regime based on the Scandinavian Simvastatin Survival Study (4S) in patients with established coronary heart disease in a district general hospital. The clinic has been established in collaboration with the cardiac rehabilitation centre. It was commissioned as an audit project by the purchasing authority, Walsall Health, a need having been shown in a previous audit. In the new clinic, audit is inbuilt, rather than being carried out as a separate retrospective exercise, and undertaken prospectively for all patients. Central to this is a database, used for routine correspondence and administration, as well as monitoring outcome. This application of information technology has improved clinical practice. Attendance at the clinic has been excellent. Half the consultations have resulted in therapeutic interventions, many of which may otherwise have been missed. Over 50% of patients were eligible for lipid-lowering medication under the protocol. Cholesterol targets based on 4S were achieved but with much lower drug doses, which may have major cost implications. Cholesterol levels measured within 24 hours of admission for myocardial infarction were poor predictors of results obtained after convalescence. After the clinic visit, most patients were taking aspirin plus one or two other secondary prevention treatments. Guidelines have been issued to primary care. Future plans for audit links with general practitioners, integration of the metabolic and cardiological assessment of survivors of myocardial infarction, and for long-term monitoring of clinical events in treated patients are discussed.

Cerebrospinal fluid oligoclonal IgM in multiple sclerosis: analytical problems and clinical limitations.

A method for detecting cerebrospinal fluid (CSF) oligoclonal IgM is described. Concentrated CSF was separated by agarose isoelectric-focusing and blotted with poly(vinyldifluoride). A double-antibody immunoperoxidase technique with avidin-biotin amplification was used to stain IgM. Special conditions were required to avoid cross-reaction with IgG. The method was applied to 99 patients on whom oligoclonal IgG analysis was performed. Positive IgM results occurred in 17 of the 27 patients positive for oligoclonal IgG, and in two patients negative for oligoclonal IgG, neither of whom had multiple sclerosis (MS). Fifteen of the patients positive for oligoclonal IgM had some IgM bands in their sera. Oligoclonal IgM was not found in the CSF of suspected MS patients without oligoclonal IgG, but occurred in several patients with oligoclonal IgG due to other diseases. As a test for MS, oligoclonal IgM was less sensitive than oligoclonal IgG and did not improve specificity.

Oligoclonal bands and the IgG index in multiple sclerosis: uses and limitations.

The relationship between two tests commonly used in the investigation of multiple sclerosis (MS), the IgG index and oligoclonal bands, has been assessed. Using an immunoblotting technique specific for IgG, analysis of cerebrospinal fluid for oligoclonal bands was found to provide greater diagnostic sensitivity than the IgG index without any loss of specificity. In patients without oligoclonal bands the IgG index had no diagnostic value for MS and in the presence of bands the magnitude of the index was unrelated to the clinical certainty of the diagnosis. High values of the IgG index were invariably associated with the presence of oligoclonal bands and the IgG index appeared to have no clinical significance independent of this relationship. Even as a screening test the IgG index has serious limitations.