Matthew Howse

‘Septrin psychosis’ among renal transplant patients with Pneumocystis jirovecii pneumonia

OBJECTIVES To report on the temporal relationship between administration of trimethoprim/sulfamethoxazole to medically immunosuppressed HIV-negative renal patients with Pneumocystis jirovecii pneumonia (PCP) and the development of an acute psychosis. METHODS We investigated a retrospective case series of renal transplant and immunosuppressed patients with PCP within an ongoing outbreak in the northwest of England since 2009. Four patients with PCP developed psychosis following treatment with trimethoprim/sulfamethoxazole. RESULTS Four of twenty patients developed acute psychoses following administration of trimethoprim/sulfamethoxazole, including one accidental re-challenge. Symptoms resolved within 24 h of changing the therapy. The striking temporal relationship between the initiation and discontinuation of the drug and the behavioural changes suggests a causal relationship. CONCLUSIONS With increasing solid organ transplantation and the use of immunosuppressants, vigilance regarding trimethoprim/sulfamethoxazole dose modification is required and the routine use of therapeutic drug monitoring should be considered.

A study to describe the health trajectory of patients with advanced renal disease who choose not to receive dialysis.

Background Some patients with end-stage renal failure (ESRF) are unlikely to benefit from dialysis and conservative management (CM) is offered as a positive alternative. Understanding the trajectory of illness by health care professionals may improve end-of-life care. Methods We aimed to describe the trajectory of functional status within our CM population through a prospective, observational study using the objective Timed Up and Go (TUG) test and subjective Barthel Index (BI) and health-related quality of life (HRQoL) [EuroQol 5D-5L (EQ-5D-5L)] measurements and correlating them with demographic and laboratory data and with sentinel events. Results There was a significant increase in TUG scores over the 6 months prior to death {2.24 [95% confidence interval (CI) 1.16–4.32], P = 0.017} and a significant decrease in EQ-5D-5L [−0.19 (95% CI −0.33 to −0.06), P = 0.006]. The only significant associations with mortality were serum albumin [hazard ratio (HR) 0.81 (95% CI 0.67–0.97), P = 0.024] and male gender [HR 5.94 (95% CI 1.50–23.5), P = 0.011]. Conclusions We have shown there is a significant decline in functional status in the last 6 months before death in the CM population. Of interest, there was a significant relationship of lower serum albumin with functional decline and risk of death. We hope that with improved insight into disease trajectories we can improve our ability to identify and respond to the changes in needs of these patients, facilitate complex and sensitive end-of-life discussions and improve end-of-life care.

Cystatin C as a surrogate for glomerular filtration rate in the presence of proteinuria

Sir, All methods for assessing glomerular filtration rate (GFR) have shortcomings. Serum creatinine has a reciprocal relationship to GFR that is related to age, race, sex and muscle mass and is affected by tubular secretion. Creatinine clearance requires a timed urine collection, and radio isotope and inulin clearance methods are expensive. Estimated GFR may only be valid in the steady state of chronic kidney disease (CKD) [1]. There has been much [2] interest in cystatin C, a serine protease inhibitor produced by all nucleated cells, freely filtered at the glomerulus and, although reabsorbed, apparently fully metabolized in tubular cells [3]. Serum cystatin C may be more sensitive to changes in GFR than serum creatinine [4,5]. Renal disease is often accompanied by proteinuria, the severity of which correlates with progression [6], possibly because protein in the tubular fluid injures tubular cells via mechanisms involving reactive oxygen species [7]. We hypothesized that proximal tubular injury by proteinuria might affect cellular handling of cystatin C, leading to an altered relationship to GFR. We measured serum cystatin C in 65 nephrology-clinic patients, with and without proteinuria, using a latex-enhanced immunonephelometric assay based on rabbit polyclonal antibodies (Dade Behring, UK) with a ProSpec analyser (Dade Behring, UK). Urinary creatinine and protein were measured using standard chemistries on Roche Modular systems (Roche/Hitachi, Roche Diagnostics, Gmbh, Germany). GFR was estimated using the modification of diet in renal disease (MDRD) formula [8]. Patients were being treated for stable CKD secondary to primary glomerulonephritis (28%), diabetes (15%), vasculitis or lupus (8%), chronic pyelonephritis (6%), hypertensive nephrosclerosis (3%), miscellaneous conditions (16%) or unknown cause (24%). They were classified as proteinuric if excreting >1 g protein/24 h (range 1–15 g/24 h, n = 24), otherwise non-proteinuric (n = 41). To normalize variance, the reciprocal relationship between serum cystatin C and GFR was analysed as −log(cystatin) versus log(GFR), grouped linear regression (StatsDirect Ltd, Cheshire, UK) being used to assess the common slope and the (statistically significant, P = 0.03) vertical separation of the regression lines in the two groups, and converted back to the linear domain for presentation (Figure ​(Figure1).1). When the regression line for the non-proteinuria group is used to predict cystatin C values for each proteinuric patient, their observed cystatin C is on average 33 ± 8% higher than expected from GFR. Fig. 1 Cystatin C versus GFR, with best-fit lines (see key) converted from a log–log fit derived by grouped linear regression. Although we did not formally measure GFR, these results suggest the need for caution in using cystatin C as a marker for GFR in proteinuria. A similar warning was sounded by anomalies in four patients with sickle cell disease [11] and also by a large study of diabetic patients in which mean cystatin C was ∼50% higher in patients with microalbuminuria than those without, despite no significant difference in mean serum creatinine [12]. The present study extends this by calculating the discrepancy for each proteinuric patient. Although the close reciprocal correlation between cystatin C and radioisotope GFR can be used to predict GFR from cystatin C with high accuracy and precision [9], such formulae may need modification in proteinuria. Longitudinal studies will be needed to determine whether changes in proteinuria in individual patients alter this relationship. More complex interactions between serum cystatin C, markers of tubular dysfunction and measures of diabetic control [13] also merit further investigation. There are two possible explanations for our finding. First, proteinuria might affect the accuracy of the MDRD equation. This significantly underestimates GFR in the presence of microalbuminuria during the hyperfiltration phase of diabetic nephropathy [10], but none of our relatively few diabetic patients were hyperfiltering (GFR > 100 ml/min). Alternatively, proteinuria might raise serum cystatin C. Since proteinuria damages proximal tubular cells cultured in vitro [6,7], we speculate that damaged cells might fail to metabolize all reabsorbed cystatin C, leaving some to re-enter the circulation. If so, a rising serum cystatin C might prove useful in monitoring tubular injury. Conflict of interest statement. None declared.

Adiponectin gene expression in human primary adipocyte culture treated with uremic serum.

End-stage renal disease (ESRD) is accompanied by an increased rate of morbidity and mortality due to cardiovascular disease (CVD). Although renal replacement therapy is required at this stage, it is associated with additional complications such as inflammation and dyslipidemia. It has been suggested that adiponectin has anti-inflammatory properties. We studied the potential role of uremic mileu on the adiponectin expression in human primary adipocyte culture. A cohort of 18 patients with ESRD (hemo-and peritoneal dialysis) and nine healthy controls were analyzed in a prospective cross-sectional study. Single blood samples were taken pre-and post-hemodialysis and in peritoneal dialysis patients. Serum concentrations of total adiponectin (7.95 ± 1.44 μg/mL; 6.73 ± 1.2 μg/mL; 13.7 ± 3.04 μg/mL, respectively) and high molecular weight adiponectin (3.03 ± 1.95 μg/mL; 3.57 ± 2.44 14 μg/mL; 8.02 ± 5 μg/mL respectively) were measured. Other biochemical parameters (cholesterol, low-density lipoprotein cholesterol and triglycerides) were assessed in all groups of patients. Adiponectin gene expression was determined using real-time polymerase chain reaction, and was found to be lower in ESRD patients compared with healthy controls with low dose but not with high-dose treatments. Serum concentrations of total adiponectin and high molecular weight adiponectin were significantly higher in the ESRD versus control group. These results provide an initial insight into understanding the putative role of adipose tissue in contributing to the association of CVD risk in patients with chronic kidney disease.

The severity of pseudohyperkalaemia is not dependent upon the stage of chronic kidney disease: a prospective study

Abstract Background: Pseudohyperkalaemia may result from delay in centrifugation and storage at 4°C. We investigated whether the stage of chronic kidney disease (CKD), its aetiology or medications influence this. Methods: Seventy-seven patients with CKD were recruited. Lithium heparin plasma samples were analysed for sodium, potassium, urea and creatinine, chloride, bicarbonate, magnesium, calcium and inorganic phosphate at 0 h and after storage of whole blood at 4°C for 6 h and 20 h. K-EDTA and fluoride-EDTA samples were analysed for full blood count and glucose at 0 h. CKD stage was determined by standard criteria. Results: K+ increased on average by 1.0 and 3.6 mmol/L after 6 and 20 h storage of whole blood at 4°C, independent of cause or stage of CKD. K+ increase at 6 h was correlated with haemoglobin but not with white blood cell count, platelet count or glucose. Patients taking ACE inhibitors and/or angiotensin receptor blockers (ARBs) had slightly higher K+ at 0 h and increased K+ after storage for 6 h. Na+ decreased on average by 3.8 mmol/L at 20 h and was independent of CKD stage, and correlated with K+ increase. Conclusions: K+ increased significantly with time in samples stored at 4°C in all stages of CKD. This was greater in some patients on ACE inhibitors and ARBs, and increased with haemoglobin, but was not related to the stage of CKD, white blood cell count or platelet count for the samples used in this study.