James Fotheringham

Transplant Glomerulopathy: Morphology, Associations and Mechanism

Transplant glomerulopathy (TG) is a lesion with specific morphology and strong evidence of an immune mechanism. The incidence of TG is approximately 20% by 5 years after transplantation. TG is characterized by proteinuria, hypertension and declining graft function. Appearances on light microscopy include thickened capillary walls and double contours, with reduplication or lamination of the glomerular basement membrane on electron microscopy. TG is associated with acute rejection, the antibody status before transplantation and de novo HLA antibodies. HLA class II and/or donor-specific antibodies incur additional risks. Desensitization protocols do not always prevent the development of TG in highly sensitized individuals. Associations between TG, past or current C4d and the presence of alloantibodies are recognised, however, C4d in the peri-tubular capillaries or glomeruli is not a prerequisite at the time of diagnosis. Clinical observation and animal models suggest that TG arises as a consequence of chronic endothelial cell (EC) injury by the humoral arm of the immune system. In some cases, this follows a period of EC accommodation after an episode of acute injury. Proposed treatments include augmentation of background immunosuppression, and trials of monoclonal therapies targeted at CD20-positive B cells are underway.

Developing a summary hospital mortality index: retrospective analysis in English hospitals over five years

Objectives To develop a transparent and reproducible measure for hospitals that can indicate when deaths in hospital or within 30 days of discharge are high relative to other hospitals, given the characteristics of the patients in that hospital, and to investigate those factors that have the greatest effect in changing the rank of a hospital, whether interactions exist between those factors, and the stability of the measure over time. Design Retrospective cross sectional study of admissions to English hospitals. Setting Hospital episode statistics for England from 1 April 2005 to 30 September 2010, with linked mortality data from the Office for National Statistics. Participants 36.5 million completed hospital admissions in 146 general and 72 specialist trusts. Main outcome measures Deaths within hospital or within 30 days of discharge from hospital. Results The predictors that were used in the final model comprised admission diagnosis, age, sex, type of admission, and comorbidity. The percentage of people admitted who died in hospital or within 30 days of discharge was 4.2% for males and 4.5% for females. Emergency admissions comprised 75% of all admissions and 5.5% died, in contrast to 0.8% who died after an elective admission. The percentage who died with a Charlson comorbidity score of 0 was 2% in contrast with 15% who died with a score greater than 5. Given these variables, the relative standardised mortality rates of the hospitals were not noticeably changed by adjusting for the area level deprivation and number of previous emergency visits to hospital. There was little evidence that including interaction terms changed the relative values by any great amount. Using these predictors the summary hospital mortality index (SHMI) was derived. For 2007/8 the model had a C statistic of 0.911 and accounted for 81% of the variability of between hospital mortality. A random effects funnel plot was used to identify outlying hospitals. The outliers from the SHMI over the period 2005-10 have previously been identified using other mortality indicators. Conclusion The SHMI is a relatively simple tool that can be used in conjunction with other information to identify hospitals that may need further investigation.

Natural history of proteinuria in renal transplant recipients developing de novo human leukocyte antigen antibodies.

Background. The relationship between humoral rejection and human leukocyte antigen (HLA) antibodies is established. Proteinuria is the hallmark of glomerular injury. The relationship between HLA antibody and proteinuria was explored in renal transplant recipients developing de novo donor-specific antibodies (DSA) and nondonor-specific antibodies (NDSA). Methods. Seventy-two patients with de novo HLA antibody (38 DSA and 34 NDSA) were identified from 475 prevalent renal transplant recipients (15.2%). Antibody surveillance occurred every 6 months, with specificity characterized by a combination of enzyme-linked immunosorbent assay, flow-bead cytometry, and Luminex bead analysis. Pooled analysis of every glomerular filtration rate (GFR) and urinary protein estimation in a 48-month window around the date of antibody detection was performed (4004 and 2084 measurements, respectively). Results. GFR slope (−5.85 vs. −3.21 mL/min/1.73 m2 per year) and graft failure rate (29% vs. 9%, P=0.039) were worse in patients with DSA. Three-year graft survival after antibody detection was worse in patients with DSA (69.5% vs. 91.1%, P=0.035). Patients with DSA had significantly more proteinuria than those with NDSA and 205 control patients with no alloantibodies, from 6 months before antibody detection (0.91 vs. 0.39 g/L, P=0.015). Graft failure was more likely in patients with DSA with excess of 0.2 g/L at antibody detection (42% vs. 0%, P=0.008). Conclusions. Proteinuria is associated with DSA detection and is likely to be an important factor that determines rapid GFR decline and earlier graft failure in patients developing de novo HLA antibodies.

The mortality and hospitalization rates associated with the long interdialytic gap in thrice-weekly hemodialysis patients

Excess mortality and hospitalization have been identified after the 2-day gap in thrice-weekly hemodialysis patients compared with 1-day intervals, although findings vary internationally. Here we aimed to identify factors associated with mortality and hospitalization events in England using an incident cohort of 5864 hemodialysis patients from years 2002 to 2006 inclusive in the UK Renal Registry linked to hospitalization data. Higher admission rates were seen after the 2-day gap irrespective of whether thrice-weekly dialysis sequence commenced on a Monday or Tuesday (2.4 per year after the 2-day gap vs. 1.4 for the rest of the week, rate ratio 1.7). The greatest differences in admission rates were seen in patients admitted with fluid overload or with conditions associated with a high risk of fluid overload. Increased mortality following the 2-day gap was similarly independent of session pattern (20.5 vs. 16.7 per 100 patient years, rate ratio 1.22), with these increases being driven by out-of-hospital death (rate ratio 1.59 vs. 1.06 for in-hospital death). Non-white patients had an overall survival advantage, with the increased mortality after the 2-day gap being found only in whites. Thus, fluid overload may increase the risk of hospital admission after the 2-day gap and that the increased out-of-hospital mortality may relate to a higher incidence of sudden death. Future work should focus on exploring interventions in these subgroups.

Estimated Albumin Excretion Rate Versus Urine Albumin-Creatinine Ratio for the Estimation of Measured Albumin Excretion Rate: Derivation and Validation of an Estimated Albumin Excretion Rate Equation

BACKGROUND Glomerular filtration rate estimation equations use demographic variables to account for predicted differences in creatinine generation rate. In contrast, assessment of albuminuria from urine albumin-creatinine ratio (ACR) does not account for these demographic variables, potentially distorting albuminuria prevalence estimates and clinical decision making. STUDY DESIGN Polynomial regression was used to derive an age-, sex-, and race-based equation for estimation of urine creatinine excretion rate, suitable for use in automated estimated albumin excretion rate (eAER) reporting. SETTING & PARTICIPANTS The MDRD (Modification of Diet in Renal Disease) Study cohort (N=1,693) was used for equation derivation. Validation populations were the CRIC (Chronic Renal Insufficiency Cohort; N=3,645) and the DCCT (Diabetes Control and Complications Trial; N=1,179). INDEX TEST eAER, calculated by multiplying ACR by estimated creatinine excretion rate, and ACR. REFERENCE TEST Measured albumin excretion rate (mAER) from timed 24-hour urine collection. RESULTS eAER estimated mAER more accurately than ACR; the percentages of CRIC participants with eAER within 15% and 30% of mAER were 33% and 60%, respectively, versus 24% and 39% for ACR. Equivalent proportions in DCCT were 52% and 86% versus 15% and 38%. The median bias of ACR was -20.1% and -37.5% in CRIC and DCCT, respectively, whereas that of eAER was +3.8% and -9.7%. Performance of eAER also was more consistent across age and sex categories than ACR. LIMITATIONS Single timed urine specimens used for mAER, ACR, and eAER. CONCLUSIONS Automated eAER reporting potentially is a useful approach to improve the accuracy and consistency of clinical albuminuria assessment.

The body composition and excretory burden of lean, obese, and severely obese individuals has implications for the assessment of chronic kidney disease

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m(2) or more versus the normal of 18.5-25 kg/m(2)) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m(2), height 1.76 m, and BMI 22 or 45 kg/m(2) had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research.

Post-Parathyroidectomy Parathyroid Hormone Levels: The Impact on Patient Survival – A Single-Centre Study in a Stage 5 Chronic Kidney Disease Population

Background/Aims: Both severe, uncontrolled and low parathyroid hormone (iPTH) levels are associated with adverse outcomes in stage 5 chronic kidney disease (CKD) patients; however, the impact of iPTH levels following parathyroidectomy (PTX) is unexplored. Methods: A total of 235 stage 5 CKD patients who underwent PTX between 1990 and 2007 were identified, and iPTH levels following surgery were used to divide patients according to the quartile of maximum iPTH recovery during the 5 years following PTX. Survival, biochemistry and pharmacotherapy were analysed. Results: The maximum iPTH level in each quartile during the follow-up period was <46, 47–139, 140–420 and >420 pg/ml. The overall 5-year survival for the group was 81%. Adjusting for age, time on renal replacement therapy and the presence of diabetes identified an increased hazard for mortality of 2.459 in the quartile of lowest iPTH recovery (p = 0.035). The median 1-alfacalcidol dose during the follow-up period was higher (0.5 µg/day) in the lower iPTH group compared to the 3 quartiles of higher iPTH recovery (0.25 µg/day). Conclusion: An association between the lowest quartile of iPTH recovery in the 5 years following PTX and poorer patient survival was found. This finding should be tested in larger datasets.

Modification of the Relationship Between Blood Pressure and Renal Albumin Permeability by Impaired Excretory Function and DiabetesNovelty and Significance

In animal models, reduced nephron mass impairs renal arteriolar autoregulation, increasing vulnerability of the remaining nephrons to elevated systemic blood pressure (BP). A feature of the resulting glomerular capillary hypertension is an increase in glomerular permeability. We sought evidence of a similar remnant nephron effect in human chronic kidney disease. In participants from the United States National Health and Nutrition Examination Surveys 1999 to 2010 (N=23 710), we examined the effect of reduced estimated glomerular filtration rate (eGFR) on the relationship between brachial artery BP and albumin permeability. Renal albumin permeability increased exponentially with systolic BP >110 mm Hg, and this association was modified by independent interactions with both excretory impairment and diabetes mellitus. Each 10 mm Hg increase in systolic BP was accompanied by an increase in fractional albumin excretion of 1.10-, 1.11-, 1.17-, 1.22-, and 1.38-fold for participants with eGFR≥90, 90>eGFR≥60, 60>eGFR≥45, 45>eGFR≥30, and eGFR<30 mL/min/1.73 m2, respectively, adjusted for age, sex, race, antihypertensive use, eGFR category, diabetes mellitus, smoking, history of cardiovascular disease, body mass index, and C-reactive protein. A 10 mm Hg systolic BP increment was associated with increases in fractional albumin excretion of 1.10- and 1.21-fold in nondiabetic and diabetic participants, respectively. Using urine albumin creatinine ratio as an alternative measure of albumin leak in eGFR-adjusted analyses gave the same conclusions. Our findings are consistent with the presence of a remnant nephron effect in human kidney disease. Future trials should consider the nephroprotective benefits of systolic BP lowering in kidney disease populations stratified by eGFR.

Differential scaling of glomerular filtration rate and ingested metabolic burden: implications for gender differences in chronic kidney disease outcomes

BACKGROUND Men commence dialysis with a higher estimated glomerular filtration rate (eGFR) than women and are more likely to transition from chronic kidney disease (CKD) to end-stage renal disease. We hypothesized that for a given estimated body surface area (BSA) men have a greater metabolic burden, and that consequently, the practice of indexing GFR to BSA results in gender differences in the degree of biochemical uraemia. METHODS Metabolic burden was assessed as estimated dietary protein, calorie, phosphorus, sodium and potassium intakes and urinary urea nitrogen excretion in the Chronic Renal Insufficiency Cohort, Modification of Diet in Renal Disease study, and National Health and Nutrition Examinations Surveys (NHANES) 1999-2010. Uraemia was characterized by serum biochemistry. RESULTS Per m(2) BSA, men had greater urea nitrogen excretion and intakes of all dietary parameters (P < 0.001 for all). For a given BSA-indexed iothalamate GFR or eGFR, male gender was associated with a 10-15% greater serum urea nitrogen (P < 0.001), giving men with a BSA-indexed GFR of 70-75 mL/min/1.73 m(2) the same serum urea nitrogen concentration as women with a GFR of 60 mL/min/1.73 m(2). However, indexing metabolic burden and GFR to alternative body size measures (estimated total body water, lean body mass or resting energy expenditure) abolished/reversed the gender associations. In NHANES, BSA-indexed eGFR distribution was very similar for men and women, so that adjusting for eGFR had little effect on the gender difference in serum urea. CONCLUSIONS Indexing GFR to BSA across genders may approximate natures indexing approach, but gives men a greater ingested burden of protein, calories, sodium, phosphorus and potassium per mL/min GFR. This has implications for gender differences in CKD outcomes.

Chapter 13 The linkage of incident renal replacement therapy patients in England (2002-2006) to hospital episodes and national mortality data: improved demography and hospitalisation data in patients undergoing renal replacement therapy.

Introduction: Missing data has hampered the comprehensive and inclusive reporting of adjusted outcomes for patients on renal replacement therapy (RRT) captured by the UK Renal Registry (UKRR). Furthermore the information collected by the UKRR does not currently include morbidity after starting RRT, details on hospital admission rates or location of death. Linking datasets offers the opportunity to enhance existing data and describe new measures of centre performance. Methods: 21,633 incident patients, starting RRT between 2002 and 2006, were linked to all hospital care recorded by the Hospital Episode Statistics (HES) database and Office of National Statistics (ONS) mortality data using a secure anonymised service. Comorbidity prior to admission was determined from ICD10 coded HES admission diagnoses before the start of RRT, along with missing data on ethnicity and socioeconomic status. Location of death was determined by comparing the ONS and UKRR date of death to concurrent hospitalisations from HES. Results: 290,443 admissions, 2.2 million haemodialysis attendances, 1.5 million outpatient attendances and 11,546 ONS deaths were returned for this cohort. Coding depth improved over time and varied between centres. Following linkage 21,271 patients were suitable for analysis, with improvements in ethnicity completeness (75.5% to 98.9%) and socioeconomic status (72.0% to 98.6%). Comorbidity improved substantially from 53.7% to 98.1% with 93% concordance in those with UKRR data. Mean comorbid scores between centres was similar (0.73–1.14) but variation in the proportion of admissions under nephrology in the first 12 months and the location of death between centres was noted, suggesting differing policies, practices and coding methods. Conclusions: Linking routine healthcare datasets with a national registry has dramatically reduced missing data and enables reporting of additional comprehensively adjusted measures of performance that allow more robust comparisons between centres. Hospitalisation frequency and associated mortality can be described in much greater detail. Linking routine datasets to national audits and registries represents an achievable, cost-effective and illuminating new way to evaluate services such as renal replacement therapy in the English NHS.