Graham Lipkin

Mutations in the Hepatocyte Nuclear Factor-1β Gene Are Associated with Familial Hypoplastic Glomerulocystic Kidney Disease

Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with early-onset diabetes and nondiabetic renal disease-particularly renal cystic disease. We investigated a possible role for the HNF-1beta gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1beta gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1beta mutations.

Case mix, outcome and activity for patients admitted to intensive care units requiring chronic renal dialysis: a secondary analysis of the ICNARC Case Mix Programme Database

IntroductionThis report describes the case mix, outcome and activity for admissions to intensive care units (ICUs) of patients who require prior chronic renal dialysis for end-stage renal failure (ESRF), and investigates the effect of case mix factors on outcome.MethodsThis was a secondary analysis of a high-quality clinical database, namely the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, which includes 276,731 admissions to 170 adult ICUs across England, Wales and Northern Ireland from 1995 to 2004.ResultsDuring the eight year study period, 1.3% (n = 3,420) of all patients admitted to ICU were receiving chronic renal dialysis before ICU admission. This represents an estimated ICU utilization of six admissions (32 bed-days) per 100 dialysis patient-years. The ESRF group was younger (mean age 57.3 years versus 59.5 years) and more likely to be male (60.2% versus 57.9%) than those without ESRF. Acute Physiology and Chronic Health Evaluation II score and Acute Physiology Score revealed greater severity of illness on admission in patients with ESRF (mean 24.7 versus 16.6 and 17.2 versus 12.6, respectively). Length of stay in ICU was comparable between groups (median 1.9 days versus 1.8 days) and ICU mortality was only slightly elevated in the ESRF group (26.3% versus 20.8%). However, the ESRF group had protracted overall hospital stay (median 25 days versus 17 days), and increased hospital mortality (45.3% versus 31.2%) and ICU readmission (9.0% vs. 4.7%). Multiple logistic regression analysis adjusted for case mix identified the increased hospital mortality to be associated with increasing age, emergency surgery and nonsurgical cases, cardiopulmonary resuscitation before ICU admission and extremes of physiological norms. The adjusted odds ratio for ultimate hospital mortality associated with chronic renal dialysis was 1.24 (95% confidence interval 1.13 to 1.37).ConclusionPatients with ESRF admitted to UK ICUs are more likely to be male and younger, with a medical cause of admission, and to have greater severity of illness than the non-ESRF population. Outcomes on the ICU were comparable between the two groups, but those patients with ESRF had greater readmission rates, prolonged post-ICU hospital stay and increased post-ICU hospital mortality. This study is by far the largest comparative outcome analysis to date in patients with ESRF admitted to the ICU. It may help to inform clinical decision-making and resource requirements for this patient population.

ABO‐incompatible live donor renal transplantation using blood group A/B carbohydrate antigen immunoadsorption and anti‐CD20 antibody treatment

Abstract: Background: Blood group ABO‐incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO‐incompatible LD renal transplantation using specific anti‐A/B antibody (Ab) immunoadsorption (IA) and anti‐CD20 monoclonal Ab (mAb) treatment.

Predicting 5-Year Risk of Kidney Transplant Failure: A Prediction Instrument Using Data Available at 1 Year Posttransplantation

BACKGROUND Accurate prediction of kidney transplant failure remains imperfect. The objective of this study was to develop and validate risk scores predicting 5-year transplant failure, based on data available 12 months posttransplantation. STUDY DESIGN Development and then independent multicenter validation of risk scores predicting death-censored and overall transplant failure. SETTING & PARTICIPANTS Outcomes of kidney transplant recipients (n=651) alive with transplant function 12 months posttransplantation in Birmingham, United Kingdom, were used to develop models predicting transplant failure risk 5 years posttransplantation. The resulting risk scores were evaluated for prognostic utility (discrimination, calibration, and risk reclassification) in independent cohorts from Tours, France (n=736); Leeds, United Kingdom (n=787); and Halifax, Canada (n=475). PREDICTORS Weighted regression coefficients for baseline and 12-month demographic and clinical predictor characteristics. OUTCOMES Death-censored and overall transplant failure 5 years posttransplantation. MEASUREMENTS Baseline data and time to transplant failure. RESULTS Following model development, variables included in separate scores for death-censored and overall transplant failure included recipient age, sex, and race; acute rejection; transplant function; serum albumin level; and proteinuria. In the validation cohorts, these scores showed good to excellent discrimination for death-censored transplant failure (C statistics, 0.78-0.90) and moderate to good discrimination for overall transplant failure (C statistics, 0.75-0.81). Both scores demonstrated good calibration (Hosmer-Lemeshow P>0.05 in all cohorts). Compared with estimated glomerular filtration rate in isolation, application of the scores resulted in statistically significant and clinically relevant risk reclassification for death-censored transplant failure (net reclassification improvement [NRI], 36.1%-83.0%; all P<0.001) and overall transplant failure (NRI, 38.7%-53.5%; all P<0.001). Compared with the previously described US Renal Data System-based risk calculator, significant and relevant risk reclassification for overall transplant failure was seen (NRI, 30.0%; P<0.001). LIMITATIONS Validation is required in further populations. CONCLUSIONS These validated risk scores may be of prognostic utility in kidney transplantation, accurately identifying at-risk transplants, and informing clinicians and patients.

Glomerular prolapse as precursor of one type of segmental sclerosing lesions

A distinctive segmental glomerular abnormality is confined to the region of the tubular opening. The hypothesis was that this followed prolapse of the tuft into the tubule. Analysis was made of 39 renal biopsy specimens with acute postinfective glomerulonephritis, later material from ten cases, four specimens from three women with pre‐eclampsia, and 21 control specimens, with morphometry of glomeruli and immunohistological examination for immunoproteins and monocytes/macrophages. Prolapse was found in 14 specimens with acute postinfective glomerulonephritis, associated in eight with adhesion to Bowmans capsule and local alterations in the tuft, which together constitute early tip changes. Another three had early tip changes only and eight others had thin adhesions between the tuft and capsule next to the tubular opening. Later material confirmed this order of development and showed another late change, with sclerosed and hyaline material in the tuft and adhesion at the tubular origin. Findings in pre‐eclampsia were comparable. Glomeruli were significantly larger in acute postinfective glomerulonephritis than in controls and were shown by others to be larger in pre‐eclampsia than in normal pregnancy. Immunohistology showed IgM and a few foamy monocytes/macrophages in early tip changes but not in prolapsed loops. Glomerular prolapse appears to be a temporary consequence of acute enlargement of the tuft, probably causes mechanical damage to epithelial cells, and is a precursor of permanent structural changes near the tubular origin. This gives a unifying hypothesis to explain how these changes can be seen in acute postinfective glomerulonephritis, pre‐eclampsia, and many other human and experimental renal disorders. Copyright

Cholestasis in pregnancy associated with ciclosporin therapy in renal transplant recipients.

Obstetric cholestasis (OC) presents with pruritis in the second half of pregnancy and is associated with increased risk of foetal distress, intra‐uterine death and premature delivery. From a tertiary referral, renal‐obstetric clinic, we report the occurrence of OC in 5/23 pregnancies of women with renal transplants maintained on ciclosporin treatment (European incidence 0.1–1.5% of pregnancies). All required premature delivery for foetal reasons at 33–37/40 (median 34/40). Ciclosporin, at therapeutic concentrations, inhibits bile salt excretion pump (BSEP) function in rats and humans. We propose that OC developed in our patients because the mild inhibition of the canalicular pumps by ciclosporin was only revealed in pregnancy when increases in progesterone metabolites overwhelmed pump function. We suggest that all pregnant women receiving ciclosporin should be closely monitored from the second trimester for the development of OC. If detected, enhanced foetal and maternal monitoring to optimize time of delivery and pregnancy outcome is required.

Controversies and research agenda in nephropathic cystinosis: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

Defining Priorities for Future Research: Results of the UK Kidney Transplant Priority Setting Partnership

Background It has been suggested that the research priorities of those funding and performing research in transplantation may differ from those of end service users such as patients, carers and healthcare professionals involved in day-to-day care. The Kidney Transplant Priority Setting Partnership (PSP) was established with the aim of involving all stakeholders in prioritising future research in the field. Methods The PSP methodology is as outlined by the James Lind Alliance. An initial survey collected unanswered research questions from patients, carers and clinicians. Duplicate and out-of-scope topics were excluded and the existing literature searched to identify topics answered by current evidence. An interim prioritisation survey asked patients and professionals to score the importance of the remaining questions to create a ranked long-list. These were considered at a final consensus workshop using a modified nominal group technique to agree a final top ten. Results The initial survey identified 497 questions from 183 respondents, covering all aspects of transplantation from assessment through to long-term follow-up. These were grouped into 90 unanswered “indicative” questions. The interim prioritisation survey received 256 responses (34.8% patients/carers, 10.9% donors and 54.3% professionals), resulting in a ranked list of 25 questions that were considered during the final workshop. Participants agreed a top ten priorities for future research that included optimisation of immunosuppression (improved monitoring, choice of regimen, personalisation), prevention of sensitisation and transplanting the sensitised patient, management of antibody-mediated rejection, long-term risks to live donors, methods of organ preservation, induction of tolerance and bioengineering of organs. There was evidence that patient and carer involvement had a significant impact on shaping the final priorities. Conclusions The final list of priorities relates to all stages of the transplant process, including access to transplantation, living donation, organ preservation, post-transplant care and management of the failing transplant. This list of priorities will provide an invaluable resource for researchers and funders to direct future activity.

Rapidly progressive intravascular primary effusion lymphoma in an HIV‐positive renal transplant recipient

We describe the clinical and post‐mortem findings of a case of rapidly progressive, ultimately fatal primary effusion lymphoma (PEL) arising in an HIV‐positive man 2 years after renal transplantation. Disseminated multi‐organ involvement associated with a peculiar intravascular pattern of growth, as seen in this case, has only been reported once previously. This is also, to our knowledge, the first detailed description of a lymphoma arising post‐transplant in an HIV‐positive patient.