Do outcomes for patients with hospital-acquired Acute Kidney Injury (H-AKI) vary across specialties in England?

BACKGROUND: Acute Kidney Injury (AKI) is a common and serious clinical syndrome. There is increasing recognition of heterogeneity in observed AKI across different clinical settings. In this analysis we have utilised a large national dataset to outline, for the first time, differences in burden of hospital acquired AKI (H-AKI) and mortality risk across different treatment specialities in the English National Health Service (NHS). METHODS: A retrospective observational study was conducted using a large national dataset of patients who triggered a biochemical AKI alert in England during 2019. This dataset was enriched through linkage with NHS hospitals administrative and mortality data. Episodes of H-AKI were identified and attributed to the speciality of the supervising consultant during the hospitalisation episode in which the H-AKI alert was generated. Associations between speciality and death in hospital or within 30 days of discharge (30-day mortality) was modelled using logistic regression, adjusting for patient age, sex, ethnicity, socioeconomic status, AKI severity, season and method of admission. RESULTS: In total, 93,196 episodes of H-AKI were studied. The largest number of patients with H-AKI were observed under general medicine (21.9%), care of the elderly (18.9%) and general surgery (11.2%). Despite adjusting for differences in patient case-mix, 30-day mortality risk was consistently lower for patients in surgical specialities compared to general medicine, including general surgery (OR 0.65, 95% CI 0.61 to 0.7) and trauma and orthopaedics (OR 0.52, 95% CI 0.48 to 0.56). Mortality risk was highest in critical care (OR 1.78, 95% CI 1.56 to 2.03) and oncology (OR 1.74, CI 1.54 to 1.96). CONCLUSIONS: Significant differences were identified in the burden of H-AKI and associated mortality risk for patients across different specialities in the English NHS. This work can help inform future service delivery and quality improvement activity for patients with AKI across the NHS.

Centre variation in mortality following post-hospitalization acute kidney injury: analysis of a large national cohort.

BACKGROUND: Routine monitoring of outcomes for patients with acute kidney injury (AKI) is important to drive ongoing quality improvement in patient care. In this study we describe the development of a case mix-adjusted 30-day mortality indicator for patients with post-hospitalization AKI (PH-AKI) across England to facilitate identification of any unwarranted centre variation in outcomes. METHODS: We utilized a routinely collected national dataset of biochemically detected AKI cases linked with national hospitals administrative and mortality data. A total of 250 504 PH-AKI episodes were studied across 103 National Health Service hospital trusts between January 2017 and December 2018. Standardized mortality ratios (SMRs) were calculated for each trust using logistic regression, adjusting for age, sex, primary diagnosis, comorbidity score, AKI severity, month of AKI and admission method. RESULTS: The mean 30-day mortality rate was high, at 28.6%. SMRs for 23/103 trusts were classed as outliers, 12 above and 11 below the 95% confidence limits. Patients with PH-AKI had mortality rates >5 times higher than the overall hospitalized population in 90/136 diagnosis groups and >10 times higher in 60/136 groups. Presentation at trusts with a co-located specialist nephrology service was associated with a lower mortality risk, as was South Asian or Black ethnicity. Deprivation, however, was associated with higher mortality. CONCLUSIONS: This is the largest multicentre analysis of mortality for patients with biochemically ascertained PH-AKI to date, demonstrating once again the considerable risk associated with developing even mild elevations in serum creatinine. Mortality rates varied considerably across centres and those identified as outliers will now need to carefully interrogate local care pathways to understand and address the reasons for this, with national policy required to tackle the identified health disparities.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Obesity modulates the association between systolic blood pressure and albuminuria.

Background: Obesity is associated with albuminuria and incident kidney disease. Increased vulnerability of the glomerular microcirculation to elevated systemic blood pressure is postulated to contribute to adverse effects of obesity on the kidney. We therefore hypothesized that obesity would modulate the association between systolic blood pressure (sBP) and albuminuria. Methods: The relationship between obesity and albuminuria [fractional albumin excretion (FEalb) or albumin:creatinine ratio (ACR)] was modelled using linear/logistic regression in the US National Health and Nutrition Examination Survey 1999-2010 cohorts (N = 23 710). Associations between sBP and albuminuria were examined across strata of waist circumference and body mass index (BMI) using interaction terms. Results: Obesity was associated with albuminuria through an interaction with sBP. Among participants in the 4th/5th quintiles of waist circumference each 10 mmHg increase in sBP was accompanied by approximately double the increment in FEalb observed among those in quintile 2 (14% versus 7%, P < 0.001). There was also evidence of a lower sBP threshold for the relationship between sBP and albuminuria in obesity. While FEalb increased with sBP >110 mmHg in quintile 5 of waist circumference, in quintile 2 FEalb did not increase until sBP was >130 mmHg. Findings were consistent when defining obesity by BMI or waist circumference and when quantifying albuminuria by ACR or FEalb. Assessing albuminuria as the odds ratio of ACR >30 mg/g also gave similar results. Conclusion: The interaction between sBP and obesity supports the premise that obesity sensitizes the kidney to increased systemic blood pressure.

National recommendations to standardise acute kidney injury detection and alerting.

BACKGROUND: National Health Service England issued a Patient Safety Alert in 2014 mandating all acute Trusts in England to implement Acute Kidney Injury (AKI) warning stage results and to do so using a standardised algorithm. In 2021, the Renal and Pathology Getting It Right First Time (GIRFT) teams found significant variation in AKI reporting across the UK. A survey was designed to capture information on the entire AKI detection and alerting process to investigate the potential sources of this unwarranted variation. METHODS: In August 2021, an online survey consisting of 54 questions was made available to all UK laboratories. The questions covered creatinine assays, laboratory information management systems (LIMS), the AKI algorithm and AKI reporting. RESULTS: We received 101 responses from laboratories. Data were reviewed for England only - 91 laboratories. Findings included that 72% used enzymatic creatinine. In addition, 7 manufacturer-analytical platforms, 15 different LIMS and a wide range of creatinine reference ranges were in use. In 68% of laboratories, the AKI algorithm was installed by the LIMS provider. Marked variation was found in the minimum age of AKI reporting with only 18% starting at the recommended 1 month/28-days. Some 89% phoned all new AKI2s and AKI3s, as per AKI guidance while 76% provided comments/hyperlinks in reports. CONCLUSIONS: The national survey has identified laboratory practices that potentially contribute to unwarranted variation in the reporting of AKI in the England. This has formed the basis for improvement work to remedy the situation, including national recommendations, included within this article.

Defining the role of renal transplantation in the modern management of multiple myeloma and other plasma cell dyscrasias.

Plasma cell dyscrasias (PCD) are due to an abnormal proliferation of a single clone of plasma or lymphoplasmacytic cells leading to secretion of immunoglobulin (Ig) or an Ig fragment, causing the dysfunction of multiple organs. Median survival of these patients has significantly improved over the last decade due to availability of treatment options such as high-dose melphalan with autologous stem cell transplantation and novel anti-myeloma agents. Renal transplantation has not traditionally been considered in these patients due to the previously limited prognosis, along with concerns relating to disease recurrence affecting the renal allograft and increased infection susceptibility following renal transplant due to immunosuppression and the PCD itself. However, with the increasing range of effective treatment options, renal transplantation could now be considered, especially in young patients with good performance status. It is therefore timely to reappraise the potential role of renal transplantation in end-stage renal disease due to multiple myeloma and other PCD. This review summarizes the literature relating to renal transplantation in PCD, including multiple myeloma, monoclonal Ig deposition disease and systemic AL amyloidosis, to attempt to identify patients who may benefit most from this approach and to explore areas for further development.

Catheter access for hemodialysis defines higher mortality in late-presenting dialysis patients.

BACKGROUND: This study explores the relationship between mortality and late presentation for dialysis, focusing on the role of catheter access for hemodialysis (HD). METHODS: We analyzed data from a cohort of 286 patients commencing dialysis in 2000-2001. Survival and factors associated with death were analyzed by univariate and multivariate analysis. Dialysis access was considered in three groups: HD-AVF, HD-Catheter, and peritoneal dialysis (PD). Late referral (LR) was defined as first review by a nephrologist less than 90 days before dialysis. RESULTS: One-year mortality was low at 10.1%. HD-Catheter patients were older (p < 0.001), more hypoalbuminemic (p < 0.001), more anemic (p = 0.005), and more likely to be LR (p < 0.001). HD-Catheter patients did not have significantly higher comorbidity (p = 0.128). HD-Catheter was strongly associated with late presentation (75% LR vs. 28% early referral, p < 0.001). Factors associated with death by univariate analysis included age (p < 0.0001), comorbidity (p < 0.0001), HD-Catheter (p < 0.0001), LR (p = 0.0001), hypoalbuminemia (p = 0.0011), and diabetes (p = 0.02). When corrected for these factors, HD-Catheter was associated with death (HR 2.226, 95% CI 1.314-3.772, p = 0.003) but LR was not (p = 0.38). CONCLUSIONS: A predominant feature of LR that predicts mortality is the use of catheter access for HD. This may be modifiable in those LR patients who do not present as uremic emergencies.

Anakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases.

Paradoxical reactions, including immune reconstitution inflammatory syndrome (IRIS), are common in patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Paradoxical reactions may confer substantial morbidity and mortality, especially in cases of central nervous system (CNS) TB, or through protracted usage of corticosteroids. No high-quality evidence is available to guide management in this scenario. Interleukin-1-mediated inflammation has been implicated in the pathophysiology of TB-IRIS. We describe two cases where anakinra (human recombinant interleukin-1 receptor antagonist) was used as steroid-sparing therapy for life-threatening protracted paradoxical inflammation in HIV-associated TB. In the first case of disseminated TB with lymphadenitis, protracted TB-IRIS led to amyloid A amyloidosis and nephrotic syndrome. In the second case of disseminated TB with cerebral tuberculomata, paradoxical inflammation caused unstable tuberculomata leading to profound neuro-disability. In both cases, paradoxical inflammation persisted for over a year. Protracted high-dose corticosteroid use led to adverse events yet failed to control inflammatory pathology. In both patients, anakinra successfully controlled paradoxical inflammation and facilitated withdrawal of corticosteroid therapy. Following anakinra therapy, nephrotic syndrome and neuro-disability resolved, respectively. Anakinra therapy for protracted paradoxical inflammation in HIV-associated TB may be a viable therapeutic option and warrants further research.

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy.

BACKGROUND: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. METHODS: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. FINDINGS: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples. INTERPRETATION: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. FUNDING: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].

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.

Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation.

Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.

Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation.

BACKGROUND: Data from matched historical cohort studies suggest that autosomal-dominant polycystic kidney disease (ADPKD) may be a risk factor for new-onset diabetes after transplantation (NODAT). METHOD: A retrospective study of 429 renal allografts transplanted from 1990 through 2004 in nondiabetic patients was performed. A multivariate analysis of risk factors for NODAT was performed with focus on ADPKD. RESULTS: A total of 6.5% of all patients developed NODAT and a further 11% developed impaired glucose tolerance. NODAT developed in 13.4% of patients with ADPKD compared with 5.2% of non-ADPKD patients (P=0.01). There were significant univariate associations between NODAT and recipient age (P=0.001) and weight (P<0.0001). There was no association between NODAT and recipient gender, human leukocyte antigen mismatch, acute rejection, or cumulative methylprednisolone dose. In a multivariate analysis, ADPKD was a strong risk factor for the development of NODAT (odds ratio [OR]=2.41, P=0.035) after correction for recipient age, weight, gender, ethnicity, and tacrolimus use. Age (OR=1.06), weight (OR=1.04), and nonwhite race (OR=5.04) were the other significant variables. CONCLUSION: We conclude that ADPKD is a significant risk factor for the development of NODAT. This may influence the follow up and management choices of these patients in the future.

Injury to a transplanted kidney during caesarean section: a case report.

As fertility is restored after renal transplant, more female recipients of a renal transplant successfully complete pregnancies that are safe for the mother, the fetus, and the renal allograft. Although the transplanted kidney lies in one of the iliac fossae, normal vaginal delivery is not impeded by this positioning. Caesarean section is indicated in many scenarios, primarily for obstetric reasons, particularly when the transplanted kidney lies in a position where it could be injured. Here, we report our experiences managing a rare instance of injury to a transplanted kidney during caesarean section and discuss the relevant aspects of its management. To our knowledge, this is the first report in the English literature of an injury to a transplanted kidney during caesarean section.

Renal artery sympathetic denervation: observations from the UK experience.

BACKGROUND: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response-particularly in those prescribed aldosterone antagonists at the time of RDN. METHODS: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. RESULTS: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p > 0.2). CONCLUSION: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response.

Modification of the relationship between blood pressure and renal albumin permeability by impaired excretory function and diabetes.

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 m(2), 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.

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 m 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.

Quality of life following live donor renal transplantation: a single centre experience.

BACKGROUND: The aim of this study was to examine the quality of life (QoL) of the live donor renal transplant (LDRTx) recipients pre- and post-transplantation and correlate with their pre-transplant (pre-Tx) dialysis status and immunosuppressive regimens post-transplantation (post-Tx). MATERIAL/METHODS: 57 LDRTx recipients and 38 healthy individuals as controls participated in the study. The Kidney Transplant Questionnaire (KTQ) and the Medical Outcome Survey Short Form 36 (SF-36) questionnaires were used to assess QoL. RESULTS: The post-Tx scores in all SF-36 dimensions were significantly higher in the LDRTx recipients, but remained lower than that of the control group. However, in the KTQ, all dimensions except Appearance (p=0.035), significantly increased post-Tx Patients transplanted pre-emptively and those on tacrolimus-based immunosuppressive drugs had significantly better QoL. CONCLUSIONS: LDRTx significantly improved QoL, which was best with preemptive transplantation and tacrolimus-based immunosuppressive regimens.