The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the ...condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.
Estimated GFR: time for a critical appraisal Porrini, Esteban; Ruggenenti, Piero; Luis-Lima, Sergio ...
Nature reviews. Nephrology,
03/2019, Letnik:
15, Številka:
3
Journal Article
Recenzirano
Since 1957, over 70 equations based on creatinine and/or cystatin C levels have been developed to estimate glomerular filtration rate (GFR). However, whether these equations accurately reflect renal ...function is debated. In this Perspectives article, we discuss >70 studies that compared estimated GFR (eGFR) with measured GFR (mGFR), involving ~40,000 renal transplant recipients and patients with chronic kidney disease (CKD), type 2 diabetes mellitus or polycystic kidney disease. Their results show that eGFR often differed from mGFR by ±30% or more, that eGFR values incorrectly staged CKD in 30-60% of patients, and that eGFR and mGFR gave different rates of GFR decline. Errors were unpredictable, and comparable for equations based on creatinine and/or cystatin C. We argue, therefore, that the persistence of these errors (despite intensive research) suggests that the problem lies with using creatinine and/or cystatin C as markers of renal function, rather than with the mathematical methods used for GFR estimation.
The current coronavirus disease 2019 (COVID‐19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35‐year‐old ...renal transplant recipient who suffered from a severe COVID‐19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence‐based COVID‐19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk‐benefit balance of experimental or off‐label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID‐19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug‐drug interactions associated with the various treatment options for COVID‐19 in renal transplant patients.
This article reports on a case of coronavirus disease 2019 in a renal transplant recipient and aims to enhance awareness and provide guidance for the clinical management of drug interactions between immunosuppressive therapy and experimental or investigational antiviral agents.
An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 ...vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.
This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed.
Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 × mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56–79), 46 (63%) of 73 (51–74), and 50 (68%) of 73 (57–79), respectively. The difference with single mRNA-1273 was -0·4% (-16 to 15; p=0·96) for 2 × mRNA-1273 and -6% (-21 to 10; p=0·49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66–91) and 31 (67%) of 46 (52–80), and a difference of 13% (-5 to 31; p=0·15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 92% of 71, 67 92% of 73, and 38 50% of 76, respectively; p<0·0001). No acute rejection occurred. There were no serious adverse events related to vaccination.
Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed.
The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this ...perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single‐center, open‐label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
TRITON, a randomized, prospective, single‐center, open‐label study, shows that autologous mesenchymal stromal cell therapy and early tacrolimus withdrawal was feasible and safe, without increased rejection and with preserved renal function.
The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft ...survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 n = 3,499 and 2008-2018 n = 3,781), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects.
The membrane attack complex-also known as C5b-9-is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of ...various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.
Kidney transplant recipients (KTRs) elicit an impaired immune response after COVID-19 vaccination; however, the exact clinical impact remains unclear. We therefore analyse the relationship between ...antibody levels after vaccination and the risk of COVID-19 in a large cohort of KTRs. All KTRs living in the Netherlands were invited to send a blood sample 28 days after their second COVID-19 vaccination for measurement of their IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD IgG). Information on COVID-19 was collected from the moment the blood sample was obtained until 6 months thereafter. Multivariable Cox and logistic regression analyses were performed to analyse which factors affected the occurrence and severity (i.e., hospitalization and/or death) of COVID-19. In total, 12,159 KTRs were approached, of whom 2885 were included in the analyses. Among those, 1578 (54.7%) became seropositive (i.e., anti-RBD IgG level >50 BAU/mL). Seropositivity was associated with a lower risk for COVID-19, also after adjusting for multiple confounders, including socio-economic status and adherence to COVID-19 restrictions (HR 0.37 (0.19-0.47),
= 0.005). When studied on a continuous scale, we observed a log-linear relationship between antibody level and the risk for COVID-19 (HR 0.52 (0.31-0.89),
= 0.02). Similar results were found for COVID-19 severity. In conclusion, antibody level after COVID-19 vaccination is associated in a log-linear manner with the occurrence and severity of COVID-19 in KTRs. This implies that if future vaccinations are indicated, the aim should be to reach for as high an antibody level as possible and not only seropositivity to protect this vulnerable patient group from disease.
The global increase in chronic kidney disease (CKD) parallels the obesity epidemic. Obesity conveys a gradual but independent risk of progression of CKD that seems irrespective of the underlying ...nephropathy. Obesity has been associated with a secondary focal segmental glomerulosclerosis coined obesity-related glomerulopathy (ORG). Pathways through which obesity might cause renal disease are not well understood, and early clinical biomarkers for incipient ORG or renal relevant obesity are currently lacking. Recent human and experimental studies have associated ectopic lipid accumulation in the kidney (fatty kidney) with obesity-related renal disease. There is enough growing insight that ectopic lipid--the accumulation of lipid in non-adipose tissue--is associated with structural and functional changes of mesangial cells, podocytes, and proximal tubular cells to propose the development of ORG as a maladaptive response to hyperfiltration and albuminuria. Recent advances in metabolic imaging might validate ectopic lipid as a biomarker and research aid, to help translate novel therapeutics from experimental models to patients.
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