Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the prevalence of diabetic nephropathy (DN) has also increased, becoming the ...main cause of end-stage renal disease (ESRD) in the developed world. DN is characterized by albuminuria, a decline in glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, glomerular basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances in the last years have been able to modify and delay the natural course of diabetic kidney disease (DKD). Nevertheless, there is still an urgent need to characterize the pathways that are involved in DN, identify risk biomarkers and prevent kidney failure in diabetic patients. Rodent models provide valuable information regarding how DN is set and its progression through time. Despite the utility of these models, kidney disease progression depends on the diabetes induction method and susceptibility to diabetes of each experimental strain. The classical DN murine models (Streptozotocin-induced, Akita, or obese type 2 models) do not develop all of the typical DN features. For this reason, many models have been crossed to a susceptible genetic background. Knockout and transgenic strains have also been created to generate more robust models. In this review, we will focus on the description of the new DN rodent models and, additionally, we will provide an overview of the available methods for renal phenotyping.
Abstract
Background
Checkpoint inhibitors (CPIs) have drastically improved metastatic cancer outcomes. However, immunotherapy is associated with multiple toxicities, including acute kidney injury ...(AKI). Data about CPI-related AKI are limited. Our aim was to determine risk factors for CPI-related AKI as well as its clinical characteristics and its impact on mortality in patients undergoing immunotherapy.
Methods
All patients under CPI at our centre between March 2018 and May 2019 and with a follow-up through April 2020 were included. Demographic, clinical and laboratory data were collected. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines. We performed a logistic regression model to identify independent risk factors for AKI and actuarial survival analysis to establish risk factors for mortality in this population.
Results
A total of 759 patients were included, with a median age of 64 years. A total of 59% were men and baseline median creatinine was 0.80 mg/dL. The most frequent malignancy was lung cancer and 56% were receiving anti-programmed death protein 1 (PD-1). About 15.5% developed AKI during the follow-up. Age and baseline kidney function were identified as independent risk factors for CPI-related AKI. At the end of follow-up, 52.3% of patients had died. The type of cancer (not melanoma, lung or urogenital malignance), type of CPI (not cytotoxic T-lymphocyte-associated protein 4, PD-1, programmed death-ligand 1 or their combination) and the presence of an episode of AKI were identified as risk factors for mortality.
Conclusions
A total of 15.5% of patients under immunotherapy presented with AKI. A single AKI episode was identified as an independent risk factor for mortality in these patients and age and baseline renal function were risk factors for the development of AKI.
The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the ...conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.
Coronavirus disease 2019 (COVD-19) emerged as a pandemic in December 2019. Infection has spread quickly and renal transplant recipients receiving chronic immunosuppression have been considered a ...population at high risk of infection, complications and infection-related death. During this year a large amount of information from nationwide registries, multicentre and single-centre studies have been reported. The number of renal transplant patients diagnosed with COVID-19 was higher than in the general population, but the lower threshold for testing may have contributed to its better identification. Major complications such as acute kidney injury and acute respiratory distress syndrome were very frequent in renal transplant patients, with a high comorbidity burden, but further studies are needed to support that organ transplant recipients receiving chronic immunosuppression are more prone to develop these complications than the general population. Kidney transplant recipients experience a high mortality rate compared with the general population, especially during the very early post-transplant period. Despite the fact that some studies report more favourable outcomes in patients with a kidney transplant than in patients on the kidney waiting list, the higher mortality described in the very early post-transplant period would advise against performing a kidney transplant in areas where the spread of infection is high, especially in recipients >60 years of age. Management of transplant recipients has been challenging for clinicians and strategies such as less use of lymphocyte-depleting agents for new transplants or anti-metabolite withdrawal and calcineurin inhibitor reduction for transplant patients with COVID-19 are not based on high-quality evidence.
We aimed to study whether worsening in markers of kidney function parallels the progression in cerebral small vessel disease (cSVD) and cognitive decline.
Data from the ISSYS (Investigating Silent ...Strokes in Hypertensives Study), a longitudinal population-based study in hypertensives aged 50–70 and dementia and stroke-free at baseline. At both visits, patients underwent a brain MRI, a cognitive diagnosis (normal aging or mild cognitive impairment, MCI) and urine and blood sampling collection.
We assessed the incidence of infarcts and cerebral microbleeds, and the progression of white matter hyperintensities at periventricular (PVH) and deep areas.
We determined changes in albumin-creatinine ratio and estimated glomerular filtration rate (eGFR). These changes were dichotomized into microalbuminuria at follow-up —either in subjects with or without baseline microalbuminuria— and significant decline in eGFR —lowest quintile of eGFR change (−10.57 mL/min/1.73m2)—.
360 patients were followed-up for 4 years. 80 (23%) patients presented microalbuminuria at follow-up and 68 (20.1%) experienced a significant eGFR decline.
Considering cSVD change, we found a relationship between microalbuminuria at follow-up and progression in PVH (β = 0.31, P-value = .01).
Regarding cognitive decline, presence of microalbuminuria at follow-up related to a steeper decrease in memory function (β = −0.36, P-value<.01). Moreover, patients with significant decline in eGFR were at higher risk of incident MCI (OR = 3.54, P-value = .02). These associations were independent of progression of cSVD.
The worsening in markers of kidney function paralleled the decrease in cognition and the progression of cSVD, and this may be explained by common shared underlying risk factors.
•We studied the changes in markers of kidney function, cognition and vascular lesions.•Microalbuminuria was associated with progression of periventricular hyperintensities.•We found a correlation between the increase in albuminuria and memory decline.•Decline in kidney function predicted the incidence of mild cognitive impairment.•The relationship between brain and kidney may be explained by shared etiologies.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19). The main organ affected in this infection is the lung and the virus ...uses the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the target cells. In this context, a controversy raised regarding the use of renin-angiotensin system (RAAS) blockers, as these drugs might increase ACE2 expression in some tissues and potentially increase the risk for SARS-CoV-2 infection. This is specially concerning in diabetic patients as diabetes is a risk factor for COVID-19.
12-week old diabetic mice (db/db) were treated with ramipril, or vehicle control for 8 weeks. Non-diabetic db/m mice were included as controls. ACE2 expression and activity were studied in lung, kidney and heart of these animals.
Kidney ACE2 activity was increased in the db/db mice as compared to the db/m (143.2% ± 23% vs 100% ± 22.3%, p = 0.004), whereas ramipril had no significant effect. In the lung, no differences were found in ACE2 when comparing db/db mice to db/m and ramipril also had no significant effect. In the heart, diabetes decreased ACE2 activity (83% ± 16.8%, vs 100% ± 23.1% p = 0.02), and ramipril increased ACE2 significantly (83% ± 16.8% vs 98.2% ± 15%, p = 0.04).
In a mouse model of type 2 diabetes, ramipril had no significant effect on ACE2 activity in either kidneys or in the lungs. Therefore, it is unlikely that RAAS blockers or at least angiotensin-converting enzyme inhibitors increase the risk of SARS-CoV-2 infection through increasing ACE2.
•The Angiotensin Converting Enzyme 2 (ACE2) is the main receptor for the SARS-CoV-2, the virus that causes COVID-19.•It has been suggested that RAAS blockade may increase the expression of ACE2 and the risk of SARS-CoV-2 infection, which is specially concerning in diabetic patients.•In kidney, ACE2 was found increased in db/db as compared to the non-diabetic littermates. Ramipril normalized ACE2 gene expression but had no effect on ACE2 activity.•In lung, no differences were found in ACE2 when comparing db/db mice to db/m and Ramipril had no effect.•RAAS blockade in db/db did not induce increase of the levels of ACE2 in the kidney and the lung which suggests that it will not exert a deleterious effect on COVID-19 patients with diabetes.
Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed ...that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.
Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology ...assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+ HLADR+ T cells, combined with a sustained enhancement of CD4+ CD25(+high) lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+ CD25(+high) T cells, which showed donor-Ag specificity. FOXP3+ CD4+ CD25(+high) Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.
Abstract
Background
Checkpoint inhibitors (CPIs) are used to treat solid organ metastatic malignancies. They act by triggering a vigorous immune response against tumoural cells, preventing their ...proliferation and metastasis. However, this is not a selective response and can cause immune-related adverse events (irAEs). The kidney can potentially be damaged, with an incidence of irAEs of 1–4%. The most frequent type of toxicity described is acute interstitial nephritis (AIN).
Methods
We conducted a study of patients with solid organ metastatic malignancies treated with immunotherapy who developed acute renal injury and underwent kidney biopsy in the last 14 months at the Vall d’Hebron University Hospital.
Results
In all, 826 solid organ malignancies were treated with immunotherapy in our centre, 125 of them (15.1%) developed acute kidney injury (AKI), 23 (18.4% of AKI) visited the nephrology department and 8 underwent kidney biopsy. The most frequent malignancy was lung cancer, in five patients (62%), followed by two patients (25%) with melanoma and one patient (12%) with pancreatic cancer. Four patients (50%) had already received previous oncological therapy, and for the remaining four patients (50%), CPI was the first-line therapy. Five patients (62%) were treated with anti-programmed cell death protein 1, three patients (37%) received anti-programmed death ligand 1 and two (25%) patients were treated in combination with anti-cytotoxic T-lymphocyte antigen 4. The time between the start of CPI and the onset of the AKI ranged from 2 to 11 months. The most frequent urine findings were subnephrotic-range proteinuria, with a mean protein:creatinine ratio of 544 mg/g (standard deviation 147) and eosinophiluria. All patients were biopsied after being diagnosed with AIN. Three patients (37%) received treatment with pulses of methylprednisolone 250–500 mg/day and five patients (62%) received prednisone 1 mg/kg/day. Seven patients (87%) experienced recovery of kidney function and one patient (12%) progressed to chronic kidney disease.
Conclusions
We report on eight patients with CPI-related AIN diagnosed in the last 14 months at our centre. The novel immunotherapy treatment of metastatic solid organ malignancies carries a higher risk of irAEs. The kidney is one of the most commonly affected organs, frequently presenting as an AIN and exhibiting a favourable response to steroid treatment.
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