Background. Subclinical rejection and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies are associated with outcome. We study the relationship between histologic lesions in early protocol biopsies and histologic diagnoses in late biopsies for cause. Materials and Methods. Renal transplants with a protocol biopsy performed within the first 6 months posttransplant between 1988 and 2006 were reviewed. Biopsies were evaluated according to Banff criteria, and C4d staining was available in biopsies for cause. Results. Of the 517 renal transplants with a protocol biopsy, 109 had a subsequent biopsy for cause which showed the following histological diagnoses: chronic humoral rejection (CHR) (n=44), IF/TA (n=42), recurrence of the primary disease (n=11), de novo glomerulonephritis (n=7), T-cell-mediated rejection (n=4), and polyoma virus nephropathy (n=1). The proportion of retransplants (15.9% vs. 2.3%, P=0.058) and the prevalence of subclinical rejection were higher in patients with CHR than in patients with IF/TA (52.3% vs. 28.6%, P=0.0253). Demographic donor and recipient characteristics and clinical data at the time of protocol biopsy were not different between groups. Logistic regression analysis showed that subclinical rejection (relative risk, 2.52; 95% confidence interval, 1.1–6.3; P=0.047) but not retransplantation (relative risk, 6.7; 95% confidence interval, 0.8–58.8; P=0.085) was associated with CHR. Conclusion. Subclinical rejection in early protocol biopsies is associated with late appearance of CHR.

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.

The majority of diabetic patients with renal involvement are not biopsied. Studies evaluating histological findings in renal biopsies performed in diabetic patients have shown that approximately one third of the cases will show pure diabetic nephropathy, one third a non-diabetic condition and another third will show diabetic nephropathy with a superimposed disease. Early diagnosis of treatable non-diabetic diseases in diabetic patients is important to ameliorate renal prognosis. The publication of the International Consensus Document for the classification of type 1 and type 2 diabetes has provided common criteria for the classification of diabetic nephropathy and its utility to stratify risk for renal failure has already been demonstrated in different retrospective studies. The availability of new drugs with the potential to modify the natural history of diabetic nephropathy has raised the question whether renal biopsies may allow a better design of clinical trials aimed to delay the progression of chronic kidney disease in diabetic patients.

Introduction: Little information exists about the impact of acute kidney injury (AKI) in critically ill patients with the pandemic 2009 influenza A (H1N1) virus infection. Methods: We conducted a prospective, observational, multicenter study in 148 Spanish intensive care units (ICUs). Patients with chronic renal failure were excluded. AKI was defined according to Acute Kidney Injury Network (AKIN) criteria. Results: A total of 661 patients were analyzed. One hundred eighteen (17.7%) patients developed AKI; of these, 37 (31.4%) of the patients with AKI were classified as AKI I, 15 (12.7%) were classified as AKI II and 66 (55.9%) were classified as AKI III, among the latter of whom 50 (75.7%) required continuous renal replacement therapy. Patients with AKI had a higher Acute Physiology and Chronic Health Evaluation II score (19.2 ± 8.3 versus 12.6 ± 5.9; P < 0.001), a higher Sequential Organ Failure Assessment score (8.7 ± 4.2 versus 4.8 ± 2.9; P < 0.001), more need for mechanical ventilation (MV) (87.3% versus 56.2%; P < 0.01, odds ratio (OR) 5.3, 95% confidence interval (CI) 3.0 to 9.4), a greater incidence of shock (75.4% versus 38.3%; P < 0.01, OR 4.9, 95% CI, 3.1 to 7.7), a greater incidence of multiorgan dysfunction syndrome (92.4% versus 54.7%; P < 0.01, OR 10.0, 95% CI, 4.9 to 20.21) and a greater incidence of coinfection (23.7% versus 14.4%; P < 0.01, OR 1.8, 95% CI, 1.1 to 3.0). In survivors, patients with AKI remained on MV longer and ICU and hospital length of stay were longer than in patients without AKI. The overall mortality was 18.8% and was significantly higher for AKI patients (44.1% versus 13.3%; P < 0.01, OR 5.1, 95% CI, 3.3 to 7.9). Logistic regression analysis was performed with AKIN criteria, and it demonstrated that among patients with AKI, only AKI III was independently associated with higher ICU mortality (P < 0.001, OR 4.81, 95% CI 2.17 to 10.62). Conclusions: In our cohort of patients with H1N1 virus infection, only those cases in the AKI III category were independently associated with mortality.

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.

Significance Statement: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. Background: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. Methods: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. Results: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38⁺ plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. Conclusions: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. Clinical Trial registration number: NCT04294459.