Novel Drugs for the Management of Diabetes Kidney Transplant Patients: A Literature Review.

The management of diabetes and renal failure is changing thanks to the appearance of new drugs such as glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i) that have benefits in terms of survival and cardiorenal protection. Based on the potential mechanisms of GLP1-RA, kidney transplant recipients (KTRs) could benefit from their effects. However, high-quality studies are needed to demonstrate these benefits, in the transplant population, especially those related to cardiovascular benefits and renal protection. Studies with SGLT2i performed in KTRs are much less potent than in the general population and therefore no benefits in terms of patient or graft survival have been clearly demonstrated in this population to date. Additionally, the most frequently observed side effects could be potentially harmful to this population profile, including severe or recurrent urinary tract infections and impaired kidney function. However, benefits demonstrated in KTRs are in line with a known potential effects in cardiovascular and renal protection, which may be essential for the outcome of transplant recipients. Better studies are still needed to confirm the benefits of these new oral antidiabetics in the renal transplant population. Understanding the characteristics of these drugs may be critical for KTRs to be able to benefit from their effects without being damaged. This review discusses the results of the most important published studies on KTRs with GLP1-RA and SGLT2i as well as the potential beneficial effects of these drugs. Based on these results, approximate suggestions for the management of diabetes in KTRs were developed.

Role of mTOR inhibitor in the cellular and humoral immune response to a booster dose of SARS-CoV-2 mRNA-1273 vaccine in kidney transplant recipients.

Background: Immunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved. Methods: Prospective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination. Results: Among COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p<0.001) and the percentage of S-protein-specific IFNγ-producing CD8-T cells (r=0.198, p=0.049) was observed. Factors related to the humoral response in naïve KTR were: lymphocytes count pre-vaccination >1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001). Conclusions: KTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.

Clinical Effectiveness of SARS-CoV-2 Vaccination in Renal Transplant Recipients. Antibody Levels Impact in Pneumonia and Death.

BACKGROUND: Few studies have described the clinical impact of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in renal transplant recipients (RTRs) in the context of omicron variant and the third vaccine dose. Antibody titer has been tried to relate to the prediction of outcomes related to SARS-CoV-2, but it results controversially in these populations. METHODS: All patients with positive SARS-CoV-2 polymerase chain reaction followed at a RTRs reference center from March 15, 2020, to March 15, 2022, were considered for analysis. Cases were analyzed by vaccination status. Breakthrough cases were then analyzed by nonantibodies (<20 arbitrary unit [AU]/mL), low (20-100 AU/mL), and high antibody titers (>100 AU/mL) against SARS-CoV-2 spike protein. Outcomes included pneumonia and mortality. We used logistic regression multivariable to assess for confounders. RESULTS: Among 186 RTRs with coronavirus disease 2019, 50.5% (n = 94) were vaccinated versus 49.5% (n = 92) unvaccinated. Of the vaccinated patients, 67.02% developed a high antibody titer (>100 AU/mL) but 14.89% achieved a low antibody titer and 18.08% nonantibodies. Pneumonia-free survival (day 20) was 95% in high antibody titer but 40% in unvaccinated RTRs. Survival in RTRs at day 60 was similar in the unvaccinated group compared with nonantibodies breakthrough cases (82%) but 92% in the low antibody titer group (relative risk, 0.027; 95% confidence interval, 0.002-0.479; P = 0.014). Only patients with >100 AU/mL showed a 100% survival on day 60 postinfection. CONCLUSIONS: Vaccinated RTRs who achieve at least a low antibody titer (>20 AU/mL) had better results in terms of pneumonia and mortality than unvaccinated RTRs. Antibody titer >100 AU/mL associate with even better results than patients with lower antibody titers.

Hemophagocytic syndrome triggered by donor-transmitted toxoplasmosis as a complication in same-donor recipients of renal transplantation: Case report and review of the literature.

BACKGROUND: Hemophagocytic syndrome (HPS) is an infrequent complication of transplantation caused by an inflammatory response with a benign proliferation of macrophages and defective lytic capability of T lymphocytes and NK cells that can lead to multiorgan failure. Transplant patients are particularly exposed as a result of the increased risk of both infections and malignancies derived from immunosuppressive drugs. There is no consensus for therapy or immunosuppression; mortality is high. We report a case and present a review of all cases of HPS occurring in solid organ transplant recipients.  CASE REPORT: We report two cases of infection by Toxoplasma gondii transmitted by the kidney allograft. One of the recipients was seronegative before transplantation and developed disseminated primary toxoplasmosis. An immune reaction compatible with an HPS ensued. Both were treated with Trimethoprim/sulfamethoxazole, immunosuppression was tapered, and after a 2-week period a complete response was obtained. CONCLUSION: HPS presents therapeutic challenges in the context of transplantation. If HPS is suspected, the search of a very likely underlying infection should be central to the management.

Should cyclosporine be useful in renal transplant recipients affected by SARS-CoV-2?

Minimization of immunosuppression and administration of antiretrovirals have been recommended for kidney transplant recipients (KTRs) with coronavirus disease 2019 (COVID-19). However, outcomes remain poor. Given the likely benefit of cyclosporine because of its antiviral and immunomodulatory effect, we have been using it as a strategy in KTRs diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We studied 29 kidney transplant recipients (KTRs) who were admitted to our institution with COVID-19 between March 15and April, 24, 2020. Mycophenolate and/or mammalian target of rapamycin inhibitors (mTORi) were discontinued in all patients. Two therapeutic strategies were compared: Group 1, minimization of calcineurin inhibitors (N = 6); and Group 2, cyclosporine-based therapy (N = 23), with 15 patients switched from tacrolimus. Hydroxychloroquine was considered in both strategies but antivirals in none. Six patients died after respiratory distress (20.6%). Five required mechanical ventilation (17.2%), and 3 could be weaned. Nineteen patients had an uneventful recovery (65.5%). In group 1, 3 of 6 patients died (50%) and 1 of 6 required invasive mechanical ventilation (16.7%). In group 2, 3 of 23 patients died (12.5%). Renal function did not deteriorate and signs of rejection were not observed in any patient on the second treatment regime. In conclusion, immunosuppressant treatment based on cyclosporine could be safe and effective for KTRs diagnosed with COVID-19.

Impact of postoperative acute kidney failure in long-term survival after heart valve surgery.

OBJECTIVES: We investigated the impact of acute kidney failure after a heart valve procedure among patients with or without chronic kidney disease (CKD). METHODS: All patients who had undergone a surgical valve procedure between 2005 and 2017 at our institution were divided into 2 groups depending on whether they had previous history of CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2) or not. Homogeneous groups were obtained by propensity score matching. Long-term mortality was compared between the 2 groups and according to the occurrence of postoperative acute kidney failure. Level of significance was set at P-value <0.008 for multiple comparison tests. RESULTS: From the 3907 patients included to this study, 1476 (37.78%) had previous history of CKD. After adjusting for propensity score 1:1, patients with preoperative impaired renal function were at a higher risk of acute kidney failure (26.83% vs 10.16%, P < 0.001) and postoperative mortality (8.48% vs 5.17%, P = 0.001). In the follow-up, they had a poorer survival at 1, 5 and 10 years as compared to patients with normal renal function (88% vs 91.95%, 78.29% vs 81.11% and 56.13% vs 66.29%, respectively; P < 0.001). Patients without postoperative kidney failure had similar survival whether they had preoperative CKD or not [hazard ratio (HR) 1.16, 99.2% confidence interval (CI) 0.87-2.52; P = 0.142]. As compared to patients with postoperative preserved renal function, those with postoperative kidney failure had a higher long-term mortality either if they had previous kidney disease or not [(HR 2.18, 99.2% CI 1.75-2.72; P < 0.001) and (HR 1.48, 99.2% CI 1.33-1.65; P < 0.001), respectively]. Preoperative CKD was the strongest predictor of acute kidney failure (odds ratio 4.45; 95% CI 3.59-5.53; P < 0.001). CONCLUSIONS: Patients with CKD are at higher risk of postoperative adverse events and have poorer long-term outcomes. Postoperative acute kidney failure increases long-term mortality.

Fallo precoz de trasplante renal y vuelta a diálisis peritoneal: estudio preliminar de permeabilidad y eficacia de diálisis / Early kidney transplant failure and return to peritoneal dialysis: preliminary study of permeability and dialysis efficacy

La vuelta a diálisis tras fallo de trasplante renal (TX) es una situación cada vez más frecuente. En la vuelta a diálisis tras TX fallido suele darse una situación clínica similar o peor a la de los pacientes nuevos en hemodiálisis o diálisis peritoneal (DP). Aunque existen bastantes estudios sobre la situación clínica de los pacientes que vuelven a DP tras períodos largos con TX funcionante, no hay apenas información sobre la evolución de un subgrupo de pacientes que vuelven a DP tras fallo de TX a los pocos días o semanas de su realización. Objetivo: Evaluar si un corto período de tiempo con TX subóptimo y tratamientos/medidas agresivas pueden influir en la permeabilidad de membrana, la situación clínica y la eficacia dialítica al volver a DP. Pacientes y métodos: En 9 pacientes (53,5 ± 15,4 años, 5 hombres, 4 mujeres) procedentes de DP con fallo precoz de TX y vuelta a DP (25 ± 23 días, rango 10-64) de los cinco últimos años, se estudian datos analíticos de inflamación, nutrición, función renal, permeabilidad y eficacia de DP, en cuatro momentos de la evolución: previo al TX, inmediatamente a la vuelta a DP, al primer mes y al tercer mes de DP. Resultados: No se detectan diferencias significativas en la evolución de los parámetros de nutrición e inflamación. La diuresis desciende de forma significativa del volumen previo al trasplante al de la vuelta a DP y al primer mes en DP (p = 0,032), manteniéndose en niveles reducidos a los tres meses en DP. La UF se reduce de 1407 a 951 ml/día (p = 0,022) y de 314 a 260 ml/4 h (p = 0,018) en el test de equilibrio peritoneal al tercer mes en DP, sin cambios en el cociente dializado/plasma de creatinina. Kt/V y aclaramiento semanal de creatinina descienden ligeramente, manteniéndose en niveles adecuados de eficacia. Conclusiones: En esta pequeña muestra de pacientes que vuelven a DP tras fallo precoz de TX, no parece que las medidas que comporta el manejo de un injerto en riesgo en un corto espacio de tiempo afecten de forma importante a parámetros clínicos y de permeabilidad o eficacia peritoneal

The return to dialysis after kidney transplant (TX) failure is increasingly common. On returning to dialysis after TX failure, there is usually a similar or worse clinical situation than in patients who are on haemodialysis or peritoneal dialysis (PD) for the first time. Although there are several studies on the clinical situation of patients who return to PD after long periods with a functioning TX, there is hardly any information on the progression of a patient subgroup returning to PD after TX failure a few days or weeks after transplantation. Objective: Assess whether a short period of time on suboptimal TX and aggressive treatment/measures may influence membrane permeability, the clinical situation and dialysis efficacy on returning to PD. Patients and method: In 9 patients (53.5±15.4 years of age, 5 males and 4 females) who had previously been on PD before early TX failure and had returned to PD (25±23 days, range 10-64) over the last five years, we studied laboratory data including inflammation, nutrition, kidney function, permeability and PD efficacy, at four points during progression: before TX, immediately after returning to PD and after one month and three months on PD. Results: We did not detect significant differences in the progression of nutrition and inflammation parameters.Diuresis decreased significantly from pre-TX volume to diuresis on return to PD and after one month on PD (p=.032), remaining at low levels after three months on PD. UF decreased from 1407 to 951ml/day (p=.022) and from 314 to 260ml/4h (p=.018) in the peritoneal equilibration test after three months on PD, without changes being observed in the creatinine dialysate/plasma ratio. Kt/V and weekly creatinine clearance decreased slightly and remained at adequate efficacy levels. Conclusions: In this small sample of patients, who returned to PD after early TX failure, it does not appear that the measures involved in managing a graft at risk over a short period of time have a major effect on clinical parameters and permeability or peritoneal efficacy

[Early kidney transplant failure and return to peritoneal dialysis: preliminary study of permeability and dialysis efficacy]. / Fallo precoz de trasplante renal y vuelta a diálisis peritoneal: estudio preliminar de permeabilidad y eficacia de diálisis.

UNLABELLED: The return to dialysis after kidney transplant (TX) failure is increasingly common. On returning to dialysis after TX failure, there is usually a similar or worse clinical situation than in patients who are on haemodialysis or peritoneal dialysis (PD) for the first time. Although there are several studies on the clinical situation of patients who return to PD after long periods with a functioning TX, there is hardly any information on the progression of a patient subgroup returning to PD after TX failure a few days or weeks after transplantation. OBJECTIVE: Assess whether a short period of time on suboptimal TX and aggressive treatment/measures may influence membrane permeability, the clinical situation and dialysis efficacy on returning to PD. PATIENTS AND METHOD: In 9 patients (53.5 ± 15.4 years of age, 5 males and 4 females) who had previously been on PD before early TX failure and had returned to PD (25 ± 23 days, range 10-64) over the last five years, we studied laboratory data including inflammation, nutrition, kidney function, permeability and PD efficacy, at four points during progression: before TX, immediately after returning to PD and after one month and three months on PD. RESULTS: We did not detect significant differences in the progression of nutrition and inflammation parameters. Diuresis decreased significantly from pre-TX volume to diuresis on return to PD and after one month on PD (p=.032), remaining at low levels after three months on PD. UF decreased from 1407 to 951 ml/day (p=.022) and from 314 to 260 ml/4h (p=.018) in the peritoneal equilibration test after three months on PD, without changes being observed in the creatinine dialysate/plasma ratio. Kt/V and weekly creatinine clearance decreased slightly and remained at adequate efficacy levels. CONCLUSIONS: In this small sample of patients, who returned to PD after early TX failure, it does not appear that the measures involved in managing a graft at risk over a short period of time have a major effect on clinical parameters and permeability or peritoneal efficacy.

Changes in peritoneal membrane permeability and proteinuria in patients on peritoneal dialysis after treatment with paricalcitol − a preliminary study.

BACKGROUND: Patients on peritoneal dialysis (PD) have protein loss through peritoneal membrane (PM) and experience changes in permeability of the membrane. Paricalcitol is a selective vitamin D receptor activator with an effect upon systemic inflammation and an inhibitory effect upon the renin-angiotensin-aldosterone system (RAAS). METHODS: This study explores the possible effect of paricalcitol upon the PM in 23 patients on PD with high iPTH levels. Peritoneal kinetic studies were performed before and after paricalcitol, measuring also ultrafiltration/ day, peritoneal protein losses and proteinuria. Results were compared with a control group of 15 patients not receiving any form of vitamin D. RESULTS: With a mean dose of 1.3 µg/day, peritoneal protein loss decreased from 0.91 ± 0.35 to 0.76 ± 0.26 g/l (15.4%) (p = 0.007) and from 7.55 to 6.46 g/d (p < 0.033), and ultrafiltration increased from 844 to 1,002 ml/d (15.8%) (p = 0.037) and from 284 to 323 ml/4 h. (NS), with minimal change in the creatinine dialysate/plasma ratio 0.67 ± 0.12 vs. 0.65 ± 0.11. Proteinuria decreased from 1.65 to 1.25 g/l (21.9%) (p = 0.01) and iPTH decreased from 668 ± 303 to 291 ± 148 pg/ml (p < 0.001). In the control group, no changes in peritoneal membrane permeability and proteinuria were found. CONCLUSIONS: The results of the study indicate that paricalcitol is effective in treating hyperparathyroidism in patients on PD, and suggest an effect upon proteinuria and PM permeability (not previously reported), with diminished peritoneal protein loss and increased ultrafiltration. The antiinflammatory, antifibrotic and RAAS-modulating actions described for paricalcitol may be responsible for these findings, and could be important for preserving the peritoneum as a dialyzing membrane.

Glomerulonefritis membranosa, psoriasis y etanercept. ¿Asociación casual o causal? / Membranous glomerulonephritis, psoriasis and etanercept. A chance or causal association?

La psoriasis es una enfermedad cutánea con afectación sistémica, cuyo daño tisular se considera inmunomediado y que en la actualidad se trata eficazmente con etanercept. El daño renal de esta patología no está completamente aclarado en la literatura. Presentamos un caso de glomerulonefritis membranosa con depósitos de C1q que posteriormente desarrolló psoriasis. En este artículo hacemos una revisión de la posible asociación entre estas patologías y la respuesta a esta molécula biológica (AU)

Psoriasis is a cutaneous disease with systemic involvement. Tisular damage is consider to be immunomediated, and actually is being effectively treated with Etanercept. Kidney damage of this patological condition is not completely clarified in the literature. We present a case of Membranous Nephropathy with C1q deposits that subsequently developed psoriasis. In this article we make a review of a possible association between these diseases and the respose to that biological molecule (AU)

Membranous glomerulonephritis, psoriasis and etanercept. A chance or causal association?

Psoriasis is a cutaneous disease with systemic involvement. Tissue damage is considered to be immune-mediated, and etanercept currently provides effective treatment. Kidney injury arising from this condition has not yet been fully explained in the literature. We present a case of membranous nephropathy with C1q deposits followed by development of psoriasis. In this article we will review the possible association between these conditions and the response to this biological molecule.

Effects of oral paricalcitol on hyperparathyroidism and proteinuria in peritoneal dialysis patients.

Severe secondary hyperparathyroidism is a complication of chronic kidney disease. Paricalcitol is a vitamin D receptor activator with efficacy in the treatment of hyperparathyroidism that also has the minor side effects of hypercalcemia and hyperphosphatemia. As a pleiotropic effect, paricalcitol reduces proteinuria in patients with chronic kidney disease stages 2-4. Oral paricalcitol offers an alternative way to treat hyperparathyroidism and proteinuria in peritoneal dialysis patients. Our prospective study enrolled 18 patients with hyperparathyroidism (6 with diabetes also) who were given oral paricalcitol at initial dose of 1-2 microg daily, depending on their level of intact parathyroid hormone (iPTH). In the 1st month, iPTH levels declinedsignificantly to 295 +/- 147 pg/mL from 670 +/- 318 pg/mL, and by the 3rd month, they declined to 192 +/- 340 pg/mL (p < 0.001). Without modifications to doses of angiotensin converting-enzyme inhibitor or angiotensin II receptor blocker, proteinuria declined in the 1st month to 1.41 +/- 1.5 g/L from 1.68 +/- 1.7 (p = 0.006) and, in the 3rd month, without statistical significance. In some patients, the dose of paricalcitol was reduced because of iPTH levels that were too low at 1 month. The patients whose doses of paricalcitol were maintained at 3 months showed a reduction in proteinuria to 2.1 +/- 2.1 g/L daily from 3.1 +/- 2. 7 g/L (p = 0.04) and to 2.3 +/- 2.1 g/day from 5.0 +/- 6.1 g/day (p = 0.012). In conclusion, paricalcitol is effective for treating hyperparathyroidism in patients on peritoneal dialysis and seems also to have an antiproteinuric effect in these patients.