Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.

BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD. METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03470454.

Renal allograft surveillance with allospecific T-cytotoxic memory cells.

BACKGROUND: Allo-antigen-specific T-cytotoxic memory cells (TcM) which express CD40 ligand (CD154) in overnight lymphocyte co-culture are strongly associated with acute cellular rejection (ACR) seen in "for cause" biopsies for renal allograft dysfunction. Specifically, when the likelihood of rejection is increased, donor-specific allospecific TcM exceed those induced by HLA-non-identical third-party cell by 1.15-fold or greater. METHODS: The performance of allospecific TcM was evaluated retrospectively in primary renal transplant recipients (RTR) at routine clinical visits, cross-sectionally at presentation for biopsies, and serially. Performance metrics were sensitivity, specificity, positive and negative predictive values (PPV and NPV). RESULTS: Twenty-two primary RTR, median age 45 years (range 19-72) were tested with allospecific CD154 + TcM. Samples were obtained at the mean ± SD time interval of 806 ± 239 days after kidney transplantation. Six of 22 patients experienced biopsy proven T- Cell Mediated Rejection (TCMR). A seventh showed antibody mediated rejection (ABMR). Of these seven patients six demonstrated increased likelihood of rejection with allospecific TcM (sensitivity 83%). Ten of these 15 patients with no rejection had a negative test (specificity 67%). False positive tests were seen in five patients. Six out of 11 patients with positive tests had ACR/ABMR with a PPV of 54%, while 10 out of 11 patients with negative tests were non-rejecters with a NPV of 91%. CONCLUSION: Allospecific T-cytotoxic memory cells distinguished primary RTR with quiescent allografts from those with dysfunction. With serial surveillance measures, this test system may facilitate decisions to manage immunosuppression in RTR.

Eosinophilia and risk of incident end stage kidney disease.

BACKGROUND: Eosinophils in kidney disease are poorly understood and are often incidental findings on kidney biopsy. Eosinophilia in blood and renal biopsy tissue is associated with a host of immune and non-immune kidney diseases. The significance of eosinophilia in renal diseases has not been well addressed. We evaluated the presence of peripheral eosinophilia (> 4% of blood leukocytes) with biopsy tissue eosinophilia and their association with end-stage-kidney-disease (ESKD). METHODS: A nested case-control (2:1) of patients who underwent kidney biopsies at Johns Hopkins Hospital and Medical University of South Carolina from 2004 to 2018 were included in the study. From the 616 eligible patients, 178 patients were identified through the registry of kidney biopsies as 18 years or older without missing biopsy reports or hematology results. Controls (n = 154) had no ESKD at the time of case (n = 24) designation and were assembled using incident density sampling and matched on age and sex. The association of peripheral eosinophilia (> 4% of peripheral blood leukocytes) with the risk of progression to ESKD was evaluated using conditional logistic model after adjusting for clinical demographics. RESULTS: Among 178 patients, 65 (37%) had peripheral eosinophilia and 113 (63%) had no eosinophilia. Compared to patients without eosinophilia, patients with peripheral eosinophilia were notably male and had a higher serum creatinine at the time of their biopsy. Peripheral eosinophilia was associated with higher risk of ESKD (OR 15.9 [1.9, 134.7]) adjusted for patient demographics including hypertension, proteinuria and eGFR at the time of kidney biopsy. Peripheral eosinophilia had a significant linear association with kidney tissue eosinophils, 22 (standard deviation [SD] 20) per high power field (hpf) in 4-10% peripheral eosinophilia, 19 (SD 18) per hpf in ≥10% eosinophilia and 3 (SD 7) per hpf in no eosinophilia (P <  0.001). CONCLUSIONS: Peripheral eosinophilia is an independent predictor of tissue eosinophilia and subsequent progression to ESKD. Peripheral eosinophilia may be an early biomarker for underlying inflammation and disease, but further studies to investigate this clinical association are warranted.

Diffuse membranoproliferative glomerulonephritis with focal sclerosis and renal amyloidosis in an adult male with autosomal dominant dystrophic epidermolysis bullosa: a case report.

Previous reports of glomerular disease in adult patients with autosomal dominant dystrophic epidermolysis bullosa (EB) are limited and include post-infectious glomerulonephritis, IgA nephropathy, amyloidosis, and leukocytoclastic vasculitis. To our knowledge, membranoproliferative glomerulonephritis (MPGN) has not been described before. We report a case of a 39-year-old male with autosomal dominant dystrophic EB, presenting with bilateral leg swelling of one-week duration. There was no other significant past medical history. The physical examination was remarkable for scars and erosions over all body areas, with all extremities with blisters and ulcers covered, absent finger and toenails and bilateral lower extremity edema. Serum creatinine was 0.9 mg/dL, albumin 1.3 g/dL and urine protein excretion 3.7 g/24 h. Viral markers (hepatitis-B, C, and HIV), complement c3 and c4 levels and auto-immune antibody profile all remained negative or within normal limits. Renal ultrasound and echocardiogram were normal. Renal biopsy recovered 14 glomeruli, all with proliferation of mesangial and endothelial cells as well as an expansion of the mesangial matrix, focal segmental sclerosis and amorphous homogeneous deposits demonstrating apple-green birefringence under polarized light with Congo red stain. Our observation emphasizes the importance of recognizing MPGN and secondary amyloidosis in patients with EB, especially with the availability of newer treatment modalities.

Acute Kidney Injury in Subjects With Chronic Kidney Disease Undergoing Total Joint Arthroplasty.

BACKGROUND: Chronic kidney disease (CKD) has been associated with higher incidence of complications after total joint arthroplasty (TJA) but the incidence, risk factors and outcomes of acute kidney injury (AKI) in this setting remains insufficiently understood. METHODS: We assessed the impact of baseline CKD on the risk of developing AKI after TJA performed between 1/2012 and 12/2016 in a single-center, retrospective cohort study. CKD was defined by estimated glomerular filtration rate <60 mL/min/1.73 m2 on 2 separate occasions within 3 months prior TJA. AKI was defined using a modified Kidney Disease: Improving Global Outcomes criteria based on serum creatinine (sCr) only to assess the severity of AKI. Complete AKI recovery was defined as the lowest post-AKI sCr within 20% of pre-AKI sCr values and partial recovery if within 30%, all within 90 days after TJA. RESULTS: Twenty-four percent of the 1,212 subjects undergoing TJA had pre-existing CKD. The overall incidence of AKI in the CKD subjects was 30%; of these, 55% had stage-1 AKI, 1% had stage-2 AKI and 44% had stage-3 AKI. AKI was more common in African Americans, those with diabetes or heart failure, requiring perioperative transfusions or receiving diuretics before surgery. While 82% of the AKI subjects achieved complete recovery of kidney function, 4% had only partial recovery and 14% did not reach a post-AKI sCr level within 30% of pre-AKI values. The incidence (P < 0.001) but not the severity (P = 0.202) of AKI correlated with stages of baseline CKD. CONCLUSIONS: The presence of CKD was associated with a high incidence of AKI after TJA. In these subjects, more than half the cases of AKI were of mild degree and had a favorable outcome. However, 18% of them did not have complete recovery of kidney function. Stages of baseline CKD were associated with increased incidence but not severity of AKI after TJA.