Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.

Background: Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects. Methods: To understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions. Results: Pathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions. Conclusion: Our data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.

A case of renal granulomatosis with polyangiitis following intravesical bacillus Calmette-Guérin therapy.

Various adverse reactions may occur after intravesical bacillus Calmette-Guérin (BCG) therapy. Although the virulence of attenuated BCG is low, serious complications such as bacterial cystitis, bladder contractures, granulomatous prostatitis, epididymitis, orchitis, and systemic reactions such as fever and malaise have been described. Disseminated granulomatosis such as hepatitis and pneumonitis have also been described, but are rare. We report here the case of a 67-year-old patient who presented with renal granulomatosis with polyangiitis following intravesical BCG therapy for superficial bladder tumor. The biological evaluation revealed the presence of perinuclear anti-neutrophil cytoplasmic antibodies with specificity for antimyeloperoxidase. Renal biopsy specimen revealed pauci-immune crescentic glomerulonephritis with segmental glomerular necrosis, presence of granulomas and no evidence of any caseating necrosis. He received antituberculosis drugs in addition to corticosteroids and cyclophosphamide without any improvement of the renal function.

Should blood pressure goal be individualized in hypertensive patients?

The aim of the present review is to consider the clinical relevance of individualized blood pressure (BP) goal under treatment in hypertensive patients according to their age, comorbidities or established cardiovascular (CV) disease. Evidence from large-scale randomized trials to support a lower BP goal, as initially recommended by guidelines in high-risk hypertensive patients, were lacking. Recently, the randomized intervention SPRINT trial studied two treatment targets for systolic BP (120mm Hg versus 140mm Hg in the intensive and standard treatment group, respectively) among high-risk hypertensive patients, without diabetes and without a history of prior stroke. The trial was stopped prematurely owing to a significantly lower rate of the primary composite outcome and all-cause mortality in the intensive treatment group. Several practical questions have to be considered. First, using an automated measurement system at an office visit during the SPRINT protocol, while the patient was seated alone after 5min of quiet rest, may likely have resulted in lower BP values than would normally be obtained with the routine BP measurement. A target systolic of 120mm Hg in SRPINT trial may be thus equated to a target systolic BP of 130mm Hg in the real-world office setting. Second, careful and repeated examinations of SPRINT participants may have led to fewer adverse events (more frequent in the intensive treatment group) than that expected in the real-world setting. The safety profile of this intensive treatment approach should therefore remain a matter of concern in clinical practice, especially in elderly patients, in diabetic patients or with established CV or renal disease. Orthostatic hypotension should alert the clinician to withhold up titration. Third, beyond the question of BP goal, choice of antihypertensive medication and effective 24-h BP control are important to consider in the context of BP-lowering strategy. In particular, ambulatory BP measurements and during nighttime should be considered for an individualized hypertension care.

Hypertension and chronic kidney disease: respective contribution of mean and pulse pressure and arterial stiffness.

Hypertension (HTN) in chronic kidney disease (CKD) is influenced by blood pressure (BP) and the progression of CKD, including hemodialysis and renal transplantation. To date, the efficacy of antihypertensive drug strategies has chiefly been assessed by measuring steady-state systolic, diastolic and mean arterial pressures (MAP). However, recently elucidated features of the BP curve have highlighted other important goals, that is, the specific roles of pulse pressure (PP), arterial stiffness, pulse wave velocity (PWV) and wave reflections as potentially deleterious factors affecting the progression of HTN and CKD. Pharmacological strategies to date have included progressive withdrawal of alpha-blocking agents; efficacy of beta-blockers for coronary prevention; use of angiotensin blockade in HTN with glomerular injury, using angiotensin-converting enzyme inhibition or receptor blockade, as mono but never double-blockade, to avoid major complications; development of combination therapies with diuretics and/or calcium channel blockers. Nowadays, most clinical trials show that SBP, DBP and MAP-lowering is an effective strategy, although results no longer show preference for any specific drug class.Studies of arterial stiffness in CKD have become crucial. In older individuals, PWV is considerably elevated. The 'stiffness gradient' disappears or is inverted (normally, aortic PWV is lower than brachial PWV). Despite BP-lowering, PP is insufficiently dampened, thus promoting microcirculatory damage, progression of arterial calcifications and disturbed wave reflections, which all increase the risk of mortality. In the absence of effective hemodialysis or graft, increased arterial stiffness is therefore a major cardiovascular risk factor in CKD.

[Chyluria presenting as milky urine and nephrotic-range proteinuria and milky urine: chyluria or glomerulopathy? Case report and literature review]. / Protéinurie de débit néphrotique et urines laiteuses: chylurie ou glomérulopathie? Cas clinique et analyse de la littérature.

A patient is admitted in hospital to explore a nephrotic proteinuria associated with milky urine. This is explained by a chyluria (presence of lymphatic fluid in the urines), which is due to a pyelolymphatic fistula probably linked to a lymphatic filariasis. Usually, the diagnosis of chyluria can be confirmed by the presence of urinary chylomicrons. The presence of an urinary-lymphatic fistula can be proved by different techniques (cystoscopy, retrograde pyelography, uroscanner, lymphoscintigraphy). The main cause of chyluria is parasitic infections (filarial infection, echinococcus, cysticercosis), but other causes can be found, such as granulomatosis, neoplasia, lymphatic malformations, or sequela of surgery or traumatism. Chyluria is one of the causes of post-nephronic nephrotic proteinuria. Depending on the impact of the chyluria for the patient, there will either be no treatment, or a treatment by sclerotherapy or surgery.