Christos Chatzikyrkou

Ribavirin treatment of acute and chronic hepatitis E: a single-centre experience.

The role of ribavirin for treatment of severe acute or chronic hepatitis E virus (HEV) infection is not well defined.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Diagnosis of subclinical and clinical acute T-cell-mediated rejection in renal transplant patients by urinary proteome analysis†

Purpose: Noninvasive diagnosis of acute renal allograft rejection may be advantageous compared with the allograft biopsy.

Microalbuminuria as a risk factor: the influence of renin-angiotensin system blockade.

Microalbuminuria, the increase in urinary albumin excretion, has most often been linked with renal disease in diabetic patients. However, accumulating data demonstrate a link between albuminuria and cardiovascular disease in both diabetic and nondiabetic patients, even at very low levels of urinary albumin excretion once considered to be ‘normal’. The reasons for the increase in cardiovascular risk may be linked to generalized vascular and endothelial dysfunction, mediated by the renin–angiotensin system and the angiotensin II type 1 receptor. Accordingly, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have demonstrated some success in treating microalbuminuria. With the prevalence of microalbuminuria at around 7% in the general population, and as high as 39% in diabetic patients, reducing and preventing microalbuminuria is becoming of increasing interest in helping to reduce cardiovascular risk. Subsequently, international guidelines have recommended screening for the presence of microalbuminuria in all patients with hypertension, diabetes or both.

Pathogenesis and management of hypertension after kidney transplantation.

Arterial hypertension is frequently encountered after renal transplantation and is associated not only with increased cardiovascular complications but also with decreased allograft survival. Adequate blood pressure control is, thus, as essential as immunologic surveillance for the long-term transplant care. Nevertheless, randomized control trials assessing treatment targets in these patients are not available and most of the evidence comes from studies in patients with native chronic kidney disease or the general population. In this regard, the renal transplant recipient is treated according to recommendations that are applicable to nontransplanted individuals at high cardiovascular risk. However, the accepted treatment targets for the nontransplanted population are recently being disputed and this makes the management of posttransplant hypertension even more challenging.

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Observational Follow‐Up Study: Benefits of RAS Blockade With Olmesartan Treatment Are Sustained After Study Discontinuation

Background The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that 40 mg Olmesartan medoxomil (OM) versus placebo delayed microalbuminuria onset in patients with type 2 diabetes and normoalbuminuria. Methods and Results One thousand seven hundred and fifty‐eight ROADMAP patients (placebo arm: 877; OM arm: 881) participated in the observational follow up (OFU) with an average of 3.3 years. They received standard medical care and micro‐ and macrovascular events were documented. During observational follow‐up 62.9% and 60.1% in the former OM and placebo group, respectively, received treatment with a RAS blocking agent. During the OFU period the systolic blood pressure (SBP) increased to mean values of 135 mm Hg in both groups. Patients who had developed microalbuminuria during ROADMAP had a higher incidence of cardio‐ and cerebrovascular events (OR 1.77, CI 1.03 to 3.03, P=0.039) during the OFU period compared with patients in whom this was not the case. Diabetic retinopathy was significantly reduced in the former OM group (8 [0.9%] versus 23 [2.6%], OR: 0.34, CI 0.15 to 0.78, P=0.011) and the rate of microalbuminuria was numerically reduced. Congestive heart failure requiring hospitalization (3 [0.3%] versus 12 [1.4%], OR: 0.23, CI 0.06 to 0.85, P=0.027) was reduced and there was a trend of reduced cardio‐/cerebrovascular events (OM versus Pb: 73 [8.3%] versus 86 [9.8%] patients). Seven (0.8%) deaths (including 2 CV events) were reported in former placebo patients versus 3 (0.3%) (non‐CV events) in former OM patients. Conclusions Development of microalbuminuria is a valid marker for future CV events. RAS blockade with Olmesartan might cause sustained reduction (legacy effect) of micro‐ and macrovascular events.

Beyond C4d: the ultrastructural appearances of endothelium in ABO-incompatible renal allografts

BACKGROUND ABO incompatibility is no longer a barrier in kidney transplantation. C4d is frequently positive in ABO-incompatible (iABO) biopsies without further signs of microcirculation injury. This phenomenon is assumed to represent graft accommodation. However, ultrastructural examination of glomerular and peritubular capillary endothelium might reveal subtle endothelial damage. METHODS We studied the ultrastructural appearance of the endothelium in 67 biopsies from 21 patients with iABO allografts and compared it with 20 patients (29 biopsies) with ABO-compatible (cABO) grafts with C4d positivity and 25 ABO-compatible control patients (25 biopsies) without serological or histological evidence of humoral rejection (C4d negative). Ten ultrastructural parameters indicative of chronic and acute glomerular and peritubular capillary damage in transmission electron microscopy (TEM) were semi-quantitatively graded and expressed in a sum score. Clinico-pathological data were compared as well as graft function at the time of biopsy and follow-up. RESULTS Ultrastructural parameters did not significantly differ between iABO and controls. In contrast, C4d-positive cABO had the highest TEM sum score (P = 0.001 versus iABO, P = 0.002 versus controls). The sum score did not differ between C4d-positive and C4d-negative iABO but did differ between patients with and without anti-HLA donor-specific antibodies (DSA). Graft function in iABO at the time of biopsy and at follow-up was similar to controls. CONCLUSIONS Our ultrastructural observations support the concept of endothelial accommodation in iABO renal transplants. C4d positivity in the ABO-incompatible situation does not indicate injurious activation of the complement cascade and does not seem to impact on the graft function, in contrast to C4d deposition in cABO with antibody-mediated rejection.

Biopsy proven acute interstitial nephritis after treatment with moxifloxacin

BackgroundAcute interstitial nephritis (AIN) is an important cause of reversible acute kidney injury. At least 70% of AIN is caused by various drugs, mainly penicillines and non-steroidal anti-inflammatory drugs. Quinolones are only rarely known to cause AIN and so far cases have been mainly described with older fluoroquinolones.Case PresentationHere we describe a case of biopsy proven interstitial nephritis after moxifloxacin treatment. The patient presented with fever, rigors and dialysis dependent acute kidney injury, just a few days after treatment of a respiratory tract infection with moxifloxacin. The renal biopsy revealed dense infiltrates mainly composed of eosinophils and severe interstitial edema. A course of oral prednisolone (1 mg/kg/day) was commenced and rapidly tapered to zero within three weeks. The renal function improved, and the patient was discharged with a creatinine of 107 μmol/l.ConclusionThis case illustrates that pharmacovigilance is important to early detect rare side effects, such as AIN, even in drugs with a favourable risk/benefit ratio such as moxifloxacin.

How to achieve renal protection in the light of ONTARGET

Inhibition of the renin-angiotensin system (RAS) either with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) has been shown to be beneficial for cardiorenal protection. The combination of both is an exciting prospect and pathophysiologically plausible. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study provides evidence that dual blockade does not further reduce cardiovascular events or worsen renal outcomes. However, in patients with existing diabetic nephropathy, a trend towards a better outcome was observed. Therefore, combination of ARBs and ACEIs could be an alternative for selected patients, but not a standard approach in the management of chronic kidney disease. The benefits of dual blockade on hard renal endpoints remain to be shown.

Diabetes: Hyperfiltration—a risk factor for nephropathy in T1DM?

Glomerular hyperfiltration has long been thought of as indicative of progression to albuminuria and nephropathy in type 1 diabetes mellitus. However, a new study supports other research in the past few years that has highlighted flaws in this model for kidney disease pathogenesis in type 1 diabetes mellitus.