Stem Cell Therapy for Microvascular Injury Associated with Ischemic Nephropathy

Ischemic nephropathy reflects progressive loss of kidney function due to large vessel atherosclerotic occlusive disease. Recent studies indicate that this process is characterized by microvascular rarefaction, increased tissue hypoxia and activation of inflammatory processes of tissue injury. This review summarizes the rationale and application of functional MR imaging to evaluate tissue oxygenation in human subjects that defines the limits of renal adaptation to reduction in blood flow, development of increasingly severe tissue hypoxia and recruitment of inflammatory injury pathways in ischemic nephropathy. Human mesenchymal stromal/stem cells (MSC) are capable of modifying angiogenic pathways and immune responses, but the potency of these effects vary between individuals and various clinical characteristics including age and chronic kidney disease and levels of hypoxia. We summarize recently completed first-in-human studies applying intrarenal infusion of autologous adipose-derived MSC in human subjects with ischemic nephropathy that demonstrate a rise in blood flow and reduction in tissue hypoxia consistent with partial repair of microvascular injury, even without restoring main renal arterial blood flow. Inflammatory biomarkers in the renal vein of post-stenotic kidneys fell after MSC infusion. These changes were associated with modest but significant dose-related increments in kidney function. These data provide support a role for autologous MSC in repair of microvascular injury associated with tissue hypoxia.

An Outline of Renal Artery Stenosis Pathophysiology—A Narrative Review

Renal artery stenosis (RAS) is conditioned mainly by two disturbances: fibromuscular dysplasia or atherosclerosis of the renal artery. RAS is an example of renovascular disease, with complex pathophysiology and consequences. There are multiple pathophysiological mechanisms triggered in response to significant renal artery stenosis, including disturbances within endothelin, kinin–kallikrein and sympathetic nervous systems, with angiotensin II and the renin–angiotensin-aldosterone system (RAAS) playing a central and key role in the pathogenesis of RAS. The increased oxidative stress and the release of pro-inflammatory mediators contributing to pathological tissue remodelling and renal fibrosis are also important pathogenetic elements of RAS. This review briefly summarises these pathophysiological issues, focusing on renovascular hypertension and ischemic nephropathy as major clinical manifestations of RAS. The activation of RAAS and its haemodynamic consequences is the primary and key element in the pathophysiological cascade triggered in response to renal artery stenosis. However, the pathomechanism of RAS is more complex and also includes other disturbances that ultimately contribute to the development of the diseases mentioned above. To sum up, RAS is characterised by different clinical pictures, including asymptomatic disorders diagnosed in kidney imaging, renovascular hypertension, usually characterised by severe course, and chronic ischemic nephropathy, described by pathological remodelling of kidney tissue, ultimately leading to kidney injury and chronic kidney disease.

Evaluation of the state of tubular epithelium in low birth weight infants with ischemic ­nephropathy

Aim. The study of the diagnostic value of KIM-1 and NGAL in urine and cystatin C in the blood plasma of low birth weight infants with ischemic nephropathy. Methods. 150 newborns were divided into 3 groups: main group 72 low birth weight infants with manifestations of ischemic nephropathy divided into three subgroups: group 1A mild (n=36), 1B moderate (n=20), 1C severe (n=16); comparioson group 28 low birth weight infants without the evidence of ischemic nephropathy; control group 50 healthy newborns (20 full-term and 30 preterm).To assess the state of tubular epithelium of the kidneys, the levels of KIM-1 and NGAL were measured in the urine of neonates, to assess the state of glomerular filtration the level of сystatin C in the blood plasma was determined. Samples of blood and urine were collected twice, on days 1 to 3 and 7 to 10. Biomarker levels were determined by solid-phase enzyme immunoassay. Results. In the main group on day 1 to 3 of life KIM-1 and NGAL in the urine were significantly elevated compared to the control group (p 0.001). On day 7 to 10 the level of KIM-1 in the urine in subgroup 1A decreased (0.980.09 ng/dl), while remaining significantly higher compared to the control group, and in subgroups 1B and 1C it increased to 1.240.10 and 1.360.12 ng/dl, respectively. On day 7 to 10 of life the concentration of NGAL in the urine of children of all three subgroups declined, remaining significantly high compared to the control values. Сoncentration of cystatin C was significantly high only in newborns of subgroup 1C (p 0.001). Conclusion. Molecules of NGAL and KIM-1 are early markers of the renal ischemic injury in low birth weight infants who suffered perinatal hypoxia, and cystatin C cannot be considered an early predictor of renal damage in low birth weight infants with ischemic nephropathy as its level in the blood rises only in severe damage.

Renovascular Hypertension and Stenosis

Renal artery stenosis (RAS) may present clinically as an incidental radiographic finding in an asymptomatic patient, or it may be the etiology of renovascular hypertension or ischemic nephropathy. Incidental RAS should be treated medically. The available clinical trial data suggest that medical management is the primary treatment for presumed renovascular hypertension. Renal artery stenting should be reserved for patients who fail medical therapy. When renal artery stenting is contemplated for presumed renovascular hypertension or ischemic nephropathy, clinical studies suggest that there are clinical predictors of outcomes that may be useful in identifying patients with a higher probability of a favorable clinical response to stenting. Clinical predictors of a favorable blood pressure response to renal artery stenting include (1) a requirement of four or more antihypertensive medications, (2) preoperative diastolic blood pressure greater than 90 mm Hg, and (3) preoperative clonidine use. The only clinical predictor of improved renal function with stenting is the rate of decline of estimated glomerular filtration rate (eGFR) in the weeks prior to stenting. Patients with a more rapid decline in eGFR have a higher probability of improved renal function after stenting compared with those with relatively stable eGFR prior to stenting. Finally, surgical renal artery revascularization remains a viable option but is usually reserved for younger, fit patients with unfavorable anatomy for stenting. Pediatric renovascular disease responds poorly to endovascular therapy and requires a surgical plan to address both renal artery stenoses and concomitant abdominal aortic coarctation if present. Renal artery stenosis in pediatric patients is best treated with reimplantation of the renal artery or interposition grafting using the autogenous internal iliac artery as a conduit. This review contains 39 references, 15 figures, and 3 tables. Key Words: chronic kidney disease, hypertension, renal artery stenosis, renovascular, stenting