The subject of organ regeneration has attracted substantial investigative attention and has been extensively reviewed. Therefore, I shall focus on several only recently emerged issues and on those aspects of stem cell-mediated regeneration which, although are important in my opinion, have nevertheless evaded the radar of scientific pursuit. Specifically, I shall describe the recent work on the prominence of local lineage-restricted stem cells, as opposed to the bone marrow-derived or circulating ones, in regeneration. This will be followed by an attempt to re-interpret a bulk of published data on the beneficial effects of cell therapy with the focus on the secretome of stem cells. Multiple factors that conspire to cause insufficient or failed regeneration in adult mammals will be screened with emphasis placed on the mechanical forces, senescence and exhaustion, each leading to phenotypical switch and/or stem cell incompetence. Finally, I shall enumerate several potential pathways to induce or restore stem cell competence. Although a significant amount of work has been performed in the non-renal field, I would hope that some of the mechanisms and concepts discussed herein will eventually trickle into kidney regeneration.

The concept of hepatorenal syndrome is well recognized, although incompletely understood. The converse clinical problem of hepatic dysfunction in patients with acute kidney injury (AKI) is less well recognized yet may be a contributor to the high patient morbidity and mortality seen in this group. This review draws together the available evidence for AKI's effect on the liver from animal models, pharmacological studies and recent clinical data. It examines liver function beyond clinically used blood tests, to determine the effect of AKI on hepatic synthetic function, acute phase response and drug metabolism. Parallels are drawn with other organ crosstalk in AKI and with liver-kidney interactions in chronic kidney disease. Definition of the pathophysiology of renohepatic crosstalk may lead to improved management strategies for this vulnerable patient group.

BACKGROUND:

Cyclosporine A (CsA) is one of the most frequently used anticalcineurinic drugs for preventing graft rejection and autoimmune disease. Its use is hampered by nephrotoxic effects, namely an impairment of the glomerular filtration rate (GFR) and hypertension. Evidence suggests that reactive oxygen species (ROS) play a causal role in the nephrotoxicity. The present study aims to investigate in vivo the effects of a new recombinant mitochondrial manganese-containing superoxide dismutase (rMnSOD), a strong antioxidant, on the CsA-induced nephotoxicity.

METHODS:

Rats were treated with CsA (25 mg/kg/day) alone or in combination with rMnSOD (10 µg/kg/day) for 7 days. At the end of the treatment, GFR was estimated by inulin clearance (mL/min/100 g b.w.) and the mean arterial pressure (MAP) was recorded through a catheter inserted in the carotid artery. Superoxide concentration within the cells of the abdominal aorta was quantified from the oxidation of dihydroethidium (DHE). In kidney tissues, ROS levels were measured by the 2'7' dichloroflurescin diacetate assay. Renal morphology was examined at the histochemistry level.

RESULTS:

CsA-treated rats showed a severe decrease in GFR (0.34 ± 0.17 versus 0.94 ± 0.10 in control, P < 0.001) which was prevented by rMnSOD co-administration (0.77 ± 0.10). CsA-injected animals presented with higher blood pressure which was unaffected by rMnSOD. ROS levels both in the aorta and in renal tissue were significantly increased by CsA treatment, and normalized by the co-administration with rMnSOD. This effect was, partly, paralleled by the recovery from CsA-induced morphological lesions.

CONCLUSIONS:

Administration of rMnSOD prevents CsA-mediated impairment of the GFR along with morphological alteration. This effect could be related to the inhibition of ROS.

Loin pain haematuria syndrome (LPHS) is a severe renal pain condition of uncertain origin and often resistant to treatment. Nephrectomy and renal autotrasplantation have occasionally been performed in very severe cases. Its pathogenesis is controversial. A 40-year-old hypertensive lady was diagnosed with LPHS after repeated diagnostic imaging procedures had ruled out any renal, abdominal or spinal conditions to justify pain. Notwithstanding treatment with three drugs, she had frequent hypertensive crises during which the loin pain was dramatically exacerbated. Vascular causes of the pain and hypertension were investigated and excluded. Her renal function was normal. The patient was referred to a multidisciplinary pain clinic, but had no significant improvement in her pain symptoms despite the use of non-steroidal anti-inflammatory drugs, adjuvant antidepressants and opioid-like agents. The pain and the discomfort were so severe that her quality of life was very poor, and her social and professional activities were compromised. Nephrectomy and renal autotransplantation have occasionally been performed in these cases. Since visceral pain signals flow through afferent sympathetic fibres, we felt that percutaneous catheter-based radiofrequency ablation of the renal sympathetic nerve fibres (recently introduced for the treatment of drug-resistant hypertension) could be valuable for pain relief. We treated the patient with radiofrequency ablation (Medtronic Symplicity Catheter) applied only to the right renal artery. After a 6-month follow-up, the patient is pain free and normotensive with all drugs withdrawn. She has experienced no hypertensive crises in the meantime. This observation suggests that percutaneous sympathetic denervation could prove to be an effective mini-invasive strategy for the treatment of chronic renal pain, and LPHS in particular.

BACKGROUND:

As in most industrialized countries, living kidney donation has increased considerably in the UK and now amounts to 38% of the total UK kidney transplant activity. Living kidney donation guidelines have been formulated by the relevant national societies. We were interested to study whether or not renal units across the UK adhere to those guidelines and to delineate areas of inconsistency and controversy.

METHODS:

Twenty-four adult kidney transplant centres and 50 adult non-transplant renal units across the UK were contacted by a postal questionnaire from January to April 2011.

RESULTS:

Twenty-one of 24 (88%) transplanting units and 23 of 50 (46%) non-transplanting units responded. Eighty-one per cent of the responding transplanting units and only 30% of the non-transplanting units have a dedicated live donor clinic. Eighty-six per cent of all units are without a set upper age limit for donors, whereas 7% of units excluded all potential donors older than 70 years. Twenty per cent of units accept donors with body mass indices (BMIs) up to 35, whereas 9% of units did not have an upper limit for BMI. Thirty-two per cent of centres exclude hypertensive donors on more than one antihypertensive drug, whereas 64% of units exclude donors only if they are on more than two anti-hypertensive drugs. of units rely on a spot urine sample to assess proteinuria, while 30% of units still perform 24 h urine collection. Sixty one per cent of units perform computed tomography (CT) angiography to assess the renal vessels prior to donation, while 32% use magnetic resonance (MR) angiography. Seventy-five per cent of centres assess split kidney function by radionuclide testing in all cases, whereas 25% perform this test only if there is a discrepancy in kidney size. The practice of suspension of recipients with potential living donor from the deceased waiting list is also remarkably inconsistent, whereby some centres suspend once a decision for living donation has been made in principle, whereas others suspend the recipient only once a date for surgery has been agreed.

CONCLUSIONS:

We demonstrate significant variability in accepting living kidney donors, particularly regarding age, BMI, and hypertension. Infrastructure setting for living donation and the live donor assessment are also remarkably inconsistent across the UK. It remains unclear as to why nephrologists decide not to adhere to established guidelines and further research should aim to find the lacking evidence in areas causing inconsistency in living donor assessment.