Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed

Podocyte number in children and adults: associations with glomerular size and numbers of other glomerular resident cells

Increases in glomerular size occur with normal body growth and in many pathologic conditions. In this study, we determined associations between glomerular size and numbers of glomerular resident cells, with a particular focus on podocytes. Kidneys from 16 male Caucasian-Americans without overt renal disease, including 4 children (= 18 years old), were collected at autopsy in Jackson, Mississippi. We used a combination of immunohistochemistry, confocal microscopy, and design-based stereology to estimate individual glomerular volume (IGV) and numbers of podocytes, nonepithelial cells (NECs; tuft cells other than podocytes), and parietal epithelial cells (PECs). Podocyte density was calculated. Data are reported as medians and interquartile ranges (IQRs). Glomeruli from children were small and contained 452 podocytes (IQR=335-502), 389 NECs (IQR=265-498), and 146 PECs (IQR=111-206). Adult glomeruli contained significantly more cells than glomeruli from children, including 558 podocytes (IQR=431-746;

Renal biopsy findings among Indigenous Australians: a nationwide review

Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote-living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Patient non-attendance at urgent referral appointments for suspected cancer and its links to cancer diagnosis and one year mortality : A cohort study of patients referred on the Two Week Wait pathway

BACKGROUND: The 'Two Week Wait' policy aims to ensure patients with suspected cancer are seen within two weeks of referral. However, patient non-attendance can result in this target being missed. This study aimed to identify predictors of non-attendance; and analyse the relationship between attendance and outcomes including cancer diagnosis and early mortality. METHODS: A cohort study of 109,433 adults registered at 105 general practices, referred to a cancer centre within a large NHS hospital trust (April 2009 to December 2016) on the 'Two Week Wait' pathway. RESULTS: 5673 (5.2%) patients did not attend. Non-attendance was largely predicted by patient factors (younger and older age, male gender, greater deprivation, suspected cancer site, earlier year of referral, greater distance to the hospital) over practice factors (greater deprivation, lower Quality and Outcomes Framework score, lower cancer conversion rate, lower cancer detection rate). 10,360 (9.6%) patients were diagnosed with cancer within six months of referral (9.8% attending patients, 5.6% non-attending patients). Among these patients, 2029 (19.6%) died within 12 months of diagnosis: early mortality risk was 31.3% in non-attenders and 19.2% in attending patients. CONCLUSIONS: Non-attendance at urgent referral appointments for suspected cancer involves a minority of patients but happens in predictable groups. Cancer diagnosis was less likely in non-attending patients but these patients had worse early mortality outcomes than attending patients. The study findings have implications for cancer services and policy

Compensatory Renal Growth after Unilateral Nephrectomy in the Ovine Fetus

Unilateral nephrectomy of the adult animal results in compensatory renal growth but does not involve formation of new nephrons. It is not clear whether compensatory growth can occur during the period of active nephrogenesis in utero and if so, whether more nephrons can be formed. Male ovine fetuses (n = 20) underwent unilateral nephrectomy (n = 10) or sham nephrectomy (n = 10) at 100 d of gestation (term, 150 d). After 27 to 34 d, ewes and fetuses were killed and the right kidney of each fetus was removed and weighed. The wet weight of the right kidney was greater in the unilaterally nephrectomized fetuses (16.3 ± 1.3 g compared with 12.2 ± 0.7 g; mean ± SEM, P < 0.05) as was the kidney to body weight ratio (5.2 ± 0.3 g/kg compared with 3.8 ± 0.2 g/kg; P < 0.001). Nephron number in the right kidney was estimated by an unbiased stereologic technique. There was a 45% increase in the number of nephrons in the kidneys from unilaterally nephrectomized animals compared with the kidneys from sham-operated animals (530,763 ± 37,136 nephrons in the unilaterally nephrectomized group compared with 365,672 ± 36,016 nephrons in the sham-operated group; P < 0.01). Mean glomerular volume was lower in the unilaterally nephrectomized group; however, total glomerular volume per kidney was not different between groups. This study demonstrates that there is a significant amount of compensatory growth and nephron endowment in a remaining kidney after unilateral nephrectomy during the period of active nephrogenesis in the sheep. This is the first time such events have been shown to occur in utero

Vasopressin Receptor Expression in the Placenta

The arginine vasopressin (AVP) type 1a receptor (V1a) is well known to mediate vasoconstriction. In pregnancy, blood flow in the placenta is crucial for sustaining normal growth and development of the fetus. This is the first AVP receptor study in the placenta and fetal membranes. The aim was to compare, quantitatively, the level of V1a gene expression with that of a known marker for vascularization, aquaporin 1 (AQP1). V1a and AQP1 gene expression did not correlate; placental V1a mRNA levels were significantly upregulated at 45 and 66 ± 1 compared with 27, 100 ± 4, and 140 days (term ~150 days). V1a mRNA levels were much lower in fetal membranes in which no significant difference across gestation was observed. In situ hybridization histochemistry localized V1a gene expression in the maternal component of the placenta similar to the receptor-binding studies using 125I-labeled [d(CH2)5, sarcosine7] vasopressin. No AVP gene expression was observed in the placenta and fetal membranes, which eliminates local AVP production. This increase in V1a expression at 45 and 66 ± 1 days of gestation correlates with the period of maximal placental growth in the sheep and suggests that AVP and V1a receptors may play a hitherto unrecognized role in placental growth, differentiation, and/or function, particularly in the deleterious effects of heat stress, early in pregnancy, on fetal growth