Meguid El Nahas

CKD and Poverty: A Growing Global Challenge

Approximately 1.2 billion individuals worldwide live in extreme poverty (<

Growth Hormone Treatment during Hemodialysis in a Randomized Trial Improves Nutrition, Quality of Life, and Cardiovascular Risk

1/d), and 2.7 billion live in moderate poverty (<

Socioeconomic status and chronic kidney disease at presentation to a renal service in the United Kingdom.

2/d). Poverty is most prevalent in developing countries, but does not spare richer economies, where huge income discrepancies have been reported. Poverty is a major health care marker affecting a number of chronic, communicable, and noncommunicable diseases. Poverty and social deprivation are known to affect the predisposition, diagnosis, and management of chronic diseases; they directly impact on the prevalence of such conditions as obesity, diabetes, and hypertension. Also, growing evidence links poverty to chronic kidney disease (CKD). This may be caused by a direct impact of poverty on CKD or indirectly through the increased health care burden linked to poverty-associated diabetes and hypertension. Furthermore, data have shown that the poor and socially deprived have a greater prevalence of end-stage renal disease. Access to renal care, dialysis, and transplantation may also be affected by social deprivation. Overall, poverty and social deprivation are emerging as major risk markers for CKD in both developing and developed countries. Their impact on CKD warrants careful analysis because it may confound the interpretation of CKD risk factors within communities. This review therefore aims to look at the evidence linking poverty to CKD and its major risk factors, namely, diabetes and hypertension.

Microalbuminuria: Marker or Maker of Cardiovascular Disease

Nutritional markers, such as lean body mass (LBM) and serum albumin, predict outcome in dialysis patients, in whom protein-energy malnutrition is associated with increased morbidity and mortality. The metabolic effects of human growth hormone (hGH) may improve the nutritional and cardiovascular health of these patients and consequently reduce morbidity and mortality. The aim of this study was to establish clinical proof of concept of hGH treatment for the improvement of the nutritional status in adult patients who are on maintenance hemodialysis. A total of 139 adult patients who were on maintenance hemodialysis and had serum albumin levels < or =40 g/L were randomly assigned to 6 mo of treatment with placebo or 20, 35, or 50 microg/kg per d hGH. Change in LBM and serum albumin (primary outcomes), health-related quality of life, and secondary efficacy and safety parameters were monitored. The study showed that hGH treatment increased LBM significantly at all dosage levels (2.5 kg [95% confidence interval 1.8 to 3.1] versus -0.4 kg [95% confidence interval -1.4 to 0.6]; P < 0.001 for pooled hGH groups versus placebo). Serum albumin tended to increase (P = 0.076), serum transferrin (P = 0.001) and serum HDL (P < 0.038) increased, and plasma homocysteine was reduced (P = 0.029). TNF-alpha also tended to decrease with treatment (P = 0.134). An improvement in the Role Physical SF-36 quality-of-life subscale was observed (P = 0.042). There were no differences in clinically relevant adverse events between groups. In conclusion, hGH therapy safely improves LBM, other markers of mortality and morbidity, and health-related quality of life in adult patients who are on maintenance hemodialysis. A long-term study is warranted to investigate whether these treatment benefits result in reduced mortality and morbidity.

Chronic Kidney Disease in Older People: Physiology, Pathology or Both?

BACKGROUND AND OBJECTIVES Low socioeconomic status (SES) is associated with both development and progression of chronic kidney disease (CKD). The impact of SES on severity of CKD at presentation to a renal service is less well known. This study investigated the relationship between SES and severity of CKD in a retrospective, cross-sectional analysis involving 1657 patients at the Sheffield Kidney Institute (Sheffield, UK). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS SES was assigned to each patient according to electoral ward of residence by postcode and ranked according to the corresponding British Index of Multiple Deprivation score, which comprises five deprivation quintiles (Q1, least deprived; Q5, most deprived). National Kidney Foundation Kidney Disease Outcomes Quality Initiative classification of CKD was used for stratification and analysis. Binary logistic regression analysis was applied for the association of variables/risk factors with CKD (lower GFR) at presentation. RESULTS The age-adjusted prevalence of diagnosed CKD at presentation by area of residence, across the five deprivation quintiles, per million population was Q1 = 1495, Q2 = 3530, Q3 = 3398, Q4 = 3989, and Q5 = 19,599. Logistic regression models showed that living in the lowest SES quintile area (Q5) as compared with the highest SES (Q1) was associated with a greater risk for presenting with a lower estimated GFR, after adjustment for sociodemographic, lifestyle, and clinical variables. CONCLUSIONS Low SES is related to severity of CKD at presentation. Further studies are needed to examine this issue across the various SES categories in the United Kingdom.

An Age-Calibrated Classification of Chronic Kidney Disease

Advancing age is associated with albuminuria and vascular changes. This review will explore the putative links between the two. Vascular ageing involves endothelial dysfunction as well as increased arterial diameter, wall thickness and stiffness, ultimately leading to arterial sclerosis. This process is accelerated by a defective vascular repair process. Endothelial dysfunction is likely to be involved in the initiation and development of microalbuminuria. It is often followed by the development and progression of atherosclerosis. Initially, microalbuminuria is reversible but becomes fixed with the progression of vascular structural changes including glomerulosclerosis. The prevalence of microalbuminuria increases with age and has been shown to be a marker of widespread microvasculopathy at various levels including cerebral, cardiac and renal microcirculations. This has been linked to endpoint clinical events, with microalbuminuria increasing the risk of cognitive impairment and strokes, cardiovascular disease outcomes, and progression to end-stage renal failure. Evidence of microvascular damage such as microalbuminuria associated with increased cardiovascular risk may suggest that microvascular damage and dysfunction predate overt macrovascular disease. Microalbuminuria and reduced glomerular filtration rate (GFR) may be markers of different pathologic processes. It is likely that microalbuminuria and reduced GFR simply represent, respectively, the spectrum of renal vascular manifestations from systemic endothelial dysfunction (microvascular disease) to systemic atherosclerosis (macrovascular disease).

Early histological changes in the kidney of people with morbid obesity

The global population is aging due to a reduction in youthful deaths and an extension of the later stages of life. With aging comes a decline in the physiologic functions of various organs and systems. Vascular aging is associated with structural and functional changes of the arterial wall leading to loss of elasticity and compliance. Renal vasculature is not spared as aging is associated with arterial, arteriolar and capillary, glomerular changes (glomerulosclerosis). It is likely that age-related vascular changes are linked to the decline in renal function observed with aging. These changes occur at varying stages of aging depending on predisposing genetic factors and associated life course exposure to cardiovascular risk factors including hypertension and diabetes. The decline in renal function with ‘normal’ aging in the absence of associated progressive cardiovascular disease is slow and does not seem to be of major clinical significance. The current definition of chronic kidney disease (CKD), including microalbuminuria, and the method of estimation of glomerular filtration rate have inadvertently resulted in an exaggerated prevalence of CKD in the elderly. This is combined with the fact that most of the studies showing decline in renal function with aging are limited by the absence of a correction for associated comorbid confounding factors, resulting in difficulty separating the effect of physiological aging on kidney function from pathological aging due to comorbidities. Such a correction is difficult, if not impossible, to objectively construct. We suggest that only those fractions of older patients with underlying progressive vascular pathology likely to involve the kidneys will, in the future, warrant attention to reduce vascular risk and the associated kidney damage.

Modulation of tissue transglutaminase in tubular epithelial cells alters extracellular matrix levels : A potential mechanism of tissue scarring

Should current guidelines be changed to require age calibration for diagnosis and classification of chronic kidney disease? —Yes. The classifications of chronic kidney disease (CKD) used both for epidemiological studies in populations and for diagnosis in individual patients have evolved since the original Kidney Disease Quality Outcome Initiative iteration published more than one decade ago. The categorization of CKD, using glomerular filtration rate (GFR) and proteinuria (albuminuria), has undoubtedly raised the profile of CKD among physicians and the general public. However, concern has arisen that this approach incorrectly labels individuals, particularly older persons, as having CKD, thus inflating the prevalence of a generic CKD in the aging population. A paradox arises in that a steadily increasing frequency of such alleged CKD is accompanied by an unchanged or decreasing incidence of treated end-stage renal disease (ESRD), at least in developed nations.1,2 Although several explanations are possible for this paradox, one is that it may be a direct consequence of flaws in the current diagnostic classification of CKD. Specifically, the persistent and serious criticism that successive iterations of the CKD classification systems, including those promulgated in 2013 by the Kidney Disease: Improving Global Outcome (KDIGO) CKD Work Group2 and in 2014 by NICE (UK National Institute of Health and Care Excellence),3 have not incorporated an age-based approach to diagnosis and classifications of CKD. Consequently, defining CKD on the basis of an absolute threshold of GFR regardless of age has resulted in overdiagnosis in a substantial proportion of the general population with potentially serious and unwarranted effects. The arguments underlying this assumption are simple and straightforward. First, the CKD diagnostic approach that uses an absolute, single (not calibrated by age), arbitrary threshold of GFR and estimated GFR (eGFR) of less than 60 mL/min/1.73 m2 (persisting for 3 months even in the absence of corroborating features of kidney injury) as disease defining fails to clearly distinguish the common age-related decline in kidney function (most likely physiological organ senescence)4 from that of more progressive CKD due to intrinsic renal diseases. Consequently, the most common category of CKD detected in community-based programs is 3A (ie, GFR of 45-59 mL/min/1.73 m2), which predominantly affects older persons and is seldom progressive (there are only 0.6 to 0.8 cases of ESRD per 1000 patientyears in patients >65 years) in the absence of significant proteinuria.5 This contrasts sharply with referred CKD, often accompanied by overt proteinuria, reflecting an underlying pathology that commonly progresses to ESRD. Age is a major determinant of outcomes in CKD. In an analysis of more than 200 000 veterans with CKD, the threshold for eGFR below which the risk of ESRD exceeded the risk of death was 45 mL/min/1.73 m2 among persons aged 18 to 44 years, whereas this threshold declined to less than 15 mL/min/1.73 m2 among individuals older than 65 years.6 Older patients with CKD are much more likely to die of complications related to aging and cardiovascular disease (due to lifetime exposure to associated risk factors; eg, diabetes and hypertension) before developing ESRD. In addition, the remaining life expectancy for individuals aged 30 to 80 years with an eGFR of 45 to 59 mL/min/1.73 m2 (CKD category 3A) is not different from those with normal renal function.7 Second, the eGFR criteria used in these classifications have led to the medicalization of the common process involving organ functioning with aging; namely, the slow and inexorable decline in function, including that of the kidney. With an aging population, the problem of medicalization will only increase. This phenomenon of medicalization has inevitably led to millions of older, and seemingly otherwise healthy, individuals to be inappropriately labeled as having CKD, and claims that an astonishing 40% to 50% of the US population is predicted to develop this disease in their lifetime, mostly at an advanced age.8 Despite this assertion, the individual risk of older patients with CKD ever requiring treatment for ESRD remains very low.9 In essence, the global and threatening “epidemic” of CKD merely reflects the changing worldwide aging population. Third, such CKD misclassifications have generated increased confusion as to which patients should be screened for this disease. Some advocate universal population-based screening for CKD, whereas others promote a more measured “targeted or opportunistic screening” stance based on risk factors (eg, diabetes, hypertension, family history of CKD) or no screening at all.10 Fourth, the hazards of all-cause mortality appear to increase at around an eGFR of 60 mL/min/1.73 m2 regardless of age5; however, this observation may be due to the selection of an inappropriate reference group. For instance, with a more appropriate reference group having an eGFR that is normal for adults aged 20 to 30 years, the hazard for all-cause mortality does not increase in patients older than 65 years until eGFR has declined to less than 45 mL/min/1.73 m2. Age is clearly a modulating factor in risk associated with changes in eGFR. These issues can be adequately addressed by a simple age-adjusted revision in the diagnostic criteria for CKD. The threshold for defining CKD category 3A should be adjusted to less than 45 mL/min/1.73m2, as VIEWPOINT

OPPORTUNITY™: A Randomized Clinical Trial of Growth Hormone on Outcome in Hemodialysis Patients

BACKGROUND Morbid obesity represents a major health problem with increasing incidence worldwide. The clinical manifestation of renal involvement in obesity is proteinuria, and the histological feature is glomerulomegaly with or without focal and segmental glomerulosclerosis (FSGS). In this study, we have investigated the very early histological changes in kidneys of people with morbid obesity and no proteinuria. Patients and methods. Eighteen patients with body mass index (BMI) >50 kg/m(2) who underwent a variant of biliopancreatic diversion with Roux-en-Y reconstruction (BPD-RYGBP) and consented to undergo a renal biopsy during the surgical procedure were included in the study. The estimation of early histological changes was performed on light (n = 18) and electron microscopy (n = 13). RESULTS The mean glomerular cross-sectional area was 30 943 +/- 10,984 microm(2) that is higher than that observed in non-obese individuals. In 21% of the examined glomeruli, the glomerular planar surface area (GPSA) was >40,000 microm(2). Thickening of the glomerular basement membrane (GBM) and scattered paramesangial deposits were identified in 9 of 13 patients (70%) whose renal tissue was examined by electron microscopy. A reduction in the slit pore frequency was observed in obese patients due to extensive foot process effacement. Significant positive correlations between mean GPSA and body weight (r = 0.462, P = 0.05), and between GBM thickness and HbA1c, serum total cholesterol and triglyceride levels (r = 0.60, P = 0.05; r = 0.789, P = 0.004; r = 0.70, P = 0.016, respectively), were observed. CONCLUSIONS Glomerulomegaly as well as histological lesions resembling those of early diabetic nephropathy are observed in kidney biopsies of patients with morbid obesity even before the appearance of microalbuminuria. The potential regression of these changes after weight loss needs to be clarified.

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

The up-regulation and trafficking of tissue transglutaminase (TG2) by tubular epithelial cells (TEC) has been implicated in the development of kidney scarring. TG2 catalyses the crosslinking of proteins via the formation of highly stable epsilon(gamma-glutamyl) lysine bonds. We have proposed that TG2 may contribute to kidney scarring by accelerating extracellular matrix (ECM) deposition and by stabilising the ECM against proteolytic decay. To investigate this, we have studied ECM metabolism in Opossum kidney (OK) TEC induced to over-express TG2 by stable transfection and in tubular cells isolated from TG2 knockout mice. Increasing the expression of TG2 led to increased extracellular TG2 activity (p<0.05), elevated epsilon(gamma-glutamyl) lysine crosslinking in the ECM and higher levels of ECM collagen per cell by (3)H-proline labelling. Immunofluorescence demonstrated that this was attributable to increased collagen III and IV levels. Higher TG2 levels were associated with an accelerated collagen deposition rate and a reduced ECM breakdown by matrix metalloproteinases (MMPs). In contrast, a lack of TG2 was associated with reduced epsilon(gamma-glutamyl) lysine crosslinking in the ECM, causing reduced ECM collagen levels and lower ECM per cell. We report that TG2 contributes to ECM accumulation primarily by accelerating collagen deposition, but also by altering the susceptibility of the tubular ECM to decay. These findings support a role for TG2 in the expansion of the ECM associated with kidney scarring.