Glomerular adaptation after kidney transplantation

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Abstract

In renal transplantation, surrogate variables of low nephron endowment are associated with a decreased allograft survival. However, total glomerular number can only be precisely estimated in experimental models or autopsy studies because the whole kidney is necessary for this purpose. The combination of magnetic resonance imaging of the kidney and a renal biopsy allows estimating total glomerular number in vivo, and the application of this approach to stable renal allografts has shown that total glomerular number is a major determinant of graft function.

Protocol biopsies performed in stable grafts have allowed the characterization of subclinical rejection (SCR) and chronic allograft nephropathy as well as their predictive value on graft outcome. However, glomerular adaptation after transplantation has not captured the interest of the transplant community despite only one kidney is transplanted and a large proportion of transplant recipients will receive an insufficient nephron number for their metabolic demand.

Using protocol biopsies, it has been shown that glomeruli enlarge after transplantation to provide an adequate filtration surface area to the recipient metabolic demand. Glomerular size increases during the first year and this adaptation process is necessary to achieve an adequate renal function. This adaptation is impaired in patients with SCR and/or chronic allograft nephropathy. Furthermore, glomerulosclerosis is also increased in patients with impaired glomerular adaptation. Taken together, these data suggest that the primary target of SCR is the tubulointerstitial compartment leading to interstitial fibrosis/tubular atrophy and to impaired glomerular adaptation/glomerulosclerosis thereafter.

Introduction

There is a precisely matched relationship between energy flux, protein metabolism, and renal function. Metabolic rate is the parameter that sets glomerular filtration rate (GFR) as well as pulmonary, cardiac, and other body functions. From the structural point of view, GFR depends on the glomerular filtration surface area, and this parameter is determined by the number and size of glomeruli. To provide an adequate renal function during the different periods of life, healthy kidneys adapt their structure by increasing glomerular and tubular size when metabolic demand increases as it occurs during normal growth, pregnancy, and obesity. Moreover, renal adaptation is also necessary after reduction of total glomerular number as it occurs in renal disease, aging, or renal mass ablation.

Renal transplantation constitutes the best treatment of renal failure despite that in most patients, one kidney transplant implies that the renal filtration surface area and renal function are lower than those in healthy subjects. Consequently, transplanted kidneys should adapt their structure to the metabolic characteristics of the recipient. However, the adaptation of the transplanted kidney to the metabolic requirements of the recipient has not been properly studied. This adaptation process should be influenced by the amount of transplanted renal mass as well as by the different insults the transplanted kidney is exposed to and might be related to graft outcome.

Allometric studies have shown that glomerular number varies between different species and is closely associated with body size, a surrogate parameter of basal metabolic rate. The bigger the animal, the higher the glomerular number. Glomerular number in a mouse kidney is approximately 25 × 103 and in a whale kidney 25 × 106 (Fig. 1). On the contrary, glomerular volume only slightly increases with body size between species. Thus, renal adaptation between species to an increasing metabolic demand mainly depends on nephron number and only marginally on glomerular volume. However, in the same species, fine tuning of renal function according to body size of each individual depends on glomerular and tubular enlargement because the number of nephrons do not increases after birth [1], [2].

In humans without known renal disease, autopsy studies have shown that there is an important variability in the glomerular number between subjects, ranging between 0.2 and 1.8 × 106 glomeruli per kidney. Glomerular tuft volume between subjects without renal disease varies by 13-fold factor. An inverse relationship between glomerular number and glomerular tuft volume has been described in autopsy studies, suggesting that glomerular enlargement constitutes an adaptation mechanism to provide an adequate filtration surface area in subjects with a variable nephron number. Accordingly, glomerular volume constitutes a surrogate measure of glomerular number [3], [4].

Glomerular number is set at birth and is closely associated with birth weight [5], [6]. There is an association between low birth weight and a higher risk to develop hypertension, and cardiovascular and renal diseases in adulthood. These observations suggest that low nephron endowment at birth is a major determinant of the susceptibility to renal disease [7], [8], [9], [10]. Genetic and environmental factors are associated with renal development and nephron number. Maternal malnutrition, iron or vitamin deficiencies, smoking, alcohol consumption, and exposure to different drugs are associated to low birth weight and reduced nephron number [11], [12], [13].

After birth, glomeruli enlarge in proportion to body growth to adapt the filtration surface area to an increasing metabolic demand [14]. Moreover, glomerular number decreases and glomerular volume increases with aging [4]. Once glomerular size reaches a certain threshold, glomerulosclerosis, hypertension, proteinuria, and renal failure develop [15], [16].

Hypertension and renal failure are more prevalent in certain populations that are characterized by an increased prevalence of low birth weight and adult obesity. This observation suggests that in such populations the imbalance between nephron number and metabolic demand is inadequate [17]. These data are in agreement with the observation that the only independent predictor of the development of renal insufficiency after nephrectomy was an increased body mass index [18]. Conversely, follow-up of living donors, which have been only considered for donation after a strict selection process, has shown that after 20 years the prevalence of end-stage renal disease is not different from the general population despite a higher risk for hypertension and proteinuria [19].

Taking into consideration the large variability of glomerular number between subjects without renal disease, and considering that only one kidney is transplanted, a large proportion of transplant recipients will receive an insufficient nephron number for their metabolic demand. Nephron deficiency after transplantation may be further worsened by ischemia-reperfusion injury, acute rejection, and drug toxicity. At the experimental and clinical settings, available data strongly suggest that an imbalance between nephron supply and recipient metabolic demand is associated with a poorer graft outcome.

In experimental models, chronic allograft lesions progress slower in rats with one retained native kidney after transplantation in comparison to rats with both native kidneys excised [20], [21]. This finding is in agreement with the observation that prolonged bilateral warm renal ischemia induces less damage in the long term when both kidneys are retained in place as opposed to the severe renal scarring when warm renal ischemia is combined with contralateral nephrectomy [22].

Large epidemiologic studies have shown that conditions of suspected inadequate renal mass after transplant such as transplantation of small kidneys from young children, transplants into large recipients weighting more than 100 kg, grafts from females to males in comparison to grafts from males to females, kidneys suffering a rejection episode, and grafts from deceased donors compared with living grafts have a reduced renal allograft survival [23], [24]. In a study in which the influence of recipient size was compared in pairs of recipients receiving a kidney from the same donor, it was observed that a relatively small differences in recipient body surface area was associated with a higher prevalence of delayed graft function, hypertension, and an increased degree of proteinuria [25]. Body mass index was also an independent predictor of delayed graft function and death-censored graft survival [26]. The proportion of donor kidney weight to recipient body size has also been associated with graft outcome [27], [28]. Furthermore, the susceptibility to acute rejection seems to be also modulated by the amount of transplanted renal mass. In this regard, it has been observed that acute rejection was the lowest in recipients of en bloc pediatric kidneys, intermediate in recipients of kidneys harvested from young donors, and the highest in recipients of an old kidney [29].

Section snippets

Estimation of total glomerular number in a clinical setting

Estimation of glomerular number “in vivo” may be an exceptional tool to evaluate the risk for hypertension and chronic renal failure. Moreover, this may be useful to predict the renal capacity to adapt to an increased metabolic demand or to a reduced nephron supply.

Unfortunately, precise methods to estimate glomerular number can only be used in experimental or autopsy studies because the whole kidney is required. Since the end of the 19th century, many methods have been used to count the number

Monitoring graft damage by protocol biopsies

Studies of protocol biopsies have contributed to the characterization of early renal allograft lesions [38]. These studies have focused their interest on the characterization of inflammatory lesions, especially tubulointerstitial inflammation that has been referred as subclinical rejection (SCR) and chronic allograft lesions, the so-called chronic allograft nephropathy that since the publication of the 2005 Banff criteria is known as interstitial fibrosis/tubular atrophy (IF/TA) [39], [40].

Conclusions

Total glomerular number and mean glomerular volume can be estimated in functioning renal allografts with reasonable precision.

Glomerular number is a major determinant of graft function in stable grafts. Despite that it has been suggested that glomerular number might also be a major determinant of graft survival, this information has only been demonstrated at the experimental but not at the clinical setting. Estimation of glomerular number in vivo should contribute to the better understanding of

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