Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Macroscopic view of a solitary kidney compared to a control kidney. Representative demonstration of size of a normal kidney (left) compared to a solitary kidney (right). doi:10.1371/journal.pone.0049735.g001
Source publication
Patients with unilateral MultiCystic Kidney Dysplasia (MCKD) or unilateral renal agenesis (URA) have a congenital solitary functioning kidney (CSFK) that is compensatory enlarged. The question whether this enlargement is due to increased nephron numbers and/or to nephron hypertrophy is unresolved. This question is of utmost clinical importance, sin...
Context in source publication
Context 1
... whether this would be sufficient to eliminate the (patho-) physiological stimulus for glomerular hyperfiltration and nephron hypertrophy. In this study, widely available pig kidneys, comparable to human kidneys in structure, relative size and function were used as a model for human kidneys. [18]. Because current technology does not allow for accurate determination of nephron size and number in human patients with a CSFK, we set out to explore this issue in a comparative analysis in slaughterhouse pigs with one or two kidneys. The CSFKs and the control kidneys were obtained by veterinary supervisors responsible for the official meat inspection (H. Rooijakkers and P. van Krieken) from 26 week old pigs that were slaughtered for meat consumption (VION Boxtel B.V.) and were stored on ice for 1–2 days. In a cohort of 32,000 slaughter pigs, 7 were identified to have a congenital monokidney without other anomalies. For comparison 7 kidneys were harvested from random control pigs in the same cohort. The number and volume of glomeruli were estimated with use of a modified 3-dimensional approach presented by the group of Kerstin Amann. [8] After halving the kidneys, they were immersed and fixated in formaldehyde. After weighing, the entire kidney was cut into 2-mm slices in a cranial-to-caudal direction, and the medullary pyramids were removed from the cortex. The cortex was weighed, and the cortical volume was determined using the volume-replacement method. To avoid bias, fifteen random blocks of 6 by 6 mm throughout the entire cortex were dissected for further analysis from 15 random 2 mm slices. The blocks (of 6 by 6 by 2 mm) were embedded in paraffin and serially sectioned (3 m m) and PAS stained. Shrinkage due to embedding was measured. Every first and eighth section from each block was selected for analysis. An area touching the left and bottom side of the section plane measuring 4.18 by 3.53 mm (1280 by 1080 pixels) of the selected sections was photographed using a Nikon Eclipse E800 microscope with a Nikon DXM1200 digital camera using the Nikon ACT-1 software version 2.70 (Nikon Netherlands, Lijnden, The Netherlands). The photographs (original magnification 20x) were analyzed full screen on a 22 inch HP Compaq LA2205 WG screen. Only those glomeruli were counted that appeared in the first plane but not in the eighth plane, and that did not touch the forbidden lines (bottom and right). To estimate the mean glomerular volume per kidney, we outlined Bowman’s capsule of each individual glomerulus in the first plane using the image analysis software ImageJ (v1.44o Rasband WS, U. S. National Institutes of Health, Bethesda, Maryland U) to determine the total glomerular area found in the section. The sampling volume was calculated by multiplying total tissue area by the thickness of the section (e.g., 3 m m * 8 sections = 24 m m). A correction for tissue shrinkage (29%) was made, and the resulting volume, multiplied by the weight of the fixed kidney, yielded the mass of the portion of the cortex being examined (m exam ). The weight of the cortex being examined was divided by the weight of the total cortex (M total ) to calculate the ratio. The number of glomeruli was calculated using the following equation: number = 1 : (m exam : M total ) * g Q-, where Q- is the number of glomeruli found in the first section but not in the eight section. Nephron volume was calculated by dividing total kidney volume by the number of glomeruli. The number of papillae of CSFKs was determined by close inspection of the pyelum in a longitudinally halved kidney and compared to the number of papillae of control kidneys. Of these halved kidneys the total area, the cortical area, the pyelum area and the surface area of the medullary pyramids was determined using ImageJ ((v1.44o Rasband WS, U. S. National Institutes of Health, Bethesda, Maryland U). In addition to the stereologic analysis, all kidneys were examined by light microscopy. The number of heavily sclerosed glomeruli per 100 glomeruli in the cortex was counted. To estimate the number of cells within the glomeruli, 3 m m thick slides were stained for WT-1 (NCL-L-WT1-562, Leica) to distinguish the podocytes from the other glomerular cells. For each kidney, the number of podocytes and the total cell number were determined in 10 glomerular tuft cross sections. (Count tool, Adobe Photoshop CS5). For determination of intra- and inter-observer variation, two investigators familiar with the 3-D stereologic method, both examined one kidney three times, being unaware of the kidney being CSFK or control. The coefficient of variation was calculated. The results are expressed as mean / 2 standard deviation. The statistical significance of results was calculated with a student’s t- test. The mean total weight of the CSFKs was 84 percent higher than that of control kidneys (Table 1). The cortex weight and volume were 81 and 83 percent higher in the CSFKs than in the control kidneys (Table 1, Figure 1). The mean number of glomeruli counted per field was 4.31 + / 2 2.41. The mean number of glomeruli counted per pig was 64.77 + / 2 19.14. The mean number of glomeruli was 50 percent higher in the CSFKs than in the control kidneys, but the mean glomerular volume was not increased (Table 1). The mean number of glomeruli in the CSFKs was 2,301,441 + / 2 330,670 compared to 1,536,302 + / 2 538,809 in the control kidneys. As shown in figure 2A, the increase in cortex volume (83%) of CSFKs exceeded their increase in glomerular number (50%). As illustrated in figure 2B, the total cortical volumes and glomerular numbers of CSFKs were, although generally lower, mostly within the range of two controls. In figure 2C, the median of the number of glomeruli per mm 3 for CSFKs and control kidneys are shown. In CSFKs, the mean number (8.51) of glomeruli per mm 3 did not differ significantly from the mean number (10.13) of glomeruli per mm 3 in the control kidneys (p = 0.21). The higher number of glomeruli in combination with a comparable microanatomy (Figure 3) resulted in a 52 percent higher total glomerular volume in the CSFKs than in the control kidneys (Table 1). The mean total glomerular volume was in the CSFKs 19,175 mm 3 + / 2 5,066 mm 3 compared to 12,654 mm 3 + / 2 5,040 mm 3 in the control kidneys. As demonstrated in Table 1, mean volume of individual nephrons in CSFKs 0.14 mm 3 + / 2 0.02 was comparable to that of control kidneys 0.13 mm 3 + / 2 0.05. The number of papillae per kidney in CSFKs (11.4 / 2 1.52) was increased by 39% compared to control kidneys (8.2 + / 2 0.45). The total surface area in CSFKs was 105.2 cm 2 + / 2 21.0 compared to 71.6 cm 2 + / 2 9.3 in control kidneys. The percentage surface area comprised of total of cortex, medullary pyramids, and pyelum was 54.2% + / 2 4.8; 17.6% + / 2 3.9; and 27.5% + / 2 5.4 in CSFKs and 51.9% + / 2 5.3; 20.6 + / 2 3.3; and 27.5 + / 2 3.0 in control kidneys respectively. There was no difference (p = 0.76) between the percentage of sclerosed glomeruli in CSFKs (mean 0.57%) and the control kidneys (mean ...
Citations
... Throughout this phase, the formation of nephrons occurs, and the final number that is established before birth becomes the lifelong kidney endowment. A literature analysis reveals considerable variability in the number of nephrons, observed in both humans [7] and various animals, such as mice [8], rats [9], pigs [10], and sheep [11]. According to Bhat and Manolescu [7], the number of nephrons in a healthy human kidney typically ranges from 0.3 to 1.3 million. ...
A well-balanced diet is integral for overall health, aiding in managing key risk factors for kidney damage like hypertension while supplying necessary precursors for metabolite production. Dietary choices directly influence the composition and metabolic patterns of the gut microbiota, showing promise as therapeutic tools for addressing various health conditions, including chronic kidney diseases (CKD). CKD pathogenesis involves a decline in the glomerular filtration rate and the retention of nitrogen waste, fostering gut dysbiosis and the excessive production of bacterial metabolites. These metabolites act as uremic toxins, contributing to inflammation, oxidative stress, and tissue remodeling in the kidneys. Dietary interventions hold significance in reducing oxidative stress and inflammation, potentially slowing CKD progression. Functional ingredients, nutrients, and nephroprotective phytoconstituents could modulate inflammatory pathways or impact the gut mucosa. The “gut–kidney axis” underscores the impact of gut microbes and their metabolites on health and disease, with dysbiosis serving as a triggering event in several diseases, including CKD. This review provides a comprehensive overview, focusing on the gut–liver axis, and explores well-established bioactive substances as well as specific, less-known nutraceuticals showing promise in supporting kidney health and positively influencing CKD progression.
... Although there is currently almost no technological technique in clinical settings to detect the number of nephrons in living subjects, an 80% and 56% increase in kidney weight and number of nephrons, respectively, has been reported in a single human case of pSFK compared with age-matched control [125]. Moreover, various animal models of kidney mass reduction during nephrogenesis have reported a compensatory nephron formation, with a 4-50% increase in the number of nephrons [126][127][128]. The underlying stimulus and mechanisms mediating kidney hypertrophy in SFK remain unclear. ...
... The underlying stimulus and mechanisms mediating kidney hypertrophy in SFK remain unclear. However, increase in the number of medullary papillae [127,129], NO system, the renal sympathetic nerves, and the RAAS have been implicated in the compensatory nephrogenesis [123]. ...
Glomerular hyperfiltration (GHF) is a phenomenon that can occur in various clinical conditions affecting the kidneys such as sickle cell disease, diabetes mellitus, autosomal dominant polycystic kidney disease, and solitary functioning kidney. Yet, the pathophysiological mechanisms vary from one disease to another and are not well understood. More so, it has been demonstrated that GHF may occur at the single-nephron in some clinical conditions while in others at the whole-kidney level. In this review, we explore the pathophysiological mechanisms of GHF in relation to various clinical conditions in the pediatric population. In addition, we discuss the role and mechanism of action of important factors such as gender, low birth weight, and race in the pathogenesis of GHF. Finally, in this current review, we further highlight the consequences of GHF in the progression of kidney disease.
... With regard to the function of the remnant kidney, it is crucial to determine whether this hypertrophy is associated with an increased number of nephrons or enlargement of the existing nephrons. It has been demonstrated in animal studies that compensatory nephrogenesis in the contralateral kidney, leading to an increase in the number of nephrons, is responsible for its enlargement [10,12]. However, no human studies have reported similar results, yet better long-term glomerular filtration rates have been observed in children with congenital solitary kidney compared to those with acquired solitary kidney [11]. ...
Background
Given the importance of the function of the remnant kidney in children with unilateral renal agenesis and the significance of timely diagnosis and treatment of reflux nephropathy to prevent further damage to the remaining kidney, we aimed to determine the prevalence of reflux nephropathy in this subgroup of pediatric patients.
Methods
In general, 274 children referred to pediatric nephrologists in different parts of Iran were evaluated, of whom 199 had solitary kidney and were included in this cross-sectional study. The reasons for referral included urinary tract infection (UTI), abnormal renal ultrasonography, being symptomatic, and incidental screening. Demographic characteristics, including age and gender were recorded. History of UTI and presence of vesicoureteral reflux (VUR) were evaluated.
Results
Of the 274 children evaluated in this study with the mean age (SD) of 4.71 (4.24) years, 199 (72.6%) had solitary kidney. Among these, 118 (59.3%) were male and 81 (60.7%) were female, 21.1% had a history of UTI, and VUR was present in 23.1%. The most common cause of referral was abnormal renal ultrasonography (40.2%), followed by incidental screening (21.1%), being symptomatic (14.1%), and UTI (5.5%). In 116 children (58.3%), the right kidneys and in 83 (41.7%) the left kidneys were absent. Besides, 14.6% of the participants had consanguineous parents and 3% had a family history of solitary kidney. Upon DMSA scan, the single kidney was scarred in 13.1%, of which only 7.5% were associated with VUR. In addition, proteinuria and hematuria were observed in 6.5% and 1.5% of children, respectively.
Conclusions
The prevalence of reflux nephropathy was 7.5% in children with solitary kidney with a male predominance. Given the relatively high prevalence of reflux nephropathy in these children, screening for VUR in the remnant kidney appears to be essential in this population.
... Pyramid number also varies in animal models with multipapillated kidneys, and pyramid number or size may reflect kidney functional capacity. For example, in a study of pigs with a congenital solitary kidney, single kidneys had more glomeruli than a kidney from a pig with two kidneys (44). This larger N glom was also associated with more pyramids. ...
Kidney pathologies are often highly heterogenous. To comprehensively understand kidney structure and pathology, it is critical to develop tool to map tissue microstructure in the context of the whole, intact organ. Magnetic resonance imaging (MRI) can provide a unique, three-dimensional (3D) view of the kidney and allows for measurement of multiple pathologic features. Here, we develop a platform to systematically render and map gross and microstructural features of the human kidney based on 3D MRI. These features include pyramid number and morphology, and associated medulla and cortex. in a subset of these kidneys, we also map individual glomeruli and glomerular volumes using cationic ferritin enhance-MRI to report intra-renal heterogeneity in glomerular density and size. Finally, we render and measure regions of nephron loss due to pathology and individual glomerular volumes in each pyramidal unit. This work provides new tools to comprehensively evaluate the kidney across scales, with potential applications in anatomical and physiological research, transplant allograft evaluation, biomarker development, biopsy guidance, and therapeutic monitoring. These image rendering and analysis tools could eventually impact the field of transplantation medicine to improve longevity matching of donor allografts and recipients and reduce discard rates through the direct assessment of donor kidneys.
... In a single human case study of a congenital SFK autopsied from a healthy 27-year-old male, it was observed that the congenital SFK weighed twice as much and had twice as many nephrons as a single kidney from an age-matched control (Maluf, 1997). In a study in 26-week-old pigs born with a congenital SFK, an 80% increase in kidney weight and using stereology, a 50% increase in nephron number in the SFK compared with a single control kidney was observed but individual glomerular volumes were similar to that of control (Van Vuuren et al., 2012a). In our ovine model of congenital SFK, fetal unilateral nephrectomy at 100 days of a 150-day gestation, resulted in a ∼45% greater nephron number in the SFK compared with a single kidney of a sham operated control sheep at 130 days of gestation but individual glomerular volumes were lower in the SFK compared with control at this age (Douglas- Denton et al., 2002). ...
Children born with a solitary functioning kidney (SFK) have an increased risk of hypertension and kidney disease from early in adulthood. In response to a reduction in kidney mass, the remaining kidney undergoes compensatory kidney growth. This is associated with both an increase in size of the kidney tubules and the glomeruli and an increase in single nephron glomerular filtration rate (SNGFR). The compensatory hypertrophy and increase in filtration at the level of the individual nephron results in normalization of total glomerular filtration rate (GFR). However, over time these same compensatory mechanisms may contribute to kidney injury and hypertension. Indeed, approximately 50% of children born with a SFK develop hypertension by the age of 18 and 20–40% require dialysis by the age of 30. The mechanisms that result in kidney injury are only partly understood, and early biomarkers that distinguish those at an elevated risk of kidney injury are needed. This review will outline the compensatory adaptations to a SFK, and outline how these adaptations may contribute to kidney injury and hypertension later in life. These will be based largely on the mechanisms we have identified from our studies in an ovine model of SFK, that implicate the renal nitric oxide system, the renin angiotensin system and the renal nerves to kidney disease and hypertension associated with SFK. This discussion will also evaluate current, and speculate on next generation, prognostic factors that may predict those children at a higher risk of future kidney disease and hypertension.
... 4 However, a study we performed on slaughter pig CSFKs showed nephron hyperplasia (ie, an increase in number of functioning nephrons) with a concurrent increase in renal papilla number (RPN). 5 We aimed to investigate whether hyperplasia is also present in human CSFK. Because we could not perform invasive kidney biopsies on fetuses, we measured RPN with conventional (2D) and 3-dimensional (3D) fUS. ...
... Additional studies comparing fUS to histology to assess nephron number with certainty are warranted to further research this hypothesis. 5,9 In theory, higher nephron endowment (ie, hyperplasia) would lead to lower risk for developing renal injury. 10 Thus, the main limitation of our study is the lack of comparison between RPN number and postnatal renal injury outcomes, something we hope to investigate in future studies. ...
... Compensatory hypertrophy is mostly seen as a physiological adaptation to the presence of only one functional kidney, and its absence is considered a less favorable sign for renal function at later age 31 . Animal models suggest that loss of functional renal mass during fetal life stimulates both nephrogenesis, leading to enhanced formation of nephrons in the remaining kidney (hyperplasia), and glomerular and tubular hypertrophy 32,33 . This is different from the compensatory hypertrophy occurring after unilateral nephrectomy performed after birth, which is solely due the increase in nephron size and hyperfiltration 34 . ...
Objective:
To evaluate renal blood flow and renal volume for the prediction of postnatal renal function in fetuses with solitary functioning kidney (SFK).
Methods:
74 SFK fetuses (unilateral renal agenesis (12), multicystic dysplastic kidney (36) and severe renal dysplasia (26)) were compared with 58 healthy fetuses. Peak systolic velocity (PSV), Pulsatility Index (PI ) and Resistance Index (RI) of the renal artery (RA) were measured; 2- and 3D (VOCAL) volumes were calculated. Renal length and glomerular filtration rate (GFR) were obtained in SFK children (2 years).
Results:
Compared with the control group, the PSV RA was significantly lower in non-functioning kidneys and significantly higher in SFK. Volume measurements indicated a significantly larger volume of SFK compared to healthy kidneys. All but four children had GFR above 70 ml/min/1.73 m2 and compensatory hypertrophy was present in 69% at 2 years. PSV RA and SFK volume correlated with postnatal renal hypertrophy. No correlation between pre-and postnatal SFK volume and GFR at 2 years was demonstrated.
Conclusion:
Low PSV RA might have a predictive value for diagnosing a non-functioning kidney in fetuses with a SFK. We demonstrated a higher PSV RA and larger renal volume in the SFK compared to healthy kidneys.
... Compensatory mechanisms in congenital renal malformations have been investigated in animals with difficult translation of the data to humans because renal ontogeny is species specific [19,20]. However, the ovine kidney development process is very similar to that of human kidney. ...
... Congenital functioning solitary kidneys in 26 week-old pigs have been anatomically compared with normal controls by van Vuuren et al. Both kidney weight and nephron number were found to be significantly increased in congenital solitary kidney [19]. A comparison of histological patterns was also conducted showing that glomerular and tubular size in congenital solitary kidneys is similar to controls, while the number of nephrons was found to be doubled. ...
... A comparison of histological patterns was also conducted showing that glomerular and tubular size in congenital solitary kidneys is similar to controls, while the number of nephrons was found to be doubled. The total mass of glomeruli as a percentage of cortical mass was considerably greater in the congenitally solitary kidneys than in controls [19] (Figures 1 and 2). ...
Rational: The inhibition of renin–angiotensin–aldosterone system (RAAS) is a major strategy for slowing the progression of chronic kidney disease (CKD). The utility of anti-RAAS agents in patients with congenital or acquired solitary kidney is still controversial.
Objective: A systematic literature review was conducted.
Main findings: The conclusions of the few available studies on the topic are homogeneously in agreement with a long-term reno-protective activity of anti-RAAS drugs in patients with solitary kidney, especially if patients are hypertensive or proteinuric. However, angiotensin 2 (ANG2) levels permit a functional adaptation to a reduced renal mass in adults and is crucial for sustaining complete kidney development and maturation in children. A hormonal interference on ANG2 levels has been supposed in women. Consequently, at least in children and women, the use of ARBs appears more appropriate.
Principle conclusions: Available data on this topic are limited; however, by their overall assessment, it would appear that anti-RAAS drugs might also be reno-protective in patients with solitary kidney. The use of ARBs, especially in children and in women, seems to be more appropriate. However, more experimental data would be strictly necessary to confirm this hypothesis.
... Although mammals cannot form additional nephrons after the completion of nephrogenesis, unilateral nephrectomy in fetal lambs or pigs results in a 45-50% increase in nephron number of the remaining kidney, a testament to the importance of the stage of life history in the regenerative response to renal injury. 79,80 Protection from infection and injury provided by the intrauterine environment is likely to play a role in this adaptive response: preterm birth in human infants results in impaired nephrogenesis in the very low birth weight neonate. 81,82 Urine of preterm neonates born before ...
Progressive kidney disease follows nephron loss, hyperfiltration, and incomplete repair, a process described as “maladaptive.” In the past 20 years, a new discipline has emerged that expands research horizons: evolutionary medicine. In contrast to physiologic (homeostatic) adaptation, evolutionary adaptation is the result of reproductive success that reflects natural selection. Evolutionary explanations for physiologically maladaptive responses can emerge from mismatch of the phenotype with environment or evolutionary tradeoffs. Evolutionary adaptation to a terrestrial environment resulted in a vulnerable energy-consuming renal tubule and a hypoxic, hyperosmolar microenvironment. Natural selection favors successful energy investment strategy: energy is allocated to maintenance of nephron integrity through reproductive years, but this declines with increasing senescence after ∼40 years of age. Risk factors for chronic kidney disease include restricted fetal growth or preterm birth (life history tradeoff resulting in fewer nephrons), evolutionary selection for APOL1 mutations (that provide resistance to trypanosome infection, a tradeoff), and modern life experience (Western diet mismatch leading to diabetes and hypertension). Current advances in genomics, epigenetics, and developmental biology have revealed proximate causes of kidney disease, but attempts to slow kidney disease remain elusive. Evolutionary medicine provides a complementary approach by addressing ultimate causes of kidney disease. Marked variation in nephron number at birth, nephron heterogeneity, and changing susceptibility to kidney injury throughout life history are the result of evolutionary processes. Combined application of molecular genetics, evolutionary developmental biology (evo-devo), developmental programming and life history theory may yield new strategies for prevention and treatment of chronic kidney disease.
... Studies in baboons have shown that nephron number range from 138,078 to 427,471 (57,58). In pigs, total nephron complement varies from 1,624,672 to 4,613,980 or a~3-fold difference (91,163). A fourfold difference in nephron complement is observed in sheep (200,000 -800,000) (7,49,177). ...
The kidneys play a vital role in the excretion of waste products and the regulation of electrolytes, maintenance of acid-base balance, regulation of blood pressure, and production of several hormones. Any alteration in the structure of the nephron (basic functional unit of the kidney) can have a major impact on the kidney's ability to work efficiently. Progressive decline in kidney function can lead to serious illness and ultimately death if not treated by dialysis or transplantation. While there have been numerous studies that implicate lower nephron numbers as being an important factor in influencing susceptibility to develop hypertension and chronic kidney disease, a direct association has been difficult to establish because of three main limitations: (1) the large variation in nephron number observed in the human population; (2) no established reliable non-invasive methods to determine nephron complement; and (3) to-date, nephron measurements have been done after death which doesn't adequately account for potential loss of nephrons with age or disease. In this review, we will provide an overview of kidney structure/function, discuss the current literature for both humans and other species linking nephron deficiency and cardio-renal complications, as well as, describe the major molecular signaling factors involved in nephrogenesis that modulate variation in nephron number. As more detailed knowledge about the molecular determinants of nephron development and the role of nephron endowment in the cardio-renal system is obtained, it will hopefully provide clinicians the ability to accurately identify people at risk to develop CKD/hypertension and lead to a shift in patient care from disease treatment to prevention.
