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NJBMS - volume 10 issue 4, April - June 2020

Pages: 10-15

Date of Publication: 26-May-2020


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Is Oligonephronia an origin of renal disease?

Author: Jones Ronald

Category: Biochemistry

Abstract:

We have been all taught over the years that each kidney has approximately one million nephrons. It has been found now that there is a lot of variation in nephron number between individuals. Epidemiological research now supports the hypothesis proposed two decades ago by Brenner et al, that a low nephron count at birth may result in hypertension (HTN) and chronic kidney disease (CKD) in later life. It has been found that low birth weight is a strong surrogate marker associated with low nephron numbers. Other clinical associations of low nephron numbers have been listed as female gender, short stature, smaller kidneys and most importantly, prematurity. Caucasians and Australian Aborigines have found to have low nephron number and is associated with increased incidence of high blood pressure in them. On histological examination, glomerular volume is found to be inversely proportional to the nephron number indicating compensatory hypertrophy with the triggering factor being low nephron number. This can lead to progressive decline in renal function precipitated by subsequent insults in later life. It has been now found that in infants born with low nephron number, prevalence of hypertension and chronic kidney disease are high. If the causes that lead to this low nephron number at birth could be identified and treated during the antenatal period, by a good antenatal care, it may help in reducing the global burden of hypertension and renal disease.

Keywords: Low Nephron Number, Low Birth Weight, Chronic kidney disease, Oligonephronia

DOI: //dx.doi.org/10.31975/NJBMS.2020.10401

Full Text:

INTRODUCTION:

Nephrogenesis in humans begins by the ?fth week of gestation and usually ends at 36th week. No further nephrons are formed beyond this period. Hence this number decides the number of nephrons the infant will have at birth. Though no new nephrons are formed after birth, the nephrons continue to mature thereby resulting in increase of kidney size in the childhood period. Though conventionally we learn that each kidney has one million nephrons, it has been estimated that the number of nephrons range between 300,000 to 1.1 million with an average of 600,000.The very fact that the nephron number could vary even 13 fold in the foetus, conveys the fact that there is a developmental programming defect that leads to this defect. The ?ndings of low nephron numbers (oligonephronia) has been studied extensively as a possible cause for future hypertension and kidney injury.

Factors that determine nephron number: Prenatal factors:

Studies over the years have shown that the nephron number is in?uenced by prenatal factors which include maternal factors, environmental factors and genetic factors. Maternal factors includeProtein de?cient diet during pregnancy, de?ciency of Vitamin A and Iron in the mother, alcohol consumption, exposure to drugs like steroids during pregnancy, presence of anaemia and hyperglycemia can all lead to low nephron number in the foetus. In addition, some environmental factors also have been shown to be associated with low nephron number. Painter et al reported that Dutch mothers exposed to famine during gestation, had su?ered malnutrition and the infants born had low nephron number with high incidence of proteinuria in later life.1

In addition to these, genetic factors including race, genes and gender have been found to be associated with low nephron numbers. Australian Aborigines count. Nephrogenesis has been regulated by many genes and has been instigated in causation of low nephron number. PAX 2 polymorphismand its common variant, the AAA haplotype reduces PAX2 mRNA expression and found to cause 10% reduction in kidney size and nephron numbers. RET, which is essential for branching in nephrogenesis, is also found to be associated with reduced kidney volume resulting in low nephron number.

b)Low birth weight:

Low birth weight independently stands up as an important surrogate marker for prevalence of low nephron number in humans established by many observationalstudies. Low Birth Weight (LBW) has been de?ned by World Health Organisation as a birth weight of less than 2.5 kg. An infant can have lowbirthweight by premature birth (before 37th week of gestation or intrauterine growth restriction (IUGR) during full time pregnancy. Factors like maternal malnutrition, inadequate during the antenatal period, and chronic infections which are prevalent in the third world countries can lead to low birth weight babies. Nephron numbers have been found to be low in neonates with LBW in many studies.4 Gestational age correlates with the number of nephrons and it has been observed that prematurity leads to reduced nephron number in the neonates. Though this observation has not been fully evaluated in adults, studies have shown a distinct correlation between low nephron number with the birth weight in the in the normal range in Australian Aborigines, Caucasians and Africans.

Though variability of nephron number may occur with age, signi?cant di?erences in nephron number have been found perinatally, implicating a strong developmental defect. Infants, who su?ered from intrauterine growth retardation, were found to have lower number of nephrons than those who had have been found to have low nephron number and normal growth.5, 6 Manalich et al have reported glomerulomegaly and they are identi?ed as a high risk group for renal disease and hypertension in prevalence of low nephron number in neonates with low birth weight who had died within two weeks several studies 2 , 3 . Female gender has been after birth. 7 Low birth weight, preterm birth and documented to be associated with reduced nephron SGA have been associated with lower nephron numbers at birth when compared to those born at term with appropriate weight for the age.

Methods to count the nephrons:

Till recently counting of nephrons had been done only post-mortem in humans in about 1000 cases.8 New methodologies have been developed to count the number of nephrons now. These techniques use computer tomographic or magnetic resonance imaging in combination with morphometric analysis of renal biopsies at the same time in living individuals.9

The current gold standard for estimation of total number of glomeruli – which will indicate the nephron count- is stereological method described as Physical dissector /fractionator combination. It can reasonably provide accurate estimation of the total nephron number in the kidney. This technique used a pair of light microscope ?tted with projector arm simultaneously or by virtual microscopy. It is essential that the ?elds are read simultaneously to achieve a reasonable precise count.10

A new method using MRI to measure the number of glomeruli and individual glomerular volume in perfused rat kidneys has recently been reported; this method is based on the observation that glomeruli labelled with cationic ferritin (CF) enhanced MRI in vivo, allows the whole kidney detection of each labelled glomeruli. CF binds to the glomerular basement membrane after intravenous injection, allowing direct, whole-kidney measurements of glomerular number, volume, and volume distribution.11 Functional nephron numbers have also been assessed based on the physiological functions and calculating whole kidney ultra?ltration coe?cient.12

Markers for Low nephron number

As the technique of counting of nephrons in the kidneys is not routinely available yet, other surrogatemarkers and clinical clues have been found to have de?nitive association with low nephron number. These additional clinical markers serve to indicate the possibility of low nephron number and therefore are of clinical importance. Female gender is estimated to have 12% fewer nephrons than male. In addition, adult height has been shown to correlate with nephron number positively. As adult height is readily measurable than birth weight, it becomes an easily checked marker for low nephron number.9 Glomerular volume has been consistently found to correlate inversely with glomerular number, preterm birth and low birth weight.This has been reported in many studies and is very high in populations at increased risk of hypertension and renal disease.13

Decreased glomerular density has been found to be associated with larger glomeruli and low birth weight, indirectly indicating lower number of nephrons. Kidney size correlates directly with nephron number and this has been possible by w e i g h i n g t h e d o n o r k i d n e y s b e f o r e transplantation.14 Ultrasound assessment of kidney size could give a clue to the nephron numbers. Though limited by accuracy, it is a simple reproducible method performed easily in utero to assess the kidney size of the foetus. Though the kidney volume has been found to be proportional to the nephron number in neonates, it may not be reliable in adults.

The concept of oligonephronia

It was as early as 1988 that Brenner, Anderson and Garcia hypothesised that a low nephron number (oligonephronia) occurring in utero, could be common factor in populations with high risk of hypertension and kidney disease.Brenner's hypothesis has been evaluated for more than two decades as enough evidences have come out of various studies and epidemiological observations.

Many animal studies and epidemiological observations have enough evidence to support this low nephron number hypothesis.15 It has been suggested that factors which cause LBW at birth, may lead to a programmed reduction in the number of nephrons in the kidney and be the possible causative factor resulting in hypertension and chronic renal disease in later life.It is well known that glomerulosclerosis and renal dysfunction occur over time in infants born with nephron de?cits like hypoplasic kidneys. Further evidence for this Low nephron count as a risk factor for development of high blood pressure has come from both animal experiments and autopsies in humans. Surgical loss of nephrons in rats during foetal life has been found to be followed by spontaneous onset of hypertension in adult hood but not seen in healthy animals which underwent nephrectomy later in life.16 Though association between low nephron count and hypertension has been shown in experimental studies, recent observers suggest that additional factors leading to structural and functional changes in the kidney also may play a role.

Consequences of oligonephronia

Low nephron number has been consistently found in adult Caucasians who had hypertension when compared with controls without hypertension. This showed a de?nite association of low nephron number and high blood pressure. Subsequently oligonephronia has been found in persons with hypertension belonging in Australian Aborigines and African Americans as well.17 These ?ndings were consistent with the fact that kidneys with lesser number of nephrons means reduced ?ltration area for sodium excretion and contributing to hypertension.

Single hit vs multiple hits

A low nephron number has been identi?ed over years as a risk factor for the development of hypertension in animal experiments and also has been con?rmed in human autopsy studies.18 Globally poverty and poor antenatal care leading to many non-communicable diseases (NCD) has been studied over the decades. But the association between low birth weight and preterm birth leading to later life hypertension and CKD is the one investigated extensively. Studies have con?rmed that developmental mishaps during the foetal life- the so called ?rst hit- can lead to programmed risk of hypertension in the future.

Of late, it has been argued that this developmental programming, if severe, may lead to disease. If not severe, it makes the child vulnerable to organ dysfunction when subjected to subsequent hits. Kidney with lower number of nephrons at birth naturally will have reduced capacity to cope up with any further kidney injury and the resultant nephron loss. This is called multiple hit hypotheses, is gaining momentum in various fronts. This second hit could be exogenous like nephrotoxins or any surgical procedure or endogenous like diabetes or obesity. More evidence to support this multihit hypothesis is accumulating from studies which have reported report association of lower birthweights with increased severity of primary renal diseases like nephrotic syndrome, polycystic kidney disease, and chronic pyelonephritis.19

A strong association has been found between neonatal Acute Kidney Injury (AKI) and premature birth, thereby lending further evidence to this hypothesis.20 AKI could be the second hit in infants with low nephron number. (Fig 2) and African Americans as well.17 These ?ndings were consistent with the fact that kidneys with lesser number of nephrons means reduced ?ltration area for sodium excretion and contributing to hypertension.

Hypertension has become the greatest contributor to the global disease in non-communicable diseases and the fact that the prevalence of LBW and premature birth is high worldwide; the concept of renal developmental programming is gaining lot of support. It appears that the state of the child decides the fate of the adult!

Remedies to rescue the nephrons

Now that the evidences accrue to establish oligonephronia as a causative factor for hyper- tension, proteinuria and subsequent kidney injury, a life course approach to prevent kidney disease and its consequences become pertinent, especially in third world countries. For this to happen, improvements in health system, monitoring and multisectoral cooperation becomes mandatory.

Studies have adequately shown the impact of altered developmental programming in the kidney. Hence strategies to mitigate this and rescue the nephrons should begin early and should be simple and practical to implement to prevent chronic kidney diseases. First and foremost, identi?cation of individuals who are at high risk for hypertension and chronic kidney disease should be systematically done early. This will include documentation of gestational age, birth weight, and maternal predisposing factors like poor nutrition, diabetes, preeclampsia and obesity. As the risk of neonatal AKI is quite high in preterm babies, one should be vigilant to identify and treat it early. Secondly, periodical screening of children born with low birth weight must be done regularly throughout life to detect early signs of proteinuria, hypertension and kidney injury. This will help identify infants born with risk of renal programming and help to detect and treat them early – thus preventing progression of kidney disease.21,22Finally and most important step is good antenatal care, especially for women who were born with low birth weight or preterm themselves. These mothers are at increased risk of giving birth to LBW children and hence need special attention. Preconception counselling, goodnutrition and care during the antenatal period should be the preventive strategies.23

Concept of oligonephronia leading to kidney disease is loud and clear.

Checking early, taking care will drive out the fear.

References:

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