© Borgis - Postępy Nauk Medycznych 10/2009, s. 739-743
Prenatal Programming – impact on the kidney and beyond**
Rozwój narządów w życiu płodowym – wpływ na stan nerek
Ruperto-Carlola-University Heidelberg (Germany)
There is increasing evidence that prenatal programming accounts, at least in part, for a large segment of hypertension, particularly salt sensitive hypertension and albuminuria as well as chronic kidney disease.
Apart from this it also predisposes to the metabolic syndrome which may explain the high cardiovascular risk in patients with chronic kidney disease.
W ostatnich latach wykazano, że nieprawidłowy rozwój narządów w życiu płodowym może uczestniczyć w istotny sposób w patogenezie nadciśnienia tętniczego, zwłaszcza sodozależnego, albuminurii oraz przewlekłej choroby nerek u osób dorosłych. Ponadto nieprawidłowe programowanie rozwoju narządów w życiu płodowym może również predysponować do rozwoju zespołu metabolicznego, który to z kolei może tłumaczyć zwiększone ryzyko powikłań sercowo-naczyniowych u chorych z przewlekłą chorobą nerek.
Laudatio dedicated to Professor emeritus Prof. Francicek Kokot
Professor Franciszek Kokot was born on November 24th, 1929 in Olesno Slaskie and will soon celebrate his 80th birthday. On this occasion, German nephrologic colleagues send their best wishes. We are full of admiration to see the gigantic achievements of the pioneer in clinical nephrology who covered the breadth of our specialty, a true ”uomo universale”.
This achievement is all the more admirable, since it was achieved under the most difficult conditions before the implosion of the Eastern Block.
What we in Germany particularly appreciated was his effort early on to maintain contacts with neighbouring countries including Germany. The German Society (Gesellschaft für Nephrologie) recognized this by the honorary membership for Franciszek Kokot in 1979. He was able to overcome the barriers existing in the past between Eastern and Western countries. This is reflected, amongst others, by his very successful scientific collaboration with several German groups involved in renal research. He initiated a very fruitful exchange of collaborators and several of his fellows spend some time in our country. It is common scientific work and mutual collaboration across frontiers which help to overcome bitter pages in our history.
Franciszek Kokot has achieved international recognition and served as an officer in a number of international societies, particularly the European Renal Association (EDTA-ERA) and the International Society of Nephrology (ISN).
He was highly respected as an expert in renal research and this is reflected, amongst others, by his membership in numerous editorial boards, including Kidney International, Nephrology Dialysis Transplantation, Clinical Nephrology and Nieren- und Hochdruckkrankheiten.
In old German academic tradition we wish the still sprightly octogenarian ” ad multos annos ”.
In the recent past is has increasingly been appreciated that prenatal causes account to considerably extent for chronic kidney disease. This concept goes back to past epidemiological observations which showed a relation between adult pathology and birth weight as well as conditions in early childhood. This prompted B. Brenner to propose the following hypothesis: restricted growth in utero and low birth weight cause hypertension as well as increased renal risk at adult age the common link being a lower endowment of nephrons at the time of birth.
The molecular mechanisms explaining the counterintuitive fact that the same genome will result in differing phenotypes depending on intrauterine conditions have recently been lucidly explained by the concept of ”epigenetics”, i.e. that the read-off from the primary DNA code is modulated by covalent changes in histones and DNA respectively: transcription of the genetic code is modulated by covalent modification of histones (methylation or acetylation and desmethylation or desacetylation respectively), favouring or impeding access to coding DNA. In addition methyltransferases, methylating CpG sequences, play a role amongst others in silencing genes.
Numerous animal experiments have shown that maternal pathology may impair nephrogenesis of the offspring, e.g. low protein intake, uterine underperfusion, maternal hyperglycemia, maternal hyperinsulinemia, high and low maternal salt intake as well as exposure to corticosteroids to name only a few.
Adverse intrauterine milieu causes ”nephron underdosing”
The classical studies of Oliver (The Kidney and Nephrons; Harper and Row; 1968) showed a wide variation of nephron numbers in humans at autopsy, ranging from 800 000 to 1.8 million per kidney. Manalich examined the kidneys of low birth weight newborns: the number of glomeruli was less, but their volume was larger. Recently available technologies of in vivo evaluation of kidney growth documented that children born with low birth weight have low kidney volume. This can today be monitored by sonography even in utero where small and ”sausage shaped” foetal kidneys point to impaired cell and tissue migration.
Low birth weight is associated with high blood pressure later in life even when adjustments are made for current weight. The final outcome is the end result of two processes: low birth weight on the one hand (which accounts for higher adolescent blood pressure by 2-3 mm Hg) and higher catch up growth leading to adult fatness and overweight on the other hand (further aggravating hypertension). This relation between birth weight and blood pressure has also been documented in individuals with type 1 diabetes and chronic kidney disease.
We recently compared the number of glomeruli, i.e. nephrons in hypertensive adults and matched normotensive adults both of whom had been victims of traffic accidents. As shown in table 1 the number of glomeruli was significantly lower in hypertensive individuals, whilst the volume of glomeruli was significantly higher (”oligomeganephrony”).
Table 1. Keller, New Engl J Med (2003) 348: 101.
||hypertensive individuals (n=10)
||normotensive individuals (n=10)
|number of glomeruli
||890.869 ± 158.110
||1.666.805 ± 411.690 p < 0.001
|volume of glomeruli
||5.67 ± 0.85
||2.41 ± 0.71 p < 0.001
This finding immediately raises an issue: in individuals with reduced nephrons following alive kidney donation no excess frequency of hypertension is observed and at best a minor increase of blood pressure was found in a large metanalysis. This observation is in line for instance with the 25 year follow up after uninephrectomy of American servicemen in World War 2 where Narkun-Burgess failed to see an excess of high blood pressure. This is in striking contrast with what is found experimentally following uninephrectomy after birth and with what is observed in young individuals with reduced nephron numbers as a result of congenital malformation. In 157 patients with unilateral agenesis and normal contralateral kidney Argueso found that 7% had high blood pressure; 13% reduced renal function and by age 37 years 6 individuals out of 157 had already succumbed to renal failure.
In the study of Keller we found less glomeruli of larger size; if one calculates an index of the glomerular surface area, however, the surface available for filtration remains within the normal range. Obviously developmental changes in postglomerular segments must account for high blood pressure; various postglomerular mechanisms have been identified such as upregulation of sodium channels, upregulation of angiotensin receptors, activation of the mineralcorticoid receptor by diminution of the activity of 11-beta hydroxysteroid-dehydrogenase 2, sympathetic overactivity and others.
The assumption that increased tubular sodium reabsorption plays a role is strengthened by the observation of De Boer that low birth weight is associated with salt sensitivity of blood pressure in healthy adults.
These studies mentioned addressed Caucasoids. Interestingly in hypertensive blacks no reduction of glomerular number is found. Furthermore Rostand noted no correlation between low birth weight and higher blood pressure in blacks, although this correlation was clearly demonstrated in whites.
It should also be noted that one factor raising the risk of a higher blood pressure in the offspring is maternal smoking during pregnancy; even in early childhood at age 3 a significant association was found between systolic blood pressure of the child and a smoking history of the mother – this was independent of birth weight.
Low birth weight and the risk of albuminuria, chronic kidney disease and endstage renal disease
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