Life takes too much trouble

Do humans need two kidneys?

Why humans have two kidneys is not the question that primarily concerns Wilhelm Kriz and his colleagues at the Institute for Anatomy and Cell Biology, but their research can also provide an answer to this. The scientists are targeting a very special type of cell, the "small foot cells". They ensure that the kidneys only excrete unwanted substances properly, but they also form their Achilles' heel. If, for whatever reason, they perish, they cannot be replaced. With two kidneys, nature has created a reserve cushion, so to speak. Do kidney donors therefore run the risk of suffering kidney failure themselves?

In civilized countries it has become a matter of course in people's consciousness that the kidneys can deteriorate in their function in the course of life and that kidney failure occurs. Survival is made possible through the replacement of the kidney function, either through regular blood washing, dialysis, or through transplantation of a healthy kidney. It is permissible for relatives and the medical side to donate a kidney, so that the donor and recipient can continue to live with only one kidney. It does not shorten the life expectancy of the donor, or at least there is no evidence to the contrary, and for the recipient, continuing to live with a close relative's kidney is by far the best of all possible therapies.

This first begs the question: Why do humans have two kidneys? How does that fit together? On the one hand, two kidneys, which fail relatively frequently in their function, and on the other hand, the possibility of being able to live with one kidney without impairment. To understand this contradiction, we need to study a little about the structure and function of the kidney. The kidney consists of functional subunits called nephrons. Each kidney contains around a million of these. They are all formed during prenatal development and cannot be recreated after birth. Each nephron begins with a small filter device, the kidney corpuscle or glomerulus, a spherical structure with a diameter of about a fifth of a millimeter, 200 æm, and thus just visible to the eye. Kidney corpuscles consist of a tangle of blood capillaries that are turned into a spherical cup. Its task is to filter the blood flowing through it, that is, part of the blood fluid is squeezed out through the capillary wall and ends up in the cup. In total, a person produces around 180 liters of this "primary urine" every day. The filtrate from the beaker passes into a long, intricately designed tubule, the tubule, in which most of the primary urine is reabsorbed. The urine remains in the tubule, which, to put it a little simplified, only contains the substances that the body wants to excrete. The canals of many nephrons finally unite to form the collecting tubes that open into the renal pelvis.

Both parts of the nephron, the kidney corpuscle and the kidney tubule, behave very differently when they are damaged in the course of diseases. The kidney tubules can recover well even after extensive damage and usually fully regain their functionality - during the regeneration period, however, dialysis is almost always necessary to bridge the gap. The kidney corpuscles, on the other hand, can only repair damage to a limited extent and a dead glomerulus cannot be replaced. What is more, with its demise, the associated renal tubule degenerates and with it the entire nephron.

In every person, nephrons perish in the course of their life. In old age, without having suffered any noticeable kidney disease, people often only have half of their nephrons, yes, they probably still live quite well with a quarter. Even a patient who has fully recovered from kidney disease and whose kidney function is restored will subsequently have to live with fewer nephrons, many of which may be partially damaged by the disease. As a result, following kidney disease, the "normal" death rate of the nephrons can increase and sooner or later a critical point can be reached at which the remaining kidney corpuscles can only maintain adequate blood purification with difficulty. Normally, nephrons, again to put it a little simplified, work when the workload is low, so to speak in a gentle cycle. If nephrons gradually fail, the remaining ones have to take over their work by allowing higher filtration pressures and at the same time becoming larger, hypertrophied. This makes them more sensitive to damaging influences; this becomes more and more critical as the number of nephrons decreases. A "vicious circle" is created, which marks the beginning of chronic kidney failure and is responsible for the fact that the disease progresses faster and faster until the remaining nephrons can no longer perform the necessary excretion and lead to uremia, urine poisoning, comes.

In order to understand chronic kidney failure one must therefore ask: Why do kidney corpuscles have such a poor regenerative capacity? My working group at the Institute of Anatomy and Cell Biology has been dealing with this question for about five years, and we have come to the conclusion that a very special type of cell in the kidney corpuscles, the "foot cells" or podocytes, is the crucial weak point. This becomes clear if one takes a closer look at the structure and function of the kidney corpuscles. In order to filter the blood and to form the primary urine, certain prerequisites must be met: The blood pressure must be high enough to force the liquid through the capillary wall into the cup. The capillary wall, which functions as a filter membrane, must be permeable to the water and the small molecular substances dissolved in the water, but impermeable to blood proteins and of course to the blood cells that should not be excreted.

The filter membrane consists of three parts: on the blood side of a "vascular endothelium", which has large open pores. This is followed by the "basement membrane", an (extracellular) network of various structural proteins, mainly collagen. On the urine side, the cell layer of the "foot cells" delimits the filter. These highly differentiated cells have processes with which the cell is anchored in the basement membrane. The processes of one cell grip between those of the other without ever touching each other. They leave a gap between them, the so-called "filtration slit", which is covered on the urine side by a thin (extracellular) covering layer, the "slit membrane". The liquid is pressed through the slot. This means that the "primary urine" does not have to pass through the cell interior on its way through the filter; this is the only way to understand the high permeability of the filter.

The decisive but also the most vulnerable structure of the filter membrane is the foot cell. It has two tasks, first of all a mechanical one: Every artery and every arteriole - that is the smallest artery that precedes the capillary - has a tubular jacket made of smooth muscles, which counteracts the expansion of the artery by the pressure of the blood. The pressures in the filter capillaries of the kidney corpuscle are only slightly lower than in the upstream arterioles. Here the foot processes of the podocytes take over the function of the muscle cells. The foot processes contain a contractile system, a "muscular apparatus", the tone of which counteracts the widening of the capillaries. In addition, the foot cell determines the permeability of the filter through the formation of the filtration slits and the slit membrane. If the filigree structure of the filtration slots is destroyed for any reason, the filter loses its selectivity, i.e. it can no longer hold back the substances that should not be filtered, proteins are excreted in the urine.

The crucial importance of the foot cell for the susceptibility and the limited regenerative capacity of the kidney corpuscle has been proven experimentally in several papers. It was important to realize that podocytes do enter cell division, but cannot lead it to its end. Although the nucleus divides, the subsequent cell division does not occur. Any attempt at cell division leads at best to a bi- or polynuclear cell. In addition, nuclear division, mitosis, puts the foot cell in a risky situation. It has to dissolve parts of its cell skeleton in order to form a framework, the "spindle", which is especially necessary for mitosis. At the same time, it should continue to support the capillary against blood pressure, although other podocytes can only represent it imperfectly. Any dismantling of the cytoskeleton therefore always harbors the risk of not being able to withstand the expanding forces of blood pressure and of allowing the pathological expansion of a capillary. Thereby the foot cell risks being mechanically stressed even in excess and with a certain probability of failure.

As already said, relatively high pressures are necessary for the filtration. The average blood pressure in adults is about 100 mm Hg; that's the pressure in the great arteries. At the beginning of the arterioles the blood pressure is about 70 mm Hg and then drops steeply towards the capillaries; the hydrostatic pressures in normal body capillaries are between 30 and 15 mm Hg. In the glomerular capillaries, on the other hand, hydrostatic pressures of 55 to 45 mm Hg still prevail. If the pressure in the glomerular capillaries falls below a value of 45 mm Hg, the filtration stops very quickly on, that is, pressures at the specified level are absolutely necessary for filtration. On the other hand, any increase in blood pressure in the glomerular capillaries beyond this range very quickly becomes a danger because the foot processes are weaker than the muscle cells of the arterioles. The pressure in the kidney corpuscles must therefore be regulated very precisely, high enough so that filtration takes place, but not too high so as not to damage the thin, permeable capillary walls. This "tightrope walk" characterizes the structure and function of the kidney corpuscle: high selective permeability, but nonetheless resistant.

Too high a capillary pressure in the kidney corpuscles means danger. As we know today, the systemic blood pressure, which is usually measured on the patient, is not completely safely regulated at a certain level, but physiologically fluctuates briefly upwards and downwards. Short-term increases can also affect the kidney corpuscle. Most of the time it has no consequences. It only becomes critical when increased blood pressure is permanently passed on to the kidney corpuscle, albeit weakened. There is an alarm level when, in the course of kidney disease, the setting of the blood pressure required for filtration is no longer as precise as usual, too high pressure affects the kidney corpuscles, even if only temporarily, and the structures themselves are attacked by the disease process.

Whatever the damaging effects on the kidney corpuscles are made up of in individual cases, the podocyte is always affected in the end, it is the decisive cell that limits the regeneration of the kidney corpuscle after the danger has been overcome. The podocyte is thus comparable to a nerve cell that cannot be replaced either; their loss becomes apparent in advanced stages, but does not lead to death. If, on the other hand, the number of nephrons falls below a minimum, a life-threatening situation arises that can ultimately only be managed through dialysis or transplantation.

With the increasing average age of people, chronic kidney failure is increasingly becoming a life-limiting disease worldwide. Replacement therapies, transplants and, above all, regular dialysis, are extremely expensive, are already a significant burden on health budgets all over the world, and costs will continue to rise. The number of patients who experience chronic kidney failure every year and require treatment doubles every eight years in the USA, and the situation in Germany is likely to be very similar. In addition, as treatments become increasingly successful, the life expectancy of people with chronic kidney disease is increasing, increasing the total number of patients on dialysis and transplantation even more. Chronic kidney failure has already become the most expensive disease in internal medicine. Therefore, all research efforts are justified in order to better understand the disease process.

Back to the question asked at the beginning: Do humans need two kidneys? The two kidneys, or rather the total number of nephrons present in both kidneys, represent a reserve cushion. The nephrons can work with little workload at comparatively low filtration pressures. This reduces the risk of failure. Even if a large number of nephrons perish in every person in the course of life, the minimum required number is generally not fallen below, so that adequate kidney function can be maintained even in old age. Does that mean that a kidney donor is in a critical situation? Is he at risk of chronic kidney failure himself? Yes and no - in principle, as can be easily deduced from what has been said so far, of course yes, but de facto no. First, in a civilized country with modern health facilities, a thorough examination of the donor before a kidney is removed will ensure that both kidneys are healthy and at full capacity. Later, the donor will pay much more attention to the function of his only kidney than is usually done. He will have the function of his kidneys checked regularly and his blood pressure checked regularly. You will therefore recognize any possible danger to your kidneys much earlier than normal, long before the point in time at which the entry into the vicious circle outlined begins. This opens up opportunities to intervene preventively and therapeutically in good time.

Prof. Dr. Wilhelm Kriz, Institute for Anatomy and Cell Biology, Im Neuenheimer Feld 307, 69120 Heidelberg,
Telephone (06221) 54 86 80