Endocrine disturbances of calcium metabolism in uremia: Renal causes and systemic consequences

Kidney International, Vol. 49 (1996), pp. 1765—1768

Endocrine disturbances of calcium metabolism in uremia: Renal causes and systemic consequences EBERHARD RITZ and ADAM STEFANSKI Klinikum der Universität Heidelberg, Sektion Nephrologie, Heidelberg, Germany

Endocrine disturbances of calcium metabolism in uremia: Renal causes and systemic consequences. The genesis of the hormonal disturbances in calcium metabolism of renal failure is complex, but can be understood basically as the consequence of the deranged endocrine function of the kidney, that is, failing biosynthesis of the renal secosterol hormone 1,25 0H2D3. It is of interest to note how our concepts concerning the genesis of these disturbances, and the role of 1,25 0H2D3 therein, have changed with time. We illustrate this using three examples: (i) the signals activating the parathyroid gland in early renal failure; (ii) the genesis of parathyroid hyperplasia; and (iii) the actions of 1,25 0H7D5 in renal failure unrelated to calcium control.

increase phosphate clearance. The final result would be (near) normal serum phosphate concentrations at the price of elevated PTH concentrations. Hyperparathyroidism was thus felt to be a "trade-off" for the homeostasis of serum phosphate concentration [2].

This hypothesis has proved very useful in stimulating many experiments, but it may not fully explain the findings in incipient renal failure. As shown in Figure 1, the circadian profile of serum phosphate concentrations under baseline conditions and follow-

ing a phosphate load was absolutely identical in patients with incipient renal failure and in healthy controls [3]. It may still be The work of the late Homer W. Smith was devoted to the that serum phosphate concentrations are not an adequate reflecexploration of the function of the kidney. If we go back in time, tion of the concentration of phosphate in some hypothetical the ancient wise ones were of the opinion that "the organs of the subcellular (renal?) compartment involved in control of renal body were created to perform 10 functions, among which it is the 1-a-hydroxylase activity, that is, the enzyme responsible for the function of the kidney to furnish the human being with thought" generation of calcitriol. Despite various reports to the contrary [4], when we placed patients with incipient renal failure on (Leviticus Rabba III, Talmud Berochoth 61b). This view, although

extremely flattering to the nephrologist, is unfortunately not reduced phosphate intake [5] we failed to note a return of

calcitriol concentrations into the normal range. These observations are difficult to reconcile with a crucial role of phosphate in the genesis of hyperparathyroidism in incipient fascinating recent developments is the recognition that, apart renal failure. It goes without saying that a solid body of experifrom its long-established exocrine function, the kidney has imporentirely correct. It serves to illustrate, however, that the concepts on the kidney's function have changed with time. One of the more

tant endocrine functions as well, disturbances of which have

mental and clinical evidence points to an important role of

phosphate in hyperparathyroidism of advanced renal failure. Moreover, recent in vivo evidence from experimental [6, 71 and In the following we shall discuss three topics illustrating the recent change of paradigms to explain disturbances in renal clinical studies is even compatible with a direct stimulating role of failure related to abnormal renal endocrine function, that is, phosphate on the parathyroids unrelated to ionized calcium and biosynthesis of the secosterol hormone 1,25 0H2D3 (in the calcitriol. Nevertheless, it appears that an alternative, or at least complementary, explanation must be sought. following called calcitriol). We have reasoned [8] that nephron loss or malfunction in The signal triggering secondary hyperparathyroidism in incipient renal failure diminishes the activity of 1-a-hydroxylase, incipient renal failure allowing the parathyroid to escape from negative feedback control Elevated levels of intact PTH are noted in a considerable (Fig. 2). The increase in PTH activity would stimulate renal proportion of renal patients with incipient renal failure, that is, 1-a-hydroxylase activity and thus return calcitriol levels to the GFR 60 to 80 ml/min [1]. This observation points to early (near) normal range. As a final result calcitriol levels would be hyperparathyroidism and raises the issue which signal is respon- normal but at the price of elevated PTH concentration. It is quite sible for activation of the parathyroid gland. Two decades ago Neil obvious that a simple scheme as depicted in Figure 2 neglects a Bricker proposed the following ingenious hypothesis (Table 1). As number of confounding factors which have become apparent GFR decreases, serum phosphate concentration has a tendency to recently: (i) the calcium receptor of the parathyroid that has increase, at least post-prandially; the ensuing decreased levels of recently been cloned [9] and may play a calcitriol-independent ionized calcium should trigger the release of PTH and thus role; the behavior of the receptor during Ca depletion and renal failure is currently not well established [10]; (ii) furthermore, recent studies, at least in advanced renal failure, are compatible with covalent modification and abnormal nuclear uptake of the © 1996 by the International Society of Nephrology vitamin D receptor [11]; and finally, (iii) PTH receptors [12] and important clinical repercussions.

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Ritz and Stefanski: Calcitriol in renal failure

Table 1. Two paradigms to explain secondary hyperparathyroidism of incipient renal failure

S

GFRPifCa2PTHftCP'11' normal serum phosphate final result: elevated PTH

[2]

advanced nodular than diffuse parathyroid hyperplasia.

[91

That parathyroid hyperplasia is not exclusively a regulatory phenomenon has become apparent from a number of clinical observations, such as the high rate of local recurrence after parathydroidectomy [24], the occurrence of locally invasive growth of parathyroid autotranspiants in forearms [25], the risk being particularly high in grafts with DNA content outside the

• GFR 4J' 1-a hydroxylase 'IJ' ' PTH 'fl' ' 1,25 0H2D3 'fl' final result: normal 1,25 0H2D3 elevated PTH

observation is compatible with the note that regions with low receptor expression escape from inhibition of proliferation by calcitriol receptor [21]. Recently, Fukuda et a! [23] documented that calcitriol receptor expression was lower in patients with

actions of PTH on bone [131 appear to be abnormal in renal failure. Nevertheless, despite such shortcomings, the above sim- diploid range or in the presence of increased numbers of mitoses plified scheme would be consistent with the following observa- within the gland. All these abnormalities point to abnormal growth control. tions. It has recently become obvious that there is a molecular A negative feedback system can be tested dynamically by a step-change of an input variable. Lucas, Brown and Woodhead biological basis to abnormal parathyroid growth. Falchetti et al [141 examined plasma calcitriol levels in kidney donors who [26] reported on clonal allelic loss of genes on chromosome 11q13 underwent unilateral nephrectomy. A consistent decrease of coding for putative tumor suppressor genes [26]. Using X-chroplasma calcitriol levels was noted. Levels returned to the normal mosome inactivation analysis with the M27-J3-DNA polymorrange (Fig. 3), but at the price of elevated PTH concentrations. phism, Arnold et a! [27] demonstrated monoclonal growth in at Conversely, when exogenous 1,38 hPTH, that is, the aminotermi-

least 64% of uremic patients with refractory hyperparathyroidism.

incipient renal failure, stimulation of renal biosynthesis of calcitriol, as reflected by the acute increase in calcitriol serum levels, was diminished in proportion to baseline PTH concentrations. It was most markedly diminished in those patients with the highest PTH levels [15]. This observation suggests that in incipient renal failure 1-a-hydroxylase is stimulated already to such a degree that it becomes relatively refractory to further stimulation by exogenous PTH.

fied. Apparently, somatic mutations confer a growth advantage to clones of parathyroid cells thus causing monoclonal growth and

Finally, a role for calcitriol deficiency is suggested by the following observation: reversal of parathyroid overactivity in

[28].

nal fragment of the human PTH, was infused in patients with The gene(s) responsible for monoclonality has not been identinodular parathyroid hyperplasia (although the two phenomena are not strictly linked). It appears that in the hyperproliferative environment of the parathyroid gland such mutated cells prolif-

erate in an uncontrolled fashion. This may be similar to the sequence of events that has been postulated in the genesis of papillary renal cell tumors of kidneys in end-stage renal failure

Actions of calcitriol unrelated to calcium homeostasis In the mammalian organism, calcitriol is crucial for the hormonal control of calcemia and calcium balance. It has become apparent, however, that calcitriol is a phylogenetically ancient patients with incipient renal failure and hyperparathyroidism substance that has actions on many non-classical target organs. relatively modest doses of calcitriol, that is, 0.125 tg/day are able Deficiency of calcitriol may therefore be relevant to the underto prevent a further increment of intact PTH in the absence of any standing of some aspects of uremia that are unrelated to calcium change in serum calcium, urinary calcium or serum phosphate, homeostasis [29]. Following observations that cows ingesting a plant, Trisetum thus providing further evidence for the important role of calcitriol flavescens, develop hypercalcemia from vitamin D intoxication patients with incipient renal failure following the administration of calcitriol [16] and prevention of secondary hyperparathyroidism in dogs with experimental uremia following the administration of calcitriol [17]. We have recently been able to show [181 that in

deficiency.

and are no longer able to produce milk, Zucker, Stark and

Genesis of parathyroid hyperplasia In the past it had been assumed that parathyroid hyperplasia was a regulatory phenomenon. Stimulation of parathyroid leads to (i) increased mRNA of pre-pro-PTH in individual parathyroid

Rambeck [30] were able to show UV light-dependent synthesis of

cholecalciferol by Trisetum flavescens. Another plant species, Solanum malacoxylon, has even been shown to synthesize 1,25 0H2D3 [31]. Calcitriol affects cellular calcium concentration, it cells and (ii) recruitment of hormonally active parathyroid cells by suppresses cell profileration and promotes cell differentiation, such as rhizogenesis [32]. Are these phylogenetically ancient parathyroid cell proliferation (parathyroid hyperplasia) (Fig. 2) [19]. The genesis of parathyroid hyperplasia is of great importance actions relevant in humans [33]? Ricketic children frequently die since it is poorly reversible; at least its reversal by apoptosis is an from infection; more recently, this found an explanation by the extremely slow process [20]. Experimental studies [21] document observation that calcitriol plays an important role in macrophage that parathyroid hyperplasia can easily be prevented but is difficult function and in immune regulation. Furthermore, ricketic chilto reverse [21]. The mechanisms underlying parathyroid hyper- dren exhibit a vitamin D-dependent form of myopathy [34]. It is of note that painters in Northern countries, such as the Netherlands plasia are therefore of obvious clinical relevance. One striking observation is the fact that the relative risk of the and Germany, depicted the Jesus Christ baby with a frog belly (a dialysis patient to require parathyroidectomy increases dramati- sign of ricketic myopathy), a feature which is consistently absent in cally with duration of dialysis [22]. Furthermore, staining of illustrations of Italian painters living on the sunlit shores of the parathyroid cells for nuclear calcitriol receptors shows inhomog- Mediterranean. More recently, calcitriol receptors in, and calcitriol actions on a enous nuclear uptake of stain, regions with higher staining number of non-classical target tissues have been recognized, actually being juxtaposed to regions with low staining activity. This

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Ritz and Stefanski: Calcitriol in renal failure

3.5 3.0 2.5

E ci) Cl)

C)

0

3.5

Fig. 1. Six patients with incipient renal failure (Ce, 65 mllmin) and 6 healthy control (Cr0 148 mI/mm) were studied between 9 a.m. and 3 p.m. on the first day without (—) and on the second day with (———) an oral P load administered at 9 a.m. (1 g P170 kg given as Na-K-phosphate buffered atpH Z4 and dissolved in 100 ml water). Note no difference between the circadian profile in patients with renal failure and controls [3].

0

3.0 2.5

-.4

0204060

120

240

360

140

Parathyroid

Ca sensitivity of PTH secretion

120

mRNA prepro PTH PT cell proliferation

a)

100

0 0,

80

c,J

=

0

PTH

U,

60

C',

Kidney cx hydroxylase

1

Fig. 2. Schematic representation of the endocrine feedback relationship between the parathyroid gland and the kidney. Abbreviations are: PTH, parathyroid hormone; PT, parathyroid cells.

particularly endocrine tissue, skin tissue, muscle tissue (skeletal muscle, cardiomyocytes and smooth muscle cells), endothelial cells, hematologic cells and neuronal cells. Space does not permit an in depth discussion of these findings, but it is of note that in uremic patients administration of calcitriol

E U)

40

C',

0 20

0 1

3

5

7

30

Post nephrectomy, days Fig. 3. Plasma 1,25 0H2D3 concentrations following uninephrectomy in life donors of renal transplants [14].

improved, for instance, immune functions and glucose-stimulated insulin secretion. One of the phylogenetically ancient functions of calcitriol is to

suppress cell proliferation. This has been shown in renal carcinoma cells [35] and in normal renal cells, that is, compensatory

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Ritz and Stefanski: Calcitriol in renal failure

growth after uninephrectomy [36], mesangial cells [37], and proximal tubular cell cultures [38]. Since glomerular growth is apparently a permissive factor which favors the genesis of glomerulosclerosis, the question arises whether such action of calcitriol can be harnessed to attenuate the development of glomerulosclerosis. This possibility is, indeed, suggested by preliminary studies which require further confirmation. It appears then that calcitriol deficiency, and abnormalities of such phylogenetically ancient actions of calcitriol, may account for

some aspects of uremic syndrome. We agree that there is an element to teleology in this argumentation but, according to

17. LOPEZ-HILKER S, GALCERAN T, CHAN Y-L, RAPP N, MARTIN 10, SLATOPOLSKY E: Hypocalcemia may not be essential for the develop-

ment of secondary hyperparathyroidism in chronic renal failure. J Clin Invest 78:1097—1102, 1986 18. RITZ E, KUSTER S, SCHMIDT-GAYK H, STEIN G, SCHOLZ C, KRAATZ G,

HEIDLAND A: Low dose calcitriol prevents the rise in 1,84 i PTH without affecting serum calcium and phosphate—Prospective placebo controlled multicenter trial. Nephrol Dialysis Transplant (in press) 19. SILVER J, MOALLEM E, EPSTEIN E, KILAV R, NAVEH-MANY T: New

aspects in the control of parathyroid hormone secretion. Curr Opin Nephrol Hypertens 3:379—385, 1994

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Beveridge, "teleology is a lady without whom no biologist can live;

choice. Nephrol Dial Transplant 12:1819—1821, 1994 21. SZABO A, MERKE J, BEIER E, MALL G, RITZ E: 1,25(OH)2D vitamin

and yet he is ashamed to show himself in public with her" [39].

D3 inhibits parathyroid cell proliferation in experimental uremia.

Reprint requests to Prof Dr. Eberhard Ritz, Klinikum der Universitãt

22. MIZUMOTO D, WATANABE Y, FUKUZAWA Y, YUZAWA Y, YAMAZAKI

Heidelberg, Sektion Nephrologies, Bergheimer Str. 56a, 69115 Heidelberg, Germany.

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