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McdiaJHyporhrscs(1989)M,61-64 ~L~ngmanGroup UKLtd1989 Polycystic Kidneys do, Maintain Good Endocrine Function C. ROTELLAR and M. C. GELFAND Georgetown University Hospital, 3800 Reservoir Rd, Washington DC 20007, USA Abstract - We develop here the hypothesis that polycystic kidneys (PCK) may maintain, to a certain extent, the ability to perform endocrine functions. We know that patients with adult polycystic kidney disease (APCKD) produce more erythropoietin and maintain a higher hematocrit than patients with other primary diseases of the kidneys. It is possible that they synthesize more 1,25 and 24,25 Vit D3 and metabolize better the parathyroid hormone and other hormones. If it is correct, they may have fewer signs of secondary hyperparathyroidism and less bone marrow fibrosis which along with increased erythropoietin production would explain the higher hematocrit. Introduction Massry et al (1) suggest that parathyroid hormone (PTH) may be the uremic toxin and that it plays a major role in the metabolic changes that occur in patients with chronic renal failure. They say that PTH is very much related to the genesis of the anemia which would involve an inhibitory effect on erythropoiesis, direct hemolytic effect and production of bone marrow fibrosis. Several studies show decreased transfusion requirements after parathyroidectomy in patients with chronic renal failure (CRF) as well as correlation between primary hyperparathy- roidism and anemia (2, 3). It is well recognized that patients with CRF secondary to adult poly- cystic kidney discasc (APCKD) have less degree of anemia than patients with CRF secondary to other ctiologics (4). We report here the bone changes of 17 poly- cystic kidney patients on hemodialysis (HD) and postulate that APCKD maintain to a certain extent a better endocrine function than other primary diseases of the kidney. Patients and Methods Seventeen patients with APCKD on HD were compared to 17 controls. The age and time on HD were similar in both groups (mean + SD). Table. It is difficult to assess the time from the beginning of CRF and the start of HD. The causes of CRF in the control group were: hyper- tension 7, diabetes mellitus 7, analgesic nephropathy 1, IgA nephropathy 1, and unknown 1. All patients were dialyzed with reverse osmosis. Patients in both groups were treated with a 61

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Page 1: Polycystic kidneys do maintain good endocrine function

McdiaJHyporhrscs(1989)M,61-64 ~L~ngmanGroup UKLtd1989

Polycystic Kidneys do, Maintain Good Endocrine Function

C. ROTELLAR and M. C. GELFAND

Georgetown University Hospital, 3800 Reservoir Rd, Washington DC 20007, USA

Abstract - We develop here the hypothesis that polycystic kidneys (PCK) may maintain, to a certain extent, the ability to perform endocrine functions. We know that patients with adult polycystic kidney disease (APCKD) produce more erythropoietin and maintain a higher hematocrit than patients with other primary diseases of the kidneys. It is possible that they synthesize more 1,25 and 24,25 Vit D3 and metabolize better the parathyroid hormone and other hormones. If it is correct, they may have fewer signs of secondary hyperparathyroidism and less bone marrow fibrosis which along with increased erythropoietin production would explain the higher hematocrit.

Introduction

Massry et al (1) suggest that parathyroid hormone (PTH) may be the uremic toxin and that it plays a major role in the metabolic changes that occur in patients with chronic renal failure. They say that PTH is very much related to the genesis of the anemia which would involve an inhibitory effect on erythropoiesis, direct hemolytic effect and production of bone marrow fibrosis.

Several studies show decreased transfusion requirements after parathyroidectomy in patients with chronic renal failure (CRF) as well as correlation between primary hyperparathy- roidism and anemia (2, 3). It is well recognized that patients with CRF secondary to adult poly- cystic kidney discasc (APCKD) have less degree of anemia than patients with CRF secondary to other ctiologics (4).

We report here the bone changes of 17 poly- cystic kidney patients on hemodialysis (HD) and postulate that APCKD maintain to a certain extent a better endocrine function than other primary diseases of the kidney.

Patients and Methods

Seventeen patients with APCKD on HD were compared to 17 controls. The age and time on HD were similar in both groups (mean + SD). Table. It is difficult to assess the time from the beginning of CRF and the start of HD. The causes of CRF in the control group were: hyper- tension 7, diabetes mellitus 7, analgesic nephropathy 1, IgA nephropathy 1, and unknown 1. All patients were dialyzed with reverse osmosis.

Patients in both groups were treated with a

61

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62 MEDICAL HYPOTHESES

combination of aluminium hydroxide, calcium carbonate and rocaltrol depending on their needs. Measurements of calcium phosphate, alkaline phosphatase, intact PTH (by radioim- munoassay) and hematocrit for the last three months from each patient were included in the study. Blood transfusions were noted in both groups.

We compared the bone changes shown by x- rays taken after the same period of time on HD. X-rays were read by the radiologist who knew only that the patients were on HD. The radio- logic bone changes were defined as follows: grade 1 = normal; grade 2 = mild reabsorption on the external part of the clavicles; grade 3 = mild reabsorption in both clavicles .and distal phalanges; grade 4 = moderate reabsorption in both clavicles and hands; grade 5 = severe reab- sorption in both clavicles and hands and metastatic calcifications.

Osteomalacia changes were not taken into account. Impaired t-student and Chi square tests were used for statistics.

Results

Table Biochemical result Mean f SD, * = p < .02

Patients 17 Age (years) 55 f 11.9 Male 5 Time on HD 3Y.3 + 31 (months) Ca mg’dl 9.4 k .7 PO, mg/dl 5.5 + 1.7 Alk Pho IU/ml 213.8 + 232 PTH pg/ml 783 rtr 483 Hct.% 26.8 f 6.1

(4 with transfusions)

Other Renal Diseases

17 54.5 + 12.3 6

38.8 + 26.3

9.5 t 1.0 6.3 + 1.8*

191 f 125 1048 + 491

25 + 3.4 (10 with transfusions)

Bone changes by x-ray: control group showed 7 patients with grade-l; 2 with grade 2; 2 with.grade 3; 2 with grade 4. and 1 with made 5. APCKD group showed 2 with grade lf 3 with grad; 2; 0 with grades?, 4: and 5. (Only Idhad X-rays in both groups). Chi square test with Yates correction showed a significant difference with a p < 0.05.

Discussion

Anemia is a well recognized multifactorial problem in patients with CRF which is worse in anephric patients, and decrease of erythropoietin

production by the kidney is one of the major factors. Erythropoietin production is mainly produced by the kidney and in a lesser amount by the liver (5). APCKD is well correlated with better hematocrit when compared to other primary diseases of the kidney (4). It seems that polycystic kidneys keep the ability of secreting a fair amount of erythropoietin for reasons not yet well understood, and therefore, these patients have fewer problems with anemia. The kidneys have several endocrine functions besides production of erythropoietin and these include production of both_?,25 and 24,25 vit Dj; metab- olism of PTH, msulin, growth hormone, prolactin, antidiuretic hormone, thyroid hormone, etc. (6). 25(0H)z is converted into 1,25(OH)z vit D3 by a mitochondrial enzyme (25(OH) D3-l- hydroxylase) located in the proximal tube. 25(OH) vit D3 is as well hydroxylated to 24,25(0H)z vit D3 in the kidney and to a lesser extent in the gut and cartilage (7). The blood levels of 1,25(0H)z vit D3 and 24,25(0H)z vit D3 in patients with moderate renal failure have been reported to be normal and the fall in the plasma concentration of those metabolites becomes apparent when glomerular filtration decreases to 40-50 cc/minute. Furthermore, anephric patients seem to have less quantities of these vit D3 metabolites than non anephric patients (7, 8). PTH is partially metabolized in the renal tubule and is likely that delayed degradation of PTH can result in higher levels of intact PTH after any given rate of secretion (9). Why polycystic kidneys have a higher production of erythropo- ietin is not known, but it is reasonable to think that if the polycystic kidneys maintain to some extent the synthesis of erythropoietin, they could maintain the other metabolic functions that were mentioned earlier.

The pathogenesis of bone disease in CRF is multifactorial: Disturbance in endocrine func- tion, accumulation of toxic products, drugs, etc. (10). Vitamin D metabolism seems to play a major role in the pathogenesis of renal osteo- dystrophy. Moorhead et al (11) found in their group of patients that APCKD correlated with fewer signs of secondary hyperparathyroidism than other primary kidney diseases. Henderson et al (12) and Pendras et al (13) do not seem to find the same results. In our study we could find a significant difference in bone changes between APCKD and the control group. Both phosphate and intact PTH were higher in the control groups, although the latter did not reach stat-

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POLYCYSTIC KIDNEYS DO MAINTAIN GOOD ENDOCRINE FUNCTION 63

istical significance. Rickens et al (14) measured the bone mineral content (BMC) by two dimen- sional photon scanning absorptiometry (125’). They found that patients with APCKD loose BMC quicker than patients with chronic glomer- ulonephritis. As they mention in their paper, the differences can be explained by a different entry time. Furthermore, BMC by photon absorptiom- etry does not distinguish between the causes of decreased density (9) and the differences that they found could be related to aluminium deposition (or other trace elements) and not to poor availability of vit D3 metabolites. They mentioned that influence of dialysis procedure including administration of phosphate binders were grossly identical for all patients. However, oral absorption of aluminium varies from patient to patient (16). Mawer et al (17) found negligible 1,25(OH)? vit D3 in two APCKD patients. On the other hand, Piraino et al (18) recently reported that patients with APCKD have a greater chance of being hypercalcemic than those patients with renal failure from other causes. We are in the process of measuring the vit D3 metab- olites in our group of patients once the vit Dj metabolite treatment is discontinued for a minimum of 30 days. But if indeed APCKD

produces more vit D3 metabolites and/or metab- olize PTH in better way than patients with other primary diseases of the kidney; it could explain along with the increased synthesis of erythropo- ietin why patients with APCKD have a better hematocrit than the other patients.

Hypothesis

Furthermore, it may mean that the total endo- crine function of the kidney is in some way preserved in the APCKD. Further studies are necessary to confirm this hypothesis.

Conclusions

We postulate that patients with end stage renal disease secondary to polycystic kidneys, maintain better endocrine function than patients with other kidney diseases. As it happens with eryth- ropoietin production, the synthesis of 1,25 and 24,25 (OH), vit D3 may be in some way preserved in patients with polycystic kidney disease. Furthermore the catabolism of PTH by the kidneys may also be maintained, which would decrease the PTH plasma levels, bone reabsorption and bone marrow fibrosis. All this

POLYCYSTIC KIDNEY

Other Endocrine

Maintenance of Endocrine Functions

Hyperparathyroidism

Figure

Page 4: Polycystic kidneys do maintain good endocrine function

64 MEDICAL HYPOTHESES

would explain why in our study, the patients with APCKD presented with fewer signs of renal osteodystrophy. Therefore, we believe that the higher hematocrit seen in patients on dialysis with APCKD compared to other renal diseases, is due to both preserved erythropoietin production and less degree of bone marrow fibrosis, The later is consequence of a maintained endocrine function of the kidney involving vit D3 synthesis and PTH catabolism. Further studies are necessary to confirm this hypothesis and to eval- uate other endocrine functions of the kidney (‘* insulin metabolism) in patients with AP~CKD.

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Mooradian D A, Morely J E. Endocrine dysfunction in chronic renal failure. Arch Intern Med 144: 351, 1984. Norman E M. Vitamin D in bone disease (Symposium on Pediatric Nephrology) Pediatr Clin N Am 29: 947, 1982. Horst L, Littledike E D, Gray R W, Napoli J L. Impaired, 24,25 dihydroxy vitamin D production in anephric man and pig. J Clin Invest: 67: 274, 1981. Coburn J W, Llach F. Renal osteodystrophy and main- tenance dialvsis. n 679 in Reolacement of Renal function by Dialysis. -(Drukker W , Parsons F M, Maher J F. eds) Replacement Martinus Nijhoff Publishers, Boston, 1983. Cundy T F. Kanis J A. Renal bone disease. Br J Hosp Med: 33(l): 35. 1985. Moorhead F. Tatler G L U, Baillod R A, Varghese M R, Wills S C, Farrow. Effects of age. sex and poly- cystic disease on progressive bone disease of renal failure. Br Med J 4: 557, 1974. Henderson R G, Ledingham J G, Woods C G. Renal osteodystrophy in relation to the cause of renal failure. Kidney Int 6: 62. 1974. Pendras J P. Parathvroid disease in long term mainten- ance hemodialysis. Arch Intern Med 124: 312, 1969. Rickers H, Christensen M. Rodbro P: Bone mineral content in patients on prolonged maintenance hemodi- alysis: a three year follow-up study. Clin Nephrol 20(6): 302, 1983. Alfrey A C, Smith W R. Trace metals and regular dialysis. p 804 in Replacement of Renal Function by Dialvsis. (Drukker W, Parsons F M. Maher J F edsl Martinus Nijhoff Publishers, 1983. Ihle B U, Becker G J. Gastrointestinal absorption of aluminum Am J Kidney Dis 6(5): 302, 1985. Mawer E B, Backhouse, J, Taylor C M. Lumb G A. Failure of formation of 1.25Dihydroxycholecalciferol in chronic renal insufficiency. Lancet 1: 626. 1973. Piraino B M. Rault R. Greenberg A. Dominguez J M, Wallia R. Houck P. Seere G. Chen T. Fot F. Puschett J B. Spontaneous hypeialcemia in patients undergoing dialysis. Am J Med. 80: 607, 1986.