A. Sigel

Double-Blind Study with Thiazide in Recurrent Calcium Lithiasis

The effect of 25 mg. hydrochlorothiazide twice daily on the meta-phylaxis of recurrent calcium lithiasis was compared to placebo in a double-blind study during 1 year in 51 patients. A distinct and continuous decrease in urinary calcium excretion occurred only in patients given hyrochlorothiazide. On the other hand, both groups showed a slight increase in total serum calcium levels, unchanged values for ionized and ultrafilterable calcium, and decreased urinary excretion of oxalate during the study. The activity products of calcium oxalate and calcium phosphate also were decreased in both groups but remained within the metastable range. Spontaneous passage of renal stones occurred during treatment in 6 patients given placebo and in 6 treated with hydrochlorothiazide despite decreased urinary calcium excretion in the latter group. The findings show the specific effect of hydrochlorothiazide treatment to be a decrease in urinary calcium excretion in patients with calcium lithiasis, while other changes appear to be nonspecific effects of treatment.

Citrate in Urine and Serum and Associated Variables in Subgroups of Urolithiasis

Outpatient renal stone formers belonging to the established urolithiasis subgroups and controls were examined with respect to urinary and serum citrate (Cit) and several associated variables. Only in the normocalciuric majority of calcium and in uric acid stone formers was Cit in 24-hour urine decreased, but was normal in 2-hour fasting morning, and in 3-hour postprandial urine following a Cit-free test meal. Serum Cit was elevated in normocalciuria, renal and resorptive hypercalciuria. This Cit constellation was associated with either normal (absorptive, renal hypercalciuria) or low (normocalciuria, uric acid stone formers) parathyroid gland function as assessed by serum parathyroid hormone and nephrogenous urinary cyclic AMP, except in patients with primary hyperparathyroidism. In 2-hour morning urine the magnesium/creatinine ratio (normocalciuria) and ammonia excretion (uric acid stone formers) were decreased, while ammonia in 24-hour urine was low in all stone formers. It is suggested that Cit metabolism is altered in renal stone disease in general, and that in normocalciuria, stone inhibitors (Cit; magnesium) may be deficient.

Composition of renal stones and their frequency in a stone clinic: Relationship to parameters of mineral metabolism in serum and urine

SummaryStone analyses (kidney, upper urinary tract) of the department of Urology, University of Erlangen, from a four-year-period (1974–1977) have been recorded with emphasis to stone composition, sex and age of the pertinent stone forming patients.During this time period there were no substantial changes as regards the per cent frequency of the various stone types. The most frequent type was calcium oxalate (CaOx), followed by uric acid, calcium phosphate (CaP), struvite and cystine. Stone analyses were mostly requested for patients between 46 and 55 years of age. Stone incidence in our clinic is calculated to be 1.22 times higher in males than females, especially beyond 36 years of age. The frequency peaks are: pure (=100 per cent) CaOx 36–45 years; CaOx with additional mineral phases (mostly CaP) 46–55 years; uric acid 56–65 years; CaP 26–35 years.From those patients who underwent further investigations in searching for metabolic abnormalities serum concentrations, urine mineral clearances in fasting urine samples, and activity products of stone forming mineral phases in sequentially collected specimens from 24 h and 2 h fasting urine had been measured and compared with values from healthy control subjects. In urolithiasis (idiopathic) there is a normal parathyroid hormone blood level, a generally lower serum inorganic phosphate and magnesium concentration.In pure (=100 per cent) CaOx and uric acid lithiasis serum uric acid and creatinine are higher than in controls, urine pH and calcium clearance in some groups are different too. Clearances of magnesium, uric acid, phosphate, sodium are within normal limits in urolithiasis. When expressing the propensity to form stones in terms of activity products, then only uric acid lithiasis deviates substantially from normal. All other stone types differ only slightly or not at all from each other and controls respectively.It is concluded that 1) in our geographic region the various stone types prevail in different age periods; 2) there are distinct alterations of parameters of mineral metabolism in urolithiasis; 3) measuring urine clearances may lead to assume falsely normal mean urine excretion of stone forming constituents.

Metabolic and Glucose Load Studies in Uric Acid, Oxalic and Hyperparathyroid Stone Formers

There is as yet little knowledge about the metabolic origin of idiopathic hypercalciuria (HC) and associated hyperuricosuria frequently accompanied by formation of calcium containing renal stones. Following a carbohydrate-rich meal, in 1969 Lemann and coworkers (1) observed higher urinary calcium in oxalic stone formers and their relatives than in healthy controls. Endogenous resistance to insulin and its consecutive overproduction was recently reported from patients with primary hyperparathyroidism (2), and a marked loss of insulin via urine was objectived by Ching and his group (3) in patients producing calcium stones. They failed to find disturbed glucose tolerance, but their data gave no information as to the amount of glucose administered. In earlier studies (unpublished) undertaken to screen stone people by oral glucose load (100g) we found pathological plasma glucose (2 hours) in a rather great number of stone patients without symptoms of diabetes and /or overt obesity. Also there was apparently no relation to either sex or age or, most important, the type of stone, i.e. oxalic or uric acid.

Mineral metabolism during prolonged oral calcium substitution after jejuno-ileal bypass for morbid obesity

SummaryThe influence of jejuno-ileal bypass surgery on mineral metabolism was studied in patients with morbid obesity before operation, and 2 and 5 years after-wards. When calcium and potassium were orally substituted post-operatively, in serum calcium fractions, parathyroid hormone, phosphate, potassium and the bone mineral content remained unchanged, while serum magnesium decreased. Serum 25-hydroxyvitamin D was already low before bypass operation, and did not change thereafter. Post-operatively, the urinary excretion of oxalate rose into the upper normal range, while that of calcium, magnesium and citrate was markedly reduced. The urinary activity product of calcium oxalate rose slightly, but that of brushite decreased. Since these changes were manifest in the urine of all patients, the reasons for the post-operative formation of renal stones in 4 of 19 patients remain unclear at the moment. We conclude that the recommendation for precise oral calcium substitution after jejuno-ileal bypass operation seems justified in order to avoid serious disturbances of calcium metabolism in the long term, and to reduce intestinal oxalate absorption.ZusammenfassungBei morbider Adipositas wurde der Einfluß der jejuno-ilealen Bypass-Operation auf den Mineralstoffwechsel untersucht. Mit postoperativer oraler Calcium- und Kalium-Substitution blieben 2 und 5 Jahre nach Bypass-Operation im Serum die Calcium-Fraktionen, Parathormon, Phosphat, Kalium und der Knochenmineralgehalt unverändert, während Serum-Magnesium abfiel. Serum-25-Hydroxyvitamin D war bereits präoperativ niedrig und blieb so postoperativ. Nach der Operation stieg die Urinausscheidung von Oxalat bis in den oberen Normbereich an, während diejenige von Calcium, Magnesium und Citrat stark abfiel. Das Aktivitätsprodukt von Calciumoxalat im Urin blieb unverändert, während das von Brushit abfiel. Da diese Veränderungen im Urin aller Patienten nachweisbar waren, bleiben die Ursachen der postoperativen Steinbildung bei 4 von 19 Patienten zur Zeit unklar. Wir folgern, daß die Empfehlung zur präzisen oralen Calcium-Substitution nach jejuno-ilealem Bypass gerechtfertigt erscheint, weil dadurch langfristige ernste Störungen des Calcium-Stoffwechsels vermieden, außerdem die intestinale Oxalat-Absorption reduziert werden.

Parathyroid gland function in subgroups of metabolically mediated urolithiasis as evaluated by serum parathyroid hormone, and urinary and nephrogenous cyclic nucleotides.

SummaryIn healthy controls (n=34) and in the various metabolically defined subgroups of urolithiasis patients, including primary hyperparathyroidism (pHPT), parathyroid hormone (PTH) was studied using two different antisera, as were the cyclic nucleotides (cAMP; cGMP) and related variables in both urine and plasma; in addition, the nephrogenous components of the cyclic nucleotides were also determined. In nonpHPT (so-called idiopathic) stone disease, nephrogenous cAMP (2-h fasting urine) was significantly lower than normal in the normo-calciuric majority (n=60), and also lower than normal (medians) in all the other subgroups (absorptive hypercalciuria,n=15; renal hypercalciuria,n=23; uric acid lithiasis,n=17; uric/calcium oxalate lithiasis,n=12). In contrast, it was significantly elevated in pHPT (n=20), and only in this latter condition was nephrogenous cGMP (2-h urine) elevated. The total nucleotide production (sum of nephrogenous cAMP + nephrogenous cGMP) is again significantly lower only in normo-calciuric calcium stone disease. Except for high values in pHPT, no differences in plasma nucleotides are observed. Stone patients (idiopathic and pHPT) have significantly lower-than-normal serum phosphate and phosphate threshold in common. With the exception of pHPT, the differences in serum calcium are only minute, while ionised calcium is moderately elevated within the normal range in the serum of renal hypercalciuria patients.In all subgroups of idiopathic lithiasis, PTH is either normal to low (intact hormone assay), or slightly but significantly elevated in three subgroups (absorptive and renal hypercalciuria, patients alternately forming uric acid or calcium oxalate stones), when measured in an assay recognizing only a bioinactive hormone fragment (mid-portion assay). In surgically proven pHPT, median PTH established with the same two assays, is elevated by a factor of 8 (intact hormone assay), or 3 (mid-portion assay) in comparison with healthy controls.From the results it is concluded that a) idiopathic urolithiasis is accompanied by normal or low renal bioactivity of the parathyroid glands in the presence of a low renal phosphate threshold concentration; b) the elevated serum PTH in three idiopathic subgroups measured with an antibody with recognition largely of the bioinactive mid-portion of the hormone, is not in accordance with the simultaneously normal or low urinary and nephrogenous cAMP of these individuals, but is in accord with the normal or low serum PTH measured with an antibody recognizing all regions of the human hormone; c) the activity of tubular guanylate cyclase in pHPT is probably increased, but not in situations where both hypercalcemia and a considerable excess of parathyroid hormone are absent (remaining groups).ZusammenfassungBei Gesunden (n=34) und Urolithiasis-Patienten mit den verschiedenen definierten metabolischen Untergruppen, einschließlich primärer Hyperparathyreoidismus (pHPT), wurden Parathormon (PTH) mittels zwei verschiedenen Antikörpern, sowie zyklische Nukleotide (cAMP; cGMP im Urin und Plasma studiert, außerdem deren nephrogene Komponente berechnet.Bei Nicht-pHPT-Steinkrankheit (=sog. idiopathische Form) war das nephrogene cAMP (2 h-Nüchternurin) bei der normocalciurisch verlaufenden Mehrheit (n=60) signifikant niedriger als normal, und auch in den anderen Untergruppen (absorptive Hypercalciurie,n=15; renale Hypercalciurie,n=23; Harnsäure-Lithiasis,n=17; Harnsäure/Calciumoxalat-Lithiasis,n=12) waren die Medianwerte niedriger als jener der Kontrollgruppe. Umgekehrt ist nephrogenes cAMP bei pHPT (n=20) stark erhöht, und nur bei dieser Störung war nephrogenes cGMP (2 h-Urin) ebenfalls erhöht. Die gesamte Nukleotid-Produktion (=Summe der nephrogenen Anteile von cAMP und cGMP) ist bei normocalciurisch verlaufender Steinkrankheit signifikant erniedrigt, bei pHPT erhöht. Ausgenommen hohes cAMP bei pHPT sind die Plasma-Nukleotide nicht verschieden. Steinpatienten (idiopathisch und pHPT) haben gemeinsam ein signifikant niedrigeres Serum-Phosphat und eine niedrigere Phosphatschwelle als Gesunde. Ausgenommen pHPT sind die Unterschiede in allen Gruppen beim Serum-Gesamtcalcium nur minutiös, ionisiertes Calcium ist bei renaler Hypercalciurie innerhalb des Normbereiches mäßig erhöht. PTH ist in allen Untergruppen der idiopathischen Lithiasis entweder normal bis niedrig (assay für intaktes Hormon) oder in einigen (absorptive und renale Hypercalciurie, alternativ Harnsäure oder Calcium-Oxalat-bildende Patienten) gering, aber signifikant erhöht (assay für mittlere bioinaktive Hormonregion). Mit den gleichen Bestimmungsmethoden ist das mediane PTH bei operativ bewiesenem pHPT um Faktor 8 bzw. 3 höher als bei gesunden Kontrollen. Aus den Ergebnissen wird gefolgert, daß a) die idiopathische Harnsteinkrankheit mit normaler bis niedriger renaler Bioaktivität der Nebenschilddrüsen einhergeht und diese Patienten bei normal-niedrigem Urin-cAMP eine niedrige renale Phosphatschwelle unbekannter Ätiologie aufweisen; b) das bei drei Untergruppen erhöhte Serum-PTH, gemessen mit einem Antikörper mit vorrangiger Erkennung der bio-inaktiven mittleren Hormonregion, nicht mit dem gleichzeitig normalen Urin- bzw. nephrogenen cAMP dieser Gruppen übereinstimmt, wohl aber mit normalem oder niedrigem PTH, gemessen mit einem assay, der alle Anteile des menschlichen Hormons erkennt; c) die Aktivität der tubulären Guanylat-Zyklase bei pHPT wahrscheinlich gesteigert ist, nicht jedoch in Abwesenheit von Hypercalcämie oder größerem PTH-Exzeß (übrige Gruppen).

Response of Gastrointestinal Hormones and Intestinal Calcium Absorption During an Oral Carbohydrate Meal

Little is known about changes of gastrointestinal (GI) hormones in patients with calcium lithiasis. In a preliminary study1 we reported altered responses of GI hormones to a test meal in not rigidly classified calcium stone patients. It might be possible, that these observed changes modify the intestinal calcium absorption (CaA), which is one main cause for hypercalciuria in calcium stone formers. Therefore, we studied the influence of a synthetic test meal on the CaA and the secretion of gastrin, insulin, C-peptide, glucagon and glucose in healthy volunteers and patients with recurrent calcium lithiasis.

Cyclic Nucleotides and Related Variables in Urolithiasis

Although there is good knowledge of cyclic AMP (cAMP) in urine and plasma of various disorders of calcium metabolism1 and calciurias in urolithiasis2 only little is known about cyclic GMP (cGMP), the amounts contributed by the kidney (= nephrogenous moiety), the relationship among nucleotides in established lithiasis subgroups and the associated concentrations of serum parathyroid hormone (PTH) in venous peripheral blood.

Bewertung von renalem zyklischen Adenosinmonophosphat, Serum-Parathormon und Phosphat-Rückresorption bei rezidivierender Calcium-Urolithiasis, Gesunden und Hyperparathyreoidismus

In three groups (n = 12 each) of male controls (22--43 years), patients with recurring calcium urolithiasis (21--36 years) and hyperparathyroidism (HPT; 17--71 years) proven by surgery renal cyclic adenosine monophosphate (RcAMP), fractional tubular phosphate reabsorption and serum parathyroid hormone (PTH) were measured during endogenous creatinine clearance. RcAMP (muMol/g creatinine) was: controls 1.48 +/- SEM 0.27; stone formers 2.037 +/- 0.343 (not significantly different); HPT 6.234 +/- 0.454 (p less than 0.001). There is no overlap between HPT and controls. Phosphate reabsorption is least in HPT (0.84 +/- 0.015), higher in controls (0.924 +/- 0.004) and stone formers (0.941 +/- 0.007). All differences are statistically significant. Under the conditions selected (moderate hydration of individuals) Serum PHT (pg-equiv/ml) is lowest in stome formers (less than 100--339), higher in controls (less than 100--933) and HPT (400--1150). there is no overlap in PHT between the former and the latter group but a marked one between controls and HPT. For clinical purposes the resulting diagnostic uncertainty in a given patient can be overcome by additional determinations of RcAMP and ionised serum calcium: when referring to serum PTH HPT patients fall outside, RCU patients within 2 standard deviations of either parameter in control subjects. This procedure presently appears superior to those proposed in the past (urinary cAMP etc.) but requires confirmation in larger patient populations. Moreover, since HPT prevails in middle and upper age decades, their RcAMP values and those of RCU patients should be related to a range seen in closely age- and sex-matched controls.SummaryIn three groups (n=12 each) of male controls (22–43 years), patients with recurring calcium urolithiasis (21–36 years) and hyperparathyroidism (HPT; 17–71 years) proven by surgery renal cyclic adenosine monophosphate (RcAMP), fractional tubular phosphate reabsorption and serum parathyroid hormone (PTH) were measured during endogenous creatinine clearance. RcAMP (µMol/g creatinine) was: controls 1.48±SEM 0.27; stone formers 2.037±0.343 (not significantly different); HPT 6.234±0.454 (p<0.001). There is no overlap between HPT and controls. Phosphate reabsorption is least in HPT (0.84±0.015), higher in controls (0.924±0.004) and stone formers (0.941±0.007). All differences are statistically significant. Under the conditions selected (moderate hydration of individuals) Serum PTH (pg-equiv/ml) is lowest in stome formers (<100–339), higher in controls (<100–933) and HPT (400–1150). There is no overlap in PTH between the former and the latter group but a marked one between controls and HPT. For clinical purposes the resulting diagnostic uncertainty in a given patient can be overcome by additional determinations of RcAMP and ionised serum calcium: when referring to serum PTH HPT patients fall outside, RCU patients within 2 standard deviations of either parameter in control subjects. This procedure presently appears superior to those proposed in the past (urinary cAMP etc.) but requires confirmation in larger patient populations. Moreover, since HPT prevails in middle and upper age decades, their RcAMP values and those of RCU patients should be related to a range seen in closely age- and sex-matched controls.ZusammenfassungAn drei Kollektiven (jen=12) von männlichen Gesunden (22–43 Jahre), Patienten mit rezidivierender Calcium-Urolithiasis (21–36 Jahre), Hyperparathyreoidismus (HPT; 17–71 Jahre) wurden gleichzeitig renales zyklisches Adenosinmonophosphat (RcAMP), fraktionelle tubuläre Phosphat-Rückresorption und Serum-Parathormon während endogener Kreatininclearance gemessen. Gesunde haben ein RcAMP (µMol/g Kreatinin) von 1,48±SEM 0,27; Steinkranke 2,037±0,343 (nicht signifikant); HPT 6,234±0,454 (p<0,001). Zwischen HPT und Gesunden besteht kein Überlappungsbereich. Die Phosphat-Rückresorption ist am niedrigsten bei HPT (0,84±0,015), höher bei Gesunden (0,924±0,007), am höchsten bei Steinkranken (0,941±0,007). Alle Gruppenunterschiede sind statistisch signifikant. Parathormon (pg-equiv/ml) ist unter den gewählten Bedingungen, d.h. mäßige Hydrierung der Versuchsperson, am niedrigsten bei Steinkranken (<100–339), höher bei Gesunden (<100–933), am höchsten bei HPT (400–1150). Zwischen ersteren und letzeren besteht kein Überlappungsbereich, wohl aber zwischen Gesunden und HPT. Die resultierende diagnostische Unsicherheit kann im Einzelfall durch zusätzliche Bestimmungen von RcAMP und ionisiertem Serum-Calcium umgangen werden: Serum-PTH beachtend liegt HPT außerhalb, RCU innerhalb der 2-Sigmabereiche Gesunder. Ein solches diagnostisches Vorgehen erscheint bisherigen Verfahren überlegen, bedarf aber der Ausdehnung auf ein größeres Krankengut. Da HPT eine Krankheit des mittleren und gehobenen Alters ist, muß außerdem die Erstellung von Normbereichen für RcAMP bei Gesunden dieser Altersdekaden angestrebt werden.

Experiences with Thiazides in a Double Blind Study

Thiazides are widely used in the prevention of calcific urinary calculi, as they reduce the urinary excretion of calcium and the stone recurrence rate1. In an attempt to separate specific from non-specific effects of thiazide treatment we undertook a double blind study using hydrochlorothiazide or placebo for over one year in patients with recurrent calcium lithiasis.