Acid and mineral balances and bone in familial proximal renal tubular acidosis.

BACKGROUND: Metabolic acidosis caused by increased rates of fixed acid production is associated with increased urinary excretion of Ca and negative Ca balances. Metabolic acidosis caused by a reduced capacity of the kidneys to excrete acid contributes to the development of bone disease in the course of chronic renal failure and may be associated with bone disease among some patients with renal tubular acidosis. METHODS: To assess the effects of life-long metabolic acidosis alone in the absence of other physiological disturbances, we measured the net balances of fixed acid and minerals in two brothers in a Costa Rican family with hereditary proximal renal tubular acidosis. Bone radiographs were assessed, and radial bone densities were measured. On a subsequent occasion, transiliac bone biopsies, following double-tetracycline labeling, were obtained from these two patients and an unaffected brother. RESULTS: During the balance studies, serum [HCO3-] concentrations of the two affected patients were stable at 12.5 +/- 0.9 and 19.2 +/- 0.7 mmol/L, respectively. Their rates of net fixed acid production were normal and appropriate for their body weights, averaging 0.90 and 1.02 mEq/kg/day. Because their distal renal tubular function was normal, they were capable of acidifying their urine maximally, allowing sufficient urinary excretion of titratable acid and ammonium to maintain net acid excretion at a level that matched acid production. Thus, their acid balances were near zero, as observed among healthy subjects, at -1.9 +/- 2.3 and -2.2 +/- 2.2 mEq/day, respectively. Their rates of urinary Ca excretion were normal at 1.6 +/- 0.3 and 2.7 +/- 2.4 mmol/day, and the their balances of Ca and other minerals were close to zero so that ongoing bone loss was not occurring despite the acidosis. Nevertheless, their heights, relative to their ages, were shorter than the heights of their unaffected relatives. Their radial bone densities were lower than normal for their age and sex, and their iliac cortices were thinner than that of their unaffected brother. However, they had no histomorphometric evidence of osteomalacia or osteitis fibrosa, and their rates of bone mineralization were normal. CONCLUSIONS: The results indicate that this chronic metabolic acidosis reduces growth, including that of bone. We speculate, without direct supporting evidence, that bone stores of HCO3-/CO3= are reduced, as has been observed in patients with the metabolic acidosis of chronic renal failure and in experimental metabolic acidosis in animals.

Relationship between urinary calcium and net acid excretion as determined by dietary protein and potassium: a review.

Increasing urinary net acid (titratable acid + NH4 - HCO-3) excretion is accompanied by an increased urinary Ca excretion because of reduced renal tubular reabsorption of filtered Ca. The relationships between urinary Ca excretion rates and urinary net acid excretion rates are reviewed for data: (1) among healthy adults eating constant diets when net acid excretion is increased by increasing dietary protein, administering NH4Cl, or withdrawal of dietary KHCO3 or reduced by administering KHCO3; (2) among healthy adults eating constant diets providing varying amounts of protein and potassium, and (3) among healthy adults and Ca stone formers with and without idiopathic hypercalciuria eating ad libitum. The results show that urinary Ca excretion varies directly with net acid excretion by 0.035 mmol/mEq. The urinary net acid excretion increases by 0.10-0.15 mEq/mmol urinary urea, and urinary Ca increases by about 0.04 mmol/g dietary protein, while the urinary net acid excretion decreases as the ratio of urinary K/urea, a reflection of the dietary K relative to dietary protein, increases. The relationships between net acid excretion and both urinary urea and K/urea are similar among Ca stone formers without and with idiopathic hypercalciuria, but those with idiopathic hypercalciuria exhibit increased rates of urinary Ca excretion at all levels of net acid excretion.

In hereditary nephritis angiotensin-converting enzyme inhibition decreases proteinuria and may slow the rate of progression.

The hereditary nephritides are often progressive, resulting in kidney failure and the need for renal replacement therapy. There is no currently known beneficial treatment for these disorders. We observed three patients with hereditary glomerulonephritis with plasma creatinine concentrations ranging from 1.7 to 2.0 mg/dL who were treated with angiotensin-converting enzyme inhibitors (ACEIs) for 3.5 to 6 years. Angiotensin-converting enzyme inhibitor therapy was accompanied by a decrease in the mean arterial pressure (MAP) from 115 +/- 10 mm Hg to 93 +/- 2 mm Hg (+/- SD), a decrease in the mean urinary protein/creatinine ratio from 2,910 +/- 1,720 mg/g to 391 +/- 355 mg/g, and stabilization of the decline of creatinine clearance with time in two of the three patients. Based on this apparent benefit of ACEIs in hereditary nephritis, we suggest that a prospective controlled trial of ACEIs should be undertaken among a large group of such patients. Pending the results of such a study, ACEIs should be considered for the treatment of patients with proteinuric and progressive hereditary nephritis.

Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults.

Increasing dietary calcium intake decreases urinary oxalate excretion by increasing intestinal precipitation of dietary oxalate as calcium oxalate. This mechanism was speculated to account for the decreased prospective incidence of kidney stones as estimated dietary calcium intake, adjusted for caloric intake, increased among men in a recent large epidemiological study. To further assess the relationship between estimated diet calcium and urinary oxalate, we studied 94 health adults, 50 women and 44 men, ages 20 to 70 years with weights ranging form 47 to 104 kg while they ate their customary diets. Each subject completed a semiquantitative food frequency questionnaire and collected three 24-hour urines preserved with HCl. The urines were collected accurately as judged by a mean intrasubject CV for creatinine excretion of 9.8% and direct relations between urinary creatinine excretion and body wt (r = 0.62; P < 0.0001), or predicted urine creatinine content for sex, age and weight using the Cockcroft and Gault formulas (r = 0.76; P < 0.0001). Estimated diet calcium intake ranged from 6.8 to 68 mmol/day (272 to 2720 mg/day) and averaged 29.5 mmol/day (1180 mg/day). Individual mean urinary oxalate excretion ranged from 0.079 go 0.332 mmol/day (7 to 29 mg/day) and averaged 0.198 mmol/day (17 mg/day). Among all subjects, daily oxalate excretion was directly related to creatinine excretion as an estimate of lean body mass (r = 0.61; P < 0.0001). Thus, oxalate excretion among men averaged 0.228 +/- 0.051 SD mmol/day, a value significantly higher than the average among women of 0.173 +/- 0.045 mmol/day (P < 0.001). Daily urine oxalate excretion/creatinine decreased curvilinearly as estimated dietary Ca intake increased (r = -0.30; P = 0.0035) and as the ratio of estimated dietary calcium to dietary oxalate increased (r = -0.39; P = 0.0001). We conclude that body size is the major determinant of urinary oxalate excretion among healthy adults, presumably reflecting variations in endogenous oxalate synthesis with lean body mass. Increasing estimated diet calcium intake, especially up to the range of 15 to 20 mmol/day (600 to 800 mg/day) has an additional effect to decrease during oxalate excretion, presumably by limiting intestinal absorption of dietary oxalate.

Dietary NaCl-restriction prevents the calciuria of KCl-deprivation and blunts the calciuria of KHCO3-deprivation in healthy adults.

Previous studies have demonstrated that dietary potassium deprivation in healthy human subjects eating diets otherwise containing normal quantities of NaCl is accompanied by an increase in urinary calcium excretion. This increase in urinary Ca excretion occurs in association with reductions in urinary Na and Cl excretion together with trends for weight gain and is delayed for several days after the initiation of K-deprivation, suggesting that it is mediated by NaCl retention and expansion of the extra-cellular volume. The present studies were thus undertaken to determine whether dietary NaCl restriction prevents the calciuric effect of subsequent K-deprivation. When dietary NaCl intake was limited to 5 +/- 3 mmol/day among 10 healthy adults, subsequent deprivation of KCl (-67 mmol/day) in 5 subjects of deprivation of KHCO3 (-64 mmol/day) in 5 subjects prevented any significant increase in daily urinary Ca excretion during five days of K-deprivation. There was, however, a small but significant cumulative increase above control in urinary Ca excretion at the end of KHCO3-deprivation, averaging + 1.9 +/- 0.6 mmol; P < 0.05. When KCl was restored to the diets urinary Ca excretion increased while restoration of KHCO3 to the diets caused urinary Ca to fall to rates below control. We conclude that the calciuria of K-deprivation when NaCl is present in the diet is largely dependent upon NaCl retention by the kidneys and subsequent ECF-volume expansion. In addition, HCO3 is anti-calciuric.

Potassium causes calcium retention in healthy adults.

The administration of 60 mmol/d of KHCO3 to healthy adults reduced urinary calcium excretion by 0.9 mmol/d and caused calcium balance to become equivalently more positive. Other studies showed that 90 mmol/d of KHCO3 reduced both daily and fasting urinary calcium excretion rates, whereas deprivation of either KCl or KHCO3, using synthetic diets, was accompanied by increased daily and fasting urinary calcium excretion rates. A significant inverse relationship between the changes in urinary calcium and the changes in urinary potassium was observed: delta urinary Ca (mmol/d) = 0.29-0.015 delta urinary K (mmol/d); r = -0.65. Correlative evaluation of additional data suggested that the fall in urinary calcium during potassium administration may be related to the natriuretic effects of potassium, resulting in ECF-volume contraction or to potassium-induced phosphate retention and suppression of calcitriol synthesis, or to both mechanisms.

Preeclampsia related to a functioning extrauterine placenta: report of a case and 25-year follow-up.

We report the case of a patient with preeclampsia due to an extrauterine, intra-abdominal pregnancy. After the fetus was delivered, but while the functioning placenta remained in the abdomen, preeclampsia, which was documented by clinical data and a kidney biopsy, persisted until the placenta was removed 99 days postpartum. A kidney biopsy 21 months postpartum was normal. Twenty-five years later, her kidney function and blood pressure were normal. The observation of this patient supports the view that the placenta must be intact for the development of preeclampsia and is the first description of endotheliosis in a kidney biopsy from a hypertensive woman with an intra-abdominal pregnancy.

The role of the laboratory in evaluation of kidney function.

Evaluation of kidney function by physical examination alone is imprecise and limited. Quantitative, reproducible assessment of kidney function required laboratory measurements of substances in plasma and urine, followed by reliable interpretation. Thus, glomerular filtration, urine protein excretion, water metabolism, and electrolyte disturbances may be quantified. These data are very useful in the single and serial assessment of patients with kidney disease and in evaluation of the effects of treatment.

Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults [corrected].

This study was undertaken to evaluate the effects of dietary K intake, independent of whether the accompanying anion is Cl- or HCO3-, on urinary Ca excretion in healthy adults. The effects of KCl, KHCO3, NaCl and NaHCO3 supplements, 90 mmol/day for four days, were compared in ten subjects fed normal constant diets. Using synthetic diets, the effects of dietary KCl-deprivation for five days followed by recovery were assessed in four subjects and of KHCO3-deprivation for five days followed by recovery were assessed in four subjects. On the fourth day of salt administration, daily urinary Ca excretion and fasting UCa V/GFR were lower during the administration of KCl than during NaCl supplements (delta = -1.11 +/- 0.28 SEM mmol/day; P less than 0.005 and -0.0077 +/- 0.0022 mmol/liter GFR; P less than 0.01), and lower during KHCO3 than during control (-1.26 +/- 0.29 mmol/day; P less than 0.005 and -0.0069 +/- 0.0019 mmol/liter GFR; P = 0.005). Both dietary KCl and KHCO3 deprivation (mean reduction in dietary K intake -67 +/- 8 mmol/day) were accompanied by an increase in daily urinary Ca excretion and fasting UCaV/GFR that averaged on the fifth day +1.31 +/- 0.25 mmol/day (P less than 0.005) and +0.0069 +/- 0.0012 mmol/liter GFR (P less than 0.005) above control. Both daily urinary Ca excretion and fasting UCaV/GFR returned toward or to control at the end of recovery. These observations indicate that: 1) KHCO3 decreases fasting and 24-hour urinary Ca excretion; 2) KCl nor NaHCO3, unlike NaCl, do not increase fasting or 24-hour Ca excretion and 3) K deprivation increases both fasting and 24-hour urinary Ca excretion whether the accompanying anion is Cl- or HCO3-. The mechanisms for this effect of K may be mediated by: 1) alterations in ECF volume, since transient increases in urinary Na and Cl excretion and weight loss accompanied KCl or KHCO3 administration, while persistent reductions in urinary Na and Cl excretion and a trend for weight gain accompanied K deprivation; 2) K mediated alterations in renal tubular phosphate transport and renal synthesis of 1.25-(OH)2-vitamin D, since KCl or KHCO3 administration tended to be accompanied by a rise in fasting serum PO4 and TmPO4 and a fall in fasting UPO4 V/GFR, a fall in serum 1,25-(OH)2-D and a decrease in fasting UCa V/GFR, while dietary KCl or KHCO3 deprivation were accompanied by a reverse sequence.

Hypercalciuria and stones.

Hypercalciuria, defined as the urinary excretion of more than 0.1 mmol Ca/kg/d (4 mg/kg/24 h), is observed in approximately 50% of patients with calcium oxalate/apatite nephrolithiasis and is one of the risk factors for stone formation. Urinary Ca excretion rates among such patients are higher than normal, despite comparable ranges of glomerular filtration rate (GFR) and serum ultrafiltrable Ca concentrations, and thus glomerular filtration of Ca, suggesting that hypercalciuria is the result of inhibition of net tubular Ca reabsorption. Although increased dietary NaCl or protein intake and reduced K intake increase urinary Ca excretion rates, urinary Ca excretion rates are higher among hypercalciuric stone formers than among normal subjects in relation to comparable ranges of urinary Na, SO4 (as a reflection of protein intake), or K excretion rates, indicating that these dietary factors are not primarily responsible for hypercalciuria. Hypophosphatemia is observed among a subset of hypercalciuric patients and consequent activation of 1,25-(OH)2-D synthesis increases intestinal Ca absorption and urinary calcium excretion. Other hypercalciuric patients exhibit augmented intestinal Ca absorption without elevated plasma 1,25-(OH)-2-D levels, suggesting that either the capacity of 1,25-(OH)2-D to upregulate its own receptor in the intestine or 1,25-(OH)2-D-independent intestinal Ca transport are responsible for increased Ca absorption and hypercalciuria. Hypercalciuric patients also exhibit accelerated radiocalcium turnover, negative Ca balances, reduced bone density, delayed bone mineralization, fasting hypercalciuria, and increased hydroxyproline excretion, all of which reflect participation of the skeleton and presumably a more generalized acceleration of Ca transport. Hypercalciuria may be familial.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the serum creatinine to estimate glomerular filtration rate in health and early diabetic nephropathy. Collaborative Study Group of Angiotensin Converting Enzyme Inhibition in Diabetic Nephropathy.

We evaluated 100/serum creatinine, 24-hour creatinine clearance, and simultaneously measured creatinine clearance or creatinine clearance estimated by the formula devised by Cockcroft and Gault in comparison with measurements of glomerular filtration rate (GFR) using iothalamate among 136 patients with diabetic nephropathy. We also evaluated 100/serum creatinine, simultaneously measured creatinine clearance or creatinine clearance estimated by the Cockcroft and Gault formula in comparison with measurements of GFR using inulin among 88 healthy adults, 21 hypercalciuric kidney stone formers and their hypercalciuric relatives, and one man with chronic nephritis. Creatinine clearances measured simultaneously were closely correlated to GFR (r = 0.93) as were creatinine clearances, estimated by the Cockcroft and Gault formula (r = 0.84) when GFR ranged from 16 to 175 mL/min (0.27 to 2.92 mL/s). These observations confirm the clinical use of either creatinine clearances during water diuresis or estimates of creatinine clearance by the Cockcroft and Gault formula in the assessment of kidney function.

Ketoconazole reduces elevated serum levels of 1,25-dihydroxyvitamin D in hypercalcemic sarcoidosis.

The antifungal drug ketoconazole, a cytochrome P450 inhibitor, has been shown to inhibit renal 1,25-dihydroxyvitamin D production in vitro and to lower serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with primary hyperparathyroidism. To assess the usefulness of this drug in the hypercalcemia of sarcoidosis, a condition thought to result from overproduction of 1,25-dihydroxyvitamin D by sarcoid-involved tissues, two men with sarcoidosis, hypercalcemia, and elevated serum levels of 1,25-dihydroxy-vitamin D were given ketoconazole, 600-800 mg per day, for four to six days. Serum 1,25-dihydroxyvitamin D levels were markedly reduced (by approximately 40%) in both patients during ketoconazole administration, but serum calcium was not affected. In both patients, renal function deteriorated during ketoconazole treatment. We conclude that ketoconazole administration can lower the elevated serum 1,25-dihydroxyvitamin D levels in sarcoidosis. However, deterioration of renal function during ketoconazole administration as well as failure of hypercalcemia to be affected during short-term ketoconazole treatment suggest that this drug might not be appropriate for acute treatment of hypercalcemic sarcoidosis.

The transtubular potassium concentration in patients with hypokalemia and hyperkalemia.

It is advantageous to make an independent assessment of the potassium (K) secretory process and the luminal flow rate in the renal cortex to evaluate K handling by the kidney during hypokalemia or hyperkalemia. The transtubular potassium concentration gradient (TTKG) is a semiquantitative index of the activity of the K secretory process. The purpose of this study was to define expected values for the TTKG in normal subjects with hypokalemia or following an acute K load. During hypokalemia of non-renal origin, the TTKG was 0.9 +/- 0.2; in contrast, the TTKG was significantly higher during the hypokalemia of hyperaldosteronism, 6.7 +/- 1.3. The TTKG was 11.8 +/- 3.6, 2 hours after normokalemic subjects received 0.2 mg 9 alpha-fludrocortisone (9 alpha-F). To obtain expected values during hyperkalemia, normal subjects ingested 50 mmol potassium chloride; 2 hours later, the TTKG was 13.1 +/- 3.8. Therefore, the expected value for the TTKG must be interpreted relative to the concentration of K in the plasma. Circumstances were also defined where the TTKG is low despite hyperaldosteronism, namely, during a water diuresis and pre-existing hypokalemia.

Oxalate is overestimated in alkaline urines collected during administration of bicarbonate with no specimen pH adjustment.

We compared measurements of daily urine oxalate excretion in urines collected at the prevailing urine pH with measurements of urine oxalate excretion in urines collected into 20 mL of 6 mol/L HCl. We studied eight healthy adults fed constant diets. Urines were collected during control conditions and, in each subject, during the administration of NaCl, KCl, NaHCO3, or KHCO3, 90 mmol/day. Daily urine oxalate excretion calculated for collections made in acid averaged 271 (SD 79) mumol/day and did not vary with any of the salt supplements. When urines were collected at ambient urine pH (average 5.94, SD 0.23) during control conditions, and during the administration of NaCl or KCl, urine oxalate excretion averaged 263 (SD 88) mumol/day, a value not different from that for collections in acid. However, when urine was collected with no pH adjustment during NaHCO3 or KHCO3 administration (average pH 6.90, SD 0.14), apparent urine oxalate excretion averaged 398 (SD 132) mumol/day, significantly (P less than 0.025) exceeding the mean observed when urines were collected in acid. Moreover, the percentage increase in apparent oxalate excretion increased with urinary pH. These observations reinforce recommendations that urine specimens for measurement of oxalate be collected in acid to avoid the increase in apparent oxalate content that occurs during collection of alkaline urines. This increase presumably results from the well-known in vitro nonenzymatic conversion of ascorbate to oxalate.