Fall In Urine pH Research Articles

Association of Urine Findings with Metabolic Syndrome Traits in a Population of Patients with Nephrolithiasis.

The odds of nephrolithiasis increase with more metabolic syndrome (MetS) traits. We evaluated associations of metabolic and dietary factors from urine studies and stone composition with MetS traits in a large cohort of stone-forming patients. Patients >18 years old who were evaluated for stones with 24-hour urine collections between July 2009 and December 2018 had their records reviewed retrospectively. Patient factors, laboratory values, and diagnoses were identified within 6 months of urine collection and stone composition within 1 year. Four groups with none, one, two, and three or four MetS traits (hypertension, obesity, dyslipidemia, and diabetes) were evaluated. Trends across groups were tested using linear contrasts in analysis of variance and analysis of covariance. A total of 1473 patients met the inclusion criteria (835 with stone composition). MetS groups were 684 with no traits, 425 with one trait, 211 with two traits, and 153 with three or four traits. There were no differences among groups for urine volume, calcium, or ammonium excretion. There was a significant trend (P<0.001) for more MetS traits being associated with decreasing urine pH, increasing age, calculated dietary protein, urine uric acid (UA), oxalate, citrate, titratable acid phosphate, net acid excretion, and UA supersaturation. The ratio of ammonium to net acid excretion did not differ among the groups. After adjustment for protein intake, the fall in urine pH remained strong, while the upward trend in acid excretion was lost. Calcium oxalate stones were most common, but there was a trend for more UA (P<0.001) and fewer calcium phosphate (P=0.09) and calcium oxalate stones (P=0.01) with more MetS traits. Stone-forming patients with MetS have a defined pattern of metabolic and dietary risk factors that contribute to an increased risk of stone formation, including higher acid excretion, largely the result of greater protein intake, and lower urine pH.

Hyperkalemic distal renal tubular acidosis associated with Rett syndrome

Renal function was studied in a 7-year-old girl with Rett syndrome (RS) complicated by persistent hyperchloremic hyperkalemic metabolic acidosis. The acidosis was associated with a urine pH above 5.5, positive urinary anion gap and decreased potassium excretion. Plasma renin activity, aldosterone and cortisol levels were normal. Therapy with sodium bicarbonate failed to lower urine pH below 5.5 or increase potassium excretion. Hydrochlorothiazide administration resulted in a fall in urine pH below 5.5 and an increase in potassium excretion as a result of increased distal sodium delivery and increased sodium reabsorption in the distal nephron. We conclude that a voltage-dependent type of derangement in the distal nephron, rather than aldosterone deficiency, is responsible for the impairment in urinary acidification observed in this patient. Early detection of impaired renal acidification in RS may prevent or slow the progression of growth failure.

Acid loading during treatment with sevelamer hydrochloride: Mechanisms and clinical implications

Short-term and long-term studies indicate that patients treated with sevelamer hydrochloride have lower serum bicarbonate levels than patients treated with calcium-containing phosphate binders. This observation has previously been attributed to withdrawal of a source of base with discontinuation of calcium carbonate or calcium acetate. However, understanding of the chemistry of sevelamer hydrochloride suggests at least three potential mechanisms whereby it might induce a dietary acid load. Moreover, preliminary results from an animal model demonstrate that treatment with sevelamer hydrochloride results in a fall in urine pH, as well as an increase in urinary ammonium and calcium excretion consistent with an increase in net acid excretion. Chronic metabolic acidosis in maintenance dialysis patients is associated with major systemic effects. It is independently associated with an increased risk of death in dialysis patients. Metabolic acidosis has both catabolic and antianabolic effects that may lead to a net negative nitrogen balance and total body protein balance. Metabolic acidosis also leads to physiochemical dissolution of bone and promotes cell-mediated bone resorption due to enhanced osteoclast activity and reduced osteoblast activity. It may also exacerbate secondary hyperparathyroidism and renal osteodystrophy. Given the long-term risks of chronic metabolic acidosis in maintenance dialysis patients, Kidney/Dialysis Outcome Quality Initiative (K/DOQI) guidelines have recently recommended maintaining predialysis serum levels of CO2 above 22 mmol/L in order to improve bone histology, and to ameliorate excess protein catabolism.

Introduction

Introduction

Effect of acidosis on urine supersaturation and stone formation in genetic hypercalciuric stone-forming rats

We have successively inbred over 45 generations a strain of rats to maximize urine calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls and uniformly form poorly crystalline calcium phosphate kidney stones. In humans with calcium nephrolithiasis, consumption of a diet high in acid precursors is often cited as a risk factor for the development of calcium-based kidney stones; however, the effect of this diet on urinary supersaturation with respect to the common solid phases found in kidney stones has not been determined. To determine the effect of the addition of an acid precursor on urine ion excretion, supersaturation, and stone formation, we fed these genetic hypercalciuric stone-forming (GHS) rats 13 g/day of a 1.2% calcium diet with 0.0, 0.5, 1.0, or 1.5% NH4Cl in the drinking water for 14 weeks (N = 8 for each). Urine was collected and analyzed every two weeks. As expected, the addition of dietary NH4Cl led to a progressive fall in urine pH and urine citrate, while urine ammonium increased. Urine calcium and phosphorus increased, while urine oxalate fell. Increasing dietary NH4Cl led to a fall in supersaturation with respect to CaHPO4 (brushite) and CaOx and a rise in supersaturation with respect to uric acid. In spite of differences in supersaturation, most rats in each group formed stones that contained calcium phosphate and not calcium oxalate. Thus, while the provision of additional dietary acids alters urinary ion excretion and lowers supersaturation with respect to CaHPO4 and CaOx, it does not change the character or rate of stone formation in the GHS rats.

Pathophysiology of the renal acidification defect present in the syndrome of familial hypomagnesaemia-hypercalciuria.

A distal acidification defect is frequently observed in the syndrome of familial hypomagnesaemia-hypercalciuria and hence this condition can be confused with primary distal renal tubular acidosis (RTA). This study demonstrates that in four unrelated patients with familial hypomagnesaemia-hypercalciuria the acidification defect is functionally different from that present in primary distal RTA. All patients exhibited hypomagnesaemia, hypermagnesuria, hypercalciuria, hyposthenuria, nephrocalcinosis and slight reduction of glomerular filtration rate (GFR). A moderate degree of metabolic acidosis was also present and basal data showed an inappropriately high urine pH (5.7-5.9) and a positive urine anion gap (Na + K-Cl = 11-28 mmol/l). Stimulation of distal acidification induced a fall in urine pH (4.7-5.6), but ammonium excretion remained low despite factoring by GFR (26-46 mumol/min per 1.73 m2, 35-54 mumol/100 ml GF). The urine to blood PCO2 gradient also remained low after sodium bicarbonate loading (1.3-17.7 mmHg). These results are best explained by both defective ammonia transfer to the deep nephron and impaired hydrogen ion secretion at the level of the medullary collecting duct, and probably are secondary effects of the medullary interstitial nephropathy.

Chronic neutral phosphate supplementation induces sustained, renal metabolic alkalosis.

The aim of the present study was to test whether intravenous neutral phosphate supplementation, recently shown in our laboratory to acutely stimulate proton secretion in the distal nephron, was able to induce a sustained metabolic alkalosis. Neutral Na and K phosphate supplementation for seven days, with equivalent reduction in chloride supply and unchanged intake of sodium and potassium, in ADX rats receiving fixed physiological doses of aldosterone and dexamethasone (group 1, N = 7), was responsible for a severe metabolic alkalosis (MA; delta [HCO3] 11 +/- 1.3 mM, and delta pH 0.11 +/- 0.06 unit). Metabolic alkalosis was at least in part of renal origin, since net acid excretion (NAE) transiently increased, principally due to an increment in titratable acid excretion rate. Balances were equilibrated for sodium and negative for chloride and potassium, which may have contributed to the severity of the MA. Chronic i.v. neutral Na phosphate, without change in potassium and chloride supply, in ADX rats receiving the same doses of steroids (group 2, N = 5), was responsible for a less severe MA (delta [HCO3] 7.5 +/- 0.9 mM, and delta pH 0.07 +/- 0.01 unit), also of renal origin. In this group, balances were positive for chloride and sodium and equilibrated for potassium. Finally, neutral Na and K phosphate supplementation with reduction in chloride supply in intact rats (group 3, N = 4) was also able to induce a MA (delta [HCO3] 5.5 +/- 1.8 mM, and delta pH 0.06 +/- 0.01 unit) of renal origin, with balances negative for chloride and equilibrated for potassium and sodium. In all groups, the generation and maintenance of MA probably resulted from stimulated proton secretion in the distal nephron, as suggested by the observed increase of PCO2 over HCO3 concentration ratio in the urine and a fall in urine pH despite augmented urinary buffer content throughout the phosphate infusion period. Glomerular filtration rate did not significantly vary in any group. In conclusion, chronic supplementation of neutral phosphate appears to stimulate per se proton secretion in the distal nephron, independently of sodium, chloride, and potassium balances, and adrenal steroid secretion. Thus neutral phosphate supplementation should be added to the previously known factors able to induce MA.

Renal responses to exercise-induced lactic acidosis.

Five healthy males performed four 30-s bouts of maximal exercise, separated by 4 min of rest, on an isokinetic cycle ergometer. Arterial blood and urine samples were taken from indwelling catheters at rest, immediately postexercise, and for 90 min of recovery. Inulin was continuously infused to measure glomerular filtration rate (GFR). Arterial plasma [Na+], [K+], and [Cl-] increased (P less than 0.05) with exercise; plasma lactate concentration ([Lac-]) increased from 1.3 +/- 0.2 to 21.0 +/- 1.0 (SE) meq/l (P less than 0.05). A significant decrease in the GFR occurred after exercise and during recovery associated with reductions in renal Na+ and K+ excretion (P less than 0.05). Renal excretion of Lac- reached a maximum of 293 +/- 79.4 mu eq.kg-1.h-1 (P less than 0.05), with Cl- excretion reaching a minimum of 4.8 +/- 0.95 mu eq.kg-1.h-1 (P less than 0.05). Urine [Lac-] was 189 +/- 25.6 meq/l, and urine [Cl-] was 6 +/- 1.7 meq/l at 30 min of recovery. There was a curvilinear relationship between urine [Cl-] and [Lac-] (r = -0.86; P less than 0.0001). Net Lac- production was estimated from arterial [Lac-] and after assuming a distribution volume. Less than 2% (13.1 meq) of the total estimated Lac- produced (678 meq) was excreted in the urine. Decreases in urine [Cl-] act to limit the fall in urine pH that accompanies increases in urine [Lac-].

Effects of antidiuretic hormone on urinary acidification and on tubular handling of bicarbonate in the rat.

Paired micropuncture experiments were carried out in plasma-replete volume-expanded rats to examine the acute effects of 1-desamino-8-D-arginine vasopressin (dDAVP) on urinary acidification and tubular handling of bicarbonate and chloride. No effect was detected on the fractional absorption of water, total CO2, and chloride at end-proximal and early distal sites of superficial nephrons in intact animals; dDAVP, however, inhibited the fractional absorption of total CO2 in Henle's loop while stimulating that of chloride in thyroparathyroidectomized (TPTX) somatostatin-infused rats. In the distal tubule accessible to micropuncture, net total CO2 secretion was observed during hypotonic volume expansion, which reversed to net total CO2 absorption during dDAVP infusion in intact Wistar rats. Marked stimulation of urinary acidification occurred in all animals as attested by a fall in urine pH and bicarbonate excretion. Net acid excretion almost doubled in intact rats. We conclude that (a) antidiuretic hormone (ADH) inhibits fractional bicarbonate absorption in the thick ascending limb while stimulating that of chloride at least in TPTX somatostatin-infused rats, and (b) ADH stimulates proton secretion (or inhibits bicarbonate secretion) in the distal tubule and cortical collecting ducts, which leads to enhanced urinary acidification.

Segmental characterization of defects in collecting tubule acidification

The aim of this study was to investigate cortical collecting tubule (CCT) function in normal individuals and in patients with distal renal tubular acidosis (DRTA) using furosemide (80 mg orally) as a tool to stimulate H+ and K+ secretion by enhancing Na delivery and transport in this nephron segment. In ten normal subjects, furosemide resulted in a fall in urine pH below 5.5 and an increase in net acid and K+ excretion. These effects were obliterated by amiloride, a drug which decreases transtubular epithelial voltage (lumen-negative) in the CCT by blocking Na reabsorption. In 13 patients with DRTA, defined by failure to lower urine pH below 5.5 during acidemia, three distinctive responses to furosemide were found. In six patients with the hyperkalemic variety, furosemide failed to lower urine pH below 5.5 and resulted in a blunted increase in K+ excretion, thereby suggesting that a normal transtubular voltage in the CCT could not be generated in such patients. In five patients with classic RTA, furosemide failed to lower urine pH below 5.5, but K+ excretion increased normally. The increase in K+ excretion indicated that a normal transtubular voltage in the CCT could be generated, while the inability to lower urine pH denotes the presence of a proton pump defect involving the CCT. In two patients with classic RTA, furosemide resulted in both a normal fall in urine pH and an increase in K+ excretion, thereby indicating that the CCT was normal in regards to both proton pump function and in its ability to generate a normal transtubular voltage.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium-dependent urinary acidification in patients with aldosterone deficiency and in adrenalectomized rats: Effect of furosemide

Urinary acidification during metabolic acidosis and in response to stimulation of sodium-dependent hydrogen ion secretion using furosemide administration was evaluated in 12 patients with hyperkalemic hyperchloremic metabolic acidosis associated with mild chronic renal insufficiency and aldosterone deficiency. During spontaneous metabolic acidosis, the urine of all patients was acidic (pH less than 5.5), but ammonium excretion was markedly reduced (6.6 ± 1.3 μEq/min) comprising only about 20% of net acid excretion (30.5 ± 5.7 μEq/min). Furosemide (80 mg orally) resulted in a further fall in urine pH (from 5.29 ± 0.06 to 4.97 ± 0.09, P < 0.02) and a significant increase in net acid excretion (from 30 ± 5.8 to 38 ± 5.1 μEq/min, P < 0.02) while plasma aldosterone did not change (from 9.8 ± 1.7 to 9.7 ± 1.6 μg/dL). To investigate whether the acute stimulatory effect of furosemide on distal acidification requires some degree of mineralocorticoid activity, studies were conducted in adrenalectomized rats. The fall in urine pH and the increase in net acid excretion elicited by furosemide in adrenalectomized rats were comparable to those observed in adrenal-intact animals (5.37 ± 0.10 v 5.67 ± 0.11 and 0.43 ± 0.08 v 0.41 ± 0.06 μEq/min, respectively). inhibit sodium transport in the cortical collecting tubule, furosemide failed to lower urine pH (6.44 ± 0.23) and to increase net acid excretion (0.07 ± 0.06 μEq/min). These findings demonstrate that furosemide enhances hydrogen ion secretion in the absence of aldosterone provided that sodium-transport in the cortical collecting tubule is not impaired. The data therefore lends support for the notion that this diuretic stimulates urinary acidification by increasing sodium-dependent hydrogen ion secretion in the cortical collecting tubule and that this effect is mineralocorticoid-independent.

The Influence of a High Dietary Intake of Purine-Rich Animal Protein on Urinary Urate Excretion and Supersaturation in Renal Stone Disease

1. Eight recurrent renal stone-forming patients were housed in a metabolic ward and fed on a low (LPD) and a high (HPD) animal protein diet, which were isoenergetic. Metabolic studies were made after 2 weeks on each diet. 2. There was a 90% increase in urinary urate on HPD compared with LPD, whereas serum urate did not change consistently. 3. The urinary acid excretion increased by 200%, including a 100% increase in ammonium ion excretion. A fall in urine pH by 0.9 unit was also seen. 4. The calculated ion activities of the urines revealed a profound increase in the uric acid supersaturation, from undersaturation to supersaturation, and in some cases even surpassing the formation product ratio. The ammonium urate supersaturation also increased. The sodium urate supersaturation was unchanged, despite an induced natriuresis. 5. The risk of forming uric acid or ammonium urate crystals or stones in the urine was increased on a high protein diet, whereas the risk of forming sodium urate crystals was no greater than on a low protein diet. 6. As uric acid and ammonium urate crystals under certain conditions may adsorb a macromolecular fraction of the human urine, which inhibits calcium oxalate crystal growth, it is proposed that this mechanism, along with a decrease in urine pH, may also interfere with the inhibitory activity of calcium oxalate crystal growth and aggregation.

Renal regulation of acid excretion in the red deer (Cervus elephus).

Hydrochloric acid was infused into the rumens of two red deer in experiments designed to study renal control of acid excretion. The deer were fed roughage diets and in control periods the urine was alkaline and was rich in bicarbonate and poor in phosphate. Infusion of HCl led to a fall in urine pH and to the disappearance of bicarbonate from the urine. Excretion of acid in the urine increased and nearly all of this was due to the increased excretion of ammonium ions. Excretion of calcium in the urine increased appreciably during acid infusion and was correlated with urine pH. Excretion of sodium in urine was slightly increased during acid infusion and that in faeces was slightly reduced. Faecal excretion of calcium, phosphorus and potassium were unaffected.These results indicate that renal control of acid excretion in the red deer is similar to that of sheep and calves.

Renal excretion of acid in calves fed either roughage or concentrate diets.

Calves fed a roughage diet (50 per cent hay + other components) excreted an alkaline urine rich in bicarbonate but poor in phosphorus. Infusion of HCl into the rumen led to a fall in urine pH, to a decrease in bicarbonate excretion and to the excretion of acid in the urine. Between 16–25 per cent of this acid was excreted as acid phosphate (H2PO4-) and the remaining 75–84 per cent as ammonium ions.In contrast, when the calves were fed a concentrate diet (85 per cent barley + other components) the urine was acid and contained appreciable amounts of phosphorus and ammonium ions. Infusion of HCl into the rumen produced a further increase in acid excretion, practically all of which appeared in the urine as ammonium ions.Excretion of calcium in the urine increased during infusion of HCl and was correlated with urine pH.There were few changes in faecal mineral excretion during acid infusion but less sodium and potassium were excreted in the faeces when the concentrate diet was fed compared to when the roughage diet was fed.

RENAL TUBULAR ACIDOSIS

In two patients with the biochemical features of renal tubular acidosis, urine pH decreased appreciably following infusion of either a neutral (pH 7.4) 0.15 M solution of Na2HPO4/NaH2PO4 or 0.15 M Na2SO4. The fall in urine pH is interpreted as reSultillg from the non-reabsorbable nature of PO4= and SO4=. That the fall in urine pH is mediated by an increased lumen negativity is supported by the fact that concomitant with the decrease in urine pH, the urine concentration and rate of excretion of Cldecreased significantly.

ANION PENETRATING ABILITY AND URINARY ACIDIFICATION

Bank and Schwartz¹call attention to the fact that intense acidification of the urine can be achieved without the induction of acidosis. Normal subjects stimulated to retain sodium showed a rapid fall in urine pH to 5.0 or below when infused with sodium sulfate. It appeared that increased reabsorption of sodium in the presence of a poorly reabsorbable anion was responsible for this phenomenon. These workers have demonstrated in experiments that during the infusion of sodium phosphate into dogs whose sodium and chloride excretion has been reduced by dietary salt restriction, excretion of titratable acid rises to near theoretical values in the presence of normal plasma bicarbonate concentrations. They suggest that a disproportion between the reabsorption of sodium and anion was the factor in regulating the acidity of the urine and the rate of excretion of titratable acid. This hypothesis was supported by the demonstration that administration of relatively