QJM vol. 98 no. 1 © Association of Physicians 2005; all rights reserved.
Masterclasses in medicine |
Recurrent uric acid stones
From the 1Renal Division, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada, and 2Nephrology Unit and Department of Internal Medicine, Stellenbosch University, Cape Town, South Africa
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Summary |
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 Top Summary IntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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A 46-year-old female had a history of recurrent uric acid stone formation, but the reason why uric acid precipitated in her urine was not obvious, because the rate of urate excretion was not high, urine volume was not low, and the pH in her 24-h urine was not low enough. In his discussion of the case, Professor McCance provided new insights into the pathophysiology of uric acid stone formation. He illustrated that measuring the pH in a 24-h urine might obscure the fact that the urine pH was low enough to cause uric acid to precipitate during most of the day. Because he found a low rate of excretion of
relative to that of sulphate anions, as well as a high rate of citrate excretion, he speculated that the low urine pH would be due to a more alkaline pH in proximal convoluted tubule cells. He went on to suspect that there was a problem in our understanding of the function of renal medullary NH3 shunt pathway, and he suggested that its major function might be to ensure a urine pH close to 6.0 throughout the day, to minimize the likelihood of forming uric acid kidney stones. |
Introduction |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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In this case discussion, once again the central figure is Professor McCance, an imaginary consultant, who practiced medicine around 70 years ago. As usual, the overall objective is to demonstrate how the application of principles of integrative physiology at the bedside can be extremely helpful to reveal the pathophysiology of disease, to make better clinical diagnoses, and to plan optimal therapy. Using this approach, new concepts with respect to the pathophysiology of uric acid stone formation and the physiology of ammonium (
) excretion would be revealed. |
The consultation |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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A 46-year-old female had a history of recurrent uric acid stones. There was no history of hyperuricaemia. The only positive findings on physical examination were a high blood pressure (150/100 mmHg) and moderate obesity. The composition of her urine is summarized in Table 1, which shows that the rate of excretion of total urates was not elevated and her 24-h urine pH was not low enough to cause uric acid to precipitate. Her glomerular filtration rate (GFR) and renal concentrating ability were normal. Because there was no obvious reason to explain why uric acid stones continued to form, Professor McCance was asked to help. In his usual methodical way, their Professor used simple physiological concepts to analyse the data in depth—this led to new insights into this medical problem, and into the physiology of
excretion as well.
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Synopsis of uric acid production |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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The medical registrar began with a brief review of uric acid metabolism, which he had considered when trying to resolve their dilemma. Urates are the major end product of purine metabolism in humans because the gene that encodes for uricase—the enzyme that degrades uric acid—was inactivated very early in the Myocene period (Appendix).1 On a typical Western diet, humans excrete
10 mg total urates per kg of body weight per day. Uric acid—and not the urate anion—is the focus of our attention, because its concentration can rise sufficiently to exceed its solubility product constant (Ksp) in the urine. The PK of uric acid is 5.35 at 37°C, while its Ksp is 100 mg/l; supersaturation of the urine with uric acid occurs up to a concentration of 200 mg/l. As shown in equation 1, there are two ways to elevate the concentration of uric acid in the urine: raise the total urate excretion rate or raise the urine H+ concentration.
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concentration did not yield an ion product that was well above their respective Ksp values.
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Having concluded the presentation, the registrar turned to Professor McCance to explain why their patient had recurrent uric acid stones. His first thoughts were that the total urinary urates might have been underestimated, or that there was a problem with the measurement of the urine pH. He turned to the group and asked, ‘How could the rate of excretion of total urates be underestimated?’
Question 1. How could the rate of excretion of total urates be underestimated?
Without waiting for an answer, Professor McCance pointed out that the excretion of urates could be underestimated if uric acid precipitated in a refrigerated urine sample prior to analysis. This is well known to clinical biochemists, so they add alkali to the urine collection vessel to dissolve uric acid crystals prior to assay. He went on to ask, ‘In what way might a 24-h urine collection lead to the false impression that the urine pH was not low?’
Question 2. In what way might a 24-h urine collection lead to the false impression that the urine pH was not low?
Physiology principle 1. Some compounds or ions in the urine have greater excretion rates at certain times of the day and lower ones at other times. This is called a diurnal or a circadian excretion pattern.2
Professor McCance had observed large and reproducible variations in the urine pH in normal subjects. The lowest urine pH is usually found overnight, while higher values were observed close to noon. Hence mixing urine samples with a low pH and others with a high pH could mask times in the 24-h period when the urine pH was low enough to cause uric acid to precipitate. To illustrate this point, he suggested that they all participate in an experiment where their pattern of urine pH during the 24-hour period could be compared to that of their patient. Urine would be stored in separate vials after voiding at 2–3 h intervals during the day, while one overnight sample would be collected so as not to disturb sleep. They would add a preservative to the storage vials to avoid alkalinization of the urine secondary to bacterial urease actions. For this experiment to be clinically relevant, only subjects who were healthy and not taking medications should participate. They should continue with their usual diet, water intake, and activities. The housestaff were excited by this idea, and also by the fact that their Professor would be a subject in the experiment as well. ‘Now we even have a control for age‘, said one of the team with a smile. All agreed to meet as soon as the samples were analysed.
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Results of the mini-experiment |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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Professor McCance was pleased that the intern had plotted the data, and was eager to examine the results. She began with an analysis of the diurnal changes in the urine flow rate.
(i) Diurnal variation in the urine flow rate. In the control subjects, the nadir in urine flow rate was in the overnight collection period (Figure 1). Therefore, there should be a higher total urate concentration in the urine for this portion of the 24-h period (unless the rate of excretion of urates underwent a marked diurnal variation), she said. This could be especially important for uric acid precipitation if a low urine pH were to occur in the overnight period. The housestaff were surprised by how low the urine flow rate became overnight. They asked Professor McCance, ‘What factors cause such a low urine flow rate in the overnight period?’
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Question 3. What factors cause such a low urine flow rate in the overnight period?
Physiology principle 2. When vasopressin acts, the distal nephron is permeable to water. Therefore the urine flow rate is directly proportional to the osmole excretion rate and inversely proportional to the Uosm (equation 3).
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Question 4. Why was salt excretion rate so low overnight?
Physiology principle 3. The signal to excrete Na+ is related more directly to pressure than to central blood volume.
Return to the study: Our central blood volume is likely to be highest in the overnight period, because this follows the meal with our largest intake of NaCl, and also because we are no longer in an upright posture. Thus it is reasonable to suggest that the rate of excretion of Na+ should be highest in the overnight period. Nevertheless, the opposite was observed (Figure 2). Therefore, it appears that the signal for the renal excretion of Na+ is not simply due to an increased central blood volume; perhaps what is sensed is not a rise in volume, but a rise in central venous pressure. Professor McCance pointed out that even if these vessels contain a larger volume, there could be a fall in pressure if the venous tone were to decline. A possible explanation for the decrease in ‘pressure’ is that adrenergic stimulation, which increases venous tone, is lower during sleep. This lower excretion of Na+ in the overnight period will permit undisturbed sleep, because it will slow the filling of the urinary bladder.
The housestaff, while impressed with the physiology, were curious about the clinical advice given to the patient—‘drink more water during the day’. They suggested that if the ingested water were excreted during daytime hours, the urine flow rate might remain low in the overnight period when the urine pH was lowest (Figure 3). Hence the concentration of uric acid would remain in a dangerous range overnight. Moreover, the 24-h urine volume would provide a false sense of security, if it reflected very large daytime flow rates while the overnight volume remained low. In contrast, more valuable information would be gained if multiple 2–3-hourly urine collections were obtained over the 24-h period. Armed with these insights, they were eager to examine their data on the urine pH.
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(ii) Diurnal variation in the urine pH. These data also contained several surprises (Figure 3). First, the urine pH was close to 6.0 throughout the 24-h period in the control subjects. Second, the patient had a urine pH that was low enough to cause uric acid to precipitate during much of the 24-h period. Professor McCance pointed out that this information should be useful in the design of therapy, because alkali treatment would be most effective if it raised the urine pH at times when her urine pH was low. Almost immediately, the housestaff asked, ‘Why did the patient have these low urine pH values for a significant portion of the 24-hour period?’ To deal with these issues, Professor McCance began a brief didactic discussion that focused on the urine pH.
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Issues concerning a low urine pH |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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Professor McCance began by asking, ‘What might be the basis for the periods with a low urine pH in this patient?’
Question 5. What might be the basis for the periods with a low urine pH in this patient?
Physiology principle 4. The pH of a solution is dependent on two factors, the rate of addition of free H + and the availability of acceptors that can bind H + at the pH of that solution.
Return to the bedside: Applying this principle, one can deduce that there are two groups of causes for a low urine pH (Figure 4). First, there may be a higher rate of H+ secretion in the distal nephron. Second, there may be diminished availability of acceptors for H+ in the lumen of the collecting duct. This, in essence, means decreased entry of NH3 into the medullary collecting duct (MCD) because, at a urine pH 6, there is virtually no 
in the urine to titrate secreted H+.
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One of the housestaff quickly pointed out that measuring the rate of
excretion would separate these two possible aetiologies (equation 4). excretion should be high if distal H+ secretion is elevated, but low if NH3 availability is low. Therefore they turned to the results of their experiment, and found that the patient had excreted 39 mmol of in her 24-h urine. The intern concluded that this was a normal value, because it was very similar to the group's mean excretion rate. Professor McCance raised an eyebrow, and asked, ‘How do you define ‘normal’ when considering the composition of urine?’
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Question 6. How do you define ‘normal’ when considering the composition of urine?
Physiology principle 5. In steady state, subjects should excrete metabolic wastes and ingested ions that are in excess of body needs (minus loss via non-renal routes) in their urine. Therefore a physiological rather than a statistical analysis is needed to define appropriate excretion rates.
Illustrative example: Professor McCance illustrated this physiological principle by examining the excretion of water. The urine flow rate should be assessed relative to the expected response in the presence of the stimulus of a surplus or a deficit of water in the body, rather than relative to what is the ‘usual’ rate of water excretion in a population with an unknown stimulus. Therefore, the expected urine flow rate will be as high as possible and the Uosm as low as possible if the plasma sodium (Na+) concentration (PNa) is sufficiently low due to the ingestion of a large volume of water. On the other hand, the expected urine flow rate will be as low as possible and the Uosm as high as possible in response to a deficit of water (the signal is a high PNa). Using this same logic, one cannot determine if the rate of excretion of is normal in a patient without assessing it relative to the physiological stimulus for excretion. Therefore the question is, ‘What is the physiological signal for the rate of excretion of 
?’
Question 7. What is the physiological signal for the rate of excretion of ?
Physiology principle 5 restated: The rate of excretion of 
should be compared to the stimulus for excretion— excretion should be high enough to prevent the development of metabolic acidosis or if chronic metabolic acidosis is present, its rate should be as high as can be achieved.
The non-volatile dietary H+ load is H2SO4 derived from the metabolism of sulphur-containing amino acids.3 Initially, these H+ are titrated by , and this leaves the body with a deficit of . Nevertheless, 
anions cannot bind a significant amount of H+ at the lowest possible urine pH. Hence the kidneys must generate new to restore balance; this occurs when anions are excreted in the urine with 
. Therefore, in the absence of metabolic acidosis, the number of mEq of should be approximately equal to the number of mEq of anions in the urine.
Because this patient excreted 66 mEq of 
anions but only 39 mEq of per day, she had a low rate of excretion of . Moreover, this lower rate of excretion occurred when her urine pH was decidedly low. Hence Professor McCance concluded that her persistently low urine pH reflected a low availability of NH3 in her medullary interstitial compartment. The question they now needed to examine was, ‘What is the cause for the low NH3 concentration in the medullary interstitial compartment?’ The nephrology consultant took the lead at this point, because Professor McCance was not aware of the new data that were required to answer this question.
Question 8. What is the cause of the low NH3 concentration in the medullary interstitial compartment?
Two steps are required for the generation of a high medullary interstitial concentration of NH3, said the nephrology consultant. First, cells of the PCT must produce (plus ) from the metabolism of glutamine (Figure 5). Second, is recycled in the loop of Henle (LOH) and transferred into the lumen of the MCD.
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(i) Production of
by the kidney. Glutamine must be selected as the main fuel for the proximal convoluted tubule (PCT) by having a low pH in these cells. There is an upper limit on this production of set by the availability of ADP, a required substrate for oxidation of glutamine.4 ADP is formed when the kidneys perform their work—reabsorb filtered Na+. Hence a low GFR leads to a diminished maximal rate of production in the PCT. Other fuels may compete with glutamine for oxidation in the PCT (e.g. free fatty acids provided, for example, during total parenteral nutrition) and therefore cause a lower rate of production of .5
(ii) recycling in the LOH. ions are reabsorbed in the thick ascending limb of the loop of Henle (LOH), replacing K+ on the Na-K-2 Cl-cotransporter (NKCC). This provides the ‘single effect’ for the recycling of in the LOH and the generation of a high concentration of NH3 in the medullary interstitial compartment.6
In summary, a low availability of NH3 in the medullary interstitial compartment could be due to low production of in the PCT and/or a transfer defect due to a medullary interstitial disease, concluded the nephrology consultant.
Return to the data: Because the patient is able to concentrate her urine maximally, it is unlikely that her defect is in the LOH, said the nephrology consultant. Therefore I suspect a defect in the production of in the PCT. A common cause for a low rate of production of is an alkaline PCT cell due to hyperkalaemia, but her plasma potassium (K+) concentration (PK) was not elevated. The other common cause of a low rate of production is a low GFR, but her GFR was not low. Therefore I cannot identify a cause for his low rate of production of , said the nephrology consultant.
Hence Professor McCance was now the focus of attention. He was asked to provide a possible explanation for the low rate of production of . While the step-by-step analysis of the case appeared to be logical, he wondered if the patient could have an alkaline PCT cell in the absence of hyperkalaemia or an alkaline pH of blood. Professor McCance asked, ‘Is there a non-invasive way to gauge the pH of PCT cells in vivo?’
Question 9. How can the pH of PCT cells be assessed in vivo?
The nephrology consultant pointed out that the rate of excretion of citrate could provide a ‘window’ on the PCT cell pH.7 Metabolic acidosis and hypokalaemia are conditions associated with a low pH in cells of the PCT, and there is a low rate of excretion of citrate in these settings. A notable exception is in patients with isolated proximal renal tubular acidosis (pRTA). Some of these patients have a high rate of excretion of citrate despite the systemic metabolic acidosis. Accordingly, it has been suggested that the underlying pathophysiology of this disorder is an alkaline PCT cell pH.8 Therefore, if this patient had an alkaline PCT cell pH, the consultant said he would expect to find a high rate of citrate excretion.
Return to the experimental data: The rate of excretion of citrate in the patient was higher than in the control population (Table 1). Professor McCance seemed intrigued by this observation, and said that an alkaline PCT cell might provide an explanation for the low availability of NH3 and thereby, the low urine pH. Obviously impressed by their Professor's thinking, the housestaff asked, ‘Why might her PCT cells have a more alkaline pH?’
Question 10. Why might her PCT cells have a more alkaline pH?
Although it is possible to have a low rate of production of and a high rate of excretion of citrate due to eating an alkaline diet, this was not likely in our patient, because the urine pH would be high if this were the case. Therefore, to account for a somewhat more alkaline PCT cell pH, she might have a reduced rate of export of or an increased rate of export of H+ from PCT cells, stated Professor McCance (Figure 6). He went on to point out that the putative lesion, however, should only involve PCT cells. ‘Can anyone help me as to a likely candidate for this lesion?’ he asked. The nephrology consultant said that a defect in the 
cotransporter (NBC) in the basolateral membrane of PCT cells was a possibility. A lesion that increases the Km of this transporter (the concentration of needed for exit of from PCT cells into the body) or decreases its maximum velocity (Vmax) could lead to a steady state with a more alkaline intracellular pH. In fact, mutations in the gene encoding for NBC had been recently described in patients with isolated proximal RTA.9
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The medical registrar pointed out that an alkaline PCT cell pH should lead to a diminished rate of
reabsorption by PCT. If this occurred, the patient should have metabolic acidosis with a normal anion gap and a high urine pH, he argued.
Question 11. Why might our patient not have bicarbonaturia?
While admiring his younger colleague's analysis, Professor McCance suggested that the degree of rise in the PCT cell pH could be small enough to cause only a small decrease in the rate of reabsorption in this nephron segment. If downstream nephron segments could reabsorb this small extra load that escaped reabsorption in the PCT, there would be no bicarbonaturia. Of course, the cause for an alkaline cell pH would have to be present in the PCT, but not in the distal nephron. The urine pH could be low if there was a low availability of NH3 in the medullary interstitial compartment. Professor McCance was pleased to learn that patients with isolated proximal RTA typically have a low urine pH.10
While the processes were possible, Professor McCance needed more time to consolidate his ideas about excretion and control of the urine pH. He needed to ask the nephrology consultant for more detailed information, and therefore he drew this portion of the consultation to a close, suggesting that they return to continue exploring this fascinating problem tomorrow.
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After the adjournment |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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Professor McCance met the team in their seminar room the following morning. The nephrology consultant summarized the traditional view of the excretion of
as follows. The primary factor to augment the excretion of is a very high H+ concentration in the lumen of the MCD. This permits NH3 to diffuse down its concentration difference from the interstitial compartment into the lumen of the MCD.
Professor McCance chose to provide the team with reasons why he now had doubts about this traditional interpretation of the importance of a low urine pH to enhance the excretion of during chronic metabolic acidosis—his doubts focused on the diffusion of NH3 and the recently published data on this process. To explain this new understanding, Professor McCance summarized his analysis of the data and the responses to the questions he had asked the nephrology consultant.
Question 12. Is diffusion of NH3 in the medullary interstitial compartment a physiologically important pathway?
Physiology principle 6. Diffusion is a slow process with three major elements—a high concentration of the substance that diffuses, a very short distance for diffusion, and the absence of a barrier for diffusion.
(a) Concentration of NH3. Although NH3 is transported across the basolateral membrane out of cells of the mTAL,11 with the prevailing pH of the medullary interstitium, the concentration of NH3 will be low, only 1/100 that of .
(b) Distance for diffusion: Because the mTAL is in very close contact with the MCD, perhaps this is not a major issue.
(c) Barrier for diffusion: Both the basolateral and luminal membranes of cells of the MCD have lipid as a major constituent, Professor McCance had doubts that NH3 would diffuse quickly across lipid barriers.
In summary, these reservations raised the possibility that could be the species that is important for diffusion. For this to occur, there must be a way to transport across cell membranes or a special way to convert NH4+ to NH3 in cell membranes. I shall come back to this in a few minutes, he said. Professor McCance was intrigued by another question, ‘What is the quantitative importance of this medullary shunt pathway to the excretion of ?’ His reasoning was that if the excretion of was not its major function, perhaps this shunt pathway served a different purpose.
Question 13. How much is added in the MCD during chronic metabolic acidosis?
Because invasive procedures are needed to obtain fluid from the end of the cortical collecting duct, the data to examine are from experiments performed in rats with chronic metabolic acidosis. Sajo et al.12 found that 75% of excretion in these rats was already present in the luminal fluid obtained from the end of the cortical collecting duct. Therefore, the medullary shunt of could only account for approximately 25% of the excreted during chronic metabolic acidosis.
Our Professor emphasized the results of a second experiment that he was informed about by the nephrology consultant.13 Its objective was to assess the importance of this medullary shunt pathway for the excretion of . The premise was that the rate of excretion of should decline when this recycling process in the LOH is inhibited, if its primary function were to increase the rate of excretion of . Nevertheless, the rate of excretion of rose after a loop diuretic was administered.13 This suggests that the medullary reabsorption of and its shunt across the medullary interstitial compartment may serve a different function than simply increasing the excretion of . To deduce this function, he had asked, ‘What happened to the urine pH when the transport of was inhibited?’ A striking finding was a fall in the urine pH said the nephrology consultant. ‘Aha‘, said Professor McCance, ‘perhaps we now have an idea of the function of this shunt pathway, control of the urine pH’. This insight led to his final question for the nephrology consultant.
Question 14. Is there a transporter for across the basolateral and luminal membrane of the MCD cells?
The nephrology consultant had read a recent review on this subject.14 There were two different, but highly related transporters in cells of the MCD that carried out this function. They were both Rh-glycoproteins that might serve as cation exchangers where and H+ moved in opposite directions; one was in the luminal membrane and the other in the basolateral membrane of MCD cells. Professor McCance quickly pointed out that the net effect of this electroneutral cation exchange is the net unidirectional movement of NH3. The nephrology consultant was amazed! He pointed out that these Rh glycoproteins actually are NH3 channels, but with one additional property, they have a hydrophobic mouth, which strips a H+ ion off of NH4+.15 This is akin to lowering the pK of by 3 log units in this local region.
Professor McCance speculated that the major function of the medullary NH3 shunt pathway might not be to achieve high rates of excretion of , but possibly to prevent a large fall in the urine pH. This can be accomplished by having diffusion of NH3 into the lumen of the MCD to remove H+ secreted by the MCD.15 In this process, distal H+ secretion led to the formation of into the lumen of the MCD. Hence this process would function as an adjuster of the urine pH if the NH3 channel opening were modulated appropriately.
Professor McCance drew Figure 8 on the blackboard. Let us begin with the reabsorption of from the loop of Henle, which adds NH3 to the medullary interstitial compartment (the H+ to convert it to are added at site 3 in Figure 8). Recycling of in the loop of Henle raises the concentration of in the medullary interstitium6 (site 1, Figure 8). can diffuse rapidly enough through the renal medullary interstitial compartment because its concentration is high. NH4+ in the form of NH3 diffuses across both lipid-containing cell membranes of the MCD via these two different NH3 channels, one on the basolateral and another on the luminal membrane of these cells (site 3). The NH3 entry into the lumen of the MCD could adjust the urine pH upward (towards 6.0) by removing luminal H+ despite continuing H+ secretion by the H+-ATPase. The net result is a final urine pH that is approximately 6.0 with a somewhat higher rate of excretion. Professor McCance was intrigued by how the system is ‘smart enough’ to achieve a high rate of renal new generation without requiring a large fall in the urine pH, with its associated danger of increasing the risk of forming uric acid kidney stones.
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and He had one more question for the nephrology consultant. He said that he could now understand why uric acid crystals would form in the urine, but it was unclear how they could be retained and grow within the lumen of the MCD.
Question 15. What mechanism could permit uric acid deposits to grow over weeks or months of time, yet continue to be retained in the lumen of the MCD?
The nephrology consultant had a smile on her face. Until recently, she too had been perplexed by this paradox. Fortunately, a recent publication by Evan and colleagues provided a possible answer to Professor McCance's excellent question.16 These investigators had found that the site where calcium oxalate stones began was very surprising—in the basolateral membrane of the thin ascending limb of the loop of Henle. The initial lesion was a deposit of apatite (Ca3(PO4)2), a very difficult precipitate to form, because one needs an area with appreciable alkalinization to convert divalent phosphate to its trivalent form (
). Once this nidus forms, solutes whose concentration exceeds their Ksp will be added at this site. Over time, the deposit enlarges to form what is called ‘Randall's plaque’. Continuing growth and erosion lead to its exposure in the lumen of the papilla or the papillary-collecting duct. Once exposed, urine that is supersaturated with ionized calcium and oxalate will force crystals to deposit on its surface and the precipitate grows intermittently, but progressively.17 While the above is true for calcium oxalate stone formation in patients with hypercalciuria, there are no similar data published concerning the growth of uric acid stones.
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Concluding remarks |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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Using an approach that emphasizes an understanding of simple physiological concepts, several new insights into the pathophysiology of uric acid stone formation and the physiology of
excretion were revealed (Table 3). In the clinical evaluation of these patients, more valuable information about the pathophysiology of kidney stone formation would be available if multiple 2–3-hourly collections were obtained over the 24-h period rather than from a single 24-h urine collection. Regarding the physiology of excretion, it appears that the medullary reabsorption of and its shunt across the medullary interstitium serves a primary function of controlling the final urine pH rather than contributing significantly to achieve high rates of excretion. Therefore a persistently low urine pH could be due to three lesions (Figure 8): first, there could be a primary increase in the rate of H+ secretion in the distal nephron; second, there could be a diminished open probability of either of the 
channels in the MCD; third, there could be a lower concentration of the substrate for these NH3 channels (medullary interstitial ), most likely due to a lower rate of production of in the PCT.
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In the patient discussed in this manuscript, a low rate of
excretion together with a high rate of excretion of citrate suggested that her defect was a more alkaline pH in PCT cells. |
Appendix: Possible advantages for deletion of the uricase gene in Paleolithic times |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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Most mammals possess the oxidative enzyme uricase in peroxisomes of hepatocytes, which degrades urate into the water-soluble product, allantoin, that is excreted by the kidneys. In contrast, in humans, the uricase gene is not expressed as a result of mutational silencing, and urate is the end-product of purine metabolism that is excreted by the human kidney.
During evolution, trade offs were required to accommodate many and seemingly conflicting demands. These trade-offs should provide biological advantages for survival.18 These advantages, however, may not be obvious in our modern day industrialized society, and perhaps may be even considered as a disadvantage.
An intriguing hypothesis has been recently proposed by Johnson et al.19 concerning the low availability of NaCl in primitive diets. In their hypothesis, deletion of the uricase gene led to better conservation of NaCl and thereby defense of blood pressure. They showed that when experimental animals were given a drug to cause an acute increase in serum urate, there was both improved renal conservation of NaCl and an increase in blood pressure, because of the action of urates to activate the renin-angiotensin system in response to a low salt diet. Higher plasma urate also induces renal microvascular and interstitial disease, which leads to salt sensitivity and a chronic increase in blood pressure. While this may have provided survival advantage during early development in modern society, the switch to a high salt diet in conjunction with this mutation may play an important role in the current epidemic of hypertension and cardiovascular disease. In this regard, plasma urates are an independent risk factor for both hypertension and atherosclerotic heart disease.20
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Footnotes |
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Address correspondence to Professor M.L. Halperin, St. Michael's Hospital, 38 Shuter Street, Toronto, Ontario M5B 1A6, Canada. e-mail: mitchell.halperin{at}utoronto.ca
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References |
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TopSummaryIntroductionThe consultationSynopsis of uric acid...Results of the mini-experimentIssues concerning a low...After the adjournmentConcluding remarksAppendix: Possible advantages...References |
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