Sandra Sabatini

The Effect of Pregnancy on Renal Function: Physiology and Pathophysiology

Marked changes in renal function occur with pregnancy. We present a summary of these changes in this review and give insight into possible mechanisms if they are known. Controversies exist regarding the therapy of pregnancy-induced hypertension and asymptomatic and recurrent bacteriuria. The current views on these topics are given. Specific renal diseases are summarized, including transplantation, and optimum management strategies and maternal and fetal prognosis during pregnancy are given.

Regulation of collecting tubule adenosine triphosphatases by aldosterone and potassium.

To examine the precise role of potassium and aldosterone on acid-base composition and on collecting tubule ATPases, glucocorticoid-replete adrenalectomized rats were replaced with zero, physiological, or pharmacological doses of aldosterone and were fed varying potassium diets to produce hypokalemia, normokalemia, or hyperkalemia. Radiochemical measurement of ATPase activities showed that collecting tubule H/K-ATPase changed inversely with potassium and not with aldosterone whereas H-ATPase changed directly with aldosterone but not with potassium. When both enzymes changed in the same direction, alterations in acid-base composition were profound; however, when these two acidifying enzymes changed in opposite directions or when only one enzyme changed, the effect on acid-base balance was modest. Serum bicarbonate was approximately 45 meq/liter when aldosterone was high and potassium was low; it was only 29 meq/liter when aldosterone was high but potassium was normal or when aldosterone was normal and potassium was low. Our observations may help explain the metabolic alkalosis of primary aldosteronism in which aldosterone excess and hypokalemia are combined and the metabolic acidosis of aldosterone deficiency in which hypoaldosteronism and hyperkalemia are paired. The present study also demonstrated that aldosterone plays the major role in controlling Na/K-ATPase activity in cortical collecting tubule. Hypokalemia stimulates Na/K-ATPase activity in the medullary collecting tubule; this stimulatory effect of hypokalemia supports the hypothesis that the enzyme is present on the apical membrane at this site.

Drug substitution in transplantation: A National Kidney Foundation white paper

Specific safeguards to guide the approval process and substitution practices for generic immunosuppressive agents are necessary for the effective delivery of patient care. Currently, the Food and Drug Administration (FDA) requires the demonstration of bioequivalence of generic drugs to innovator drugs in normal healthy subjects, a criterion that may be insufficient for critical-dose drugs. For generic equivalents of critical-dose drugs and for innovator critical-dose drugs, there should be a requirement for replicate studies measuring intrasubject variability and subject-treatment interactions to establish that bioequivalence holds true. Extensive testing of generic drugs in all target patient types is impractical and should not be required. However, when evidence suggests that the bioavailability of a critical-dose drug may vary substantially in certain subgroups, the FDA should require a demonstration of bioequivalence of generic versions to innovator products in these representative target populations. Changes in the approval process for generics should be accompanied by more consistent substitution practices. Pharmacists should notify the prescribing physician and patient whenever a critical-dose drug (generic or brand name) is dispensed in a different formulation from the one the patient has been taking. Therapeutic substitution for such drugs should not be made unless the prescribing physician has granted approval. The health care provider should consider instituting appropriate monitoring whenever patients are switched between generic formulations or between innovator drugs and generic formulations. Patients should be well informed about generic substitutes so that they can participate in treatment choices.

Bicarbonate Therapy in Severe Metabolic Acidosis

The utility of bicarbonate administration to patients with severe metabolic acidosis remains controversial. Chronic bicarbonate replacement is obviously indicated for patients who continue to lose bicarbonate in the ambulatory setting, particularly patients with renal tubular acidosis syndromes or diarrhea. In patients with acute lactic acidosis and ketoacidosis, lactate and ketone bodies can be converted back to bicarbonate if the clinical situation improves. For these patients, therapy must be individualized. In general, bicarbonate should be given at an arterial blood pH of < or =7.0. The amount given should be what is calculated to bring the pH up to 7.2. The urge to give bicarbonate to a patient with severe acidemia is apt to be all but irresistible. Intervention should be restrained, however, unless the clinical situation clearly suggests benefit. Here we discuss the pros and cons of bicarbonate therapy for patients with severe metabolic acidosis.

Altered sodium pump alpha and gamma subunit gene expression in nephron segments from hypertensive rats.

OBJECTIVE To determine the qualitative and quantitative expression of alpha and gamma sodium pump subunits in whole kidney and nephron segment RNA from Sprague Dawley rats, spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. DESIGN A novel reverse transcription polymerase chain reaction technique was devised which provides accurate and precise measurement of the number of molecules of specific transcript abundance, a measurement of gene expression. This allows the quantitative comparison of multiple samples across multiple subjects and, since the estimates are accurate rather than relative, can also be used to make quantitative comparisons across expressed genes, such as isoforms and subunits of the heterotrimeric renal sodium pump. METHODS We examined which catalytic isoforms were expressed and then quantified transcript abundance in whole kidney and convoluted and straight segments of the proximal tubule. RESULTS Alpha 1 and gamma transcripts, but not alpha 2, alpha 3 or alpha 4 isoforms, were consistently observed in nephron segments. Levels of alpha 1 were lower in kidney RNA from 15-16-week-old SHR than in WKY rats of the same age (P = 0.001), but were not different between SHR and WKY in 4-5-week-old animals. No significant difference was observed in gamma subunit abundance in kidney RNA from 4-5-week-old animals; however, at 15-16 weeks, the expression in SHR was one-third that in WKY rats (P = 0.003). In proximal convoluted tubules from 4-5-week-old animals, the level of alpha 1 RNA expression was lower (P = 0.03) in SHR than in WKY rats. In addition, levels of alpha 1 in proximal straight tubule from the 4-5-week-old SHR were also lower than in WKY rats (P = 0.02). This difference was even greater in 15-16-week-old animals: in SHR, alpha 1 expression was less than 20% of the level of expression in WKY rats (P = 0.0003). Expression of the gamma subunit exhibited a similar pattern of downregulation in SHR. In RNA from proximal convoluted tubules and proximal straight tubules from both 4-5- and 15-16-week-old animals, expression of the gamma subunit was demonstrated to be significantly lower in SHR than in WKY rats. CONCLUSION The results indicate a coordinate reduction in the abundance of sodium pump alpha and gamma subunits in the proximal tubules of SHR, which occurs early during the development of hypertension.

Pathophysiologic Mechanisms in Analgesic-Induced Papillary Necrosis

The nonnarcotic analgesics have been implicated as a significant cause of chronic renal failure worldwide. Epidemiologic studies of habitual abuse and necropsy studies show a strong relationship between the two. Animal studies designed to elucidate underlying mechanisms have been hampered because the lesion occurs infrequently and only after very high doses are given for prolonged periods; however, the Fischer 344 and Wistar rats appear to be more sensitive, and substantial new information should be forthcoming. In this review, some of the evidence for the possible mechanisms of papillary necrosis are presented: prostaglandin inhibition, reduction or redistribution of renal blood flow, direct cellular injury, free radical formation, and immunologic injury. At present, most data support prostaglandin inhibition and reduction or redistribution of renal blood flow, but direct cellular injury also appears to be very important.

Age-Related Changes in Renal Function, Membrane Protein Metabolism, and Na,K-ATPase Activity and Abundance in Hypokalemic F344 × BNF1 Rats

Background: Potassium depletion is a common electrolyte abnormality in elderly humans, usually as a consequence of diuretic use or poor oral intake. Hypokalemia is associated with a number of changes in renal function and an increase in some renal membrane transporters; its growth-promoting effect in young animals is well known. With aging, the renal adaptation to a number of challenges is often diminished. We hypothesized that aging is related to decreases in renal function, renal membrane protein metabolism, as well as Na,K-ATPase protein abundance and activity in both control animals as well as in those with potassium depletion. Objective: We examined the effects of dietary-induced hypokalemia in true-aged nonobese rats (30 months old) on renal function, cortical brush border membrane (BBM) and basolateral membrane (BLM) protein metabolism, and Na,K-ATPase protein abundance and activity. We compared the results obtained to those seen in their 4-month-old counterparts similarly treated. Methods: Young (4-month-old) and senescent (30-month-old) male Fisher 344 × Brown-Norway F1 rats (F344 × BNF1) were fed either a normal or potassium-deficient diet for 7 days. At 24 h, the U-14C-leucine incorporation was measured for determination of protein metabolism in renal BBM and BLM. Cortical BLM vesicle and microdissected proximal convoluted tubule (PCT) Na,K-ATPase activities were determined along with Western blot analysis of the cortical BLM α1 subunit of Na,K-ATPase. Metabolic and renal function parameters were also examined. Results: Hypokalemia caused hyperbicarbonatemia, hyperglycemia, and azotemia, but only in the senescent animals. The aged control rats had a higher basal level of urine volume, ammonium excretion, and fractional excretion of chloride. By contrast, aging in the F344 × BNF1 rats was associated with a decrease in plasma aldosterone (by 35%) and phosphate (by 40%) levels as compared with their young controls. Hypokalemia resulted in a significant reduction of plasma aldosterone and a rise in muscle sodium concentration in both age groups; it significantly increased renal BBM and BLM protein concentrations in the young group, while these parameters remained unchanged in the senescent rats. The aged potassium-depleted animals showed a 14% decrease in BBM protein biosynthesis, but there were no changes in the young hypokalemic rats. Both potassium-depleted elderly and young rats had a significant reduction (by 33%) in BLM protein biosynthesis. Hypokalemia significantly increased the Na,K-ATPase activity in both cortical BLM vesicles and in microdissected PCT. The percentage increase in microdissected PCT segments (Na,K-ATPase activity) in elderly potassium-depleted animals was significantly less than that seen in hypokalemic young ones. Aging, per se, was associated with decreased basal microdissected PCT Na,K-ATPase activity in control animals. Hypokalemia had no effect on cortical BLM α1 subunit Na,K-ATPase protein abundance in either age group. Conclusions: The present study provides the first evidence in nonobese aged rats as to the metabolic parameters, renal function, renal cortical membrane protein metabolism, and transporter Na,K-ATPase activity and abundance during potassium depletion. The aged nonobese F344 × BNF1 rats responded differently from their young nonobese counterparts following potassium depletion. These differences may contribute substantially to the effects often encountered in elderly humans receiving diuretics or having a poor dietary potassium intake.

Renal Na+, K+-ATPASE In SHR: Studies of Activity And Gene Expression

The mechanism by which increased dietary intake of calcium reduces blood pressure in the spontaneously hypertensive rat is unknown. The present studies were designed to determine if there were alterations in the activity of the major membrane ion translocating pump, sodium, potassium-ATPase (NKA), in the kidneys of hypertensive rats and whether increased dietary calcium intake affected the activity of this enzyme. Fifteen-week old SHRs were found to have lower total ATPase activity in microsomal preparations from the kidney than age matched Wistar-Kyoto animals. Both the ouabain-sensitive component (NKA) and the ouabain-insensitive component were lower in SHR. Increasing dietary calcium intake from 1% to 3% elevated both components of the ATPase activity in SHR, but was without effect in WKY. Measurement of membrane phospholipid composition suggested that altered phospholipid composition did not account for the reduced ATPase activity observed, but indicated a reduced density of ATPase in SHR. A technique has been devised for qualitative and quantitative analysis of Na, K-ATPase alpha isoforms using RT-PCR. This technique reveals that the alpha 1 isoform is the sole catalytic isoform present in the nephron. Accurate and precise quantification of the amount of gene expression in individual nephron segments is reported and will be applied to determine whether dietary calcium influences blood pressure by a mechanism which alters nephron NKA gene expression.

Effects of aging and potassium depletion on renal collecting tubule K+‐controlling ATPases

SUMMARY: The effects of aging and potassium depletion (KD) on renal cortical and medullary collecting tubule (CCT and MCT) K+‐controlling ATPase activities, Na+,K+‐ATPase and H+,K+‐ATPase, were performed in 4 and 30 month‐old male Fischer 344 x Brown‐Norway F1 (F344xBNF1) rate. Following KD, which was induced by a K+‐deficient diet for 7 days, both animal age groups had comparable levels of hypokalaemia, but the decreased fractional excretion of K+ (FEK+) was more prominent in the old‐age group. the aged animals had a 37% lower basal Na+,K+‐ATPase activity in MCT (P < 0.05), but marked increases in basal H+,K+‐ATPase activity in both CCT and MCT (P<0.001) were noted. Potassium depletion resulted in 28% (P<0.05) and 66% (P<0.01) increases in CCT and MCT Na+,K+‐ATPase activities, respectively, in the young‐age group. In the old‐age group, KD caused a 125% (P< 0.001) increase in MCT Na+,K+‐ATPase activity, but had no effect on CCT Na+,K+‐ATPase activity. the collecting tubule H+,+‐ATPase activity was increased in both the young and old‐age KD groups. the increase of magnitude in the latter was much higher than in the former. In response to KD, the more prominent rises in CCT and MCT H+,K+‐ATPase activities (with an increased percentage in MCT Na+,K+‐ATPase activity) was observed in the old‐age animals when compared with the younger ones. This could result in an increased K+ reabsorption, leading to the lower value of FEk+. Thus, the K+‐controlling mechanisms in the renal collecting tubule of aging rats are still intact and effective in coping with KD.

Women, Medicine and Life in the Middle Ages (500-1500 AD)

The status of women in the Middle Ages was ambiguous, because although they had great responsibility and expertise in practical affairs they were viewed as chattel and inferior to men. They were skilled in cookery, often of highly spiced dishes using a variety of ingredients and flavorings, and they were taught the use of medicinal herbs. They were often skilled in simple first aid, though they were not allowed to practise outside the home. An important exception of this was Hildegarde von Bingen, whose Physica brought her great renown. In it she became the first woman to discuss plants in relation to their medicinal properties. For most people in the Middle Ages, treatment revolved around herbs and diet, together with faith and holy relics and the use of (forbidden) pagan incantation and ritual. Astrology was often a necessary adjunct to treatment. In Salerno, however, medicine had been practised from classical times, and medical training could last for 7 years or more. One of the greatest medieval medical texts is the Tacuinum Sanitatis, which describes in detail the 6 essentials for the preservation of mans health. Several vegetables and herbs are mentioned in connection with the kidneys, the picking and preparation of which are imbued with magic.