Electrolyte content and ultrastructure of the kidney in hamsters with heart failure

Electrolyte (Na, K, Ca, Mg) concentrations were measured in the urine, serum, and renal tissues of cardiomyopathic (BIO 14.6) hamsters, during various stages of spontaneous congestive heart failure, and correlated with ultrastructural changes in renal tubules. The renal concentration of sodium was significantly elevated during the very early (subclinical) stages of congestive heart failure. Further increases paralleled the progress of the disease. The derived data indicate an intracellular location for the augmented load of sodium in the kidney. The magnesium concentrations in the kidney remained unchanged and the variations in renal potassium proved to be significant only during the advanced stages of cardiocirculatory insufficiency. Young cardiomyopathic hamsters had low renal calcium concentrations in spite of elevated serum calcium levels. However, during the terminal phase of congestive heart failure, the calcium values in the kidneys of cardiomyopathic hamsters were higher despite lower serum calcium values. The proximal and distal convoluted tubules as well as the cortical collecting tubules during severe congestive heart failure were characterized by marked widening of the extracellular spaces between the basilar interdigitating processes. The distal convoluted tubules exhibited edema and mitochondrial alterations and the intercellular spaces of the collecting tubules were dilated. These tubular changes indicate an increased flow of water and ions.     

Acute calcium nephrotoxicity. An electron microscopical and semiquantitative light microscopical study.

Rats were infused for three hours with doses of calcium gluconate to elevate serum calcium level and were killed either immediately after infusion or after 24 hours. Necrosis of proximal tubular cells was observed when serum calcium level was 16.0 mg/dl or higher. Above 16.0 mg/dl, an additional 5% of renal tubular profiles contained damaged cells for each 1 mg/dl in serum calcium. No difference in extent of damage was found in rats killed immediately or after 24 hours. Initial changes were formation of granular dense bodies in mitochondria, cell swelling, rupture, and extensive mitochondrial calcification. Renal tubular basement membrane changes appeared to be initiated by protrusion of cytoplasmic buds, forming ovoid bodies, which became embedded in the basement membrane. These ovoid bodies then appeared to serve as a nidus for further extensive basement membrane calcification.     

Ultrastructure of the Kidney in Acute Interstitial Nephritis

Fifteen percutaneous renal biopsies from patients with acute renal failure due to acute interstitial nephritis (AIN), in almost all cases due to drugs, were studied by electron microscopy. Differential counting of interstitial cells showed an average of 69% lymphocytes (small and large) and 11 % macrophages. Plasma cells and eosinophils were comparatively rare. The infiltrate resembled that of acute rejection, suggesting a cellular hypersensitivity reaction. Proximal and distal tubules were severely affected focally. Migration of lymphocytes through the tubular basement membrane of otherwise well-preserved tubules was considered to be the first phase. Other tubules showed extreme thinning of the tubular basement membrane, with still intact cellular walls. Rupture of the tubular basement membrane and necrotic disintegration of tubular epithelial cells are probably late phenomena. The non-necrotic tubules displayed severe reduction of proximal brush border and proximal as well as distal tubular basolateral infoldings. Focal tubular disintegration leading to tubular block and/or backleak as well as decrease of proximal tubular sodium resorption leading to a decreased glomerular filtration (a mechanism probably also acting in ischemic acute renal failure) may all be factors responsible for the acute renal failure in AIN.     

Cyclosporine A-induced kidney alterations are limited by melatonin in rats: an electron microscope study

The effect of melatonin on experimental prolonged cyclosporine A (CsA) nephrotoxicity was analyzed by electron microscopy and morphometry. Twenty female Wistar rats were divided into groups that received (1) CsA at a therapeutic dose (15 mg/kg/day) sc for 40 days; (2) olive oil, CsA vehicle, as controls; (3) CsA plus melaton (1 mg/kg) ip for the same time; (4) melatonin alone, as additional controls. All controls had normal renal ultrastructure. However, in CsA group, both tubular and glomerular alterations were observed. The authors found apoptotic and necrotic proximal tubules with disrupted brush border, swollen mitochondria, abundant lysosomes; in the glomerulus, amorphous basement membrane, and abnormal mesangial matrix. CsA plus melatonin administration partly prevented these changes. Nevertheless, fibrillar deposits in podocytes and basolateral membrane dilatations in proximal tubules were observed. Histopathological analysis on semithin sections and ultrastructural morphometry were also performed. CsA induced interstitial fibrosis, atrophy, and PAS positive inclusions in the proximal tubules. Moreover, CsA reduced glomerular and mesangial volume but enhanced mesangial matrix volume and basement membrane thickness. After CsA plus melatonin, these parameters were reduced in the proximal tubules and restored in the glomerulus. In conclusion, melatonin attenuated morpho-quantitative alterations induced by CsA in the rat kidney.     

Cyclosporine A-Induced Kidney Alterations Are Limited by Melatonin in Rats: An Electron Microscope Study

The effect of melatonin on experimental prolonged cyclosporine A (CsA) nephrotoxicity was analyzed by electron microscopy and morphometry. Twenty female Wistar rats were divided into groups that received (1) CsA at a therapeutic dose (15 mg/kg/day) sc for 40 days; (2) olive oil, CsA vehicle, as controls; (3) CsA plus melaton (1 mg/kg) ip for the same time; (4) melatonin alone, as additional controls. All controls had normal renal ultrastructure. However, in CsA group, both tubular and glomerular alterations were observed. The authors found apoptotic and necrotic proximal tubules with disrupted brush border, swollen mitochondria, abundant lysosomes; in the glomerulus, amorphous basement membrane, and abnormal mesangial matrix. CsA plus melatonin administration partly prevented these changes. Nevertheless, fibrillar deposits in podocytes and basolateral membrane dilatations in proximal tubules were observed. Histopathological analysis on semithin sections and ultrastructural morphometry were also performed. CsA induced interstitial fibrosis, atrophy, and PAS positive inclusions in the proximal tubules. Moreover, CsA reduced glomerular and mesangial volume but enhanced mesangial matrix volume and basement membrane thickness. After CsA plus melatonin, these parameters were reduced in the proximal tubules and restored in the glomerulus. In conclusion, melatonin attenuated morpho-quantitative alterations induced by CsA in the rat kidney.     

Fibroblast growth factor (FGF) 23 works as a phosphate-regulating hormone and is involved in the pathogenesis of several disorders of phosphate metabolism

Fibroblast growth factor (FGF) 23 was identified as the latest member of the FGF family. Subsequent studies showed that FGF23 reduces the serum phosphate level by suppressing proximal tubular phosphate reabsorption. This phosphaturic action of FGF23 derives from the suppressive effect of FGF23 on the expression of type 2a and 2c sodium-phosphate cotransporter in the brush border membrane of proximal tubules. At the same time, FGF23 reduces the serum level of 1,25-dihydroxyvitamin D [1,25(OH)2D] which results in suppressed intestinal phosphate absorption. Establishment of an enzyme-linked immunosorbent assay for FGF23 indicated that excess actions of FGF23 result in hypophosphatemic rickets/osteomalacia such as X-linked, autosomal dominant, autosomal recessive hypophosphatemic rickets/osteomalacia, and tumor-induced rickets/osteomalacia. In contrast, deficiency of FGF23 action causes hyperphosphatemic tumoral calcinosis. These results indicate that FGF23 is a hormone regulating serum phosphate and 1,25(OH)2D levels.     

Ultrastructural changes in the isolated rat kidney induced by conjugated bilirubin and bile acids.

The effects of bilirubin and bile acids on the ultrastructure of proximal renal tubules have been studied using an isolated rat kidney preparation, perfused with a protein-free dextran medium. Control kidneys perfused for 1 h had a normal glomerular filtration rate and effective renal plasma flow; the ultrastructure of proximal tubular cells was well preserved, with normal mitochondria, nuclear and plasma membranes, and microvilli of the brush border. When conjugated bilirubin, prepared from human hepatic bile, was added to the perfusion medium (5-0-7-5 mg/100 ml), marked alterations were observed in some cells, particularly with regard to the mitochondria and plasma membranes. These changes were greatly diminished by the inclusion of bovine albumin in the medium, indicating that the unbound fraction was primarily responsible for the tubular damage. The addition of taurocholate (450 muM), taurochenodeoxycholate (550 muM) or taurolithocholate (250 muM, bound to albumin) also produced plasma membrane changes, but only slight abnormalities were seen in the mitochondria and other structures. These ultrastructural observations support the concept that the elevated plasma levels of conjugated bilirubin and to a lesser extent bile acids are related to the renal failure associated with obstructive jaundice.     

Pathological study on beagles after long-term oral administration of cadmium.

Histopathological, histochemical, and electron microscopic examinations were performed on beagles after a long-term oral cadmium (Cd) administration of greater than 8 years. Although renal atrophy was remarkable in groups receiving doses of 50 and 100 mg/kg body weight/day, bone lesions could not be demonstrated by roentgenological and histopathologic examination. It was noticed that concomitant regeneration or recovery and cell death of the epithelium occurred in the proximal convoluted tubules. The cell death was consistent with apoptosis, a special feature of cell death, which was shown to play a major part in the tubular damage of cadmium by electron microscopic examination. Fatty degeneration of the pars recta tubules was seen to show dose-dependence. The intrarenal cadmium was localized predominantly in the cytoplasm of the proximal tubular epithelium by histochemical and ultracentrifugal cell fractionation examinations. Although no remarkable changes were found in the other organs, aggregates of siderophages in the liver and focal hemorrhage in the spleen, known as spontaneous lesions, might be related to Cd intoxication. In conclusion, the present study revealed that no bone lesions occur with Cd administration in adult beagles in spite of long-term administration. An excessive cell death to regeneration or recovery in the proximal tubules might result in the renal cortical atrophy. No remarkable changes were seen in the glomeruli and distal nephrons, which were in good agreement with Cd distribution.     

Morphology and hormonal responsiveness of renal cortical tubules in vitro

Isolated renal cortical tubules from male hamsters were prepared for studies in vitro in which the effects of parathyroid hormone (PTH) on cyclic nucleotide metabolism and efflux of intracellular calcium were investigated. Morphological studies were also conducted to evaluate the effects of the isolation procedure on the structural characteristics of the in-vitro preparation of tubules. Tubules, consisting of proximal, distal and collecting duct segments, were observed by electron microscopy to retain specific cellular membrane specializations which characterize these segments in situ (microvilli; basal infoldings and junctional complexes). Organelles were generally normal in their appearance; however, some swelling of mitochondria and endoplasmic reticulum were occasionally observed. Enzyme activity, associated with either luminal membranes (alkaline phosphatase) or lysosome-like organelles (acid phosphatase) was also retained following the isolation procedure. Preservation of the PTH-dependent, adenylate cyclase system in isolated tubules was demonstrated, indicating that membrane receptors for PTH were intact. Effects of PTH on cyclic GMP concentrations as well as efflux of ⁴⁵Ca were also demonstrated. These results indicate that the use of isolated renal tubules in vitro offers an excellent model system for further investigations concerned with mechanisms of hormonal action and regulation of cyclic nucleotide metabolism. The results also suggest a relationship in renal cortical tubules between PTH-mediated production of cyclic AMP, metabolism of cyclic GMP and transport of calcium.     

Mitochondrial Enlargement and Basement Membrane Thickening of Renal Proximal Tubules, Possible Initiators of Microalbuminuria in Non-Insulin-Dependent Diabetics (NIDDM)

To clarify the morphological changes in renal proximal tubules at the onset of diabetic nephropathy, we observed 177 biopsy samples from patients with Non-Insulin-Dependent Diabetics (NIDDM) using light and electron microscopy. Group I had no proteinuria (P.u.), group II had p.u. >0.5 g /day, group III had p.u. > 0.5 g day, group IV had serum creatine level (Cr) >1.5mg/dl. Twenty age-matched normal patients and 80 patients with IgA nephropathy were used as controls. In groups I and II, the following features were significantly different from those in the controls: spherical enlargement of mitochondria (MT) in proximal tubule cells, hypertrophy of proximal tubule cells and their nuclei, and thickening of both the proximal tubule basement membrane (TBM) and the glomerular basement membrane (GBM). Among the his-tological changes observed in group I, the thickness of the GBM and TBM indicated that the disease would lead to diabetic nephropathy. MT enlargement was positively correlated with nuclear and cytoplasmic enlargement of the proximal tubule cells in diabetic patients (p<0.05), but was not correlated with other morphological changes or disease prognosis. Glomerular nodular lesions, glomerular sclerotic change, and cortical tubulointerstitial fibrosis became evident in groups III and IV. From the above, we concluded that MT enlargement and thickening of the TBM are possible causes of reduced active transport in the proximal tubules, causing microalbuminuria in diabetics, and initial impairment of post-tubule transport. Acta Pathol Jpn 42: 793–799, 1992.     

A morphological and biochemical study of the effects of L-cysteine on the renal uptake and nephrotoxicity of cadmium.

In JCLR and Wistar-Porton rats renal concentrations of Cd2+ were maximal (21-22 micrograms Cd2+/g wet wt tissue) at 1 and 4 h respectively after the administration of CdCl2 (10 micromol, 1-12 mg Cd2+/kg body wt) together with L-cysteine (5 mmol/kg body wt). Synthesis of metallothionein in the kidney in response to the uptake of Cd2+, which occurred between 2 and 7 h after treatment in the Wistar-Porton rat, affected the distribution of Cd2+ between proteins of the renal soluble fraction, but not between the particulate components and, at both times, about 40% of the total Cd2+ was associated with the heterogeneous nuclei + cell debris fraction. Autoradiographic studies with 109CdCl2 revealed that Cd2+, accumulated by the kidney under these conditions, was not uniformly distributed throughout the renal cortex, but was concentrated unevenly in proximal tubules in the outer stripe of the outer zone of the medulla. Pathological changes, which were correlated with the concentrations of accumulated Cd2+ and were limited to the S3 segments of the proximal tubules, were apparent by light microscopy at 4 h after the administration of Cd2+ + cysteine and progressed with time. Thus by 7 h the lesion had extended to include almost the whole of the outer stripe of the outer zone of the medulla and, by 24 h the cells of the affected epithelia showed extensive necrosis and karyorrhexis. At this, as at earlier times, the cortex appeared to be undamaged. Neither these nor other morphological changes were observed in the kidneys of animals that had been dosed with either Cd2+, or L-cysteine alone. Within 60 min of the administration of Cd2+ + cysteine an increase in the number of endocytotic vesicles in the apical cytoplasm of the proximal tubular epithelium was observed by electron microscopy. Subsequent cytoplasmic vesiculation, which was conspicuous at 2 h, was extensive and widespread in both the apical and basal regions of the cytoplasm at 4 h. In some cells at this time the nuclei were irregular in shape; the mitochondria were swollen and their cristae were disorganized. As, after the administration of either Cd2+ or cadmium-metallothionein, damage is known to occur in the S1 and S2 segments of proximal tubules throughout the cortex, the Cd2+ + cysteine combination does not provide an exact model which reproduces in a short time the effects of long-term, low level exposure to Cd2+. Nevertheless it is suggested that the toxic mechanisms are the same after either treatment with Cd2+ + cysteine or continual exposure to Cd2+, but are limited to different segments of the proximal tubules. Possible mechanisms of toxicity are discussed.     

Effects of the calcium-channel blocker diltiazem on gentamicin-induced nephrotoxicity in rats

Injection of diltiazem (40 mg/kg/d) to gentamicin (75 mg/kg/d = G 75 or 100 mg/kg/d = G 100) treated rats enhances aminoglycoside-induced nephrotoxicity. As a result of this combination, acute renal failure becomes systematic and is often irreversible. The lesion is of tubular origin and is characterized by a large increase in the urinary N-acetyl-beta-D-glucosaminidase (u-NAG) activity and its NAG-B isoenzyme level. The phenomenon is twice as marked with G 75 (u-NAG x 6.8, NAG-B x 2.2) as with G 100 (u-NAG x 3.1, NAG-B x 1.1). The effect seems to be attenuated if diltiazem is administered as a preventive treatment or in drinking water. As well as its diuretic properties, diltiazem may aggravate the renal toxicity of gentamicin by reducing the proximal tubular availability of calcium. Diltiazem inhibits reabsorption and behaves like a non-competitive inhibitor of calcium. This deficiency favours the proximal tubular binding and the non-specific penetration of gentamicin in the cytosol and cellular organelles (microsomes, mitochondria). The tubular toxic symptoms which ensure (inactivation of membranaceous enzyme, reduction of microsomal protein synthesis and ATP level, decreased of solute reabsorptive flux) lead in turn to proximal tubular necrosis and acute renal failure.     

Quantitative ultrastructure of human proximal tubules and cortical interstitium in chronic renal disease (hydronephrosis)

Summary Surgically removed perfusion-fixed human kidneys with chronic renal disease (hydronephrosis) were studied by electron microscopy in order to determine whether there is a quantitative relationship between ultrastructural changes in proximal tubules in atrophy and changes in the surrounding cortical interstitium. Morphometric techniques were applied to montages of electron micrographs each covering several tubular profiles in the cortical labyrinth and to montages representing cross-sections of individual proximal convoluted tubules at a higher magnification. In order to enable a quantification of the spatial relations between individual tubular cross-sections and adjacent peritubular capillaries a tubulo-capillary index (TCI) was defined. This index was based on the mean distances between individual tubular cross-sections and adjacent peritubular capillaries and on the fraction of tubular circumference facing capillaries. Normal tissue from similarly fixed human nephrectomy specimens, which had been removed mainly because of neoplastic disorders, served as control material. In the hydronephrotic kidneys the relative volume of cortical interstitium (excluding capillaries) covered a range from 19.2–70.3%. Inverse correlations were demonstrated between the relative volume of cortical interstitium and various structural variables of proximal convoluted tubules, including tubular wall volume, the volume of mitochondria and the surface area of basolateral membranes. The TCI showed positive correlations with these tubular variables. No significant correlation was found between the volume fractions of cortical interstitium and capillaries. Finally, it was found that an increase in the volume fraction of the cortical interstitium from 16.2% in controls to 24.7% in cortical areas of hydronephrotic kidneys was associated with a 40–50% reduction in the volume of mitochondria and in the surface area of basolateral membranes in proximal tubules. The results are consistent with a pathogenic interrelationship between tubular and interstitial changes. An important factor in this relationship might be disturbed topographic associations between tubules and blood capillaries caused by the increase in cortical interstitium. The results further show that even slight increases in the cortical interstitial volume are associated with significant quantitative changes in tubular fine structure suggesting impaired tubular functions.This work was supported by grants from the Danish Medical Research Council (no 12-0528) and from the Research Foundation at the University of Aarhus     

Possible involvement of myofibroblasts in cellular recovery of uranyl acetate-induced acute renal failure in rats

Cellular recovery in acute renal failure is a form of wound healing. Fibroblast-like cells or myofibroblasts are involved in wound healing. We examined the serial changes in tubular damage and origin and kinetics of regenerating cells in uranyl acetate-induced acute renal failure, with a special emphasis on interstitial myofibroblasts. Acute renal failure was induced in rats by intravenous injection of uranyl acetate (5 mg/kg). All rats received bromodeoxyuridine intraperitoneally 1 hour before sacrifice. Serial changes in the distribution of tubular necrosis and bromodeoxyuridine-incorporated or vimentin-positive regenerating cells, and their spatial and temporal relation to alpha-smooth muscle actin-positive myofibroblasts as well as ED 1-positive monocytes/macrophages were examined. Necrotic tubules initially appeared around the corticomedullary junction after uranyl acetate injection, then spread both downstream and upstream of proximal tubules. Peritubular alpha-smooth muscle actin-positive myofibroblasts appeared and extended along the denuded tubular basement membrane, establishing network formation throughout the cortex and the outer stripe of outer medulla at days 4 to 5. Tubular regeneration originated in nonlethally injured cells in the distal end of S3 segments, which was confirmed by lectin and immunohistochemical staining using markers for tubular segment. Subsequently, upstream proliferation was noted along the tubular basement membrane firmly attached by myofibroblasts. During cellular recovery, no entry of myofibroblasts into the tubular lumen across the tubular basement membrane was noted and only a few myofibroblasts showed bromodeoxyuridine positivity. The fractional area of alpha-smooth muscle actin-positive interstitium reached a peak level at day 7 in the cortex and outer stripe of outer medulla, then gradually disappeared by day 15 and remained only around dilated tubules and in the expanded interstitium at day 21. ED 1-positive monocytes/macrophages were transiently infiltrated mainly into the region of injury. They did not show specific association with initially necrotic tubules, but some of them located in close proximity to regenerating tubules. Nonlethally injured cells at the distal end of proximal tubules are likely to be the main source of tubular regeneration, and the transient appearance of interstitial myofibroblasts attached to the tubular basement membrane immediately after tubular necrosis might play a role in promoting cellular recovery in possible association with monocytes/macrophages in uranyl acetate-induced acute renal failure.     

Absence of normal-appearing proximal tubules in the fetal and neonatal kidney: prevalence and significance

Rare fetuses and neonates with kidneys lacking normal-appearing proximal tubules have been described. In order to ascertain the prevalence of this histologic finding, and to study its associated clinicopathologic features, 500 consecutive perinatal autopsies (performed from 1981 to 1985) were reviewed. Kidneys lacking normal-appearing proximal tubules were found in six of 500 (1.2%) perinatal autopsies (one liveborn and five stillborn cases). The liveborn infant was one of a sibship with renal tubular dysgenesis. Four of the stillborn fetuses were derived from monochorionic twin gestations; the histologic abnormality was present in only one fetus from each twin pair. Three of the four twin pairs had pathologic features suggestive of twin-to-twin transfusion, with the renal abnormality present in the donor twin; renal hypoplasia existed in two instances. The fourth affected twin was a stillborn acardiac fetus with multiple congenital anomalies and unilateral renal agenesis. The fifth stillborn was a hydropic fetus with trisomy 21 and renal hypoplasia. In this series, lack of recognizable renal proximal tubules most often was not a manifestation of renal tubular dysgenesis. The histologic finding was associated with stillborn, renal hypoplasia, and congenital anomalies, and was strongly associated with monochorionic twinning (P = 0.001). In the stillborn cases in this series, we suggest that this finding may represent renal tubular degeneration resulting from renal hypoperfusion.     

Ultrastructural analysis of human proximal tubules and cortical interstitium in chronic renal disease (Hydronephrosis)

Summary A systematic ultrastructural analysis of proximal tubule atrophy and cortical interstitial changes was carried out in human chronic nephropathy. The investigation was based on human hydronephrotic kidneys, which had been surgically removed and subsequently perfusion-fixed for light and electron microscopy. Normal kidney tissue, which was derived from nephrectomy specimens with pathological changes confined to part of the kidney or to the renal pelvis, was used for control material. A slight degree of proximal tubule atrophy was characterized by reduction of mitochondria and basolateral membranes, enlargement of large endocytic vacuoles and increased numbers of lysosomes containing lamellar material. In moderate atrophy these changes were further accentuated, and in addition there was an increasing loss of microvilli and a reduction of endocytic invaginations and small endocytic vacuoles. In severe atrophy all types of organelles were sparse and the architecture of the tubule cells greatly simplified. A distinctive feature of atrophic tubules was the presence in the tubule cells of large bundles of actin-like filaments, which were often associated with outpouchings of basal cell parts and basement membrane. The reduction of mitochondria and basolateral cell membranes and the changes of endocytic vacuoles and lysosomes indicate that proximal tubule atrophy also in early stages may be associated with impairment of tubular transport processes. Comparisons with previous observations in various types of experimentally induced tubule cell degeneration and with the ultrastructure of regenerating proximal tubule cells provide some evidence that degenerative changes as well as imperfect regeneration of tubule cells may contribute to the alterations of ultrastructure in tubular atrophy. It is suggested that changes of the cortical interstitium may be of pathogenic importance for the progression of tubular atrophy by altering the spatial relationships between tubules and capillaries.This work was supported by grants from the Danish Medical Research Council (no 12-0528) and from the Research Foundation at the University of Aarhus.     

Rapid renal failure in a case of multiple myeloma: the role of Bence Jones proteins

The rapid onset of subacute renal failure in a patient without prior known kidney disease prompted the present study. A renal biopsy specimen showed the characteristic pathological changes of `myeloma kidney', including deposition of proteinaceous material in the lumen of the proximal tubules. Cellulose-acetate electrophoresis of the patient's serum failed to indicate any protein abnormalities, although Bence Jones proteinaemia was readily demonstrated by agar-gel electophoresis.

In immunofluorescence studies of kidney tissue obtained post mortem, the region of the tubular basement membrane reacted positively with anti-kappa antiserum and with antiserum to Bence Jones protein isolated from the patient's serum. The material occluding the tubular lumens, however, failed to stain with either antiserum. The occurrence of acute or subacute renal failure in patients with multiple myeloma has been attributed to occlusion of the renal tubules by deposits of Bence Jones proteins. The data obtained in this study indicate the need for re-examining this concept.

     

Studies of the urinary acidification defect induced by lithium

Experiments were carried out in rats and isolated turtle bladders to study the defect in H+ transport induced by LiCl. After 3-4 days of intraperitoneal LiCl, rats developed urinary findings of "distal" renal tubular acidosis. Proximal tubular fluid pH measured in situ by glass microelectrodes was higher in lithium-treated rats than in acidotic controls. Proximal fluid total CO2 [tCO2] was also higher, and the fraction of tCO2 leaving the proximal tubule was 14 vs. 7% (P less than 0.001). Impaired acidification was also apparent beyond distal convoluted tubules, as judged by normal distal tCO2 reabsorption but increased HCO3(-) in the urine. During NaHCO3 loading, the proximal defect was ameliorated but not the distal. Turtle bladder studies showed that mucosal lithium inhibits H+ secretion secondary to reducing transepithelial electrical potential, presumably by hyperpolarization of the luminal membrane. A similar mechanism may be responsible for lithium's effect on the distal nephron. Inhibition of proximal tubular HCO3(-) reabsorption is probably not attributable to electrical potential changes but might be due to interference of luminal membrane Na+ entry by Li+ and reduced (Na+ + Li+)-H+ exchange.