IL-1 alpha stimulated TNF alpha production by cultured human proximal tubular epithelial cells. Tumor necrosis factor alpha (TNF alpha) production by proximal tubuli was studied by immunoperoxidase staining of 20 renal biopsies from transplant patients. A positive staining for TNF alpha on proximal tubuli was seen in nine out of 15 patients with interstitial infiltrate, five without clinical significant rejection and four with moderate to severe interstitial rejection. TNF alpha was only expressed on tubuli within areas of interstitial infiltrate. Expression of TNF alpha in the mononuclear cell infiltrate was seen only in three patients with interstitial rejection. Absence of TNF alpha could be seen in biopsies with no renal abnormalities. To obtain more information on the regulation of TNF alpha production, proximal tubular epithelial cells (PTEC) cultures were established and assessed for production of TNF alpha. Heterogenicity in production of TNF alpha was found in 14 tested PTEC lines cultured under serum free conditions. The presence of IL-1 alpha in the cultures induced a time- and dose-dependent enhancement of TNF alpha production by PTEC. Enhanced production of TNF alpha was not seen after stimulation with other cytokines such as IL-2 or IFN gamma. Inhibition studies with cycloheximide indicated de novo synthesis of TNF alpha. Western blot analysis of supernatants of unstimulated and IL-1 alpha stimulated PTEC indicated a 17 kd product, a size similar to that of recombinant TNF alpha. Northern blot analysis revealed the presence of a 2.0 kb hybridization signal in total RNA of PTEC cultures and up regulation upon treatment of PTEC with 1 ng/ml of IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)


Developmental patterns of PDGF B-chain, PDGF-receptor, and alpha-actin expression in human glomerulogenesis. Expression of PDGF B-chain and the PDGF receptor beta-subunit (PDGFR beta) is detected immunocytochemically during the development of glomeruli in human kidneys of 54 to 105 days gestational age. During the early stages (vesicular, comma-shape and S-shape) of glomerulogenesis, PDGF B-chain is localized to differentiating epithelium of the glomerular vesicle, while PDGFR beta is expressed in the undifferentiated metanephric blastema, vascular structures, and interstitial cells. During this stage PDGF may be acting as a paracrine growth factor and as a chemoattractant acting to recruit mesangial progenitor cells into the developing glomerulus. As the glomerular tuft forms, both PDGF B-chain and PDGFR beta can be detected in an arboreal pattern radiating from the hilus of the glomerular tuft. Immunocytochemical studies using markers specific to endothelium (Ulex europaeus I lectin, Factor VIII related antigen), and smooth muscle (alpha-smooth muscle actin), indicate that the PDGF B-chain and PDGFR beta are both expressed primarily by mesangial cells. During this stage, PDGF may be acting primarily to provide an autocrine factor to mediate further mesangial cell proliferation. Glomerular expression of alpha-smooth muscle actin is limited to later stages of glomerulogenesis; at these stages the pattern of expression is similar to that of PDGF-B chain and PDGFR beta. The upregulation of mesangial PDGF, PDGFR beta, and alpha-smooth muscle actin expression that has been identified in some disease states in both humans and experimental animals appears to represent a recapitulation of this normal developmental process.


A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects. The erythropoietic response to graded doses of recombinant human erythropoietin (epoetin alfa) was assessed in 24 hemodialysis patients by quantitative ferrokinetic studies, and measurement of the reticulocyte count and plasma levels of transferrin receptor protein. These responses were compared to those of 22 normal subjects. Epoetin alfa was given intravenously at 15, 50 or 150 U/kg every other day for four injections. Three patients with chronic renal failure were restudied after renal function was restored following renal transplantation. The results of these three different measurements of erythroid function showed that the acute response to recombinant human erythropoietin was similar in normal subjects and patients with renal failure. We conclude that chronic uremia does not alter the responsiveness to erythropoietin in vivo.


Angiotensin II does not increase renal prostaglandin E2 in response to pressure reduction. Whether angiotensin II (Ang II) stimulates renal secretion of prostaglandin E2 (PGE2) synthesized in response to pressure reduction was examined. PGE2 and Ang II in aortic and renal venous plasma were measured before and during renal arterial constriction in anesthetized dogs, with or without an intrarenal arterial infusion of an Ang II antagonist, losartan potassium (1 mg/min), or saralasin (3 micrograms/min). In other anesthetized dogs, two doses of Ang II (30 and then 300 ng/min) were infused into the renal artery, and plasma Ang II levels and renal PGE2 secretion were measured. When renal perfusion pressure was reduced to 75 and 45 mm Hg by constriction, the renal secretion of PGE2 increased seven- and fourfold, respectively. Ang II levels in the renal venous plasma increased from 6.6 +/- 1.8 to 21.7 +/- 7.4 and then 48.1 +/- 15.3 pg/ml (both P less than 0.05) as the pressure decreased. Neither losartan nor saralasin suppressed the response of renal PGE2 secretion to the pressure reduction. The intrarenal infusion of Ang II (30 ng/min) elevated the Ang II level in the renal venous plasma from 9.8 +/- 4.6 to 33.7 +/- 4.2 pg/ml (P less than 0.01), but did not increase PGE2 secretion. The higher dose (300 ng/min) of Ang II increased it, but the Ang II level in the renal venous plasma was 166 +/- 63 pg/ml. These results suggest that the greater part of the increased renal synthesis of PGE2 in response to pressure reduction is not mediated by Ang II.


Plasma level of lipoprotein Lp(a) is high in predialysis or hemodialysis, but not in CAPD. Plasma Lp(a) lipoprotein level was determined in chronic renal failure (CRF) patients, 24 before initiation of dialysis, 18 undergoing hemodialysis, and 24 on continuous ambulatory peritoneal dialysis (CAPD). Eighteen healthy subjects were studied as controls. Median of Lp(a) level in both predialysis and dialysis patients was significantly increased: 23.5 mg/dl (range: 0 to 109) and 24.0 mg/dl (range: 1.4 to 90), respectively, as compared to healthy controls: 4.7 mg/dl (range: 1.8 to 27; P less than 0.001). By contrast, the median Lp(a) level in CAPD patients, 2.4 mg/dl (range: 0 to 39.5), was similar to the control group. Whether the CAPD procedure reduces the Lp(a) level in CRF patients has to be established in a prospective study.


A longitudinal, five year survey of urea kinetic parameters in CAPD patients. This study reports on the five years' evolution of the KT/V urea index and protein catabolic rate (PCR) in 16 CAPD patients who were treated with a constant daily dialysis dose. Total KT/V urea index decreased with time from a value of 0.96 +/- 0.06 at the start to 0.55 +/- 0.05 at five years of treatment. This decline was due to the opposite changes of two important parameters affecting the index. First, the contribution of the residual urinary KT/V gradually decreased from 28.6% at the start to 8 to 9% after four years. Second, the distribution volume of urea calculated as a constant fraction of body weight gradually increased. The body weight increased from 58.2 +/- 2.79 kg at start to 70.6 +/- 3.33 kg at five years. Peritoneal urea clearances and ultrafiltration rates remained stable. In 12 patients with stable body weight between 24 and 48 months, PCR decreased from 0.98 +/- 0.05 to 0.87 +/- 0.05 g/kg/day. A positive correlation between KT/V urea and PCR and a negative correlation between KT/V urea and number of hospitalization days, peritonitis rates and peripheral nerve conductivity was found. The same negative correlation was found when only the KT/V urea index obtained during the first year of treatment was considered. In conclusion, the KT/V urea index decreases in CAPD patients primarily because residual renal function decreases and body weight increases, while the peritoneal clearing for urea is maintained. The index correlates with some clinical parameters, and may have some prognostic value.


Prazosin attenuates the natriuretic response to atrial natriuretic factor in man. The effect of alpha-1-adrenoceptor blockade with 0.25 mg oral prazosin on the renal response to atrial natriuretic factor (ANF) 5 pmol/kg/min was examined in eight healthy male volunteers undergoing maximal water diuresis. ANF on its own decreased mean arterial blood pressure (P less than 0.05) without altering heart rate or increasing plasma norepinephrine. ANF increased urinary sodium excretion by 130% (P less than 0.01) from baseline value with accompanying 18% decrease (P less than 0.05) in PAH clearance (ERPF) without changing inulin clearance (GFR). When compared to placebo infusion, ANF infusion caused a significant increase in fractional excretion lithium (FELi), a marker of proximal tubular function. Fractional distal delivery of sodium, another marker of proximal tubular outflow as determined by free water clearance, was also increased during ANF infusion. As expected, ANF decreased distal nephron fractional sodium reabsorption as evaluated by both the "lithium method" and by the conventional "solute-free water method." Prazosin on its own had no effect on blood pressure, renal function or hormonal parameters. When given in combination with ANF, prazosin blunted the natriuretic effect of ANF from 130% to 35% (P less than 0.01). However, prazosin pretreatment did not influence the ANF-induced fall in blood pressure or ERPF nor the ANF-induced suppression of plasma aldosterone. We have therefore found evidence to support the hypothesis that at basal levels of sympathetic tone, the natriuretic effect of ANF in man is dependent on an intact sympathetic nervous system, since sympathetic blockade by prazosin blunts its sodium excretory effects.


Effect of dialyzer geometry during hemodialysis with cuprophane membranes. The effect of dialyzer geometry, both flat plate (FP) and hollow fiber (HF), on platelet and granulocyte activation during dialysis with cuprophane membranes was studied in 12 patients. A subset of six patients was restudied after correction of their anemia with recombinant human erythropoietin (EPO). Granulocyte count and aggregation in vitro fell significantly (P less than 0.01) at 20 minutes of dialysis, followed by a gradual return towards pre-dialysis values at 240 minutes. Malondialdehyde (MDA), a product of free radical reactions generated by activated granulocytes, increased significantly during dialysis [predialysis MDA (median, range): 8.4 (5.8 to 11.6) nmol/ml, 240 minutes MDA: 9.7 (6.6 to 12.5) nmol/ml, P less than 0.01 Wilcoxon test). This increase, however, was not affected by dialyzer geometry or EPO therapy. Neither type of dialyzer was associated with significant platelet loss at the end of dialysis. Whole blood platelet aggregation in vitro (spontaneous and collagen-induced) decreased significantly, (P less than 0.01) during dialysis, the fall in spontaneous aggregation being significantly less following EPO therapy [spontaneous aggregation 240 minutes; pre-EPO: 34 (13 to 52)%; post-EPO 50: (16 to 76)%, P less than 0.01)]. The ratio of the platelet release proteins beta-thromboglobulin and platelet factor 4 increased significantly during dialysis, indicating platelet activation in vivo, although there was no effect of dialyzer geometry or EPO. Factor VIII von Willebrand Factor antigen, a putative marker of endothelial damage, was raised pre-dialysis, and increased further during dialysis, irrespective of dialyzer geometry or EPO. In conclusion, dialyzer geometry had no significant effect on granulocyte and platelet counts and activity during hemodialysis with cuprophane membranes.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term comparison between captopril and nifedipine in the progression of renal insufficiency. To verify the hypothesis that angiotensin-converting enzyme (ACE) inhibitors possess a unique renoprotective effect in progressive chronic renal disease, we decided to compare the effects of an ACE inhibitor and a calcium antagonist on both hypertension and the progression of non-diabetic renal insufficiency in a long-term study. A four-year, multicenter, prospective, randomized trial was conducted on 142 hypertensive patients (pts) with established chronic renal failure from six Italian nephrology departments. They were on standard antihypertensive therapy with a low-protein diet and underwent twice-monthly surveillance for a one year pre-randomization period. After that year, 121 pts were randomly allocated to captopril or slow-release nifedipine therapies for a three-year study period. The progression of renal insufficiency was monitored every two months. Blood pressure control was significantly better after randomization than during the year of standard antihypertensive therapy. The progression rate before randomization (BR) was definitely higher before than after randomization (AR): Creatinine clearance (CCr) change BR = -0.46 +/- 0.45 ml/min/month, creatinine clearance change AR = -0.23 +/- 0.43 ml/min/month (P less than 0.01). After randomization, the mean blood pressure values were virtually the same throughout the three year period of the study in the two groups treated by captopril (group I), or nifedipine (group II).(ABSTRACT TRUNCATED AT 250 WORDS)


Cytokine regulation of adenylate cyclase activity in LLC-PK1 cells. Although several cytokines have been demonstrated to exert pleiotropic responses, there is little information on cytokine regulation of renal tubular epithelial cell function. In the present studies, we find that both T cell-derived (tumor necrosis factor-beta and interleukins 2 and 3) and monocyte/macrophage derived (tumor necrosis factor alpha and interleukin 1 beta) cytokines promote basal, arginine vasopressin- and forskolin-stimulated adenylate cyclase activity in cultured LLC-PK1 cells. No effect of TNF, IL-1 beta, and IL-2 to stimulate protein kinase C activity was observed. TNF-beta, IL-1 beta and IL-2 also modestly stimulated 3H release from 3H-arachidonic acid labeled cells. Mepacrine, a phospholipase A inhibitor, prevented TNF-beta stimulation of 3H release from 3H-arachidonic acid labeled cells and TNF-beta potentiation of adenylate cyclase activity. TNF-beta potentiation of adenylate cyclase activity and stimulation of 3H release from 3H arachidonic acid labeled cells was not prevented by pertussis toxin. These results demonstrate that several cytokines can stimulate adenylate cyclase activity while not affecting protein kinase C activity in cultured renal tubular epithelial cells. The effect of TNF-beta to stimulate adenylate cyclase appears to occur independent of pertussis toxin-sensitive substrate and may involve activation of phospholipase A.


Glomerular hemodynamics and hormonal evaluation during starvation in rats. The effects of total food deprivation on renal function were evaluated in normal Munich-Wistar rats submitted to starvation (S) periods of two to eight days (Groups S2 to S8). A prompt and sustained decrease in renal plasma flow (RPF) and an increase in total renal vascular resistance (TRVR) were observed after the second day, together with a gradual decrease in glomerular filtration rate (GFR) until the fourth day (40% in the S4 group, P less than 0.05). After this period, a spontaneous and progressive increase in GFR occurred in spite of continuing low RPF and high TRVR. Glomerular hemodynamics were evaluated in additional animals from groups S4 and S7. As observed for whole kidney GFR, mean single nephron (SN) GFR was reduced in group S4, but not in group S7. The decline in SNGFR in S4 was the result of a decline (approximately 40%) in glomerular plasma flow rate (QA) and glomerular capillary hydraulic pressure (PGC), due to a predominant increase (approximately 60%) in afferent arteriolar resistance. In S7, SNGFR and its determinants did not differ from the control. Angiotensin II (Ang II), prostaglandin (but not thromboxane A2, TxA2) inhibition blunted the alterations in whole kidney function observed in S4. Conversely in S7, the inhibition of vasoconstrictor agents (Ang II and TxA2) did not normalize GFR, suggesting that the intrarenal vasoconstriction could be an important factor to maintain GFR after a prolonged period of starvation.(ABSTRACT TRUNCATED AT 250 WORDS)


Metabolic effects of 4-pentenoate on isolated dog kidney tubules. The effects of 4-pentenoate (0.01 to 10 mM) were studied on suspensions of cortical tubules and of thick ascending limbs (TAL) prepared from dog kidneys. When cortical tubules were incubated with 1 mM glutamine, 4-pentenoate accelerated glutamine uptake, ammoniagenesis, and the production of alpha-ketoglutarate, lactate and pyruvate, but decreased gluconeogenesis. With 5 mM glutamine, the marked accumulation of alpha-ketoglutarate reversed the net fluxes through the alanine and aspartate aminotransferases. When cortical tubules or TAL were incubated with lactate, its utilization and gluconeogenesis (in cortical tubules) were markedly decreased by 4-pentenoate. The mitochondrial NAD+/NADH ratio was markedly increased by 4-pentenoate in cortical tubules but not in TAL. The production of 14CO2 from 14C[1]-pyruvate or 14C-[1]-alpha-ketoglutarate was decreased by approximately 60% by 4-pentenoate in cortical tubules but not in TAL. In cortical tubules, these findings are best explained by depletion of mitochondrial free CoA, inhibition of pyruvate and alpha-ketoglutarate dehydrogenases and decreased mitochondrial NADH. By contrast, in TAL, accumulation of reducing equivalents probably resulted from the metabolism of 4-pentenoate itself.


Influence of ammonia and pH on protein and amino acid metabolism in LLC-PK1 cells. Metabolic acidosis inhibits protein synthesis (PS) and stimulates protein degradation (PD) in muscle and cultured myocytes but causes hypertrophy of the proximal tubule. The reason for this tissue-specific difference in response to acidosis is unknown, but it might be related to stimulation of renal ammonia production since ammonia reportedly increases PS and inhibits PD in cultured kidney cells. We examined how ammonia and pH could interact to change protein turnover in confluent LLC-PK1 cells. Varying extracellular pH from 6.95 to 7.60 did not alter PS or PD even though intracellular pH changed predictably. Six millimolar NH4Cl did not change PS while 20 mM inhibited PS; there was no interaction with pH. This unexpected difference from the reported stimulation of PS by NH4Cl could be explained by our use of L-[U-14C]phenylalanine rather than radiolabelled leucine to measure PS. NH4Cl was found to inhibit leucine degradation which would increase radiolabelled leucine available for incorporation into protein. Either 6 mM or 20 mM NH4Cl inhibited PD measured as the release of L-[14C]phenylalanine from prelabelled protein. Experiments with an inhibitor of lysosomal function, chloroquine, suggest that NH4Cl inhibits lysosomal proteolysis. There was no interaction of cell pH and ammonia-induced changes in PD. Thus, the response of renal cells to acidification differs markedly from myocytes and ammonia changes protein turnover primarily by suppressing PD.


Decreased O2 consumption by PMNL from humans and rats with CRF: role of secondary hyperparathyroidism. Bactericidal ability of polymorphonuclear leukocytes (PMNL) is impaired in chronic renal failure (CRF). This function of PMNL is mediated by the generation of oxidizing radicals and the latter event requires O2 consumption by these cells. The present study examined both basal and FMLP-stimulated rise in cytosolic calcium ([Ca2+]i) and O2 consumption of PMNL from normal subjects and hemodialysis patients and from CRF rats, and evaluated the potential role of secondary hyperparathyroidism of CRF on these properties of PMNL. Basal levels of [Ca2+]i were significantly higher, and FMLP-induced increments in [Ca2+]i were significantly lower in PMNL of both humans and rats with CRF than in normals. Basal and FMLP-stimulated O2 consumption were significantly lower in CRF subjects and rats than in normals. These derangements were prevented by prior parathyroidectomy of CRF rats or by their treatment with verapamil from day one of CRF. Also, therapy of rats with pre-existing CRF with this drug reversed the abnormalities in [Ca2+]i and in O2 consumption of PMNL. The data indicate that: (1) CRF is associated with derangements in the homeostasis of [Ca2+]i of PMNL and their oxygen consumption, (2) these abnormalities are, most likely, mediated by the state of secondary hyperparathyroidism of CRF, and (3) verapamil, which blocks the PTH-induced entry of calcium into cells, and prevents as well as reverses these PMNL dysfunctions. These results implicate the excess PTH of CRF in the genesis of the defective bactericidal function of PMNL, and assign a new dimension to PTH toxicity in CRF.


Mild renal ischemia activates primed neutrophils to cause acute renal failure. The role of neutrophils (PMN) in acute renal failure (ARF) is controversial. Although the development of acute renal failure (ARF) frequently occurs in situations where there is partial activation of PMN (primed PMN) and mild renal ischemia, the interaction between primed PMN and ischemic organs has not been studied in any biological system. To define the interaction between primed PMN and mild renal ischemia, kidneys were made ischemic for 10 minutes in situ and reperfused by the isolated kidney technique with untreated PMN or PMN primed with low concentrations of lipopolysaccharide (LPS) or phorbol myristate acetate (PMA). We found that primed PMN had no effect on control (non-ischemic) kidneys and that untreated PMN did not cause injury to kidneys previously subjected to mild ischemia. However, addition of primed PMN to mildly ischemic kidneys caused severe injury. To determine the nature of renal injury, ischemic kidneys were reperfused with primed PMN and catalase (CAT) or the elastase inhibitor, Eglin C. In ischemic kidneys reperfused with LPS-primed PMN, Eglin C (but not CAT) was partially protective while in ischemic kidneys reperfused with PMA-primed PMN, CAT (but not Eglin C) was partially protective. Reperfusion with both CAT and Eglin C completely prevented the damaging effects of either LPS- or PMA-primed PMN. In conclusion, addition of primed but not untreated PMN causes ARF in mildly ischemic kidneys by PMN oxidant- and/or protease-mediated mechanisms. This synergism could account for the high frequency of ARF in conditions associated with prerenal azotemia and primed PMN.


Ontogeny of aromatic L-amino acid decarboxylase-containing tubule cells in rat kidney. Dopamine plays an important role in regulation of renal sodium transport. Proximal tubule cells produce dopamine after decarboxylation of L-DOPA via the enzyme aromatic L-amino acid decarboxylase (AADC). The presence and cellular localization of AADC-like immunoreactivity (-LI) and AADC mRNA were examined during pre- and postnatal development in rat kidney by indirect immunofluorescence and in situ hybridization histochemistry. Few scattered condensations of AADC-immunoreactive (-IR) tubule cells forming a lumen were detected on gestational day 18. From gestational day 21, many AADC-IR tubule cells were observed in the inner cortex, whereas the outer cortex lacked AADC-LI. Within 24 hours of birth, AADC-IR cells in the inner cortex could be identified as proximal tubule cells. During day 3 and 5 there was an increase in number of AADC-IR proximal tubule cells in the inner cortex, leaving less amount of AADC-negative cells in the outer cortex. Starting from day 8, AADC-IR cells could be seen in the outer cortex. An apparent decrease in AADC-immunofluorescence intensity was observed at 40 days, and at 80 days virtually no AADC-LI could be demonstrated. Intrarenal levels of dopamine showed a tendency to increase between 3 and 20 days, and showed significant decreases between 20 to 40 days and between 40 to 80 days. AADC mRNA was not detected in the kidney at 18 hours after birth, but could be observed in the inner cortex at 6 days. At 12, 19 and 40 days AADC mRNA was seen in the entire cortex.(ABSTRACT TRUNCATED AT 250 WORDS)


Renal function after release of ureteral obstruction: role of endothelin and the renal artery endothelium. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) are decreased and mean arterial pressure (MAP) is increased after unilateral release of bilateral ureteral obstruction (BUO). An imbalance between vasoconstrictor and vasodilator substances may explain the hemodynamic alterations seen in this setting. The present study examines the role of endothelin-1 in such alterations. Rats with BUO (N = 10) had significantly lower GFR and ERPF (ml/min/kg body wt) than sham-operated rats (SOR, N = 9) (1.40 +/- 0.14 vs. 6.20 +/- 0.38 and 5.12 +/- 0.68 vs. 20.2 +/- 2.20, respectively) and significantly higher MAP (mm Hg) than SOR (154.9 +/- 3.2 vs. 120.6 +/- 1.7). Rats with BUO given a specific antiendothelin antibody (N = 8) had significantly higher GFR (2.10 +/- 0.12) and ERPF (7.46 +/- 0.95) than BUO control rats, but there were no significant changes in MAP (159.5 +/- 5.8). In SOR (N = 6), mechanical denudation of the main renal artery endothelium did not significantly affect renal function when compared to renal function in control SOR. However, the same maneuver significantly lowered GFR (0.64 +/- 0.17) and ERPF (1.67 +/- 0.36) in BUO rats (N = 5) when compared to BUO control rats. We conclude that: (1) endothelin-1 has a significant vasoconstrictor role in rats with BUO of 24 hours duration and accounts for a portion of the decrease in glomerular filtration rate seen in rats after unilateral release of bilateral ureteral obstruction, and (2) in the BUO setting, the net role of the renal artery endothelium is vasodilatory.


A new method to localize active renin in tissues by autoradiography: application to dog kidney. A method was developed to localize active renin in dog kidney sections using autoradiography to detect in vitro binding of the radiolabeled renin inhibitor, 125I-H77. Light fixation by prior perfusion of the kidney with paraformaldehyde was used to immobilize renin without denaturing its binding activity. Snap frozen sections were cut on a cryostat and incubated with 125I-H77. Dry film autoradiography revealed discrete binding of 125I-H77 to the vascular pole of glomerulus as well as diffuse binding to the outer medulla and to the cortex. Binding of 125I-H77 to other aspartyl proteases in the latter two regions was then suppressed by addition of the aspartyl protease inhibitor, N-acetyl-pepstatin (1 microM). This revealed only the juxtaglomerular binding and successfully suppressed binding of the radioligand to other sites. Light microscopic emulsion autoradiography revealed highly selective discrete labelling of the juxtaglomerular apparatus. Competition for this 125I-H77 binding by a series of structurally different renin inhibitors showed a close correspondence between their reported inhibitory potency for renin and potency in the binding system. This strongly suggests that the radioligand binds to the active site of renin immobilized in the kidney. These results demonstrate a new method to localize active renin in tissues using in vitro autoradiography and radioinhibitor binding. The method shows promise for localization and quantitation of tissue renin in extra renal tissues.


Outcome of renal transplantation in children less than two years of age. Twenty-two renal transplants were performed in 21 children less than two years of age at Children's Hospital. Fourteen were from living related donors and eight were from cadaveric donors. The five year patient and graft survivals of these recipients were compared to all other pediatric recipients between two and 18 years of age who received renal transplants over the same time period. Five year graft survival for recipients less than two years of age was 86% following living-related donor transplantation and 38% following cadaver donor transplantation. Older pediatric recipients aged between two and 18 years had a five year graft survival of 73% following living-related donor renal transplantation, which was similar to that for recipients less than two years of age. Although older cadaveric recipients had a comparable five year graft survival to younger recipients, at 42%, the patterns of graft loss were different. Graft failures in young recipients occurred within the first seven months post-transplant, whereas the older recipient's grafts failed more gradually. Actuarial five-year patient survival in recipients less than two years of age was 86% following living-related donor renal transplantation and 70% following cadaver-donor renal transplantation. Recipients less than two years of age had a poorer patient survival than older recipients following both living-related donor renal transplantation (P = 0.06) and cadaver-donor renal transplantation (P less than 0.05). These findings suggest that the graft survival of living-related donor renal transplantation in recipients less than two years of age is better than that of cadaver-donor renal transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)


Recombinant human erythropoietin treatment improves platelet function in uremic patients. The effect of recombinant human erythropoietin (rHuEPO) on primary hemostasis was tested in 19 hemodialyzed patients. Bleeding time, platelet aggregation and platelet interaction with vessel subendothelium (SE) under flow conditions were determined before treatment and after patients reached hematocrits greater than or equal to 30%. Two thrombotic events (an acute myocardial infarction and an AV fistula clotting) were recorded during the early stages of treatment. A shortening of average bleeding times (P less than 0.01), an increase in platelet count (P less than 0.01) and an improvement of platelet aggregation (P less than 0.01) and of platelet-SE interaction (P less than 0.01) were observed. A low correlation index was found between hematocrit and bleeding time (r = -0.351, P less than 0.05). To assess a possible effect of rHuEPO on platelet function, the same parameters were evaluated before and after receiving three doses of rHuEPO (40 U/kg i.v. post-hemodialysis) in 14 of the patients. No changes in platelet or erythrocyte counts were observed, the mean bleeding time remained unchanged, but platelet aggregation induced by arachidonic acid (P less than 0.05), ADP (P less than 0.01) and ristocetin (P less than 0.05) improved. Perfusion studies confirmed moderate but significant increases in the parameters that quantify platelet-SE interaction (P less than 0.05). Improvement of ADP-induced aggregation correlated with the increase of platelet adhesion to SE (r = 0.675, P less than 0.05). We conclude that rHuEPO treatment improves primary hemostasis in uremia through an increase of red cell mass but also through a beneficial effect on platelet function, which is independent of the hematocrit rise.


Role of inhibition of atrial natriuretic factor release in the down-regulation of salt excretion. We investigated the role of atrial natriuretic factor (ANF) in the down-regulation of sodium excretion (UNaV). Seven subjects were sequentially studied while ingesting a normal-salt diet (220 mmol NaCl/day, NSD), a very low-salt diet (20 mmol NaCl/day, VLSD) for six days, and again at NSD for nine days. After one day of VLSD, a negative salt balance of 85 mmol was achieved and plasma ANF decreased from 19.1 (SE 2.5) to 7.2 (SE 2.1) pg/ml, whereas plasma renin activity (PRA) and plasma aldosterone (ALD) increased after the third and second day, respectively. During restoration of volemia (NSD), ANF increased after the third day; in contrast, PRA and ALD decreased earlier. Seven other subjects kept at low-salt diet (50 mmol NaCl/day) were studied during ANF infusion (at 2, 4, 8 ng/min/kg body wt). Increases of ANF from 10.3 (SE 0.9) pg/ml (basal condition) to levels of 24.0 (SE 1.9) pg/ml (infusion study), occurring physiologically in the same subjects after NSD, evoked increases in UNa V that accounted for 62% of UNa V rise necessary to balance the NSD, whereas PRA or ALD did not change. Plasma ANF, unlike PRA or ALD, was directly correlated with UNa V. (a) ANF changes earlier than PRA and plasma aldosterone during VLSD; (b) PRA and ALD respond more promptly than ANF in the recovery from hypovolemia; (c) during ingestion of a low-salt diet, changes in plasma ANF by infusion account for more than half the increase in UNa V following the shift from low- to normal-salt diet independently of alterations in PRA and ALD.


Uremic serum effects on peripheral blood mononuclear cell and purified T lymphocyte responses. We have studied the effects of uremic serum on the activation state and function of normal lymphocytes in vitro, by examining both accessory cell-dependent and accessory cell-independent responses. Uremic serum was obtained from patients on conservative treatment and from the same patients after they have undergone six months of maintenance hemodialysis. Uremic serum inhibited the proliferative responses to mitogens and to recombinant IL-2 (rIL-2) of both peripheral blood mononuclear cells (PBMC) and purified T cell populations. However, the responsiveness to IL-2 of pre-formed lymphoblasts, obtained from both PBMC and purified T cells, in the presence of uremic serum was similar to that obtained in the presence of normal serum, or was even enhanced. Uremic serum did not affect the cellular IL-2 receptor alpha (IL-2R) generation though it inhibited significantly the release of soluble IL-2 receptor (sIL-2R) and the production of IL-2 after mitogenic stimulation. Uremic serum from patients after six months of hemodialysis enhanced, but did not completely restore, proliferative responses and IL-2 production by control PBMC. Neither IL-1 nor IL-2R, which are present at elevated concentrations in uremic serum, appeared to be responsible for serum effects on in vitro responses of control lymphocytes. In conclusion, our results indicate that uremic serum affects both accessory cell-mediated and accessory cell-independent normal T cell responses. Uremic serum inhibition of T cell proliferation is associated with down-regulation of IL-2 synthesis by lymphocytes and the induction of an abnormal state of activation of lymphoblasts which is further enhanced following chronic hemodialysis.


A monoclonal antibody (1G10) recognizes a novel human mesangial antigen. We have identified a unique mesangial matrix protein of the human glomerulus by using a monoclonal antibody, 1G10, generated against culture human glomerular cells. By immunofluorescence, the antigen recognized by 1G10 (1G10 antigen) is present in mesangium and smooth muscle tissue and cannot be detected in any other tissue examined. Immunoelectron microscopy of glomeruli indicated that 1G10 antigen is present exclusively in the mesangial matrix at the endothelial-mesangial interface. The 1G10 antigen is also expressed by cultured mesangial cells, but not by cultured glomerular epithelial cells, umbilical endothelial cells or fibroblasts. 1G10 did not react with the mesangial matrix proteins [fibronectin (FN), laminin (LAM), collagen types I, III, IV, V, and VI (Col I, III, IV, V, VI), heparin sulfate proteoglycan (HSPG), or thrombospondin (TS)] present under normal and diseased states or smooth muscle antigens (myosin, actin), but did react with a 4 M urea extract of renal cortex and a 0.3% deoxycholate extract of isolated glomeruli. Two dimensional immunoblot analysis using the urea extract demonstrated the binding of 1G10 to an approximately 200 KDa polypeptide with pI 6.0. On one dimensional immunoblot this band did not show cross react with polyclonal antisera to FN, LAM, Col IV, V, VI, HSPG or TS. This mesangial matrix component is trypsin and periodate sensitive, suggesting that it has the character of glycoprotein. In renal biopsy specimens from patients with mesangial proliferative glomerulonephritis (GN) and membranoproliferative GN, the expression of the 1G10 antigen increased along with mesangial hypercellularity or increased accumulation of mesangial matrix, but decreased in completely sclerosed glomeruli. No significant changes in 1G10 antigen expression was observed in membranous GN or minimal change nephrosis compared to normal glomeruli. This study suggests that the 1G10 antigen may not only be a useful marker for the clinical assessment of GN, but may also serve as a potential tool for the study of the pathogenesis of glomerular diseases characterized by cellular proliferation and mesangial matrix expansion.


Differential effects of calorie restriction on glomeruli and tubules of the remnant kidney. We have previously shown that 40% calorie restriction (CR) prevents renal injury 21 weeks after 5/6 nephrectomy (Nx) in rats, regardless of whether protein intake was concurrently restricted or not. Growth retardation appeared to be a necessary prerequisite for the protective effects of CR. To further study these mechanisms, we performed 5/6 Nx in male F344 rats and pair-fed them with a control diet (ad lib group) or a high protein diet restricted by 40% so that protein intake was similar, but calorie consumption was reduced (CR group). Four weeks after 5/6 Nx, when glomerulosclerosis had not yet developed, we compared various parameters as follows in both dietary groups and sham operated rats: urinary protein excretion (uPr), GFR (14C inulin clearance), mean nephron GFR (MNGFR; GFR divided by total number of glomeruli), glomerular volume (VG), tubulointerstitial index (TII), a measure of tubular damage kidney weight (kidney wt), kidney IGF-I content by RIA, and IGF-I immunohistochemistry. CR ameliorated the increase of MNGFR, but not glomerular hypertrophy. TII, kidney wt and kidney IGF-I content were increased in the ad lib Nx group; these changes were alleviated by CR. Two weeks after 5/6 Nx, immunohistochemistry for IGF-I showed increased staining in superficial distal nephrons in the ad lib group, and this was also suppressed by CR. The occurrence of tubulointerstitial pathology prior to glomerulosclerosis, and the beneficial effects of CR on all parameters except Vg indicate a dissociation of mechanisms which result in tubular versus glomerular hypertrophy and damage.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of the venous system in hemodynamics during ultrafiltration and bicarbonate dialysis. A reduced venous compliance (VC) and inadequate venoconstriction may impair hemodynamics during hemodialysis, the first by impairing plasma volume preservation and by inducing a steep fall in central venous pressure (CVP) during minor plasma volume loss, the second by inadequate mobilization of hemodynamically inactive blood volume. For the protocol A, the relation between VC, the fall in plasma volume and the decline in central venous pressure (CVP) was assessed in 12 hemodialysis (HD) patients, aged 40 to 74 years, during isolated ultrafiltration (UF). The patients were ultrafiltrated for one hour at an UF rate of 1 to 1.5 liter/hr. VC was measured by strain gauge plethysmography with direct i.v. pressure measurements. CVP was assessed directly via a subclavian catheter. PVP was measured using the serial hematocrit method. VC correlated inversely with the fall in plasma volume (r = -0.66; P less than 0.025) and with the fall in CVP (corrected for UF volume) (r = -0.62; P less than 0.025). In the protocol B, the constriction of veins and resistance vessels was assessed sequentially during isolated UF and during UF combined with bicarbonate HD (UF + HD) by measuring the change in venous tone (VT) and vascular resistance (FVR) of the forearm. Twelve HD patients were studied (age 30 to 64 years). VT and FVR were measured using strain gauge plethysmography. The UF rate was equal during isolated UF and UF + HD (1 liter/hr). In six patients, the measurements were started with isolated UF and in six patients with UF + HD.(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans. The effects of chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any species. We studied four normal male subjects during a four-day control period (residence at 500 m), during six days of chronic respiratory alkalosis induced by hypobaric hypoxia (residence at 3450 m), followed by a six-day eucapnic recovery period (500 m) under metabolic balance conditions. Chronic respiratory alkalosis (delta PaCO2, -8.4 mm Hg, delta[H+] -3.2 nmol/liter) resulted in a sustained decrement in plasma ionized calcium concentration (delta[IoCa++]p, -0.10 mmol/liter, P less than 0.05) and a sustained increment in plasma phosphate concentration (delta[PO4]p, +0.14 mmol/liter, P less than 0.005) associated with increased fractional excretion of Ca++ (+0.5%, P less than 0.005), decreased phosphate clearance (-6.1 ml/min, P less than 0.025) and decreased excretion of nephrogenous cAMP (-1.5 nmol/100 ml GFR, P less than 0.0025). Urinary phosphate excretion decreased by 15.4 mmol/24 hr on day 1 of chronic respiratory alkalosis (P less than 0.0025), but returned to control values by day 6 despite hyperphosphatemia. Serum intact [PTH] did not change. Sustained hypomagnesuria (-0.8 mmol/24 hr, P less than 0.05) occurred during chronic respiratory alkalosis and was accounted for, at least in part, by decreased fractional excretion of Mg++ (-0.7%, P less than 0.05) in the absence of change in plasma magnesium concentration. Serum 1,25(OH)2D levels were unchanged by chronic respiratory alkalosis. In conclusion, the decrease in nephrogenous cAMP generation despite unchanged serum intact PTH concentration suggests that chronic respiratory alkalosis results in impaired renal responsiveness to PTH as manifested by alterations in PTH-dependent renal calcium and phosphate transport.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of alpha 1-proteinase inhibitor in restraining peritoneal inflammation in CAPD patients. The concentration and functional state of alpha 1-proteinase inhibitor (alpha 1-PI) may modulate the expression of peritoneal phlogosis by affecting the activity of proteases and synthesis of autacoids. alpha 1-PI is detectable in peritoneal effluents of peritonitis-free patients. alpha 1-PI purified from peritoneal fluid of these patients was biologically active both in terms of inhibition of elastase activity and of synthesis of platelet activating factor (PAF). The biological activity of alpha 1-PI could therefore explain the absence of detectable amounts of PAF in peritonitis free patients despite the presence of intraperitoneal concentrations of tumor necrosis factor-alpha (TNF alpha) that would be sufficient per se to induce the synthesis of PAF. In patients with acute infectious peritonitis, the concentration of immunoreactive alpha 1-PI was significantly increased in respect ot stable patients. However, alpha 1-PI purified from patients with acute peritonitis was functionally inactive both on proteolytic activity on elastase and on TNF alpha-induced PAF synthesis by purified human PMN. The loss of alpha 1-PI activity correlated with the number of peritoneal leukocytes and was probably dependent on oxidative inactivation. Indeed, treatment with reducing agent restored the inhibitory function of alpha 1-PI. The inactivation of alpha 1-PI in patients with peritonitis was associated with the presence of PAF in peritoneal dialysates. These results suggest that alpha 1-PI prevents the proteolytic action and cell activation leading to PAF synthesis in peritonitis free patients. However, inactivation of its function by oxidants generated during the inflammatory process may lead to proteolytic injury and unrestrained synthesis of inflammatory mediators during peritonitis.


Role of pathology indices in the management of severe lupus glomerulonephritis. Lupus Nephritis Collaborative Study Group. The principal value of the renal biopsy in patients with SLE is as a therapeutic guide. Although semiquantitative indices of nephron loss (chronicity = CI) and acute potentially reversible inflammation (activity = AI) are reported by some to have separate values from traditional classifications of glomerular pathology as predictors of outcome and therapeutic guides, this point remains controversial. We have tested the predictive value of the AI and CI in a large group of patients with severe lupus glomerulonephritis (SLE GN) and a mean follow-up of 281 weeks +/- 116 (mean +/- SD). A total of 86 patients entered into the study of plasmapheresis in severe SLE GN by the Lupus Nephritis Collaborative Study Group, and long-term follow-up was available in 83. The predictive value of the AI and the CI was described over the entire range of cut-off points by the method of receiver operator characteristics (ROC). ROC analysis demonstrated that there was no level of either AI or CI that predicted the outcome of death or renal failure with sufficient sensitivity and specificity to be useful in the individual patient. The CI signifies renal damage and nephron loss, whereas the AI describes potentially reversible pathology. Neither the CI nor the AI taken by itself predicts individual outcomes of renal failure or death in patients with aggressively treated SLE GN. Since the indices fail to identify the patient whose disease will progress to renal failure, they are both insufficient as therapeutic guides and add little to the management of the patient with severe SLE GN.


Up-regulated MHC-class II expression and gamma-IFN and soluble IL-2R in lupus nephritis. Expression of MHC-class II molecules (HLA-DR and -DQ), serum gamma-interferon (gamma-IFN) and soluble interleukin-2 receptor (sIL-2R) levels were studied in 35 Japanese patients with lupus nephritis (LN) to clarify intraglomerular cellular activation and cytokine involvement in human LN. In 11 normal kidney specimens, HLA-DR(Ia1) was noted in glomerular tufts, but HLA-DQ was either not or was faintly detected in glomeruli by the indirect immunofluorescence technique. HLA-DR and -DQ were observed mainly on the surface of glomerular endothelial cells in 100% and 50% of 28 lupus kidney specimens except for necrotic or sclerotic lesions. HLA-DQ was expressed in a high incidence of 67%, 86% in patients with proliferative LN (WHO Class III-IV) and active lesions, respectively. Serum gamma-IFN and sIL-2R levels were 1.2 +/- 0.2 U/ml and 190 +/- 24 U/ml (mean +/- SEM; N = 30) in normal controls, and elevated in patients with proliferative LN (4.1 +/- 1.0 U/ml, 383 +/- 81 U/ml, N = 25), especially with active lesions (6.2 +/- 1.5 U/ml, 500 +/- 110 U/ml, N = 14). Overall, glomerular lesions such as HLA-DQ expression, the activity index and leukocyte infiltration correlated positively with serum gamma-IFN levels (r = 0.55; P less than 0.01 for HLA-DQ, r = 0.68; P less than 0.001 for activity index, r = 0.38; P less than 0.05 for leukocyte infiltration), but not with serum sIL-2R levels, anti-DNA antibody titers and CH50 titers.(ABSTRACT TRUNCATED AT 250 WORDS)


A PCR method for the quantitative assessment of mRNA for laminin A, B1, and B2 chains. Laminin, a basement membrane glycoprotein, is involved in the development of normal kidney and its dysregulation contributes to glomerulosclerosis in renal disease. Studies designed to assess the regulation of this molecule at the level of transcription have been hindered by the relatively low abundance of the mRNA, making standard techniques such as Northern hybridization and RNase protection difficult and inaccurate. In this report, we have utilized the polymerase chain reaction (PCR) to quantitate differences in laminin mRNA expression during normal development of the mouse kidney. We have constructed a synthetic template to be used as an internal standard for mRNA quantitative of laminin chains A, B1 and B2, and beta-actin. This DNA template can be used to generate complementary RNA which can be reverse transcribed and amplified simultaneously with 0.5 microgram of total cellular mRNA allowing for accurate and absolute quantitation of laminin mRNA by PCR.


Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity. Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


A mechanism of glycine and alanine cytoprotective action: stimulation of stress-induced HSP70 mRNA. Studies done both in vitro and in vivo have shown that glycine and alanine protect kidney cells from stress injury. However, the mechanism(s) of this cytoprotection is unknown. Our aim was to test the hypothesis that the cytoprotective action is in part due to stimulation of gene(s) expression encoding stress protein synthesis. Experiments were carried out using heat shock as a model for stress in the opossum kidney cell line (OK cells). The induction of HSP70 mRNA was evaluated in cell monolayers exposed to 45 degrees C for 15 minutes followed by a recovery period at 37 degrees C for either 0.5, 1, 2, 3, 4, 6 or 24 hours. The results demonstrate that the maximum level of HSP70 mRNA occurred at approximately three hours after heat treatment. Although the mRNA levels declined thereafter, appreciable amounts were still seen even 24 hours after heat-shock. To examine the effect of glycine or alanine on HSP70 mRNA levels and on the synthesis of stress protein, cultures were preincubated for 30 minutes with Krebs-Henseleit buffer, pH 7.4, supplemented with either 1, 2, 5 or 10 mM glycine or alanine, or with no added amino acids. Comparative studies were performed with 10 mM glutamate, aspartate, arginine or leucine. Following preincubation, cultures were heat-shocked (45 degrees C for 15 min) and then reincubated at 37 degrees C for three hours. Both glycine and alanine enhanced the level of HSP70 mRNA and the synthesis of 72, 73 kDa stress proteins, but neither amino acid induced HSP70 mRNA without concomitant heat treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


15-Lipoxygenase products as leukotriene antagonists: therapeutic potential in glomerulonephritis. In the first few hours following immune complex deposition and complement-mediated neutrophil (PMN) infiltration, glomerular generation rates of the arachidonate 5-lipoxygenase (5-LO) derivatives leukotrienes (LT) C4, D4, and B4 are stimulated markedly. These LTs exert effects on glomerular functions which include reduction in the glomerular ultrafiltration coefficient and glomerular filtration rates, exacerbation of proteinuria, and amplification of PMN-provoked glomerular damage through LTB4-induced PMN chemotaxis, adhesion, and activation. Following this early burst, glomerular LT synthesis is suppressed, macrophages replace PMNs, and glomerular generation of 15-S-hydroxyeicosatetraenoic acid [15-(S)-HETE], a 15-lipoxygenase derivative of arachidonic acid and a precursor molecule for lipoxin (LX) biosynthesis, increases progressively over the ensuing days to weeks. Here, we summarize evidence supporting the notion that the activation of the 15-LO pathway in the wake of early 5-LO activity is a specific counter-inflammatory signal which limits and antagonizes the proinflammatory actions of leukotrienes.


Clinical strategies for arresting progression of renal disease. The incidence of end-stage renal disease is increasing and this results in an enhanced requirement of renal replacement therapy facilities. This brings about a significant burden on health care budgets and makes strategies that slow down or even prevent deterioration of the renal function mandatory. Although large scale randomized, controlled and prospective clinical trials on the effect of blood pressure control on the course of renal function are lacking, there is circumstantial evidence from animal, epidemiological and clinical studies to state that treatment of hypertension to blood pressure values well within the normal range is most important to ameliorate the downhill course of renal function in patients with chronic renal failure. Moreover, treatment of hypertension is critical to reduce morbidity and mortality of cardiovascular disease in these patients, who have an increased risk for such events. Low-protein diets, if possible with ketoacid supplement, are advocated to slow down the deterioration of renal function. However, based on the results of recent studies, low-protein diets may only have a moderate effect in patients with diabetic nephropathy and, possibly, in patients with chronic glomerulonephritis. The possibility of influencing renal ammoniagenesis by protein restriction or calcium carbonate administration, and an attenuation of alternative complement pathway activation and tubulo-interstitial injury, are challenging. Finally, in animal studies it has been found that abnormalities in serum lipid profile contribute to the progression of chronic renal failure, which may be prevented by pharmacological treatment of hyperlipidemia. Studies in humans concerning this subject are lacking at this moment, but treatment of hyperlipidemia is proper to reduce cardiovascular events.


Treatment of immunologically mediated glomerular disease. Many immunologically mediated glomerular diseases can be successfully treated, but clinicians should be wary of unproven claims of efficacy, be cognizant of long-term deleterious effects of treatment, and should select patients with a careful eye on the natural history of the untreated disorder. It is hoped that as we gain a better understanding of the etiology and pathogenesis of the specific entities that a more rational form of therapy will emerge. The powerful tools of molecular biology and our better understanding of the inflammatory and scarring processes may provide new, highly effective and safe approaches to treatment. Like their predecessors, these approaches, however, will require very careful evaluation in human subjects by prospective controlled clinical trials. Even if we cannot favorably influence the immunological processes responsible for glomerular disease, attention to non-immunologic factors responsible for progression of disease, such as hypertension, may substantially slow the rate of progression of disease even in those patients whose fundamental disease process cannot be arrested or cured.


Natriuretic peptides and the kidney: current concepts. The field of study of natriuretic peptides becomes more complex as we enter the second decade since their discovery. The attractive hypothesis that a single peptide secreted by the atria could regulate the physiological responses to salt and water loading has proven simplistic. Rather the atrial natriuretic peptide story has opened the door on a whole family of peptides, secreted from the atria, the ventricles, the brain, and even the kidney itself, all working in concert to achieve this regulation. The regulation of renal function by natriuretic peptides is presumably the result of the integration of these different peptides effects. Thus while atrial derived NP circulates and has direct effects on the glomerulus, other sources of NP (such as the kidney) may be responsible for some of the tubular effects of NP. Further definition of the mechanisms of regulation of the kidney derived NP are needed before any further conclusions can be drawn.


Is the aggressive management of hyperlipidemia in nephrotic syndrome mandatory? The development of the nephrotic syndrome is associated with a lipid profile characterized by increased total and low density lipoprotein cholesterol. Although total high density lipoprotein (HDL) values may be in the normal range, there is frequently abnormalities of HDL subclasses, with reduction of the mature HDL2 subfraction. While these lipid changes may be considered a risk for atherosclerosis, they revert to normal with remission of the nephrotic syndrome. However, with chronic nephrotic range proteinuria, these abnormalities persist and may also be associated with increased levels of lipoprotein (a), increased levels of very light density lipoprotein and further reductions in HDL. These factors could all contribute to greater risk for atherosclerosis. Although coronary artery disease is frequently seen in patients with end-stage renal disease, and many uncontrolled studies in patients with chronic nephrotic syndrome have suggested an increased prevalence of cardiovascular disease, no prospective studies to evaluate relationship between lipid abnormalities and cardiac disease have been performed in patients with the nephrotic syndrome. Recent experimental data have also suggested a relationship between hyperlipidemia and progressive renal injury. Unfortunately, human epidemiological data are incomplete in correlating lipid changes with renal disease in patients with chronic nephrotic syndrome. No therapeutic trials have tested whether or not pharmacologic interventions will benefit either the cardiac or renal disease that ensues in patients with chronic persistent nephrotic syndrome. Thus, considerably more data are needed to help clarify this important area.


What's new in peritoneal dialysis--an overview. Patient survivals on continuous ambulatory peritoneal dialysis (CAPD) seem similar to survivals on hemodialysis (HD) in comparable populations. Technique survivals are improving on CAPD as peritonitis rates fall with the use of disconnect devices. Advances in catheter design and catheter care appear to be improving catheter survivals. The peritoneal membrane appears usable for many years provided that recurring peritonitis can be avoided. Mesothelial cell transplantation, low calcium solutions, and urea kinetic modeling are important new areas of interest with potentials to improve the therapy. Evidence continues to mount that residual renal function is better preserved in CAPD than in HD.


Improved solutions for peritoneal dialysis: physiological calcium solutions, osmotic agents and buffers. Theoretical and clinical studies suggest that reduction of PD fluid calcium to 1.25 mmol/liter allows administration of larger doses of calcium carbonate, improves phosphate control and obviates the need for aluminum gels in most CAPD patients, without increasing hypercalcemia or hyperparathyroidism. Hypermagnesemia can also be avoided by reducing PD fluid magnesium concentration to 0.25 mmol/liter. Although glucose is a safe, effective an cheap osmotic agent, it provides a short duration of ultrafiltration, and contributes to significant metabolic abnormalities. Amino acids and glucose polymer are potential alternatives to glucose, and early clinical studies are encouraging. The unphysiological concentration of lactate in PD fluids has been shown to have pathological consequences, and undoubtedly bicarbonate would be a preferable buffer. Manufacturing techniques are being developed to produce such a fluid. A fluid containing bicarbonate and the peptide glycylglycine (30:10 mmol/liter) gives a stable buffer with a pH of 7.35, but has only undergone animal studies so far. Glucose solutions have deleterious effects on the peritoneal membrane, particularly during episodes of severe peritonitis, and the high osmolality is toxic to peritoneal host defense cells. Prompt treatment of peritonitis, early removal of the catheter where necessary, and minimization of glucose exposure, may do much to lengthen the dialysis life of the peritoneum.


The dose of hemodialysis according to dialysis prescription in Europe and the United States. Prior research has shown that, controlling for age and diabetes, patients with end-stage renal disease in Europe generally have better rates of survival than do ESRD patients in the U.S. This analysis compares the dose of hemodialysis prescription in the two regions. Based on the European Dialysis and Transplant Association Registry (EDTA), the U.S. Renal Data System (USRDS), and other sources, European and U.S. ESRD patients were compared by demographic and anthropometric characteristics, dialyzer characteristics, and duration of dialysis treatment times. Average body weight and body mass indices were found to be similar for the ESRD populations of the two societies, suggesting the same overall requirements for dialysis therapy. During 1986 to 1988, dialyzers selected in Europe had a larger surface area by at least 20 percent compared to those selected in the U.S. In addition, duration of hemodialysis treatment times were on average 23.5% longer for EDTA patients. Dialyzer blood flows were not available for EDTA patients, but if EDTA blood flows resemble U.S. practices, total urea clearance per week was at least 29% higher in Europe than in the U.S. Combining similar patient characteristics with substantially greater total urea clearance per week, the hemodialysis prescription in Europe was substantially higher than in the U.S. for the time period of this study.


Adequacy of CAPD: a quantitative approach. In prescribing CAPD, general clinical practice is to use the standard regimen of 2L x 4 exchanges/day without regard to patient size, nutritional status, or residual kidney function. The standard regimen is usually adjusted in a trial and error manner reacting to clinical symptoms, life style issues, and patient compliance. The purpose of this paper is to recommend an alternative, quantitative approach based on urea kinetics that is prospective rather than reactive, and objective rather than subjective. The value of urea kinetic-based hemodialysis therapy prescription is well established and applying this knowledge to CAPD is a good starting point. The importance of small solute clearances for CAPD adequacy can be established on both theoretical and clinical grounds. The value of the KT/V urea index, its calculation, scaling factors for CAPD-hemodialysis comparisons, and the correlation between KT/V and weekly creatinine clearances are examined. Residual renal function has a significant impact on small solute clearances, and failure to adjust the therapy prescription to compensate for declining residual kidney function will have a detrimental impact on KT/V and the protein catabolic rate.


Nutritional aspects on peritoneal dialysis. Peritoneal dialysis is associated with metabolic and nutritional abnormalities due to the combined effects of uremia per se, glucose absorption from the dialysate and a variety of catabolic factors, such as protein and amino acid losses into the dialysate, poor appetite possibly reflecting insufficient removal of small solutes, and recurrent episodes of peritonitis. Signs of protein-energy malnutrition are common, especially in patients with minimal or no residual renal function. Variables that best correlate with the degree of malnutrition include serum albumin, midarm muscle circumference, clinical signs of muscle wasting and loss of subcutaneous fat, and a history of anorexia. The incidence of malnutrition is higher in females than in males and in diabetics than in non-diabetics. CAPD patients generally have a lower protein intake than HD patients, but may have a lower average protein requirement than HD patients. Progression of malnutrition may occur in CAPD patients due to the synergistic effects of loss of residual renal function, underdialysis, anorexia and inadequate dietary intake. In underdialyzed CAPD patients, the amount of dialysis should be increased and measures should be taken to increase the supply of energy and protein. The use of amino acid-based dialysis fluid may provide new opportunities for compensation of dialytic losses of protein and amino acids, normalization of essential amino acids, supplementation of inadequate dietary protein intake, and improvement of the nutritional status in CAPD patients.


HLA matching effect on five-year graft survival and half-life in the cyclosporine era. From 1984 to 1990, a 6 to 10% increase in one-year graft survival was noted for patients matched or mismatched for HLA A, B, or DR locus antigens. This improvement was not attributable to matching. In the cyclosporine era, five-year graft survival of 0-ABDR mismatched first cadaver donor transplants was 61% in contrast to 45% survival for the worst 6-antigen mismatched grafts. The long-term half-life of 0-ABDR mismatched grafts was 10.7 years, compared with 6.4 years for the 6-antigen mismatched transplants. The cumulative survival years (a measure of impact) were twice as high for 0-ADR, 0-BDR and 0-AB mismatched grafts compared with 0-ABDR mismatches. On the basis of cumulative survival, five-year survival, and half-life, one might suggest sharing kidneys for 1-2 ABDR mismatch, 1 BDR, 1-2 AB mismatch, and 1-ADR mismatch. Young patients (5 to 25 years old) had lower graft survival rates when receiving poorly mismatched grafts. HLA matching did not influence graft survival in Black recipients, whose half-lives were 3.8 to 4.6 years for all matching categories.


How to deal with the hyperimmunized potential recipients. End-stage renal disease (ESRD) patients with high levels of anti-HLA panel reactive antibodies (PRA) represent an increasing group in which sensitization, induced by pregnancies, previous transplants, and blood transfusions, considerably delay the opportunity to receive a graft. Currently, more than 50% of the 4700 patients awaiting transplantation in France are sensitized, of which 33% are defined as hyperimmunized (PRA greater than = 80%), and only 9.5% of the total number of transplants have been done in highly sensitized recipients. The magnitude of this problem, similar in Europe and North America, explains why more active strategies for managing hyperimmunized patients have been introduced during the past decade. Clearly, the simplest is finding of a well-matched organ that does not carry the HLA antigens against which the recipient has generated antibody, but that is limited by the number of shared grafts. The second is the development of a new cross-matching technique prior to transplantation. Attempts at immunoregulation of secreting B cell clones have been carried out using either hypertransfusions or injection of polyclonal Ig. Finally, removal and prevention of the resynthesis of HLA antibodies is a most attractive approach using immunoadsorption (IA) system with sepharose-bound protein-A columns. In our unit, fifteen ESRD patients with high levels of PRA were treated with IA. Infectious complications were not observed after IA and transplantation, and the procedure was well tolerated. In spite of the use of adjunctive immunosuppressive treatment with cyclophosphamide and prednisolone, this method produced only variable effects in lowering PRA levels, and was hampered by high de novo resynthesis of anti-HLA antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)


New organ preservation solutions.

New organ preservation solutions. In 1969 we described a method for kidney preservation that used a brief flush with a new "intracellular" solution followed by ice storage. This paper stimulated research into optimizing solution composition culminating in the UW solution which is now the accepted standard. Further developments in the design of solutions for hypothermic organ preservation have proceeded along several paths, including: (1) modification and simplification of UW solution, (2) investigation of organ specific requirements, (3) addition of pharmacologic agents particularly calcium antagonists to flush solutions, (4) the concept of "microperfusion" for control of acidosis, (5) the use of solutions containing polyethylene glycol, and (6) the use of a terminal rinse solution. Broadly speaking, the results of these studies have shown that it is possible to improve upon the UW solution by simplification, eliminating several of the components, and that sodium variants, and pharmacological additives, such as chlorpromazine, may yield better results in experimental and clinical trials. It has also been found that there are special requirements for individual organs, rendering the concept of a universal solution unlikely. Of the promising new ideas, microperfusion and polyethylene glycol have been found to be very effective for heart preservation yielding for the first time virtually perfect 24-hour preservation. The concept of a terminal rinse to diminish reperfusion injury has strong experimental support and awaits clinical evaluation.


Race and diabetes as death risk predictors in hemodialysis patients. Case mix and laboratory predictors of death risk were evaluated in 17,185 hemodialysis patients. The laboratory variables most closely associated with the increased death risk borne by diabetic patients (relative to non-diabetics) and White patients (relative to non-Whites) were identified. The analyses of laboratory death risk predictors were similar to those previously reported. Serum albumin concentration is the most powerful death risk predictor among all of the variables, both case mix and laboratory. Statistical models including only case mix variables reveal both race (RRWhites = 1.42) and diabetes (RRdiabetes = 1.43) as significant predictors. Adding creatinine, albumin, and BUN concentrations to the model eliminated diabetes as a significant predictor. Creatinine and albumin accounted for most of the change. Adding only creatinine eliminated race. The data suggest that reduced visceral and somatic protein mass and/or metabolism may be important determinants of mortality in dialysis patients. Because differences in the concentrations of creatinine and albumin explain much of the risk associated with being White or diabetic, differences in nutritional status may explain the reduced survival observed in those groups. Therefore, clinicians should not simply accept without question the notion that diabetics and Whites are doomed to inferior survival.


Which comes first, Kt/V or PCR--chicken or egg? We previously hypothesized that PCR is dependent on Kt/V (urea). To test the hypothesis, 30 patients from two hemodialysis (HD) units with PCR values consistently less than 1 regardless of the Kt/V (urea) without an obvious cause (such as malignancy, peptic ulceration, etc.) were identified. These patients were randomized into an experimental group where an increase in the Kt/V (urea) was made or into a control group where a Kt/V (urea) remained unchanged. In the experimental group the minimal increment in Kt/V (urea) was 0.3 plus a minimum requirement of a Kt/V (urea) greater than or equal to 1. The control group were to maintain the existing Kt/V (urea) within +/- 0.2. Urea kinetic modeling was monitored monthly and the patients followed for three months. Of 30 patients, 18 fulfilled the criteria (9 experimental; 9 controls). In the experimental group, the initial Kt/V (urea) was 0.82 +/- 0.19 (means +/- SD); the final Kt/V (urea) was 1.32 +/- 0.21 (P = 0.000). These patients had an initial PCR of 0.81 +/- 0.08. This increased to 1.02 +/- 0.15 (P = 0.005). The control group had an initial Kt/V (urea) of 0.82 +/- 0.16. The final Kt/V (urea) was 0.87 +/- 0.15. Their initial PCR was 0.87 +/- 0.14 and the final PCR was 0.86 +/- 0.087 (P = NS). In the experimental group, the mean increments in Kt/V (urea) and PCR were 0.49 +/- 0.17 and 0.21 +/- 0.16 (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)


Disturbed calcium metabolism in renal failure--pathogenesis and therapeutic strategies. Absolute or relative deficiency of 1,25(OH)2 vitamin D3 is thought to play a key role in the genesis of secondary (renal) hyperparathyroidism. Elevated concentrations of PTH and--less consistently--diminished concentrations of 1,25(OH)2 vitamin D3 are demonstrable in a considerable proportion of patients with incipient renal failure. Increased PTH concentrations counteract to some extent the trend of 1,25(OH)2 vitamin D3 production to decrease. When iPTH is elevated, prophylactic administration of 1,25(OH)2 vitamin D3 is a logical procedure, even when patients have not yet reached end-stage renal failure. With the use of low doses, the incidence of side effects is low, and excessive lowering of PTH and bone turnover presumably can be avoided. Acute administration of 1,25(OH)2 vitamin D3 to achieve brief episodes of peak plasma levels causes prolonged suppression of pre-pro-PTH mRNA in the parathyroid cell. This provides a rationale to treat symptomatic hyperparathyroidism with intermittent high dose 1,25(OH)2 vitamin D3, either per os or i.v.


Use of alkaline calcium salts as phosphate binder in uremic patients. In order to prevent aluminum toxicity induced by the association of aluminum phosphate binder with 1 alpha(OH) vitamin D3 derivatives and the use of deferoxamine with its own hazards to diagnose and treat this toxicity, we have shown in 1982 that it was possible to replace the iatrogenic association of aluminum phosphate binder with 1 alpha OH vitamin D derivatives by oral calcium carbonate taken with the meals in order to bind phosphate and correct the negative calcium balance. This led to the disappearance of the crippling aluminic osteomalacia and adynamic bone diseases in our center. The effectiveness of CaCO3 without 1 alpha(OH)D3 derivatives in the control of hyperparathyroidism in dialysis patients has been proven by the appearance in four patients of our dialysis population of an histological idiopathic adynamic bone disease associated with relative hypoparathyroidism, and by the finding that more than 50% of our dialysis population treated by this sole treatment have plasma concentration of intact PTH below twice the upper limit of normal (that is, the threshold above which only significant histological osteitis fibrosa is observed). Besides the compliance problem, the limit of CaCO3 is the occurrence of hypercalcemia which occurs in about 8% of the measurements. Since calcium acetate binds twice as much phosphate for the same dose of elemental calcium as CaCO3, its use has been recommended. However, clinical experience has shown that in spite of the fact that half the dose of calcium element given as acetate does actually control predialysis plasma phosphate as well as CaCO3, the incidence of hypercalcemia is not decreased, probably because calcium availability at the alkaline pH of the intestine is much greater with Ca acetate. When hypercalcemia is frequent (and not explained by autonomized hyperparathyroidism, adynamic bone disease, overtreatment with vitamin D, granulomatosis or neoplasia) it is necessary either to decrease the dose of calcium and complete the necessary binding of phosphate by adding small doses of Mg(OH)2 or Mg carbonate, provided the dialysate Mg is decreased to 0.2 to 0.35 mmol/liter to prevent hypermagnesemia or to decrease the dialysate calcium (DCa) concentration. The decrease of DCa can be made either just when hypercalcemia occurs or on a systemic basis according to the amount of CaCO3 used and to the necessity of associating 1 alpha(OH) vitamin D3 derivatives.(ABSTRACT TRUNCATED AT 400 WORDS)


Risk of adynamic bone disease in dialyzed patients. Renal osteodystrophy presents with a spectrum of histologic abnormalities. A new entity characterized by a marked decrease in bone turnover without osteoid accumulation, that is, adynamic bone disease, has recently emerged. This new form was thought to be primarily related to aluminum accumulation. Since aluminum-containing phosphate binders have been widely replaced by calcium salts, adynamic bone disease would be expected to disappear over time. However, not only is adynamic bone disease observed in the absence of aluminum intoxication, its incidence does not seem to have decreased. We conducted a retrospective study in 1,803 patients on chronic maintenance dialysis who were biopsied during the last 10 years and assessed the incidence of adynamic bone disease over time in an effort to elucidate the factors associated with its occurrence. Adynamic bone disease was first seen in 1984 in the laboratory. Its incidence increased gradually over the years and, in 1991, still affected approximately 20% of the patients. The primary factors associated with the occurrence of adynamic bone disease include: (a) aluminum accumulation which is currently found in 60% of the patients on chronic maintenance dialysis undergoing biopsies, (b) increasing age of the patients on dialysis, (c) diabetes, and, possibly, (d) chronic ambulatory peritoneal dialysis. The clinical relevance of adynamic bone disease deserves further study. At present, this entity is associated with a tendency towards hypercalcemia, aging of bone due to stunted bone remodeling, a condition which might be associated with impaired repair of physiologic microdamages, and accumulation of microfractures leading to mechanical incompetence and ultimately to higher risk of fractures.


Dialysis related amyloidosis: a disease of chronic retention and inflammation? Dialysis related amyloidosis (DRA) has become a major complication of long-term therapy in chronic hemodialysis or peritoneal dialysis patients. DRA is characterized by the presence of beta 2-microglobulin (beta 2m) in the amyloid fibrils. The pathogenesis of DRA is incompletely understood, but most likely is based on the uremic retention of beta 2m. In contrast, current evidence does not favor a significant role of an enhanced beta 2m synthesis rate in uremic patients. Apart from the beta 2m retention, posttranslational modification of the molecule also seems to be an important step in the amyloidogenesis, since, in addition to intact beta 2m, fragmented beta 2m or beta 2, with altered isoelectric properties can be detected in the DRA fibrils. The occurrence of these beta 2m species could be linked to a chronic intermittent stimulation of monokine release or other subclinical inflammatory processes during renal replacement therapy. Thus, it is possible that, as a consequence of repeated cellular activation, protease release and/or intracellular processing of beta 2m occurs. Renal transplantation has been shown to arrest the further progression of DRA. However, since transplantation is not feasible for a significant number of patients, non-transplant strategies to prevent DRA also need to be evaluated. Some, but not all, retrospective studies on DRA associated symptomatology in patients on chronic hemodialysis with high flux membranes have suggested a lesser prevalence in these patients as compared to patients treated with standard cellulosic membranes. To further clarify this issue and to test whether non-transplant therapies indeed may play a role in the prevention of DRA, prospective studies will be needed.(ABSTRACT TRUNCATED AT 250 WORDS)


Polymorphonuclear cell function and infection in dialysis. End-stage renal disease is characterized by enhanced susceptibility for infectious diseases, carrying an important risk of morbidity and mortality. In the host's defense against bacterial infection, a central role is played by phagocytic ingestion of bacteria, followed by their destruction after metabolic production of oxygen free radical species. Our studies have concentrated on the energy delivery by the hexose monophosphate shunt (HMS) to NAD(P)H-oxidase, the enzyme responsible for free radical production. This evaluation was realized by measuring, in whole blood, the CO2 produced from standard quantities of radiolabeled glucose, with data normalized for the number of polymorphs in each sample. Our studies indicate that: (1) glycolysis is disturbed in uremic outpatients from a SCrea of 6 mg/dl and a CCr of 15 ml/min; (2) similar functional disturbances are found in pre-dialysis blood samples of hemodialyzed patients; (3) this functional disturbance is further intensified during dialysis with cuprophan, which is not the case for non-complement activating dialyzers; (4) the response is especially suppressed towards Staphylococcus Aureus, the bacterial species responsible for the majority of infections in uremia; (5) that functional disturbances are mainly related to uremic toxicity, dialyzer membrane bio(in)compatibility, and uremic anemia. Biochemical disturbances in PMNL, induced by a multifactorial patho-physiologic process, may therefore be related to the enhanced incidence of infection in uremic patients.


[Foreign body aspiration in childhood].

[Foreign body aspiration in childhood]. Damage to the airways and lung parenchyma from aspiration is a common clinical problem with diagnostic and therapeutic challenges. The insult may be acute or chronic. The amount of concentration, chemical composition, and size of particles vary, and the lesion produced may be reversible or irreversible. Death may be immediate or late. Recovery may be complete, or crippling pulmonary disease may follow. In this review is reported on the aspiration of foreign bodies or liquids into the respiratory tract. Specialty: in infancy, esophageal foreign bodies may cause mainly respiratory symptoms. Adequate diagnosis and therapy are discussed.


[Complex high altitude climate therapy for children and adolescents with neurodermitis constitutionalis atopica]. Neurodermitis constitutionalis atopica is a multifactor conditioned disease with a very wide range of aetiopathogenetic factors. A standard therapy does not exist. For children and young adults we have come to terms with a treatment concept, that consists in essence of 5 elements. Our basis is the dermatological and allergical treatment plan. We added and integrated factors of high mountain climate, psychotherapy as well as teaching- and children-garden-activities. This complex therapy is condition for optimal results in treating children and young adults.


[Screening for fragile X syndrome in handicapped boys]. From a group of 201 mentally retarded boys 149 were clinically and somatometrically examined. Chromosomal analysis for detection of a fra(X)-syndrome was undertaken, when more than 3 of the chosen examination parameters were suspicious or when anamnestic clues for X-chromosomally linked mental retardation were present. 89 boys fulfilled above requirements, 14 of these had a fra(X)-syndrome (15.7%). The following symptoms were found with outstanding frequency: hyperactivity, hypotonic muscles, enlargement of testes, increased length of hands, retarded development of speech, dermatoglyphic abnormalities. If more than 3 of these findings occur, a chromosomal analysis for exclusion of a fra(X)-syndrome should be performed.


[Eye diseases and visual disability in extremely low birth weight infants]. 79 consecutively treated very low birth weight newborns (less than 1000 g) were systematically examined in the postpartal period and after a follow-up of 2 to 5.5 years. Retinopathy of prematurity was found in 19 eyes of 10 children (maximum stage III-IV). At a minimum age of 2 and maximum age of 6 years, when 42 of these children could be reexamined, including all children with earlier retinopathy of prematurity, 10 children suffered from minimal to moderate retinal pathology due to inactive retinopathy of prematurity (4 eyes with dragging of vessels and macula), but 9 children exhibited a minor visual disability due to strabism, higher ametropia, anisometropia, and amblyopia. This stresses the need for opthalmological follow-up in low birth weight babies with 6 months and 3-4 years of age.


[Biometric data of eyes after the onset of acute glaucoma]. Biometric measurements were performed in 67 patients after acute glaucoma and in 67 patients of a matched control group. For patients with acute glaucoma the subjective refraction was +0.91 +/- 2.82 dpt, ocular axial length was 21.73 +/- 0.96 mm, lens thickness was 4.95 +/- 0.63 mm and the ratio lens thickness to ocular axial length amounted to 2.27 +/- 0.29. There was a statistically significant difference between the glaucoma and the control group concerning the parameters subjective refraction, ocular axial length, lens thickness and the lens thickness to axial length ratio. A statistically significant positive correlation was found between corneal radius and axial length, both, in the control and the glaucoma group, a significant negative correlation between axial length and subjective refraction only in the control group. In contrast to other authors, who reported on patients with narrow angle glaucoma with and without acute attack; we found no significant difference. These results support the suggestion that biometric data do not allow a prediction whether a patient with narrow anterior chamber angle will suffer glaucoma attack or not. The etiology of this disease seems to have a multifactorial origin.


[Perforating keratoplasty in endogenous eczema. An indication for systemic cyclosporin A--a retrospective study of 18 patients]. Endogenous eczema represents a considerable risk for perforating keratoplasty because of the associated chronic surface disorders and complex immunological disturbances. Between December 1986 through October 1991 we performed 24 perforating keratoplasties in 20 eyes of 18 patients with endogenous eczema suffering from keratokonus, atopic keratokonjunctivitis and bullous keratopathy after intracapsular cataract extraction. During the follow-up period of 16 (3-48) months 6 transplants failed mostly due to surface problems as well as immune reactions and bacterial transplant infections. Systemically administered ciclosporin A was found to eliminate many of the previously unsolved problems. In summary, 18 out of 20 eyes achieved an improved visual acuity with clear transplants.


[Eye changes in acanthosis nigricans maligna--possible effect of growth factors in the etiopathogenesis of this paraneoplastic disease picture]. A 64-year-old white male presented to our hospital with hyperplastic tarsal and to a lesser degree bulbar conjunctivae. Approximately one month later the full clinical picture of acanthosis nigricans maligna developed. In addition to ectropia of the lower eyelids he showed madarosis; neither the linea grisea nor the lacrimal points were discerneable. On gastroscopy a diffusely growing gastric adenocarcinoma adjacent to the cardia was found and later confirmed histopathologically. The computertomography of the abdomen demonstrated one solitary metastasis to one parapancreatic lymphnode. It is generally assumed that in the course of paraneoplastic syndroms products secreted by the tumor induce changes in the target organs, e.g. the conjunctiva and the skin. In the presented case (1) southern blot analysis of the tumor tissue proved an increase of Epidermal Growth Factor-receptors, (2) immunohistochemistry showed prominent staining for Transforming Growth Factor-alpha. In conclusion, this case is suggestive of a possible link between growth factors and acanthosis nigricans maligna.


[Canthaxanthin retinopathy. Follow-up of over 6 years]. After long-term treatment with high dosages, canthaxanthin causes a characteristic retinopathy with circular, macula surrounding crystals. As changes in retinal functionning disappear relatively easily after withdrawal of the drug, the crystals dissolve rather slowly--over about several years. Five patients showing a profound crystalline retinopathy were re-examined with an average of 69.7 months after withdrawal of the canthaxanthin-containing drug. Three of the patients were treated for erythropoetic protoporphyria (EPP) with Phenoro (2/5 beta-carotene, 3/5 canthaxanthin), two sisters took a canthaxanthin-containing formulation (1/8 beta-carotene, 7/8 canthaxanthin) for cosmetic reasons. Two female patients complained about an increased glare sensitivity, which was explainable for one of them with a subcapsular cataract. The retinal crystals decreased quite differently. Minor deffects of the retinal pigment epithelium remained unchanged in two patients. They increased slightly in the female patient with the smallest crystal formation but highest plasma cholesterol. Shortly after withdrawal of the drugs usually an increase of a-wave amplituded of the electroretinograms was found. The a-waves returned to normal and the b-wave amplitudes showed an increase up to the final control paralleling the reduction of the retinal crystals. A- and b-wave peak latencies which were prolonged under treatment returned to normal.


[Surgery of Tenon's capsule in squint operations]. There is a good chance to reduce the scaring between conjunctiva, Tenon's capsule, muscle and sclera after surgical treatment of rectus and oblique muscles if a careful reconstruction of Tenon's capsule is made. In the rare cases that you have to reoperate, you will experience the benefit of these additional stitches (7-0 vicryl) that restore the integrity of Tenon.


["Erroneous orthograde" direction of flow in the supratrochlear artery as a cause of Doppler ultrasound diagnostic error in severe (filiform; 90%) stenosis of the carotid bifurcation]. Author reports on mistake in Ultrasound-Doppler-Sonography by an neurologist. A 82-year-old women with leftside Amaurosis fugax was referred by her family doctor, internist. Neurological examination, above all Doppler-Sonography, results in "normal findings". Examination by author however detected filiforme stenosis of left internal carotid artery in spite of "orthograde" direction of blood-flow in final branches of ophthalmic artery. This perhaps was the cause of neurological misdiagnosis.


[Choroid ganglioneuroma in childhood].

[Choroid ganglioneuroma in childhood]. The authors report on a case of a 4 1/2-year-old male child, who was referred because of a convergent microstrabisms of the right eye combined with amblyopia and minimal anisometropia and progressive decrease of the visual function from 0.6 to 0.05 although occlussion-therapy was performed. Funduscopy showed a melanoma-like choroidal tumor temporal-inferior of the macula with shallow retinal detachment and severe cellular vitreal infiltration. Because of the progression the tumor was resected by the transscleral technique of Foulds (1983). Histology showed a ganglioneuroma of the choroid, which has not been reported in this localisation up to now. Usually it is found in the retroperitoneal area and in the mediastinum, specially in case of neurofibromatosis (Recklinghausen). This disease could not be objectified in this meanwhile 7-year-old boy. At the last control visual acuity was 1/20, ophthalmoscopy showed gross streaky depigmentation in the macular region, the retina was attached.


[Retinal lymphoma--simulating uveitis].

[Retinal lymphoma--simulating uveitis]. A rare form of malignant large-cell non-Hodgkin's lymphoma or reticulum cell sarcoma is confined to the eye and central nervous system (CNS). We report the case of a 62-year-old man, who presented with recalcitrant progressive uveitis in his right eye. Although lymphoma was suspected, the patient refused to undergo vitrectomy. Over one year he developed large blister-like solid scattered lesions of the retinal pigment epithelium (RPE) in the same eye. Repetitive neuroimaging detected no CNS involvement. After developing optic disc-swelling and discrete RPE-changes in the left eye also, the patient agreed to enucleation of his right eye. Histopathology and Immuno-histochemistry revealed malignant intraocular large cell-lymphoma invading all eye-tissues. Liquor cytology showed lymphomatous cells. Suffering from high grade malignant lymphoma with CNS ivolvement, the patient had to undergo radiation therapy of the orbits and neuroaxsis as well as intravenous and intrathecal chemotherapy. Papilledema of the left eye resolved quickly and completely, RPE-infiltrations disappeared and led to discrete punched out lesions with no scarring, the lens remained transparent over the whole observation period of 25 months. the patient has been surviving for more than 52 months after first suspicion of malignant lymphoma, he has retained full vision in his left eye until now.


[Quantifying suture tension of corneal sutures with the suture forceps with strain gauge strips]. To achieve uniform tensions on corneal stiches a modified tying forceps was developed. This forceps provides the possibility to measure the tension which is put to a nylon thread (10-0) by means of surface mounted strain gauges detecting the forceps jaws' bending. The results are registered and displayed electronically. To obtain a preselected tension, a limit value switch and a tare unit is used. A first series of registrations showed reproduceable values and confirmed a linear correlation between forceps jaw bending and traction force. A prototype and possibilities of technical improvement are demonstrated.


[PC software for evaluating the Farnsworth-Munsell 100-Hue test]. This computer program is designed for faster elaboration of the Farnsworth-Munsell 100-Hue test. It is thus made user friendly, in that faultless input of data can be achieved, even by an untrained person. Evaluation is facilitated by the opportunity of representing two results at the same time. Examples of typical colour vision deficiencies are stored in a file and can then also be called up. Storing the results in a special data file helps to avoid the time consuming printing process. However, a hardcopy is supported by storing the last grafic in a standard PostScript-file, thus giving easy access to any printer. This program is applicable for IBM- or compatible PCs. Extensive use is possible by means of a software interface with the wide spread database-system DBASE.


[125 years ophthalmopathology in Tübingen. Change in the times and spectrum of findings]. The beginning of ophthalmopathological activities at the University Eye Clinic Tübingen, Germany, can be dated back to the year 1868, as at this time the continuous counting of investigated, ophthalmological specimens was started. So the ophthalmopathological department in Tübingen will be 125 years old in 1993. In a review its history is described with particular regard to the first period and the change in the kind and frequence of diagnoses.


[The most frequent causes of loss or impairment of vision in children and adolescents]. On the basis of examination of 100 persons aged 3-18 years registered in the Olsztyn Division of the Union of the Blind the authors determined the causes which led to the loss of vision or of its impairment. The most frequent cause of the invalidism of the visual system were: errors of refraction (32%), optic atrophy (24%), congenital cataract (16%), retinal and choroidal degeneration (9%), retrolental fibroplasia (6%), anophthalmia or malformation of the globe (4%), coloboma of the iris or choroid (3%), retinoblastoma (3%), injuries (2%) and congenital glaucoma (1%).


[Eye burns in children and adolescents]. The authors present a material of 91 eyes in 66 children aged 2 days to 16 years, who sustained burns of the eyes. Fifty one eyes (1st group) was burned by thermal or chemical means, mainly by lime; 40 eyes (2d group) sustained chemico-mechanical injuries caused by explosions of petards or miner's detonators. Bilaterality of the injuries was seen in 50 p.c. of cases of the 1st group and in 25 p.c. of cases of the second group. Reduction of the visual acuity down to light perception was observed in 19.7 p.c. of cases of the 1st group and in 22.5 p.c. of cases in the 2d one; at the same time 2 cases of this group became blind. The cause of deterioration of the visual acuity in the group of chemico-thermal trauma were the corneal opacities, in the group of mixed injuries--changes in the posterior segment of the eye.


[Late results of the treatment of eye burns]. An analysis of patients treated in the Ophthalmic Department in Bydgoszcz for eye burns in the 10 years period from 1980 till 1990. Taken into account were the causes of burns, the treatment installed in the early period and in cases of late complications. All the patients were asked to call in for a control examination in order to compare the condition of the eyes at the date of discharge and in the long-lasting time. Among 118 eyes in 91 the visual acuity amounted 0.5-1.0, in the remaining 25 it was only hand movements--0.4. The main causes of low visual acuity were: corneal leucoma, secondary glaucoma, complicated cataract. The eye was enucleated in 2 patients because a painful ocular atrophy developed in the course of the pathological process. These were the cases of thermal burns combined with a mechanical injury. The obtained results were evaluated as sufficiently favourable and comparable to the data of other authors.


[Prevention of amblyopia by active production of the macular fixation reflex in infants]. Among 1455 examined babies aged 3 months the authors found a lack of normal fixation reflex in both eyes in 155 and in 52 in one eye only. In these eyes the parents applied 3 times a day an alternate occlusion of eyes or of the master eye only showing the babies interesting toys. After 2 weeks 83 babies showed normalization of fixation and after following 2 weeks of over described occlusion only 8 of them did not reveal a normal fixation reflex. These babies exhibited also a convergent squint. The pleoptic treatment by means of an euthyscope was installed, followed by normalization of the fixation reflex in 3. The rest of the patients was treated with spheroprismatic glasses by localization method.