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Context.—Coronavirus disease 2019 (COVID-19) has been shown to have effects outside of the respiratory system. Placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a topic of great interest because earlier studies have shown mixed results.Objective.—To ascertain whether maternal SARS-CoV-2 infection is associated with any specific placental histopathology, and to evaluate the virus's propensity for direct placental involvement.Design.—Placentas from 65 women with polymerase chain reaction–proven SARS-CoV-2 infection underwent histologic evaluation using Amsterdam consensus group criteria and terminology. Another 85 placentas from women without SARS-CoV-2 constituted the negative control group. A total of 64 of the placentas from the SARS-CoV-2–positive group underwent immunohistochemical staining for SARS-CoV-2 nucleocapsid protein.Results.—Pathologic findings were divided into maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammatory lesions, amniotic fluid infection sequence, increased perivillous fibrin, intervillous thrombi, increased subchorionic fibrin, meconium-laden macrophages (M-LMs) within fetal membranes, and chorangiosis. There was no statistically significant difference in prevalence of any specific placental histopathology between the SARS-CoV-2–positive and SARS-CoV-2–negative groups. There was no immunohistochemical evidence of SARS-CoV-2 virus in any of the 64 placentas that underwent staining for viral nucleocapsid protein.Conclusions.—Our study results and a literature review suggest that there is no characteristic histopathology in most placentas from women with SARS-CoV-2 infection. Likewise, direct placental involvement by SARS-CoV-2 is a rare event.

Highlights • Approximately one-fifth of uterine serous carcinomas (USC) will express WT-1. • WT-1 expression is associated with a significant improvement in platinum sensitivity. • Improved platinum sensitivity among WT-1 positive tumors contributes to a superior PFS vs. WT-1 negative tumors., Background Wilms tumor gene 1 (WT1) expression is a hallmark of ovarian serous carcinoma and considered to be diagnostic marker of these tumors, differentiating them from uterine serous carcinoma (USC), historically thought to rarely express WT1. However, more recent data indicates a significant percentage of USC may express WT1. The clinical implications of WT1 positivity in USC remain unclear. Methods A multicenter retrospective analysis of patients with USC was conducted from 2000 to 2019. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking with archival tissue available for WT1 assessment via immunohistochemistry (IHC). Chemosensitive patients were defined as those recurring >6 months from last platinum-based chemotherapy. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results WT1 status was evaluated in 61 patients with USC. 13 (21.3%) were positive for WT1 by IHC. Stage distribution included 32% stage I, 5% stage II, 25% stage III and 38% stage IV. There was no difference in the stage (p = 0.158), race (p = 0.227) or distribution of recurrence sites (p = 0.581) between WT1 positive and WT1 negative tumors. The majority of patients were chemosensitive (63%). Chemosensitivity was significantly improved in WT1 positive (92.3%) vs. WT1 negative tumors (55.8%) (p = 0.016). We observed a trend towards improved PFS among WT1 positive tumors (21 vs. 16-months, respectively) (p = 0.544). On MVA, stage (p

Objectives: Wilms tumor gene 1 (WT1) expression is a hallmark of ovarian serous carcinoma (OSC) and considered to be diagnostic marker of these tumors, differentiating them from uterine serous carcinoma (USC), traditionally thought to rarely express WT1. However, recent data indicates a significant percentage of USC may express WT1, limiting its use as a differentiating marker between these two tumors. Additionally, the clinical implications of WT1 positivity in USC remain unclear. Methods: A multicenter retrospective analysis of patients with USC was conducted from 2000 - 2019. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking with archival tissue available for WT1 assessment via immunohistochemistry (IHC). Platinum-sensitive patients were defined as those recurring >6 months from last platinum-based chemotherapy. Differences in the frequencies of stage, race, chemosensitivity and sites of disease recurrence were identified using Pearson's chi-square test. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: WT1 status was evaluated in 61 patients with USC. 13 (21.3%) were positive for WT1 by IHC. Of these 61 patients, 56 had follow-up information available for review and were included in final analysis. The mean age was 67-years and the majority of patients were African American (97%). Stage distribution included 32% stage I, 5% stage II, 25% stage III and 38% stage IV. The majority of patients were designated as platinum-sensitive (63%). 36 (64%) patients recurred during the study period, 8 (62%) of the WT1 positive and 28 (65%) of the WT1 negative cohort. The most common location of recurrence was the abdomen followed by the pelvis and extra-abdominopelvic sites. There was no difference in the stage (p=0.158), race (p=0.227) or distribution of recurrence sites (p=0.581) between WT1 positive and WT1 negative tumors. Platinum-sensitivity was significantly improved in WT1 positive (92.3%) vs. WT1 negative tumors (55.8%) (p=0.016). For the entire cohort, the median PFS was 20 months and the median OS was 29 months. The median PFS and OS did not differ significantly based on WT1 status (p=0.544 and p=0.759, respectively). However, we did observe a trend towards improved PFS among WT1 positive tumors (21 vs. 16 months, respectively). On MVA, stage (p Download : Download high-res image (147KB) Download : Download full-size image Conclusions: WT1 positivity is observed in over 20% of USC, limiting its utility to differentiating OSC and USC. Additionally, WT1 status holds prognostic significance as expression was associated with improved platinum-sensitivity and a clinically significant 5-month improvement in PFS.

Background Malignant transformation of mature cystic teratomas (MCTs) is a rare phenomenon. The most common histology of a malignant transformation is squamous cell carcinoma, and there are limited reports of multiple malignancies arising in a single MCT. Further data are necessary to guide management of these atypical cases. Case We present the case of a 48-year-old with MCT containing a malignant papillary thyroid carcinoma (PTC) arising in the context of struma ovarii and a carcinoid tumour. Conclusion Malignant transformations of MCTs are exceedingly rare with no guidelines on management. We use this case to demonstrate an approach for the workup and management of malignantly transformed MCTs.

Introduction/Objective Inflammatory myofibroblastic tumor (IMT) is an uncommon spindle cell lesion that can involve various organs and occurs in multiple body sites. While older terminology (i.e. inflammatory pseudotumor) suggested otherwise, recent molecular studies point toward a neoplastic pathogenesis for IMTs. Herein, we report a case of an abdominal IMT and discuss the morphologic and immunohistochemical pitfalls pertaining to this entity. Methods A 75-year-old woman presented with complaints of generalized abdominal pain and distention. An abdominal CT scan showed multiple peritoneal masses, the largest of which measured 23 cm. Biopsy revealed compact fascicles of bland spindle cells exhibiting diffuse actin and caldesmon immunoreactivity, consistent with a spindle cell tumor with smooth muscle differentiation. Mitotic activity was low-to-unapparent. Surgical excision was performed. The cut surface of the tumor was tan-white with hemorrhagic foci. Histopathologic examination of the tumor showed elongated spindle cells set in a loose myxoid stroma rich in blood vessels and a mixed inflammatory infiltrate. Deeper sections of the tumor were more cellular, showing a similar morphology to that seen in the original biopsy, which was virtually devoid of inflammatory cells. Immunohistochemistry showed diffuse staining for desmin, caldesmon, smooth muscle actin, and ALK. FISH analysis showed ALK gene rearrangement in 52% of tumor cells, confirming the diagnosis of IMT. Results Studies in the literature show that IMTs express smooth muscle markers such as SMA (90%) and desmin (50%). However, immunoreactivity for caldesmon is rarely reported. ALK immunoreactivity is seen in about 35–60% of cases, and when gene rearrangement involving ALK is detected the diagnosis can be confirmed. Conclusion Historically, several terms have been used to describe IMTs, including inflammatory pseudotumor and inflammatory pseudosarcomatous fibromyxoid tumor. While the nomenclature consistently implies an inflammatory infiltrate, this tumor could have various morphological patterns with some areas showing very little to absent inflammation, as demonstrated in our case. Hence, making an accurate diagnosis could be challenging on a limited biopsy. Therefore, ALK testing should be included as part of the diagnostic workup of spindle cell neoplasms with smooth muscle differentiation.

Introduction Proper placental gross examination requires weighing the placental disc trimmed of fetal membranes and the umbilical cord. However, untrimmed placental weights are often reported, both in cases submitted for consultation and in publications. Thus, determining the contribution of membranes and cords to untrimmed placental weights would be helpful in estimating the true trimmed weight of placentas. We sought to report the average weights of membranes and cord in term placentas and to correlate these weights with common placental pathologies. Methods A total of 500 consecutive placentas delivered between 36 and 42 weeks gestational age were subjected to a modified grossing protocol, in which the weight of the trimmed and untrimmed placentas, fetal membranes, and umbilical cords were recorded. Acute chorioamnionitis, meconium, maternal vascular malperfusion, and fetal vascular malperfusion were included as pathologic correlates. Clinical data such as the presence of fetal hydrops, intrauterine growth restriction, intrauterine fetal demise, and maternal diabetes were also recorded. Results The mean weights of the trimmed placenta, fetal membranes, and umbilical cords were 442 g (180–805 g), 47.2 g (16–108 g), and 37.9 g (9–126 g), respectively. The fetal membranes and umbilical cord weights contributed a mean of 16% to the total untrimmed placental weight. Meconium was associated with heavier fetal membranes. Fetal vascular malperfusion was associated with longer umbilical cord and thus also with heavier umbilical cords. Maternal vascular malperfusion and intrauterine growth restriction were associated with lighter placentas. Discussion The trimmed placental disc weight may be estimated by subtracting 16% (ie, weight of the fetal membranes and umbilical cord) from the untrimmed placental weight, or alternatively by subtracting the mean weight of the membranes and umbilical cord. It is important to consider the effects of meconium, fetal and maternal vascular malperfusion, and intrauterine growth restriction on membrane and cord weights when estimating the trimmed placental disc weight.

The incidence of glomerulonephritis, as a manifestation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has always been considered low. Though renal infiltration is usually detected at post-mortem, it does not often interfere with kidney function [1]. Though immunoglobulin (Ig) levels in most CLL patients are subnormal, small monoclonal Ig peaks are occasionally detected in serum. They were present in a number of reported CLL nephropathy patients, and not all were cryoglobulins; serum and glomerular staining were concordant for Ig type [2,3,4]. Myeloma, which secretes monoclonal light chains, causes nephropathy in 25% of patients. But the little presumably secreted by small plasma cell clones, without myeloma, may also be nephrotoxic. The same is true of the low secretory CLL cells, which may occasionally be associated with cryoglobulins and other nephrotoxic Igs [5]. We report a patient with early stage CLL (Rai stage 0) with cryoglobulins, which led to membranoproliferative glomerulonephritis (MPGN), and death. We located reports of 51 patients with CLL-associated nephrotic syndrome or nephropathy, mostly from MPGN related to local Ig deposits. In those patients screened for cryoglobulins, about half tested positive. Many were early stage cases, where MPGN developed long after CLL presentation, and responded to its treatment. As early diagnosis and treatment CLL-related nephropathy may be curative, we propose a prospective study to determine the incidence of hyperalbuminuria development after presentation.

Background The goal of this work was to determine whether there are clinically significant fluctuations in the level of serum creatinine on serial determinations, especially in the borderline range (1.1–1.3 mg/dl), after specimen storage. Methods Sixty-one serum samples were analyzed. They were divided into three categories based on the initial serum creatinine measurement: low (≤1.0 mg/dl), borderline (1.1–1.3 mg/dl), and high (≥1.4 mg/dl). The specimens were stored at 4°C and run on the Siemens Advia 1800 chemistry analyzer on days 1, 3, and 11. Results Statistical comparisons of the three groups were made using the unpaired t-test, yielding a two-tailed P-value for each group comparison. The P-values ranged from 0.0829 to 0.3892, indicating no statistically significant difference between the standard deviations of each group. Conclusions Mild-to-moderate fluctuations in precision occur in successive serum creatinine determinations. The overwhelming majority of these fluctuations should not affect clinical decision making.

Plasma catecholamines, hand-grip exercise and orthostatic stress were used to assess sympathetic nerve function in 14 hypertensive patients with mild to moderate renal failure and, for comparison, in 14 age-matched normal subjects. Furthermore, acute and chronic administrations of clonidine were used to determine a participation of the sympathetic nervous system in the maintenance of hypertension in these patients. Baseline mean blood pressure (MBP), plasma norepinephrine (NE), plasma renin activity (PRA) and aldosterone were elevated in patients with renal failure. During hand-grip exercise, the rise in MBP and in heart rate was blunted in these patients. During orthostasis, MBP decreased more while the increments in NE were greater in hypertensive patients that in normal subjects. Acute administration of clonidine (200 micrograms orally) resulted in a significant decrease in MBP, heart rate, NE, PRA, and aldosterone. There was a significant (p less than 0.01) correlation between the decrease in NE and the fall in MBP. After 6 weeks of treatment, clonidine produced a significant decrease in MBP, heart rate, NE and aldosterone, but not in PRA. Chronic treatment with clonidine produced a slight but significant (p less than 0.05) rise in serum potassium and in serum creatinine. Exchangeable sodium and plasma volume did not change significantly. The data indicate that abnormalities in the function of the sympathetic nervous system are already evident in patients with mild to moderate renal failure. The data also suggest that the sympathetic nervous system may participate in the maintenance of the hypertension in these patients.

The function of the hypothalamic-pituitary-gonadal (HPG) axis was examined in 20 male patients with acute renal failure. During the oliguric phase of the disease, the serum concentrations of follicle stimulating hormone (FSH) and total and unbound testosterone were markedly reduced, those of prolactin were elevated while those of luteinizing hormone (LH) were normal. The serum concentrations of sex hormone binding globulin were normal. During the diuretic phase of the illness, the serum levels of FSH and testosterone remained low but those of prolactin fell towards normal. After recovery of renal function, the abnormalities in the serum concentrations of these hormones were reversed. The responses of LH and FSH to gonadotropin releasing hormone and of prolactin to thyrotropin releasing hormone were abnormal and became normal after recovery of renal function. The results demonstrate that: (1) abnormalities in HPG axis occur early in the course of acute renal failure; (2) many features of these derangements are similar to those seen in chronic renal failure, and (3) the alterations in the function of the HPG axis are reversible when renal function is restored. The data suggest that loss of renal function, uremia per se and/or a metabolic consequence of uremia such as secondary hyperparathyroidism are responsible for these derangements.

A noninvasive method for diagnosing thrombosis in the nephrotic syndrome could be useful clinically. We measured hematocrit, fibrinogen, creatinine, antithrombin III, plasminogen, and alpha-2-plasmin inhibitor levels in 20 patients with nephrotic syndrome objectively studied for the presence of thrombosis, and found that by using combinations of three or more of these variables good discrimination could be obtained between those patients with and without thrombosis. We conclude that it is possible to predict risk of thrombosis in nephrotic syndrome using relatively simple noninvasive laboratory tests.

Dysfunctions of the autonomic nervous system (ANS) are frequent complications of chronic renal failure. It is not clear, however, whether these dysfunctions occur in patients with acute renal failure.

1. The effect of clonidine on the relationship between sympathetic nervous system activity and the state of sodium-volume balance was studied in 15 patients with essential hypertension and normal renal function (group 1) and in 14 patients with hypertension and mild to moderate renal failure (group 2). 2. Acutely, clonidine (200 μg) produced significant falls (P < 0.01) in mean blood pressure, plasma noradrenaline, plasma renin activity and plasma aldosterone in both groups of patients. The changes in mean blood pressure were significantly correlated (P < 0.01) with the changes in plasma noradrenaline. 3. Chronic therapy with clonidine also produced significant falls in mean blood pressure and plasma noradrenaline, but not in plasma renin activity or aldosterone. 4. Exchangeable sodium and plasma volume decreased significantly in patients of group 1 but not in patients of group 2. 5. The data indicate that sympathetic nerve activity may be important for the abnormal relationship between pressure and natriuresis in subjects with essential hypertension and normal renal function, but not in hypertensive subjects with impaired renal function.

Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. To examine the mechanisms underlying the sensitivity to sodium intake in a subset of patients with essential hypertension, we studied the effects of different sodium intake (10, 100, 200 mEq/day) on blood pressure, the function of the renin-angiotensin-aldosterone system, and on blood levels of catecholamines in 20 patients with essential hypertension and 10 normal subjects. Mean blood pressure (MBP) was not different in hypertensive and normal subjects during low sodium diet. But, with high sodium intake, MBP increased by at least 10% in 12 patients (salt-sensitive), whereas in the remaining 8 patients (salt-resistant) and in normal subjects, MBP did not change significantly. This phenomenon cannot be attributed to differences in sodium retention because the percent change in body weight and the urinary sodium excretion in the salt-sensitive patients was not different than it was in salt-resistant patients or in normal subjects. The observed difference in blood pressure response to high sodium intake in salt-sensitive patients is also not dependent on an impaired suppressibility of the renin-angiotensin-aldosterone system because there were no significant differences in the basal levels of PRA and aldosterone between the groups, and because the orthostatic increments in PRA were significantly lower in salt sensitive than they were in the salt-resistant patients and in normal subjects. Plasma norepinephrine (NE) levels were not significantly different between normal subjects or hypertensive patients while on low sodium intake. But during high sodium intake, they decreased significantly (P < 0.05) in normal subjects (from 22 ± 3.4 to 12 ± 2.3 ng/dl) and in salt-resistant patients (from 17 ± 4.5 to 13 ± 2.4 ng/dl) but not in salt-sensitive patients (from 20 ± 1.9 to 22 ± 3.2 ng/dl). Furthermore, the majority of salt-sensitive patients displayed inappropriately high plasma NE in relation to their urine excretion of sodium during high sodium intake. Finally, the increments in plasma NE after 5min of standing were significantly greater in salt-sensitive patients than they were in salt-resistant patients and normal subjects during both low or high sodium intake. These data indicate that a subset of patients with essential hypertension may have impaired suppressibility of plasma NE during high sodium intake, which suggests hyperactivity of the sympathetic nervous system in these patients. These aberrations may be responsible for the increase in MBP in the salt-sensitive patients during high sodium intake.Relation anormale entre l'ingestion de sodium et l'activité du système nerveux sympathique chez les malades atteints d'hypertension essentielle sensibles au sel. Afin d'étudier les mécanismes qui sous-tendent la sensibilité à l'apport de sodium dans un sous-groupe de malades atteints d'hypertension essentielle, les effets de différents apports de sodium (10, 100, 200 mEq/jour) sur la pression artérielle, la fonction du système rénine-angiotensine-aldostérone, et les concentrations sanguines de catécholamines ont été évaluées chez 20 malades atteints d'hypertension essentielle et chez 10 sujets normaux. La pression artérielle moyenne (MBP) n'était pas différente chez les malades hypertendu et les sujets normaux recevant une alimentation pauvre en sodium. Mais, avec le régime riche en sodium, MBP a augmenté d'au moins 10% chez 12 malades (sensibles au sel) alors que chez les autres 8 malades (résistants au sel) et chez les sujets normaux MBP n'a pas changé de façon significative. Ce phénomène ne peut pas être attribué à des différences de rétention de sodium parce que le pourcentage de modifications du poids corporel et l'excrétion urinaire de sodium chez les malades sensibles au sel ne sont pas différents de ceux observés chez les malades résistants au sel ou chez les sujets normaux. La différence de pression artérielle observée chez les malades sensibles au sel au cours de l'alimentation riche en sodium n'est pas non plus dépendante d'une altération du freinage du système rénine-angiotensine-aldostérone parce qu'il n'a pas été observé de différences significatives dans les concentrations basales de PRA et d'aldostérone entre les groupes, et parce que l'augmentation orthostatique de PRA était significativement plus faible chez les malades sensibles au sel que chez les malades résistants au sel et les sujets normaux. Les concentrations plasmatiques de la norépinéphrine (NE) n'étaient pas significativement différentes entre les sujets normaux et les malades hypertendus soumis à un régime pauvre en sel. Mais, au cours du régime riche en sel ils ont diminué significativement (P < 0,05) chez les sujets normaux (de 22 ± 3,4 à 12 ± 2,3 ng/dl) et chez les malades résistants au sel (de 17 ± 4,5 à 13 ± 2,4 ng/dl) mais non chez les malades sensibles au sel (de 20 ± 1,9 à 22 ± 3,2 ng/dl). De plus, la majorité des malades sensibles au sel ont eu une concentration plasmatique de NE élevée de façon inappropriée par rapport à leur excrétion urinaire de sodium au cours du régime riche en sel. Enfin, les augmentations de NE plasmatique après 5min de position debout ont été significativement plus grandes chez les malades sensibles au sel que chez les malades résistants au sel et les sujets normaux aussi bien au cours du régime riche que du régime pauvre en sodium. Ces résultats indiquent qu'un sous-groupe de malades atteints d'hypertension essentielle peut avoir une altération du freinage de la NE plasmatique au cours de l'ingestion d'un régime riche en sodium ce qui suggère une hyperactivité du système nerveux sympathique chez ces malades. Ces désordres peuvent être responsables de l'augmentation de MBP chez les malades sensibles au sel au cours de l'ingestion d'une régime riche en sodium.

Venous and arterial thromboembolism frequently complicate the nephrotic syndrome. Increased platelet aggregation, high levels of fibrinogen and other procoagulants, and depressed levels of antithrombin III and plasminogen are commonly cited as reasons. Less attention has been paid to changes in the hemostatic system which might protect against thrombosis. We found a high frequency of reduced alpha 2-antiplasmin levels in 40 patients with nephrotic syndrome, correlating with serum albumin and with antithrombin III levels. Since alpha 2-antiplasmin is a major determinant of the sensitivity of fibrin thrombi to lysis, and since reduced levels would be expected to promote fibrinolysis, we conclude that in many patients with nephrotic syndrome depressed antiplasmin levels may help reduce the risk of thrombosis posed by diminished antithrombin III levels.

A twenty-seven year old female evaluated for gastrointestinal bleeding following ingestion of C. molybdites was found to have hematologic abnormalities consistent with disseminated intravascular coagulation. We suggest that the gastrointestinal hemorrhage was due to disseminated intravascular coagulation, a toxic effect of the mushroom.

The present study evaluated thyroid hormone indices of patients with acute renal failure without other systemic illnesses (n = 12), as compared to patients with critical illnesses in the presence (n = 16) and absence (n = 6) of acute renal failure. Abnormalities in the group with acute renal failure alone included decreased serum levels of total T4 and T3, and elevated levels of free rT3. Serum levels of free T4 by equilibrium dialysis and the enzyme immunoassay, T3 uptake ratios, TSH and total rT3 were normal. These findings are consistent with the presence of decreased binding of T4 and rT3 to their serum carrier proteins. Critically ill patients with acute renal failure differed in that they had lower total T4 and T3 levels and elevated T3 uptake ratio values. As in the group with acute renal failure alone, total rT3 levels were normal and free rT3 values were elevated. The group with critical illness alone differed only in that the total rT3 concentrations were elevated in all patients. The alterations of thyroid hormone indices in acute renal failure are similar to those of other nonthyroidal illnesses with the exception of the normal total rT3 levels. This suggests that the failing kidney or the metabolic consequences of uremia specifically affect rT3 metabolism.

The relationship between abnormalities in nocturnal penile tumescence (NPT) and autonomic function, measured by the Valsalva maneuver, was evaluated in 25 uremic patients and 22 normal subjects. NPT in uremic patients (45 +/- 6.8 min/night) was lower (p less than 0.01) than in normals (85 +/- 10.4 min/night). Valsalva ratio in uremics (1.58 +/- 0.07) was also lower (p less than 0.01) than in normal subjects (2.05 +/- 0.11). NPT and Valsalva ratio were significantly correlated in uremic patients (r = 0.62, p less than 0.01). The 12 uremic patients with abnormal Valsalva maneuver had NPT of 22 +/- 5.2 min/night, a value lower (p less than 0.01) than that (67 +/- 8.7 min/night) observed in the 13 uremic patients with normal Valsalva maneuver. There was also a significant correlation (r = 0.56, p less than 0.05) between the Valsalva ratio and the frequency of intercourse per month in the uremic patients, who had steady and active sexual partners. The data suggest that a dysfunction of the autonomic nervous system may be an important factor in the genesis of erectile abnormalities in patients with uremia.