Suitability of Estimated Glomerular Filtration Rate for Live Kidney Donor Selection.

INTRODUCTION: The assessment of the glomerular filtration rate (GFR) in kidney donor candidates is required for determining donor candidate acceptability. This assessment can be done using an estimated GFR (eGFR) or a measured GFR (mGFR). The primary objective of the present study was to compare, in healthy adult kidney donor candidates, GFR measured by the clearance of iothalamate to GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and to determine if eGFR was a suitable stand-alone assessment. A secondary objective was to explore demographic factors that affect the relationship of the eGFR and the mGFR. METHODS: A retrospective review of kidney donor candidates' records at the J. C. Walter, Jr., Transplant Center, Houston Methodist Hospital, from January 2013 to March 2016 was undertaken. GFR was measured by the plasma clearance of radioisotopic iothalamate and estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The median mGFR was 108 mL/min/1.73 m2. The eGFR underestimated the mGFR by 11.5%. The underestimation was greatest in subjects with an mGFR of ≥90 mL/min/1.73 m2. The eGFR overestimated the mGFR in donor candidates of black race. CONCLUSIONS: The Chronic Kidney Disease Epidemiology Collaboration eGFR can be used for screening potential kidney donors restricting the use of iothalamate (mGFR) to those donors with an eGFR below the transplant centers' acceptable GFR threshold for donation, thereby effecting cost savings and greater donor convenience. The eGFR in black donor candidates should be used with caution.

Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.

Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings.

New aspects of posttransplant nephrotic syndrome: clinicopathologic correlations with outcomes.

Although posttransplant nephrotic syndrome is frequent, its structural basis and prognosis have not been clearly defined. The biopsy findings of 54 patients with this disorder posttransplant, among 375 total renal transplant recipients engrafted during a 10-year period, were correlated with clinical follow-up data. The mean patient age was 41.7 +/- 12.3 years, female/male ratio 22/32, and cadaveric/living-related donor ratio 37/17. The nephrotic syndrome developed 3 to 91 months posttransplant. At the onset the mean values of serum creatinine was 2.9 +/- 1.8 mg/dL and proteinuria 4.5 +/- 0.8 g/d. The index biopsy findings showed chronic allograft nephropathy (CAN) in 33; de novo glomerulonephritis (GN) in 6, recurrent GN in 9, and undetermined GN in 6 who had an unknown primary renal disease. Among 21 follow-up biopsies during a mean of 44.3 +/- 28 months the CAN progressed but the GN remained the same. The treatment included augmented steroids alone (n = 1) or in combination with cyclophosphamide (n = 2) and with plasmapheresis (n = 1); angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) along (n = 5); calcium channel blockers (CCB) alone (n = 24); or the two types of drugs together (n = 22). Complete or partial remission was achieved in 8 and 5, respectively, but nephrotic syndrome recurred in 3 of these patients at 45.1 +/- 18 months later. Sustained remission was more likely in cases of GN (minimal change disease and IgA nephropathy) and ACEI-ARB treatment (P <.01). Graft failure, which occurred in 35 patients, correlated strongly with serum creatinine at onset, being significantly greater in patients with CAN (P <.005). Both remission of the nephrotic syndrome and graft survival were greater among patients with GN as compared to those with CAN.

Nonlupus nephritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature.

Renal biopsy specimens from patients with systemic lupus erythematosus (SLE) rarely show changes that are pathogenetically and morphologically unrelated to SLE. The morphology and behavior of these nonlupus nephritides are not well known. Two hundred fifty-two renal biopsies performed on 224 patients with SLE collected from 3,036 native kidney biopsies performed between 1975 and 1998 were reviewed, and those that showed nonlupus nephritides (index biopsies) were selected for studies. Thirteen biopsy specimens with nonlupus nephritides were identified in 13 patients, who belonged to 3 clinically distinct groups. Group I included 6 patients in whom SLE was diagnosed at the time of index biopsies. The index biopsies in these patients showed focal segmental glomerusclerosis (FSGS; 3 cases), Immunoglobulin (Ig) M nephropathy (1 case), and thin basement membrane disease (1 case). The diagnostic features for FSGS included segmental sclerosis involving at least 1 glomerulus, absence of lupus nephritis or other conditions that may cause nonspecific segmental sclerosis of glomeruli such as ischemia or nephrosclerosis, and nephrotic-range proteinuria. There was uniform, global, diffuse and marked thinning of the glomerular basement membrane in the case of thin basement membrane disease. Group II included 3 patients in whom SLE was diagnosed 2 to 9 years before the time of index biopsies and SLE was active at the time of biopsy. The index biopsies in these patients showed FSGS (2 cases) and hypertensive nephrosclerosis (1 case). Group III included 4 patients in whom SLE was diagnosed 5 to 36 years before the time of index biopsies and SLE was inactive at the time of biopsy. The index biopsies in these patients showed 1 case each of amyloidosis, FSGS, hypertensive nephrosclerosis, and allergic acute tubulointerstitial nephritis. Previous renal biopsies, performed in 5 patients, showed IgM nephropathy (1 case), diffuse proliferative lupus GN (1 case), focal proliferative lupus GN (1 case), and mesangial proliferative lupus GN (2 cases). Follow-up biopsies, performed in 3 patients, confirmed the diagnosis of FSGS (2 cases) and hypertensive nephrosclerosis (1 case) noted in the index biopsies. Nonlupus nephritides may occasionally be encountered in SLE patients, regardless of clinical or serologic disease activity. These renal lesions display a broad morphologic spectrum in which FSGS seems most frequent. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinct from those of lupus nephritis.

Renal cell apoptosis in chronic obstructive uropathy: the roles of caspases.

BACKGROUND: Apoptosis of tubular and interstitial cells is well documented in kidneys with chronic obstructive uropathy (COU) and probably plays an important role in the pathogenesis of this condition. The molecular control of apoptosis in COU remains poorly understood. Apoptosis in general is known to proceed initially along distinct pathways, which later converge into a common arm characterized by orderly activation of caspases. Caspases are cytosolic enzymes that belong to a 12-member family and serve as effector molecules for apoptosis. The role of individual caspases in mediating renal cell apoptosis in kidneys with COU is studied. METHODS: Kidneys were harvested from sham-operated mice and mice with COU created by left ureter ligation at days 4, 7, 15, 20, and 30. The following studies were performed: (1) determination of dried kidney weight; (2) in situ end labeling of fragmented DNA to detect apoptotic tubular and interstitial cells; (3) ribonuclease protection assay with specific anti-sense RNA probes for caspases 1, 2, 3, 6, 7, 8, 9, 11, and 12 to detect the expression of individual caspases; (4) immunostaining for caspases; and (5) assay for caspase 3. To assess the role of caspases in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of individual caspases. RESULTS: The obstructed kidneys showed progressive tissue loss (60% of control at day 15). Apoptosis of both tubular and interstitial cells was seen in obstructed kidneys. Tubular cell apoptosis peaked at four days after ureter ligation (13-fold of control), remained high between days 4 to 15, and thereafter decreased rapidly. Apoptotic interstitial cells were scanty initially, but gradually increased throughout the entire experiment. Apoptosis was minimal throughout the experiment in control and contralateral kidneys. In control and contralateral kidneys, caspases 2, 3, 6, 7, 8, and 9 mRNAs were expressed at low levels, whereas those for caspases 1, 11, and 12 were not detected. The obstructed kidneys displayed increased expression of all tested caspases. Caspases 1, 11, and 12 mRNAs were detected in obstructed kidneys in a common pattern characterized by a sharp increase at day 4, followed by a decrease until day 20, and a subsequent sharp increase until the end of the study at day 30. A similar pattern was noted for other caspases (2, 3, 6, 7, 8, and 9), which maximally reached twofold to fourfold that of controls. Immunostaining for caspases 1, 2, 3, 6, 7, 8, and 9 showed the same pattern characterized by focal and weak expression in proximal tubules of control or contralateral kidney, contrasting with increased staining in atrophic or dilated tubules of obstructed kidneys. Interstitial cells also displayed staining for several caspases, which paralleled the increasing density of interstitial cells toward the end of the experiment. Caspase-3 assay showed a marked increased activity in obstructed kidneys that reached fourfold and sevenfold of control at days 4 and 30, respectively. The rise and fall of caspase mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. CONCLUSIONS: Urinary obstruction in mice induces apoptosis of both tubular and interstitial cells in the affected kidney in a distinctive pattern that parallels an increased expression of caspases. This correlation suggests that these caspases mediate COU-associated renal cell apoptosis. Among the evaluated caspases, increased renal caspase 3 activity implies its central role in renal cell apoptosis associated with urinary obstruction.

Guidelines for the referral and management of patients eligible for solid organ transplantation.

Members of the Clinical Practice Committee, American Society of Transplantation, have attempted to define referral criteria for solid organ transplantation. Work done by the Clinical Practice Committee does not represent the official position of the American Society of Transplantation. Recipients for solid organ transplantation are growing in numbers, progressively outstripping the availability of organ donors. As there may be discrepancies in referral practice and, therefore, inequity may exist in terms of access to transplantation, there needs to be uniformity about who should be referred to transplant centers so the system is fair for all patients. A review of the literature that is both generic and organ specific has been conducted so referring physicians can understand the criteria that make the patient a suitable potential transplant candidate. The psychosocial milieu that needs to be addressed is part of the transplant evaluation. Early intervention and evaluation appear to play a positive role in maximizing quality of life for the transplant recipient. There is evidence, especially in nephrology, that the majority of patients with progressive failure are referred to transplant centers at a late stage of disease. Evidence-based medicine forms the basis for medical decision-making about accepting the patient as a transplant candidate. The exact criteria for each organ are detailed. These guidelines reflect consensus opinions, synthesized by the authors after extensive literature review and reflecting the experience at their major transplant centers. These guidelines can be distributed by transplant centers to referring physicians, to aid them in understanding who is potentially an acceptable candidate for transplantation. The more familiar physicians are with the exact criteria for specific organ transplantation, the more likely they are to refer patients at an appropriate stage. Individual transplant centers will make final decisions on acceptability for transplantation based on specific patient factors. It is hoped that this overview will assist insurers/payors in reimbursing transplant centers for solid organ transplantation, based on criteria for acceptability by the transplant community. The selection and management of patients with end-stage organ failure are constantly changing, and future advances may make obsolete some of the criteria mentioned in the guidelines. Most importantly, these are intended to be guidelines, not rules.

Ceftriaxone is an efficient component of antimicrobial regimens in the prevention and initial management of infections in end-stage renal disease.

BACKGROUND: Infection is a frequent complication in patients with end-stage renal disease. The most common organisms isolated are gram-positive cocci and gram-negative bacilli. Therefore, the usual initial therapeutic approach in these situations is the simultaneous intravenous administration of vancomycin plus an aminoglycoside. This treatment's adverse effects include ototoxicity, nephrotoxicity, and less than ideal tissue penetrance. METHODS: We assessed the efficacy of intravenous ceftriaxone in the prevention and in the initial empirical treatment of infections in end-stage renal disease patients, and tested the stability of blood levels of this antibiotic in this population. We studied 104 patients, 65 of them falling into the prevention group (1 g of ceftriaxone i.v. for 5 days) and 39 into the treatment group (1 g of ceftriaxone i.v. or intraperitoneally for 10-14 days). RESULTS: Peak serum ceftriaxone concentrations were well above the minimal inhibitory concentration for 90% of strains. Trough serum concentrations of the drug prior to the next dose were also considerably in excess of the minimal inhibitory concentration. In the prevention group, 8 of 65 developed an infection, which was sensitive to ceftriaxone, whereas in 22 of the 39 patients from the treatment group, cultures showed organisms sensitive to ceftriaxone and in the remaining 17 patients sensitivity was not done. CONCLUSIONS: The present study demonstrates the efficacy of a simplified dosing schedule in achieving blood levels of the antibiotic well in excess of minimal inhibitory concentration of any of the organisms encountered. It also shows the usefulness of ceftriaxone in the prevention and/or treatment of bacterial infections and the lack of the side effects vancomycin and/or aminoglycosides possess.

Mechanism of chronic obstructive uropathy: increased expression of apoptosis-promoting molecules.

BACKGROUND: We have demonstrated that renal tubular and interstitial cells undergo pronounced apoptosis during the course of chronic obstructive uropathy (COU). Apoptosis is a complex cellular process consisting of multiple steps, each of which is mediated by families of related molecules. These families may include receptor/ligand molecules such as Fas, Fas ligand, tumor necrosis factor receptor-1 (TNFR-1), and TNF-related apoptosis inducing ligand (TRAIL); signal transduction adapter molecules such as Fas-associated death domain (FADD), TNFR-1 associated death domain (TRADD), receptor-interacting protein (RIP), Fas-associated factor (FAF), and Fas-associated phosphatase (FAP); or effector molecules such as caspases. However, the mechanism of tubular cell apoptosis, as well as the pathogenetic relevance of these apoptosis-related molecules in COU, remains poorly understood. METHODS: Kidneys were harvested from sham-operated control mice and mice with COU created by left ureter ligation sacrificed in groups of three at days 4, 15, 30, and 45. To detect apoptotic tubular and interstitial cells, in situ end labeling of fragmented DNA was performed. To detect the expression of apoptosis-related molecules, ribonuclease protection assay was used with specific antisense RNA probes for Fas, Fas ligand, TNFR-1, TRAIL, FADD, TRADD, RIP, FAF, FAP, and caspase-8. Immunostaining for Fas, Fas ligand, TRAIL, TRADD, RIP, and caspase-8 was also performed. To assess the role of these molecules in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of apoptosis-related molecules. RESULTS: The obstructed kidneys displayed increased apoptosis of both tubular and interstitial cells. Tubular cell apoptosis appeared at day 4 after ureter ligation, peaked (fivefold of control) at day 15, and decreased gradually until the end of the experiment. In contrast, interstitial cell apoptosis sustained a progressive increase throughout the experiment. Apoptosis was minimal at all experimental time points for control and contralateral kidneys. Compared with control and contralateral kidneys, the ligated kidneys displayed a dynamic expression of mRNAs for many apoptosis-related molecules, which included an up to threefold increase for Fas, Fas ligand, TNF-R1, TRAIL, TRADD, RIP, and caspase-8, and an up to twofold increase for FADD and FAP, but there was little change for FAF. These mRNAs increased between days 4 and 15, decreased until day 30, but then increased again until day 45. The rise and fall of mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis in that period. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. We demonstrated a positive immunostaining for Fas and Fas ligand in the tubular cells at early time points as well as in interstitial inflammatory cells at later time points. Although increased expression of TRAIL, TRADD, RIP, and caspase-8 was noted in tubular cells, there was no staining for these molecules in interstitial cells. CONCLUSION: The current study documents a dynamic expression of several molecules that are known to mediate the most crucial steps of apoptosis. It implicates these molecules in COU-associated renal cell apoptosis and in the pathogenesis of this condition. It also lays the foundation for interventional studies, including genetic engineering, to evaluate the molecular control of apoptosis associated with COU.

Changes in plasma free and phospholipid-bound choline concentrations in chronic hemodialysis patients.

BACKGROUND: Choline deficiency may develop in malnourished patients, those with cirrhosis, and those who require total parenteral nutrition. Previous data has suggested an important role for the kidneys in the maintenance of choline homeostasis. OBJECTIVE: This study was undertaken to determine the change in plasma choline during hemodialysis and to determine if it was lost in the dialysate. DESIGN: Thirteen adult patients (10 men, 3 women) who had required hemodialysis for a mean of 10.8 years were studied. Dialysis was performed 3 times weekly for 4 hours using either a cellulose acetate or polysulfone dialyzer membrane. Venous and arterial blood, and dialysate samples were taken for measurement of plasma free and phospholipid-bound choline concentration before beginning dialysis and after each hour of dialysis. An in vitro system was devised to determine if choline could bind to a significant degree to the dialysis membrane. RESULTS: Plasma free choline concentration was increased above normal (11.7 +/- 3.7 nmol/mL) at baseline and declined progressively during dialysis. In contrast, plasma phospholipid-bound choline concentration increased progressively during dialysis. The decrease in plasma free choline (-1.8 +/- 0.3 nmol/mL(-1)/h(-1); P = 1.6 x 10(-6)) was almost entirely related to that which was removed during dialysis, although the magnitude of the loss was not correlated with the increase in plasma phospholipid-bound choline concentration (125 +/- 20.5 nmol/mL(-1)/h(-1); P < 1.2 x 10(-6)). Patients lost a mean of 246 pmol of free choline during hemodialysis. Choline did not bind to the dialysis membrane. CONCLUSION: Plasma free choline concentration is elevated before dialysis, and choline is lost to a significant degree in the dialysate. Further investigation is necessary to determine whether a transient, dialysis-induced choline deficiency develops, and whether there is a role for choline supplementation in these patients. The choline homeostatic mechanism requires further investigation in renal failure patients.

Expression of adhesion molecules in kidney with experimental chronic obstructive uropathy: the pathogenic role of ICAM-1 and VCAM-1.

BACKGROUND: Chronic obstructive uropathy induced by maintained unilateral ureter ligation in the rat is characterized morphologically by interstitial inflammation, interstitial fibrosis, and tubular atrophy. Infiltrating mononuclear inflammatory cells, particularly T lymphocytes and macrophages, may contribute to the progression of this lesion by mediating tubular injury and by the activation of interstitial fibroblasts, with resultant tubular atrophy and interstitial fibrosis, respectively. Altered expression and activation of adhesion molecules by leukocytes, vascular endothelial cells, and parenchymal cells likely contributes both to the infiltration of inflammatory cells into the tubulointerstitial compartment and to the interaction of activated inflammatory cells with parenchymal cells. METHODS: In the current study, we examined changes in the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in a 90-day model of maintained unilateral ureter ligation in male Sprague-Dawley rats. RESULTS: Rat kidneys showed constitutive expression of ICAM-1 mRNA and constitutive immunostaining for ICAM-1 in peritubular capillaries, glomeruli, and a small percentage of cortical tubules. Ureter ligation resulted in a rapid increase in ICAM-1 mRNA, which was almost 2-fold greater than those of the contralateral and control kidneys as early as 3 h and which was maintained at a 4- to 6-fold higher level in the ligated vs. contralateral kidneys throughout the entire 90-day time course. There was a marked increase in ICAM-1 immunostaining within the tubular epithelium, with up to 80% of both cortical and medullary tubular cross-sections showing strong apical immunostaining from day 6 to 25, with a subsequent decrease throughout the remainder of the experiment. ICAM-1 immunostaining in the expanding interstitium in the ligated kidneys showed a gradual increase throughout the duration of the experiment. In contrast, glomerular immunostaining for ICAM-1 was decreased in the ligated compared to the contralateral kidneys throughout the entire experiment. There was a later but prominent increase in VCAM-1 mRNA in ligated kidneys, which was first evident at 2 days and which was maintained 2- to 10-fold greater than the contralateral kidneys throughout the entire time course. VCAM-1 immunostaining increased in the expanding interstitium, but decreased in glomeruli in obstructed vs. contralateral kidneys. Tubular staining for VCAM-1 did not change after ureter ligation. CONCLUSION: Increased ICAM-1 and VCAM-1 may contribute to the prominent inflammatory cell infiltration in the chronic tubulointerstitial nephritis accompanying maintained unilateral ligation. Tubule expression of ICAM-1, which occurs during a similar time course as previously documented for tubular cell proliferation and especially tubular cell apoptosis in this model, may contribute to injurious interactions of activated inflammatory cells with tubular epithelium.

Peritubular capillary loss is associated with chronic tubulointerstitial injury in human kidney: altered expression of vascular endothelial growth factor.

Chronic tubulointerstitial injury (CTI) including tubular atrophy and interstitial fibrosis represents one major determinant for the progression of chronic renal disease regardless of cause. Although peritubular capillaries (PTCs) are essential to maintain the normal structure and function of renal tubules, little is known about the role of PTCs in the development of CTI. The integrity of PTCs seems to be regulated by growth factors. Vascular endothelial cell growth factor (VEGF) has recently been recognized as a potent regulator of angiogenesis, vascular survival, and vascular permeability. Knowledge of the role of VEGF in renal disease is still rudimentary, and its role in CTI has not been explored. We analyzed the morphologic changes of PTCs and correlated them with other morphologic parameters of CTI in 32 human kidneys with various types of chronic tubulointerstitial disease. The VEGF expression was immunohistochemically evaluated. Compared with normal kidney, PTC loss (41% to 55% of control) and reduced size of PTCs (55% to 88% of control) were noted in kidneys with CTI. The PTC density was positively correlated with the proximal tubular density (r = 0.66, P <.0001), proximal tubular size (r = 0.54, P <.001), and negatively correlated with interstitial volume (r = -0.84, P <.0001). Compared with normal kidney, where podocytes were the only cell type that constantly expressed VEGF, an interesting pattern of increased VEGF expression by renal tubules, especially morphologically intact or hypertrophic ones, was shared by all cases with CTI. Loss of VEGF in sclerotic glomeruli was noted. PTC injury is pathogenetically linked to tubular atrophy, tubular loss, and interstitial fibrosis in human kidneys with CTI and might be a key factor for the progression of chronic tubulointerstitial disease. The characteristic and uniform pattern of altered VEGF expression in kidneys with CTI may result from ischemia induced by PTC loss and represent a protective mechanism against further PTC injuries. HUM PATHOL 31:1491-1497.

[Effects of the statins in kidney transplantation]. / Efectos de las estatinas en el trasplante renal.

A retrospective analysis was performed to assess the immunosuppressive activity of statins in kidney transplantation, determining their effects on serum cholesterol and triglyceride levels post-transplantation, on the incidence of acute rejection episodes and on renal function. A total of 97 patients who underwent a kidney transplant in a three-year period, had more than one-month graft survival, and a minimum of one year of follow-up, were included. Group A consisted of 38 patients who received statins; this group was subsequently divided into four subgroups, according to the time post-transplant when statins were prescribed. Group B consisted of 59 patients (control Group). Initial and final serum total cholesterol levels in Group A were not different (218 +/- 7.8 mg/dl vs 222 +/- 7.5 mg/dl); however, final levels were higher than initial values in Group B (216 +/- 6.0 mg/dl vs 189 +/- 6.4 mg/dl, P = 0.0021). Initial serum triglyceride levels were higher than final levels in Group A (305 +/- 25.5 mg/dl vs 188 +/- 10.6 mg/dl, P < 0.0001). Group A showed a better allograft survival (P = 0.0350), a reduction in the incidence of acute rejection episodes (1 vs 38 events, P < 0.0001) and a lower serum creatinine level (1.96 +/- 0.21 mg/dl vs 2.77 +/- 0.27 mg/dl, P = 0.0374). In Group A subgroups, kidney function was significantly better in patients who received statins early after transplantation. These data suggest that in kidney transplantation statins exert additional immunosuppressive effects, reduce the number of acute rejection episodes, improve allograft survival and kidney function and are effective in preventing serum cholesterol from rising; these effects correlate with a significant decrease in serum triglyceride but are independent of a hypocholesterolemic action.

Efectos de las estatinas en el trasplante renal. / [Effects of the statins in kidney transplantation]

A retrospective analysis was performed to assess the immunosuppressive activity of statins in kidney transplantation, determining their effects on serum cholesterol and triglyceride levels post-transplantation, on the incidence of acute rejection episodes and on renal function. A total of 97 patients who underwent a kidney transplant in a three-year period, had more than one-month graft survival, and a minimum of one year of follow-up, were included. Group A consisted of 38 patients who received statins; this group was subsequently divided into four subgroups, according to the time post-transplant when statins were prescribed. Group B consisted of 59 patients (control Group). Initial and final serum total cholesterol levels in Group A were not different (218 +/- 7.8 mg/dl vs 222 +/- 7.5 mg/dl); however, final levels were higher than initial values in Group B (216 +/- 6.0 mg/dl vs 189 +/- 6.4 mg/dl, P = 0.0021). Initial serum triglyceride levels were higher than final levels in Group A (305 +/- 25.5 mg/dl vs 188 +/- 10.6 mg/dl, P < 0.0001). Group A showed a better allograft survival (P = 0.0350), a reduction in the incidence of acute rejection episodes (1 vs 38 events, P < 0.0001) and a lower serum creatinine level (1.96 +/- 0.21 mg/dl vs 2.77 +/- 0.27 mg/dl, P = 0.0374). In Group A subgroups, kidney function was significantly better in patients who received statins early after transplantation. These data suggest that in kidney transplantation statins exert additional immunosuppressive effects, reduce the number of acute rejection episodes, improve allograft survival and kidney function and are effective in preventing serum cholesterol from rising; these effects correlate with a significant decrease in serum triglyceride but are independent of a hypocholesterolemic action.

Shared cadaver donor-husband HLA class I mismatches as a risk factor for renal graft rejection in previously pregnant women.

During the last few years, we have observed four cases in which accelerated rejection of a cadaver donor kidney in a previously pregnant woman could be clearly attributed to the rapid emergence of anti-human leukocyte antigen (HLA) antibodies that had been stimulated by mismatched paternal antigens but were completely undetectable at the time of transplantation. In addition to reviewing those cases, we also reviewed data on 19 other women with a history of at least one pregnancy who underwent transplantation with a first cadaveric kidney since 1991 and were followed for at least six months. The HLA antigens of the husbands had to have been determined and all accelerated rejection or early graft losses due to confirmed or presumed immunological causes were considered. Of the 19 additional women meeting these inclusion criteria, three suffered early immunological graft loss. As in our index cases, two of these women had also received kidneys from donors who shared at least one major immunogenic mismatched antigen with the respective husband for a total of six of seven women with early immunological graft loss. Only one of the 16 women without accelerated rejection or early immunological graft loss had a donor who shared a mismatched antigen with her husband. The difference between the two groups is statistically significant (p = 0.0005). These findings, considered with individual cases reported by other groups, indicate that transplantation from a cadaver donor with immunogenic mismatched class I HLA antigen(s) shared with the husband should be avoided in women with a previous history of pregnancy even when anti-HLA antibodies are not currently detected.

Relapsing membranous nephropathy. Response to therapy of relapses compared to that of the original disease.

BACKGROUND: Although controversial, treatment of membranous nephropathy appears to yield a reduction in the degree of proteinuria and conservation of renal function. METHODS: We report herein our experience with the treatment with steroids alone (group II, n = 13), or in combination with immunosuppressants (group III, n = 19) of patients with membranous nephropathy and the nephrotic syndrome, with a mean follow-up of 8.37 years. RESULTS: All patients underwent a first remission, with 24-hour urine protein excretion falling to 0.63 +/- 0.25 g in group II and 0.62 +/- 0.26 g in group III (p = NS) after 12.69 +/- 10.94 months of treatment in group II and 18.95 +/- 13.17 months in group III (p = NS). Three patients from group II (23%) and seven patients from group III (36.8%) experienced four and eight relapses, respectively (proteinuria in 24 h 4.0 +/- 0.80 g in group II relapsers and 4.4 +/- 0.87 in group III relapsers; p = NS). On treatment, all relapses remitted (second remission) after 7 +/- 6.93 months of therapy for group II and 8.6 +/- 6.70 months of treatment for group III (p = NS). Thereafter, no patients from group II, but 3 patients from group III (33.3%) had a second relapse. After treatment, all relapses remitted (third remission) in 3.3 +/- 1.53 months of therapy. CONCLUSIONS: These studies show that relapses, which occur in one-third of patients, respond favorably to treatment albeit remitting in approximately half the time, and that the duration of remission gets progressively longer in the later compared to the earlier remission.

Focal segmental glomerulosclerosis in a 32-year-old kidney allograft after 7 years without immunosuppression.

In kidney allografts, focal segmental glomerulosclerosis (FSGS) has been described as recurrent, de novo, or a histological variant of chronic transplant glomerulopathy. We describe a unique case of de novo FSGS in a renal transplant not accompanied by any feature of rejection in a patient who had not been immunosuppressed for several years. A 58-year-old woman received a histoidentical living-related kidney transplant for end-stage renal disease due to chronic pyelonephritis. Twenty-four years after the transplant she voluntarily discontinued all immunosuppressive medication. Seven years later she presented with nephrotic syndrome, mild renal failure, and positive serology for hepatitis C virus (HCV) antibody. The kidney transplant biopsy disclosed de novo FSGS. Features of acute or chronic rejection, including chronic transplant glomerulopathy, were not seen. The pathogenesis of this lesion is probably related to sustained and prolonged glomerular hyperfiltration; alternatively, HCV infection may have triggered or accelerated the appearance of FSGS.

Diuretic resistance.

Resistance to diuretic action is frequently encountered in the clinical setting. This is best managed by systematically optimizing the pharmacodynamic-pharmacokinetic factors that may be involved. Important pharmacodynamic measures include improving the underlying disease state, restriction of salt intake, limiting the use of vasodilators which may cause hypotension, lowering protein excretion, and eliminating drugs which may modify the response to the diuretic. Pharmacokinetic measures include using doses which result in diuretic excretion rates which fall on the steep part of the dose-response curve, sustaining diuretic excretion in this range by frequent drug administration, or constant infusion, using more bioavailable drugs and drugs which have less hepatic elimination, and by increasing the diuretic concentration in blood by coadministration with albumin. Using diuretic combinations to systematically inhibit absorption in the proximal tubule, Henle's loop, distal convoluted tubule, and connecting/collecting tubule will usually effect diuresis in all but the most refractory of cases.

FK506-associated thrombotic microangiopathy: report of two cases and review of the literature.

BACKGROUND: FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication. METHODS: We report two cases of FK506-associated TMA and review the 19 previous reported cases. RESULTS: From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported. CONCLUSIONS: TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patient's death.