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.

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.

Nephrotic syndrome associated with focal segmental glomerulosclerosis in a patient with systemic lupus erythematosus and membranous glomerulonephritis in remission

Renal involvement is frequent in systemic lupus erythematosus (SLE). This lesion, termed lupus nephritis, has been reported clinically in at least 50% of the patients. It is generally assumed that in patients with SLE, renal abnormalities detected clinically are caused by lupus nephritis, especially lupus glomerulonephritis (GN). Thus, renal biopsy is performed not for diagnostic purposes, but rather for determining the type and extent of renal involvement. However, clinically significant renal abnormalities unrelated to lupus nephritis have rarely been described in patients with SLE. The reported case serves to emphasize this consideration. The patient was a 41-year-old woman who presented 11 years previously with severe hypertension, nephrotic syndrome, and a serum creatinine level of 2.9 mg/dL. Renal biopsy showed membranous GN and ischemic damage. After a prolonged remission induced by steroids and cyclophosphamide, the patient presented with nephrotic syndrome and a serum creatinine level of 2.1 mg/dL. Although she was normotensive at that time, there were features of SLE. Repeated renal biopsy showed focal segmental glomerulosclerosis without the changes of membranous GN or any type lupus GN. This case illustrates two interesting observations, ie, resolution of membranous GN and nonlupus renal lesions in patients with SLE.

Use of bethanechol chloride to increase available ultrafiltration in CAPD.

Reabsorption of peritoneal dialysis fluid during the prolonged dwell time of continuous ambulatory peritoneal dialysis (CAPD) reduces the efficiency of ultrafiltration and sacrifices effective dialysis adequacy. Studies by Nolph indicate a predominant role of lymphatics in this fluid loss. Khanna has reported that lymphatic flow may be influenced by acetylcholine. This study was designed to determine if bethanechol chloride (BC) would increase the availability of drained volume during CAPD. Nine patients were studied, including 7 patients who exhibited inadequate ultrafiltration. During a 5-day control period, total dialysate drained volume was collected and a standard peritoneal equilibration test (PET) performed. This was followed by a corresponding 5-day test period in which BC (mean dose 0.27 +/- 0.13 mg/kg/day) was administered orally. Drained volume during the control standard 4-hr PET was 1996.68 +/- 279.87 mL. The result for the test period was 2363.33 +/- 321.13 mL (p < 0.05), indicating an 18.4% increase using BC. The PET indicated no change in transport of urea, creatinine, and glucose. In conclusion, the total drained volume can be effectively increased with a subsequent increase in metabolite clearance using BC. Patients exhibiting inadequate ultrafiltration were able to be maintained on CAPD using this cholinergic drug.

Influence of intraperitoneal gentamicin on peritoneal transport in IPD patients.

We have investigated the effect of intraperitoneal gentamicin on dialysis efficiency in 10 intermittent peritoneal dialysis (IPD) patients. The following parameters were measured: net ultrafiltration (UF); concentration ratios (D/P) of urea, creatinine, potassium; peritoneal clearances (ml/min) of urea, creatinine, potassium; mass transfer of sodium (MTNa); sodium sieving index (SCNa). It has been found that gentamicin significantly decreased D/P urea (p < 0.056) and D/P creatinine (p < 0.05). We found also a significant decrease of mean clearances of urea (p < 0.05) and creatinine (p < 0.05). The mean clearance of potassium did not significantly change. There was no significant change in UF, MTNa and SCNa. Our preliminary data suggest that gentamicin decreases the permeability of the peritoneum for certain low molecules in IPD patients, which may have a negative impact on dialysis efficiency.

Peritoneal dialysis adequacy during the r-Hu EPO treatment.

The dialysis adequacy was considered as the treatment method which eradicated the symptoms and signs of uremia and led to the full rehabilitation of treated patients. The chronic renal failure patients substitutional treatment using both peritoneal dialysis and hemodialysis assures correction of biochemical disturbances but only 33% of dialyzed patients are fully rehabilitated. Such situation is caused by the uremic anemia. The erythropoietin deficit is the main reason of the uremic anemia. The clinical effects of the erythropoietin treatment in hemodialyzed, peritoneal dialyzed and pre-dialyzed patients were proved. The erythrocytes increment to the normal or almost normal levels may caused the dialysis kinetics changes. During the r-Hu EPO treatment in both hemodialyzed and peritoneal dialyzed patients the dialysis effectiveness changes occurred. The dialysis therapy adequacy is mainly caused by the dialysis efficiency and additionally by the residual renal function and metabolism state. Taking into account own peritoneal dialysis kinetics parameters research results during the r-Hu EPO treatment the dialysis adequacy was evaluated. The aim of this study was the optimal dialysis scheme definition when the peritoneal transfer changes occurred as the r-Hu EPO treatment effect.

[Treatment of systemic lupus erythematosis with high doses of cyclophosphamide]. / Leczenie tocznia rumieniowatego trzewnego duzymi dawkami cyklofosfamidu.

A case is presented of a female patient with systemic lupus erythematosus in whom a dramatic development was observed of life-threatening symptoms and signs from the central nervous system, haemopoietic system, and the kidneys. After introduction of therapy with high doses of cyclophosphamide administered in intravenous in combination with steroids, beneficial therapeutic effects were achieved. That suggests the conclusion that in early active form of lupus the risk of intensive treatment is acceptable.

Hematocrit influence on peritoneal dialysis effectiveness during recombinant human erythropoietin treatment in patients with chronic renal failure.

Seven intermittent peritoneal dialysis (IPD) patients were investigated before and after correction of anemia with recombinant human erythropoietin (r-HuEPO). When hematocrit exceeded 30%, the peritoneal equilibration test was performed at 1, 2, 4, 8 hours. Correction of anemia was associated with a mean value increment in creatinine and phosphate clearance in 1- and 2-hour dwells. Differences in clearance of sodium, potassium, and urea in protein loss and glucose absorption before and after r-HuEPO therapy were not statistically significant. Increased creatinine and phosphate clearance during short dwells can be effected in IPD patients.