Karl M. Koch

Use of Doppler Ultrasonography to Predict the Outcome of Therapy for Renal-Artery Stenosis

BACKGROUND Prospectively identifying patients whose renal function or blood pressure will improve after the correction of renal-artery stenosis has not been possible. We evaluated whether a high level of resistance to flow in the segmental arteries of both kidneys (indicated by resistance-index values of at least 80) can be used prospectively to select appropriate patients for treatment. METHODS We evaluated 5950 patients with hypertension for renal-artery stenosis using color Doppler ultrasonography, and we measured the resistance index ([1 - end-diastolic velocity divided by maximal systolic velocity] x 100). Among 138 patients who had unilateral or bilateral renal-artery stenosis of more than 50 percent of the luminal diameter and who underwent renal angioplasty or surgery, the procedure was technically successful in 131 (95 percent). Creatinine clearance and 24-hour ambulatory blood pressure were measured before renal-artery stenosis was corrected; 3, 6, and 12 months after the procedure; and yearly thereafter. The mean (+/-SD) duration of follow-up was 32+/-21 months. RESULTS Among the 35 patients (27 percent) who had resistance-index values of at least 80 before revascularization, the mean arterial pressure did not decrease by 10 mm Hg or more after revascularization in 34 (97 percent). Renal function declined (defined by a decrease in the creatinine clearance; of at least 10 percent) in 28 (80 percent); 16 (46 percent) became dependent on dialysis and 10 (29 percent) died during follow-up. Among the 96 patients (73 percent) with a resistance-index value of less than 80, the mean arterial pressure decreased by at least 10 percent in all but 6 patients (6 percent) after revascularization; renal function worsened in only 3 (3 percent), all of whom became dependent on dialysis; and 3 (3 percent) died (P<0.001 for the comparison with patients with a resistance-index value of at least 80). CONCLUSIONS A renal resistance-index value of at least 80 reliably identifies patients with renal-artery stenosis in whom angioplasty or surgery will not improve renal function, blood pressure, or kidney survival.

Sympathetic and Hemodynamic Response to Volume Removal during Different Forms of Renal Replacement Therapy

Sympathetic and hemodynamic response to a constant volume removal was investigated during pure ultrafiltration, hemofiltration, acetate hemodialysis, and bicarbonate hemodialysis in the same ESRD patients. Small solute removal rates were matched. The sympathetic response resulting in an increase of total peripheral vascular resistance was found to be qualitatively adequate in ultrafiltration and hemofiltration, but not in acetate and bicarbonate hemodialysis. This inadequate response to volume removal explains the clinically observed hemodynamic instability during hemodialysis. The purpose of the study was to substantiate the, compared to hemodialysis, improved tolerance to fluid withdrawal during ultrafiltration and hemofiltration with hemodynamic data and to correlate hemodynamic and sympathetic changes during the different treatment modalities of uremia.

Incidence of Pneumocystis carinii pneumonia after renal transplantation : Impact of immunosuppression

The incidence and potential risk factors of Pneumocystis carinii pneumonia (PCP) in our population of renal transplant recipients were analyzed retrospectively. Of 1427 patients who received transplants between January 1986 and June 1994, 1192 were evaluated. Four different immunosuppressive regimens were applied: (1) cyclosporine (CsA) + prednisolone (Pred), (2) CsA + azathioprine (Aza, 2 mg/kg/day) + Pred, (3) CsA + Aza + antithymocyte globulin, and (4) (after December 1, 1993, European multicenter trial) FK506 + Aza (1 mg/kg/day) + Pred. No prophylaxis against PCP was performed. Before December 1, 1993, three PCPs in 494 patients on protocol 2 or 3 occurred (0.6%). Afterward, seven PCPs in 77 patients occurred (9%): three in 38 patients on protocol 2 (7.8%) and four in 28 patients on protocol 4 (14.3%). Comparing patients with PCP on CsA and FK506, the mean Aza dose was 2.40 and 1.32 mg/kg/day, five and two patients received additional steroids, antibody treatment was used in three and no patients, and CMV infections occurred in five and two patients, respectively. The incidence of PCP with a moderate CsA-based immunosuppressive regimen is low and seems to occur only in cases of additional immunosuppressive cofactors. Despite a general increase of PCP, its incidence was highest in patients on FK506 with fewer immunosuppressive cofactors. Thus, prophylaxis against PCP after renal transplantation should be performed, if not in every renal transplant recipient, at least in case of treatment with additional steroids, antibodies, or FK506.

Plasma Interleukin-1 Activity during Hemodialysis: The Influence of Dialysis Membranes

Plasma interleukin-1 (IL-1) activity was measured in 7 stable ESRD patients on regular hemodialysis for no less than 5 months. Predialysis levels were significantly raised compared to 8 normal control subjects. During hemodialysis with four different membranes, plasma IL-1 activity rose with Cuprophan and Hemophan and was unchanged or reduced with Gambrane and Polysulfon. In spite of these differences, body temperature rose in all forms of hemodialysis. Factors responsible for the predialysis elevation included the absence of renal function and/or the repeated stimulus of human blood monocytes by hemodialysis. In view of the uniform increase of body temperature during hemodialysis, the differences in changes of plasma IL-1 activity observed with the various membranes may not be caused by a variable stimulation of monocytes but rather by the presence or absence of the membranes ability to remove and/or absorb IL-1. Thus, the consequences of monocyte hemodialysis stimulation may be obtained locally, even in the presence of unchanged or reduced plasma IL-1 activity.

Hemodialysis-Related Induction of Beta-2-Microglobulin and Interleukin-1 Synthesis and Release by Mononuclear Phagocytes

We have investigated beta 2-microglobulin (beta 2M) synthesis and release by blood leukocytes and isolated mononuclear phagocytes. Recent interest in beta 2M has developed since the discovery that this protein forms amyloid fibrils in patients undergoing long-term, chronic hemodialysis and that these patients have greatly elevated levels of monomeric beta 2M in their circulation. Since hemodialysis-related factors that increase beta 2M production are unknown, we evaluated beta 2M production by freshly prepared leukocytes and monocyte-derived macrophages under a variety of conditions. We utilized a novel enzyme-linked immunoabsorbant assay to quantitate beta 2M concentrations, and monitored interleukin-1 and beta 2M synthesis by immunoprecipitation. Incubation of leukocytes with Cuprophan or Hemophan does not increase beta 2M release. Adherence of macrophages onto polystyrene or Cuprophan membranes induces neither interleukin-1 nor beta 2M synthesis or release. In contrast, interaction of macrophages with lipopolysaccharide, gamma-interferon, tumor necrosis factor, or interleukin-1 induces synthesis and release of beta 2 M, indicating that beta 2 M synthesis is increased during macrophage activation. Exposing leukocytes or macrophages to changes in osmotic or oncotic pressure induces a rapid release of beta 2M and interleukin-1 into the cellular medium. These results suggest that during hemodialysis, beta 2M production is more likely to result from endotoxin contamination, or osmotic and oncotic changes, rather than direct interaction of mononuclear phagocytes with Cuprophan membranes.

How best to use tacrolimus (FK506) for treatment of steroid- and OKT3-resistant rejection after renal transplantation.

Nineteen patients with biopsy-confirmed ongoing acute rejection of renal allografts were converted from standard immunosuppression to FK506. Eight grafts showed vascular rejection and 11 had cellular rejection on biopsy. All patients had already received intravenous high-dose steroid treatment. Ten patients also had additional OKT3 rescue therapy. Initial FK506 doses were 0.13 +/- 0.06 mg/kg/day; the FK506 whole blood trough level after 3 days of treatment was 9.3 +/- 4.5 ng/ml. After conversion to FK506 all but four patients also received azathioprine, 1.5-2 mg/kg/day, and all patients received oral prednisolone. Concomitant with initiation of FK506, an anti-infective prophylaxis was prescribed, consisting of ganciclovir and trimethoprim/sulfamethoxazole. Sixteen out of 19 of the grafts (84%) were rescued successfully, including two grafts of patients already on hemodialysis at the time of conversion. Graft function of the responders improved from an average serum creatinine level of 364 +/- 109 mumol/L to 154 +/- 49 mumol/L. Of the patients receiving high-dose steroids alone prior to FK506 initiation, 8/9 responded to FK506 treatment, compared with 8/10 of those who had also received OKT3. During the mean follow-up of 35 weeks after conversion, no clinically apparent cytomegalovirus infection and no pneumonia were seen. Treatment with FK506 may successfully suppress ongoing acute rejection, even if antilymphocyte preparations have failed. FK506 can be used at a lower dose than so far recommended without impairing the antirejection potential. An additional anti-infective prophylaxis seems effective in preventing severe complications in the first months after rejection therapy.

Recurrence of Membranoproliferative Glomerulonephritis after Renal Transplantation in a Patient with Chronic Hepatitis C

Chronic hepatitis C (HCV) infection may be associated with membranoproliferative glomerulonephritis (MPGN) with or without concomitant cryoglobulinemia. We report on a patient with end-stage renal disease caused by MPGN I in association with replicative HCV infection. Two years after successful renal transplantation, this patient developed nephrotic syndrome caused by recurrence of MPGN I in the renal transplant. The recurrence of renal disease after transplantation in this patient with chronic replicative HCV further elucidates the role of the viral infection in the pathogenesis of MPGN and suggests anti-viral treatment as, e.g., with interferon.

High mortality from urothelial carcinoma despite regular tumor screening in patients with analgesic nephropathy after renal transplantation

Patients with end-stage renal failure due to analgesic nephropathy have an increased risk of developing a urothelial carcinoma. To determine the impact of renal transplantation on the frequency of urothelial carcinomas, we analyzed 2072 patients who underwent 2371 renal transplantations between 1968 and 1993, including 78 (3.8%) with clinically proven analgesic nephropathy. Before and after transplantation a regular tumor screening was performed in patients with analgesic nephropathy by urine cytology and abdominal sonography. In 11 of the 78 patients with analgesic nephropathy (14.1%; age 51–66 years, 40–108 months after initiation of dialysis treatment, 5–77 months after transplantation), a urothelial carcinoma of the native urinary tract, especially the kidneys, was diagnosed. Therapy comprised nephroureterectomy (n=6), transurethral resection (n=6) and/or cystectomy (n=2). Seven patients died due to tumor progression 16.3 (4–33) months postoperatively and one patient died due to a perioperative complication. Despite regular tumor screening after transplantation, the diagnosis of a urothelial carcinoma was made very late, leading to a high tumor-related mortality. As a consequence, we suggest that a bilateral nephroureterectomy should be performed prophylactically in patients with proven analgesic nephropathy. In addition, a cystoscopy with lavage cytology testing of the bladder should be performed twice a year.

Interstitial Nephritis Associated with 5-Aminosalicyclic Acid

A patient with severe Crohns disease was treated with 5-aminosalicylic acid (5-ASA). Following initiation of treatment, serum creatinine increased slowly from 105 to 530 mumol/l (creatinine clearance 16 ml/min). The diagnosis of an interstitial nephritis was made based on normal urinary findings and the renal biopsy histology of interstitial mononuclear infiltrates and normal glomeruli, 5-ASA was discontinued and serum creatinine decreased to 245 mumol/l (creatinine clearance 40 ml/min) during the following 3 months. Partial reversibility of renal failure following discontinuation of 5-ASA and the absence of other drugs possibly causing interstitial nephritis suggest a causal relationship between 5-ASA and interstitial nephritis.

Serum Erythropoietin Concentration in Anephric Patients

In 13 bilateral nephrectomized patients serum erythropoietin (SEp) activity could be measured quantitatively by use of the highly sensitive fetal mouse liver cell assay. SEp concentration in the majority of the cases was below the mean of normal controls. There was a significant positive correlation between SEp levels and hematocrits, suggesting erythropoietin (Ep) deficiency to be a causative factor in the anemia of the anephric state. Androgen therapy stimulated extrarenal Ep production in all of 5 anephric patients studied.