Gerd Offermann

The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation-data on four cases and review of the literature

Two women and two men were infected with the human immunodeficiency virus type 1 (HIV-1) transmitted by renal transplantation from i.v. drug-addicted donors in 1984. The four recipients were treated with cyclosporin and methylprednisolone (one patient only for three months because of early graft failure). Two patients died 66 and 74 months after transplantation, one of endocarditis and one of cerebral hemorrhage. Despite several infections including urinary tract infection (n=8), peritonitis (n=1), shunt infection (n=1), bronchitis (n=1), salmonellosis (n=1), herpes stomatitis (n=2), herpes zoster (n=1), and cytomegalovirus (n=1), and despite treatment of several rejection episodes (n=8), none of them had or has infections typical of the acquired immunodeficiency syndrome (AIDS). However, two patients developed cervical lymphadenopathy and one.

Recurrent and De Novo Renal Disease After Kidney Transplantation With or Without Cyclosporine A

We evaluated the clinical course of 700 renal transplantations, including 1,305 transplant histologies performed in 611 patients between 1970 and 1988, to estimate the influence of cyclosporine A (CsA) after kidney transplantation on the incidence of recurrent or de novo renal disease. Primary renal disease recurred in 11 of 583 functioning transplants (1.9%) with transplant loss in seven patients (1.2%): focal segmental glomerulosclerosis (FSGS, three patients); membranous glomerulonephritis (GN, one patient); mesangiocapillary GN (one patient); rapidly progressive IgA nephropathy (one patient); hemolytic-uremic syndrome (HUS, three patients); and oxalosis in two transplants (one patient). De novo renal disease occurred in six patients (1.0%), including mesangiocapillary GN type I (three patients); nonpurulent focal GN in septicemia (one patient); HUS (one patient); and nodular glomerulosclerosis in steroid diabetes (one patient). De novo membranous GN was seen in 14 additional cases (2.4%). No statistically significant difference could be established between the treatment groups without (n = 225) and with (n = 358) CsA in recurrent and de novo renal disease (n = 7/225 v 10/358, NS); in recurrent and de novo GN (n = 4/225 v 6/358, NS); in recurrent FSGS (n = 1/7 v 2/8, NS); in recurrent and de novo HUS (n - 1/1 v 2/7, NS); and in de novo membranous GN (n = 7/225 v 7/358, NS). Transplant loss by recurrent and de novo GN was higher without than with CsA (n = 4/4 v 1/6, P = 0.004). On the basis of our investigation, we conclude that recurrent and de novo renal disease in the transplant occur rarely and are not prevented by CsA. However, even if the incidence of transplant GN is unchanged by CsA treatment, its clinical course seems to be mitigated. CsA treatment also does not increase the incidence of HUS.

IMPACT OF DE NOVO MEMBRANOUS GLOMERULONEPHRITIS ON THE CLINICAL COURSE AFTER KIDNEY TRANSPLANTATION

Besides rejection-induced transplant glomerulopathy, de novo membranous glomerulonephritis (MGN) is the most frequent cause of nephrotic syndrome after renal transplantation. We evaluated 1029 renal transplantations (271 without and 758 with cyclosporine treatment), performed on 848 patients between 1970 and 1992, which resulted in 872 functioning grafts. De novo MGN was seen in 30 biopsy specimens from 21 patients (about 2%), of whom 10 had received immunosuppressive treatment without and 11 with cyclosporine. Taking into account the longer periods of observation of patients without compared with those with cyclosporine treatment (88±60 vs. 41±31 mo., respectively, P=0.001), the two treatment groups did not differ significantly in prevalence of de novo MGN (4.0% vs. 1.5%). De novo MGN was diagnosed by biopsy 62.7±44.4 mo. after transplantation; its incidence increased significantly with time (from 0% to 5.3% over 8 years; 95% confidential interval: 1.7–8%). Proteinuria (mean, 3.2±2.9 g/L) was first observed 47.5±51.3 mo. after transplantation. Thirteen of the 21 patients (62%) were nephrotic (proteinuria, over 1.5 g/L). Steroid pulses were given to 12 patients with de novo MGN and high proteinuria, which did not decline after treatment. Signs of chronic viral infection (hepatitis B antigen, hepatitis C antibody, or human immunodeficiency virus antibody) were found in 8 of the 21 patients (38%). Signs of vascular or interstitial rejection were seen in 17 and 12 of the 21 patients with de novo MGN, respectively, and cyclosporine arteriolopathy was diagnosed in four. Graft loss occurred in 14 of the 21 patients and was due to rejection in 13 and to de novo MGN in only one, who developed additional transplant vein thrombosis. Patients with de novo MGN did not differ significantly from the other 851 patients in graft survival (71.4±9.9% vs. 60.8±2.2% after 5 yr). De novo MGN is a late, often asymptomatic, complication of initially well tolerated grafts and is neither prevented by cyclosporine treatment nor reversed by further steroid medication. It is often associated with vascular changes caused by rejection or cyclosporine toxicity.

Effects of Parathyroidectomy on Renal Allograft Survival

Background: Hyperparathyroidism is a common problem secondary to renal insufficiency and is often not entirely resolved after renal transplantation (TX). Methods: In this retrospective analysis, the effects of parathyroidectomy (PTX) on allograft function were evaluated and the risk factors involved in allograft deterioration in patients after PTX will be discussed. Results: The rise in creatinine was steeper 1 year after PTX compared to 2 years before PTX in the majority (13 of 22) of patients. Compared to a cohort without PTX, graft survival was significantly decreased by 60% in 6 years (p < 0.0001). After multivariate adjustment, risk factors attributed to graft function included baseline creatinine (p = 0.02), baseline systolic blood pressure (p = 0.04) and time between TX and PTX, but not PTX itself. The peri-PTX drop in serum calcium was significantly more accentuated in patients exhibiting a worsening of graft function after PTX (p = 0.04). Conclusions: In patients requiring PTX, graft function is in danger of worsening. Since many factors contribute to this negative correlation and no association with parathyroid hormone (PTH) levels before PTX has been observed, we do not recommend prophylactic PTX on the basis of PTH levels only. However, appropriate management of peri-PTX risk factors is highly important. If the clinical situation, e.g. progressive renal osteodystrophy, requires removal of parathyroid glands, the procedure should be performed, if possible, in the presence of stable graft function.

Effects of diltiazem upon metabolism and immunosuppressive action of cyclosporine in kidney graft recipients

It is widely believed that calcium antagonists such as diltiazem exert immunosuppressive effects in kidney graft recipients--however, the mechanism is unclear. In a randomized controlled trial, kidney graft recipients who received diltiazem during transplantation and for an average of 12 months thereafter experienced significantly fewer rejection episodes than patients treated with cyclosporine and steroids alone. Furthermore, 1-year (97% vs. 85%) and 4-year (80% vs. 70%) graft survival rates were higher in diltiazem-treated patients, but the difference was not statistically significant. In vitro, diltiazem had little immunosuppressive activity. Concentrations of diltiazem which blocked the proliferation of PHA-stimulated human peripheral blood mononuclear cells, or prevented activation-associated accumulation of interleukin-2 mRNA, or p50- and p70-IL-2 receptor mRNA exceeded pharmacological concentrations by more than 100-fold. Both, CsA and high doses of diltiazem caused an increase of IL-6 mRNA. In contrast to these findings, the IL-6 plasma concentrations were comparable in both groups, whereas the serum concentration of soluble IL-2 receptors was decreased in patients treated with diltiazem. Administration of diltiazem caused an alteration of CsA metabolism. The whole-blood concentration of CsA metabolite 17 was significantly increased in diltiazem-treated patients, resulting in a five-times-higher concentration of this metabolite in the cellular blood compartment compared with the parent drug. Changes in metabolites 1, 8, and 18 levels were less pronounced. Although direct immunosuppressive properties of diltiazem are unlikely, diltiazem could support immunosuppression by altering CsA metabolism, and promoting accumulation of certain metabolites.

Hygroma Renale: Pararenal Lymphatic Cysts Associated with Renin-Dependent Hypertension (Page Kidney). Case Report on Bilateral Cysts and Successful Therapy by Marsupialization

A total of 42 cases of large symptomatic parapelvic or pararenal lymphatic cysts has been reported since 1890, of which 54% were associated with hypertension and 14% were bilateral. We report on a patient in whom during a 3-month period abdominal pain and distention developed successively on both sides associated with hypertension. Initially, ultrasound and computerized tomography revealed a large multicystic pararenal lymphatic mass on the right side and small parapelvic hilus lesions on the left side. Two months after resection and marsupialization of the large cyst on the right side the small hilus lesions on the left side developed into large pararenal cysts requiring the same therapeutic measures. Hypertension was reversible after surgery in both instances; at the second operation high preoperative and lower postoperative renin activity, active renin, total renin, aldosterone and atrial natriuretic factor in plasma were noted. Immunoreactive active and total renin levels in the lymph fluid were elevated, a finding that may be explained by the renal origin of the lymph. Marsupialization is a kidney preserving measure that reverses all symptoms of large pararenal cysts, including Page kidney hypertension.

Severe Calciphylaxis in a Renal Patient on Long-Term Oral Anticoagulant Therapy

The pathogenesis of calciphylaxis, a potentially life-threatening condition, is not well understood. Several factors such as end-stage renal disease (azotemia), hyperparathyroidism, hyperphosphatemia, hypercalcemia, a high calcium-phosphate product, and the use of steroids and cytotoxic drugs after kidney transplantation are believed to interact in calciphylaxis. Recently, hypercoagulability due to functional protein C deficiency has been suggested to play a pathogenic role in this condition. Here, we present a renal transplant patient, with secondary hyperparathyroidism and on long-term oral anticoagulant therapy, who developed calciphylaxis with severe skin necrosis of her legs. The patients condition improved dramatically after total parathyroidectomy. Hypercoagulability, therefore, does not appear to have played a significant role in this case of calciphylaxis.

Impaired Renal Allograft Function is Associated with Increased Arterial Stiffness in Renal Transplant Recipients

It is important whether impairment of renal allograft function may deteriorate arterial stiffness in renal transplant recipients. In a cross‐sectional study, arterial vascular characteristics were non‐invasively determined in 48 patients with renal allograft using applanation tonometry and digital photoplethysmography. Mean age was 51 ± 2 years (mean ± SEM), and studies were performed 17 ± 1 months after transplantation. The stage of chronic kidney disease was based on the glomerular filtration rate. We observed a significant association between the stage of chronic kidney disease and arterial stiffness of large arteries S1 and small arteries S2 in renal transplant recipients (each p < 0.05 by non‐parametric Kruskal–Wallis test between groups). Multivariate linear regression analysis showed that male gender of patients with renal allograft (p < 0.01) reduced glomerular filtration rate (p = 0.01), and older age of kidney donor (p = 0.04) were independently associated with an increase of large artery stiffness S1. Furthermore, a significant association between the stage of chronic kidney disease and arterial vascular reactivity during reactive hyperemia was observed (p < 0.05 by non‐parametric Kruskal–Wallis test between groups). It is concluded that impairment of renal allograft function is associated with an increased arterial stiffness in renal transplant recipients.

Pharmacokinetics of methylprednisolone and rejection episodes in kidney transplant patients.

Rejection crises after kidney transplantation could be associated with individual variability of pharmaco-kinetic parameters of steroids. We therefore investigated the individual pharmacokinetics of methylpred-nisolone on day 2 (60 mg intravenously) and day 4 (60 mg per os) in 40 patients after kidney transplantation. Methylprednisolone was determined in serum by HPLC. Within 6 months, all rejection episodes were recorded and confirmed by kidney transplant biopsy. Values are given as nonparametric medians with the 95% confidence interval (0.95 CI). The 7 patients with a rejection within the first 10 days had a methylpred-nisolone clearance of 437 ml/min (162–756) that was significantly higher than the 220 ml/min (121–604) in the 22 patients without a rejection episode (P=0.04). In the complete group of 18 patients having a transplant rejection episode within 6 months, the methylpred-nisolone elimination half-life after oral dosage was 2.5 hr (1.6–3.9) and significantly shorter than 2.9 hr (1.7–4.0) in 22 patients without rejections (P=0.03). No differences were seen for body weight, number of mismatches, cold ischemia time, immunosuppressive regimens, and other pharmacokinetic parameters of methylprednisolone (e.g. bioavailability, distribution volume, trough levels). We conclude that pharmacokinetic variability may contribute to the lack of immunosuppressive efficacy in patients with a short half-life of steroids. Therefore, a twice daily dose fraction

Soluble interleukin 2 receptor and tissue polypeptide antigen serum concentrations in end-stage renal failure

Serum concentrations of soluble interleukin 2 receptor (IL-2R) were measured in 65 hemodialysis patients and compared with serum levels of beta 2-microglobulin and tissue polypeptide antigen (TPA). Elevated IL-2R levels, found in 85% of examined patients, correlated with elevated TPA serum concentrations (p less than 0.05). Patients with high IL-2R levels were significantly younger (p less than 0.05) than patients with low levels. Primary renal disease and residual renal function had no significant influence on TPA or IL-2R serum concentrations. In 16 patients with carpal tunnel syndrome, increased serum concentrations of IL-2R (p less than 0.005) and TPA (p less than 0.001) were found. We conclude that a non-specific dialysis-induced activation of epithelial and lymphoid cells rather than a specific immune response could explain the concomitant elevation of IL-2R and TPA serum concentrations in hemodialyzed patients. Patients with pronounced cell turnover, reflected by elevated IL-2R and TPA levels, may show an increased susceptibility to dialysis-associated amyloidosis.