Jørgen Ladefoged

Lithium treatment: does the kidney prefer one daily dose instead of two?

Renal structure and function were investigated in two groups of long‐term lithium treated patients. Lithium was administered in two different ways either in a one‐dose per day schedule where the whole dose of lithium was given between 8 and 10 p.m. or in a schedule where the lithium dose was given, divided into two or three doses, during the day. Kidney biopsy was performed, and structural changes in the kidney tissue were determined together with 24‐h urine volume in the individual patients. The functional as well as the structural changes were most pronounced in patients given their lithium in divided doses during the day. Lithium may be more harmful to the kidney when the lithium administration gives a relatively constant serum lithium level than when the administration causes greater variations including peak values and low minimum levels in serum lithium. The reason for this might be that a number of regenerative processes only occur in periods with low lithium concentrations.

Vascular complications in 155 consecutive kidney transplantations.

In 155 kidney transplantations in 142 patients a total of 19 arterial complications occurred: failing anastomosis in one patient, arterial occlusion in three, and stenosis in 15 patients. The occlusions led to graftectomy in all the cases. Arterial reconstruction was made in 3 patients with stenosis, but the blood pressure was normalized in only one patient.Venous complications occurred in 28 patients: six cases of thrombosis in the graft vein, which in 5 of the patients led to graftectomy; two cases of hemorrhage from the venous anastomosis, 19 cases of peripheral vein thrombosis, and one case of fatal pulmonary embolism.

Lithium: long-term effects on the kidney. II: Structural changes

Forty-six patients treated with lithium for an average of 8 yr participated in a follow-up study involving a kidney biopsy. The results were compared with renal biopsy specimens from an age-matched group of controls never treated with lithium. The average number of totally scelerotic glomeruli and atrophic tubuli was higher in lithium-treated patients. The histopathological changes showed significant correlations with lithium dosage schedule. Both the proportions of sclerotic glomeruli, atrophic tubuli and focally distributed interstitial fibrosis were higher in patients receiving their lithium two or three times a day than when lithium was given in a single daily dose.

The immunosuppressive potency in vitro of physiological and synthetic steroids on lymphocyte cultures.

The immunosuppressive potency of five natural and seven synthetic steroids were tested in vitro on phytohemagglutinin (PHA) stimulated peripheral lymphocytes (PBL) and T-lymphocytes and compared to their anti-inflammatory potencies. The physiological glucocorticoid, hydrocortisone, was of intermediate immunosuppressive potency in vitro, whereas the metabolites of hydrocortisone (cortisone, dihydrocortisol, and tetrahydrocortisol) and aldosterone were without effect. The synthetic steroids, methylprednisolone and fluorohydrocortisone were both highly potent in suppressing the PHA responses of both lymphocyte subsets. Prednisolone and dexamethasone were of intermediate potency and ranked similar to hydrocortisone which is in contrast to their anti-inflammatory properties. Prednisone, the biologically inactive metabolite of prednisolone, was without immunosuppressive properties. Deoxy-deflazacort, the biologically active metabolite of deflazacort (a new oxazoline derivative of prednisolone) was comparable to prednisolone and hydrocortisone in suppressing lymphocyte proliferation but again there was a large discrepancy between the in vitro immunosuppressive effect and the anti-inflammatory potency. In conclusion, the present assay may therefore separate the immunosuppressive properties from the anti-inflammatory properties of glucocorticoids. These findings may be useful for comparison of new synthetic steroids.

Lithium: long-term effects on the kidney. III. Prospective study.

ABSTRACT— Renal function in 32 patients treated with lithium for an average period of 10 years was reexamined 2 years after the first examination. A markedly influenced tubular function leading to increased urine volume (average 3 litres/24 h) and decreased renal concentrating capacity was still found, whereas glomerular function remained unimpaired in nearly all of the patients. No statistically significant changes in renal functions were observed at the follow‐up examination.

A Model of Reversible Uremia Employing Isogenic Kidney Transplantation in the Rat: Reversibility of Secondary Hyperparathyroidism

Kidney transplanted patients with normalized kidney function may still exhibit a variety of problems such as bone problems, vascularly problems, and hormonal dysfunctions. A part of the symptoms may be persisting uremic symptoms, secondary to the pretransplanted period of chronic uremia. An experimental rat model, designed to the study of the reversibility of the chronic uremic implications is therefore described. A stable, severe chronic uremia was induced by 5/6 nephrectomy to inbred Lewis rats. Ten weeks later uremia was reverted by a successful isogenic rat kidney transplantation. During the period of chronic uremia the p-urea was elevated to an average of 21.8 +/- 0.9 mmol/l and p-creatinine to 105.7 +/- 5.7 microM/l. The isogenic kidney transplantation resulted in reestablishment of normal kidney function with an average level of p-urea of 7.6 +/- 0.2 mmol/l and p-creatinine 42.5 +/- 1.9 microM/l perfectly corresponding to the sham-operated rats, i.e. one-kidney rats. Reversibility of the secondary hyperparathyroidism due to chronic uremia was investigated in the model. In rats with chronic renal failure PTH increased from 52 +/- 4.9 pg/ml to 152 +/- 12.2 pg/ml and was normalized after transplantation. It is therefore concluded that the present described technique of introducing long term uremia followed up by a successful kidney transplantation in the rat may be a useful model to study the reversibility of different uremic manifestations.

Kidney functioning during lithium treatment: a prospective study of patients treated with lithium for up to ten years.

A cohort of 53 patients with affective disorders who originally carried through renal functional tests before start of prophylactic lithium treatment were followed up prospectively after an average period of 8.5 years (range 7–10 years). Ten patients who had continued lithium treatment were re‐examined. In this subgroup, the glomerular function was unaffected by the treatment, whereas the average urine volume increased during lithium treatment (NS). Polyuria and low renal concentrating abilities were also found before start of treatment and these findings underline the importance of access to renal baseline information prior to lithium treatment.

Long-term effects of lithium on the kidney: Functional-morphological correlations

Correlations between quantitative kidney biopsy findings and clinical renal function in 46 unselected patients treated with lithium for an average of eight years were studied. A significant relationship between maximum renal concentrating capacity and degree of tubular atrophy was found. GFR correlated significantly with sclerotic glomeruli as well as atrophic tubules in patients on a multiple dosage schedule, whereas no relationship was seen in patients receiving lithium in a single daily dose. Thus, renal dysfunction may have a structural basis in a subgroup of lithium-treated patients on a multiple dosage schedule.

DEGREE AND COURSE OF SKELETAL DEMINERALIZATION IN PATIENTS WITH CHRONIC RENAL INSUFFICIENCY

To Study the degree and course of skeletal demineralization in patients with chronic renal failure gamma-ray bone densitometry of the radius was performed (1) in a cross-sectional study of 88 uremic patients and (2) in a longitudinal study over 13.5 months in 26 of these patients. The results were compared to measurements of bone mineral content/width (BMC/W) in 191 normal adults. Furthermore to evaluate the importance of calcium-metabolic changes in skeletal demineralization of uremic patients measurements of serum ionized calcium (Ca++), phosphate, alkaline phosphatase, immunoreactive parathyroid hormone (i-PTH), intestinal calcium absorption, skeletal X-ray and 99mTechnetium-polyphosphate bone scintigraphy were performed in the majority of the patients. An accelerated bone loss (mean 3.1% per year) was demonstrated in uremic patients together with a significant reduction in BMC/W. The duration of uremia was correlated with the BMC/W values, whereas dialysis treatment as such did not affect BMC/W. The m...

In vitro immune functions in patients with minor, moderate, and severe kidney impairment

We examined the in vitro immune response of lymphocytes from 86 non‐dialyzed patients with progressive renal failure and 48 healthy control subjects by comparing the production of interleukin‐2, the mitogen‐in‐duced proliferative response and sensitivity to glucocorticoid of lymphocyte cultures. The patients were divided in three groups with minor, moderate, and severe uremia. The uremic lymphocyte responses to stimulation with concanavalin A (Con A) were significantly lower than those of control lymphocyte cultures. A similar but not significant decrease was also seen in phytohemagglutinin (PHA) and pokeweed mitogen stimulated cultures. There was no trend towards diminishing mitogen responses with decreasing renal function. The median interleukin‐2 activity in the uremic cell cultures was decreased by 50% during the culture period but the decrease was not significant. However, PHA and Con A stimulated lymphocyte cultures from all groups of patients were significantly more sensitive to the immunosuppressive effect of methylprednisolone. Thus an increased sensitivity to the immunosuppressive effect of glucocorticoid can be demonstrated in vitro at an early stage of progressive renal disease.