Diabetic nephropathy. Management of the end-stage patient.

Diabetic nephropathy is currently the leading cause of new patients requiring dialysis in the United States. Management of the diabetic patient with ESRD is complicated by the frequent coexistence of complications affecting other organ systems, including retinopathy, cardiovascular disease, peripheral neuropathy, or autonomic neuropathy, manifested as gastroparesis, diarrhea or obstipation, cystopathy, or orthostatic hypotension. Associated clinical syndromes must be followed and treated, if possible, while preparing the patient to receive renal replacement therapy. Both the clinical condition and the psychosocial environment are key factors in choice of ESRD therapy for an individual patient. Rehabilitation data are best for patients who undergo kidney transplantation, but these data are confounded by the fact that the healthiest patients are referred for this treatment modality. Living, related kidney transplant is the preferred initial choice for the diabetic patient with kidney disease. At most centers, both in the United States and abroad, the cadaveric transplant is the second choice for uremia therapy. At the appropriate institution, the patient with type I diabetes may also be considered for a simultaneous cadaveric pancreas transplant. While awaiting cadaveric transplantation, or if contraindication to transplantation is present (chronic infection, recent malignancy, or severe cardiac disease), diabetic patients with severe impairment of the glomerular filtration rate (less than 10-15 ml/min) are referred for vascular access placement and/or insertion of a peritoneal catheter. The decision regarding the choice of CAPD vs. hemodialysis must be made on an individual basis. Rehabilitation and survival data for these therapies are similar, although technique survival rates for CAPD decline dramatically as time progresses because of infectious complications. In-center hemodialysis has the worst survival and rehabilitation profile, but the sickest, most debilitated patients with the highest number of comorbid conditions tend to be referred for that therapeutic modality. Most studies of rehabilitation were performed before use of recombinant human erythropoietin, and comparison between ESRD treatment modalities will have to be reevaluated now that the drug is routinely used.

Hyperlipidemia after organ transplantation.

Hyperlipidemia, long recognized as a difficult and common problem following organ transplantation, may be the underlying cause of the accelerated atherosclerosis observed in heart transplant recipients and children with renal transplants. In addition, hyperlipidemia may play a role in late renal graft loss. The cause of post-transplant hyperlipidemia is unclear. In patients treated with azathioprine and prednisone, hypertriglyceridemia is the commonest finding and probably results from an increased consumption of calories from carbohydrate and fat following resolution of uremia, in conjunction with glucose intolerance secondary to steroid administration. In patients treated with cyclosporine, hypercholesterolemia is the most common form of hyperlipidemia. Cyclosporine is a lipophilic drug that is transported in the plasma, largely in association with lipoproteins, and may require the low-density lipoprotein (LDL) receptor for internalization into cells. Hypercholesterolemia may result from interference with the basic cholesterol feedback mechanism via the LDL receptor. In addition, cyclosporine affects bile acid synthesis and worsens glucose tolerance, both factors that may promote hyperlipidemia. The first therapeutic approach to hyperlipidemia in the transplant recipient is dietary calorie-fat restriction and supplementation with soluble fiber. Ongoing clinical trials of the available pharmacologic lipid-lowering agents are addressing the safety and efficacy of these agents in the setting of immunosuppression; until that time, they should be used cautiously and in low doses.

The beneficial effects of steroid withdrawal on blood pressure and lipid profile in children posttransplantation in the cyclosporine era.

Steroid therapy posttransplantation has been correlated with hyperlipidemia and hypertension. With improved graft survivals in the cyclosporine (CsA) era, post-tx hyperlipidemia and hypertension may place children at high risk for early atherosclerosis. Presently there are no large studies assessing the metabolic effects of steroid withdrawal in tx children. Thus, we report on the effect of prednisone withdrawal on blood pressure, weight, and serum lipid levels in children post-tx maintained on CsA alone. Pred taper is attempted in patients on CsA (6-7 mg/kg/day) with stable graft function and is extended over a 6-month period. Once a rejection is diagnosed pred is restarted and no future attempts to withdraw are made. BP, weight, and overnight fasting serum cholesterol (Schol) levels were measured 1 month prior to complete withdrawal (A), and after 6 months without pred (B). In patients requiring the restart of pred, subsequent measurements were obtained 6 months later (C). Of 74 tx children, 7 had primary nonfunction. Pred was successfully withdrawn in 49% (33) of the remaining 67. Of these patients, 42% (14/33) are still maintained off pred with stable renal function for a mean duration of 58.5 months (range 8-99 months). Nineteen patients had to be restarted on pred secondary to rejection between 7-36 months after withdrawal. Three of the patients subsequently lost their grafts to further rejection episodes. Univariate and multivariate analysis failed to identify clinical predictors of successful steroid withdrawal. The Schol at B, 171 +/- 5.4 mg/dl (mean +/- SEM) was lower (P < .001) than at A (249 +/- 10 mg/dl) or C (257 +/- 20 mg/dl). The systolic BP at B (108 +/- 2.8 mmHg) and diastolic BP at B (68 +/- 2.6 mmHg) were also lower (P < .001) than at A (122 +/- 3.2, 76 +/- 2.7 mmHg) or C (130 +/- 5, 80 +/- 3.2 mmHg), respectively. No difference in weight was noted. Lipid profile (total chol, triglyceride, HDL, VLDL, LDL) was measured in 10/14 patients off pred (mean age at sample 16.25 years) and was compared with 13 patients on pred (mean 15.5 years). Both the total chol (176 +/- 9.2, 265 +/- 8.3 mg/dl) and LDL (109 +/- 10, 167 +/- 9.2 mg/dl) were higher (P < .001) in the group on pred. Based on our findings of increased LDL and total chol, children on long-term pred therapy post-tx may be at increased risk for atherosclerotic disease.

Common iliac artery stenosis presenting as renal allograft dysfunction in two diabetic recipients.

BACKGROUND: Suprarenal common iliac artery stenosis is an uncommon but reversible cause of allograft dysfunction in renal transplant recipients. METHOD: We describe two diabetic renal transplant recipients with worsening hypertension, edema, and azotemia. Magnetic resonance angiography (MRA) demonstrated tight stenoses in the common iliac artery proximal to the allograft anastomosis site with patent renal transplant artery in both cases. These findings were later confirmed with carbon dioxide angiography. RESULTS: No acute rejection was noted on renal biopsy in either case. Placement of percutaneous iliac artery Wallstents resulted in decrease of serum creatinine from 6.5 to 2.0 mg/dl and 1.7 to 1.0 mg/dl within 2 and 4 weeks, respectively. CONCLUSION: Common iliac artery stenosis should be suspected in renal transplant recipients presenting with worsening hypertension, edema and azotemia. MRA for screening followed by carbon dioxide angiography and placement of intravascular stents for focal vascular obstructive lesions reverses allograft dysfunction.

The effect of kidney size on cadaveric renal allograft outcome.

Chronic rejection is the commonest cause of long-term renal allograft loss. Though immunologic factors are thought dominant in its pathogenesis, nonimmunologic factors, in particular, hyperfiltration damage related to reduced renal mass, have also been proposed as factors in the causation of chronic allograft rejection. We assessed the influence of renal size on graft survival and function in all cyclosporine-treated cadaver donor adult renal allograft recipients engrafted at a single center between June 1989 and July 1994, whose grafts functioned for > or = to 3 months (n=169). Patients were divided into 4 groups based on the ratio of kidney volume to recipient body surface area (volume/BSA) (ml/m2), and outcome in groups compared by methods including Cox's proportional hazards and Kaplan-Meier analysis. No significant differences between groups existed for serum creatinine levels, presence of significant proteinuria, or 1- and 5-year graft survival. There was no correlation between volume/BSA and either serum creatinine or degree of proteinuria at 3, 6, 12, 36, and 60 months posttransplant. Volume/BSA was similar in patients with good or poor renal function (58 +/-21 vs. 56 +/- 28 ml/m2), with or without significant proteinuria (57 +/- 24 vs. 60 +/- 25 ml/m2) or in patients who lost their grafts to chronic rejection compared with those with stable allograft function (64 +/- 34 vs. 59 +/- 24 ml/m2). Volume/BSA was not a predictor of graft survival on multivariate regression. We conclude that donor kidney size has no apparent effect on cadaveric renal allograft outcome in the short and intermediate-term, suggesting that close matching of donor kidney size to recipient size is not presently indicated.

Outcome of twin pregnancy in a renal transplant recipient treated with tacrolimus.

Our report describes the outcome of a twin pregnancy in a woman who was maintained on tacrolimus after a living related renal transplant. Both babies born at 32 weeks of gestation developed severe respiratory distress requiring ventilator assistance and went on to develop congestive heart failure. Echocardiograms on both babies showed dilated heart chambers. Twin A succumbed to complications, but twin B, who was treated more aggressively with vasopressors, recovered. Autopsy findings on twin A revealed a thrombotic cardiomyopathy with degeneration of cardiac muscle. We believe that the unusual outcome in this set of twins may have been a result of cardiomyopathy secondary to tacrolimus used by the mother during her pregnancy.

Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?

BACKGROUND: Despite use of lower doses of corticosteroid hormones after renal allotransplantation in the era of cyclosporine and tacrolimus, posttransplant diabetes mellitus remains a common clinical problem. METHODS: We prospectively investigated the effect of posttransplant diabetes on long-term (mean follow-up, 9.3+/-1.5 years) graft and patient survival in the 11.8% of our renal transplant population (n = 40) who developed diabetes after kidney transplantation, and we compared outcome in 38 randomly chosen nondiabetic control patients who had received transplants concurrently. RESULTS: Twelve-year graft survival in diabetic patients was 48%, compared with 70% in control patients (P = 0.04), and Cox's regression analysis revealed diabetes to be a significant predictor of graft loss (P = 0.04, relative risk = 3.72) independent of age, sex, and race. Renal function at 5 years as assessed by serum creatinine level was inferior in diabetic patients compared to control patients (2.9+/-2.6 vs. 2.0+/-0.07 mg/dl, P = 0.05). Two diabetic patient who experienced graft loss had a clinical course and histological features consistent with diabetic nephropathy; other diabetes-related morbidity in patients with posttransplant diabetes included ketoacidosis, hyperosmolar coma or precoma, and sensorimotor peripheral neuropathy. Patient survival at 12 years was similar in diabetic and control patients (71% vs. 74%). CONCLUSIONS: Posttransplant diabetes mellitus is associated with impaired long-term renal allograft survival and function, complications similar to those in non-transplant-associated diabetes may occur in posttransplant diabetes, and, hence, as in non-transplant-associated diabetes, tight glycemic control may also be warranted in patients with posttransplant diabetes.

Care of the diabetic patient with end-stage renal disease.

Diabetic nephropathy is now the leading cause of renal failure in patients referred for uremia therapy. The diabetic patient is a complicated treatment problem from the first detection of microalbuminmuria, at which time decisions regarding choice of antihypertensive and strictness of metabolic control assume increasing importance. At present, our policy is to advocate strict control of blood pressure, aiming for a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of less than 80 mm Hg. We attempt to maintain hemoglobin Alc levels at less than 8%, if the patient does not develop frequent episodes of hypoglycemia. We extend these recommendations to the patient with frank proteinuria, nephrotic syndrome and early uremia, understanding that strict metabolic control may be impossible as patients lose GFR. In addition, we recommend avoidance of a high protein diet in the early nephropathic diabetic, with diet of approximately 1 gm/kg/d. As renal failure progresses, we embark on an analysis of the patient's abilities, lifestyle, and social support. At a GFR of approximately 10 mL/min, we initiate preparations for uremia therapy. If a willing and appropriate living related kidney donor is available, the patient is referred for cardiovascular evaluation and kidney transplantation performed subsequently. If no donor is immediately available, we refer the patient for vascular access placement and/or insertion of a Tenckhoff peritoneal catheter, if preferred. Most of these predialysis patients also undergo screening for placement on the cadaveric kidney transplant list, including cardiac work-up as is done for the patients who receive living-related renal transplants. Because of the long waiting list in Brooklyn, and the universal shortage of organ donors, many of these patients eventually end up on dialysis for some period of time. Other extrarenal problems (urologic, ophthalmologic) are addressed at initial referral and followed up, in hopes of maintaining the patient in optimal physical shape as uremia progresses. The care of the diabetic patient with ESRD ideally involves a consortium of caregivers. We include a nurse-educator familiar with options for uremia therapy, a podiatrist, a cardiologist, and often a urologist, an endocrinologist, and a gastroenterologist. In addition, a social worker is helpful to assess psychologic difficulties in adjustment to uremia, socioeconomic considerations, and rehabilitation status. Finally, the nephrologist, as coordinator of this team works with the vascular or transplant surgeon, to facilitate the transition to ESRD and its therapy.

Vascular access surgery for maintenance hemodialysis. Variables in hospital stay.

Access surgery in support of maintenance hemodialysis is a major factor contributing to prolonged hospitalization in the hemodialysis patient population. In surveying 140 consecutive patients admitted for access surgery, average length of stay was 14 days, independent of race or underlying cause of renal disease. Extended length of stay was most commonly encountered in older patients admitted for thrombosed fistulae or grafts. Postoperative fever, the need for repeated femoral catheterization, delay in access revision or placement due to infection, and the need for adequate social service support resulted in prolonged hospitalization. Understanding and preventing factors that prolong hospitalization may allow the minimization of length of stay in the future and improve quality of life for the end-stage renal disease patient, while also decreasing the cost of care.

Intermediate-term outcome of renal retransplants in the cyclosporine era.

To determine the influence of selected parameters on intermediate-term outcome of renal retransplants, univariate and multiple regression analyses were performed on all 100 consecutive cyclosporine treated retransplants performed between 1984 and 1990 (mean follow up, 4.6 +/- 2.3 years). Actual 1 year and actuarial 5 year graft survivals were higher in living compared with cadaver donor transplants (84% and 79% vs 69% and 56%, respectively; p < 0.05). Among cadaver donor transplant recipients, allografts with immediate early function had better 1 and 5 year graft survivals when compared with those with delayed function (81% and 62% vs 59% and 38%, respectively; p < 0.05). Recipients with acute rejection had inferior 1 year and 5 year graft survivals when compared with rejection free patients (65% and 35% vs 80% and 57%, respectively; p < 0.05). Graft survival time of primary transplants was also a significant predictor of retransplant outcome with 1 and 5 year graft survivals of 50% and 36%, respectively, in patients in whom primary grafts survived less than 3 months, compared with 75% and 58% in those in whom grafts survived longer than 3 months (p < 0.05). Recipient age, race, renal disease, and levels of panel reactive antibodies had no effect on intermediate-term outcome. In a multiple regression analysis, delayed graft function, acute rejection, and primary graft survival time less than 3 months correlated inversely with long-term survival of retransplants (multiple r = 0.65). A total of 39 grafts were lost due to rejection (22), sepsis (6), graft nonfunction (5), death with a functioning graft (4), noncompliance (1), and recurrent renal disease (1).(ABSTRACT TRUNCATED AT 250 WORDS)

Erythrocytosis after renal transplantation. A prospective analysis.

A prospective analysis of all cyclosporine treated renal transplants performed between 1987 and 1990 was performed to determine the incidence and etiologic factors of post transplant erythrocytosis (PTE) and its effect on short-term outcome. PTE developed in 25 (8.1%) recipients (mean age, 41 +/- 10 years). PTE occurred more frequently in men (12.8%) than women (1.6%) (p < 0.001), diabetic patients (22.9%) than nondiabetic patients (6.2%) (p < 0.001), and rejection-free recipients (11%) compared with those with early rejection (4%) (p < 0.05) but was independent of recipient race and donor source. Sixteen patients in whom PTE subsequently developed had pretransplant hematocrits above 30%. PTE occurred most frequently in the first year posttransplant (range, 2-29 months). Serum erythropoietin levels were inappropriately elevated in all patients (mean, 24 +/- 2.2 mU/ml), but serum iron, folate, and B12 levels were all normal. Mean serum creatinine and creatinine clearance were 1.7 +/- 0.5 mg/dl and 58 +/- 20 ml/min, respectively. Twenty-three patients underwent phlebotomy (mean, 3.5 +/- 0.5 units) and six had PTE-related complications. In 14 patients, PTE persisted with hematocrit of 53 +/- 1.5% (range, 51-56) compared with 57 +/- 2.6% (range, 54-64) at the time of PTE onset. In conclusion, PTE occurs primarily in the first year posttransplant and is characterized by inappropriate elevation of erythropoietin. Predictors for PTE include male gender, diabetes mellitus, pretransplant hematocrit above 30%, absence of rejection, and excellent renal allograft function.

Deficiency of serum ionized magnesium in patients receiving hemodialysis or peritoneal dialysis.

Serum total magnesium (TMg) measurements in dialysis patients are variable, with some groups reporting hypermagnesemia and some hypomagnesemia. It had not been possible to measure the biologically active fraction, ionized magnesium (IMg2+). The authors utilized an ion-selective electrode to measure IMg in 26 hemodialysis patients and 10 peritoneal dialysis (CAPD) patients and compared the results with those from 66 age matched control subjects. Dialysate magnesium was 0.375 mM/L for the hemodialysis and 0.25 mM/L for the CAPD patients. When compared with control subjects, both hemodialysis and CAPD patients had significantly lower IMg2+ (0.55 +/- 0.02 and 0.50 +/- 0.02 vs. 0.60 +/- 0.004 mM/L; p < 0.05) and greater or normal TMg values (0.99 +/- 0.04, different at the p < 0.001 level, and 0.85 +/- 0.04 vs. 0.84 +/- 0.008). Ionized calcium (ICa2+) values were similar for all three groups (1.15 +/- 0.02 and 1.21 +/- 0.04 vs. 1.17 +/- 0.01), resulting in increased mean ICa2+/IMg2+ ratios (2.14 +/- 0.07 and 2.42 +/- 0.06 vs. 1.95 +/- 0.02 for the control subjects; p < 0.05). The percent of total magnesium that was ionized (%IMg2+) was low in both the hemodialysis and CAPD patients (55.6 +/- 0.93 and 59.2 +/- 1.05) compared with that of control subjects (72 +/- 0.61; p < 0.05). IMg2+ values correlated with TMg values in both hemodialysis (r = 0.93; p < 0.0001) and CAPD (r = 0.92; p < 0.0001) patients did not correlate with age, time on dialysis, weight, fasting cholesterol or triglyceride, albumin, blood urea nitrogen (BUN), creatinine, hematocrit, phosphate, or PTH values.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical studies with the NOVA ISE for IMg2+.

The Nova ISE for IMg2+ was utilized to examine IMg2+ in plasma and serum of patients with a variety of pathophysiologic and disease syndromes (e.g., long-term renal transplants [LTRT], during and before cardiac surgery, migraine headaches, head trauma, pregnancy, chronic fatigue syndrome [CFS], non-insulin dependent diabetes mellitus [NIDDM], asthma and after excessive dietary intake of Mg). The results indicate that LTRT treated with cyclosporin A, migraine, head trauma, pregnancy, NIDDM, diseased pregnant, and asthmatic patients all on the average, exhibit significant depression in IMg2+ but not total Mg (TMg). Patients with CFS failed to exhibit changes in serum IMg2+ or TMg levels. Increased dietary load of Mg, for only 6 days, resulted in significant elevations of serum IMg2+ but not TMg. Correlations between the clinical course of several of these syndromes and the fall in IMg2+ were found. The Ca2+/Mg2+ ratio appears to be an important guide for signs of peripheral vasoconstriction and or spasm and possibly enhanced atherogenesis. Overall, the data point to important uses for ISE's for IMg2+ in the diagnosis and treatment of disease states.

Preferential adherence to immunosuppressive over nonimmunosuppressive medications in kidney transplant recipients.

Successful kidney transplantation continues to be associated with an increased risk of death from cardiovascular disease. Treatment for hypertension, hyperlipidemia, and hyperglycemia adds to the pre-existing medication burden of immunosuppression. We postulated that patients are selectively adherent, preferentially taking some medications and choosing not to take others. To test this hypothesis, a random cross-sectional sample of outpatient kidney transplant recipients was interviewed by a person previously unknown to them using a structured closed-ended interview. Nonadherence was defined as missing any dose of medication over the preceding 1 month. By this criteria, 18.4% of patients were nonadherent to immunosuppressive medications, whereas 44.9% of patients were nonadherent to nonimmunosuppressive medication (antihypertensives, antidiabetic agents, and lipid-lowering agents). More patients were selectively nonadherent to their nonimmunosuppressive medications than to their immunosuppressive medications (P = .028). Patients who were nonadherent to nonimmunosuppressant medications were on a higher number of total medications and were more likely to be diabetic. We conclude that patients are more likely to miss or change doses of nonimmunosuppressive medications than immunosuppressive medications. The importance of nonimmunosuppressive medications must also be stressed at clinic visits to facilitate adherence to all classes of medication. Whether nonadherence to medications that treat cardiovascular risk factors contributes to the persistently high cardiovascular death rate in kidney transplant recipients remains to be determined.